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The Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Placebo and Best Supportive Care in Subjects With Red Blood Cell (RBC) Transfusion-Dependent Anemia and Thrombocytopenia Due to International Prognostic Scoring System (IPSS) Low Risk Myelodysplastic Syndrome (MDS)

Sponsor
Celgene (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT01566695
Collaborator
(none)
216
Enrollment
214
Locations
2
Arms
116.1
Anticipated Duration (Months)
1
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Evaluation of the Efficacy and Safety of Oral Azacitidine plus Best Supportive care versus Placebo and Best Supportive care in subjects with red blood cell (RBC) transfusion-dependent anemia and thrombocytopenia due to International Prognostic Scoring System (IPSS) lower risk myelodysplastic syndromes (MDS).

Condition or Disease Intervention/Treatment Phase
  • Drug: Oral Azacitidine
  • Drug: Placebo
  • Other: Best Supportiv Care (BSC)
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
216 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Multicenter, Randomized, Double-blind Study to Compare the Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Subjects With Red Blood Cell Transfusion-dependent Anemia and Thrombocytopenia Due to IPSS Lower-risk Myelodysplastic Syndromes.
Actual Study Start Date :
Apr 26, 2013
Actual Primary Completion Date :
Jan 25, 2019
Anticipated Study Completion Date :
Dec 30, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Oral Azacitidine

Arm 1: Oral azacitidine tablets 300 mg daily (QD) + best supportive care (BSC) on days 1 through 21 of each 28-day treatment cycle.

Drug: Oral Azacitidine
300 mg daily, days 1 to 21 of each 28-day treatment cycle
Other Names:
  • CC-486

    • Other: Best Supportiv Care (BSC)
    BSC included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.
    Placebo Comparator: Placebo

    Arm 2: Identically matching placebo tablets plus best supportive care on days 1 to 21 of each 28-day treatment cycle.

    Drug: Placebo
    Identically matching placebo tablets on day 1 to 21 of each 28-day treatment cycle.

    Other: Best Supportiv Care (BSC)
    BSC included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days [Each participant was assessed for at least 56 days or more; from the date of randomization of study drug up to the data cut-off date of 25 January 2019, approximately 5 months.]

      RBC transfusion (tfx) independence was defined as the absence of any RBC transfusion during any consecutive "rolling" 56 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 56 days (i.e., day 1 to day 56, day 2 to day 57) were considered as a 56-day RBC transfusion independent responder.

    Secondary Outcome Measures

    1. Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days [From the date of randomization of study drug up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 56 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 56 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In the event a participant had more than one ≥56 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis. Participants who maintained RBC TI through the end of the treatment period were censored at the date of treatment discontinuation, death, or 1 day before the start of the subsequent MDS treatment (if any), whichever occurred first, or the particiapnts latest available assessment date in the database if the treatment was still on-going.

    2. Time to RBC Transfusion Independence for at Least 56 Days Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days [From the date of randomization of study drug up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Time to RBC transfusion independence of ≥ 56 days was defined as the time between randomization and the date onset of transfusion independence was first observed (ie, Day 1 of 56 without any RBC transfusions).

    3. Duration of RBC Transfusion Reduction for Participants Who Achieved RBC Transfusion Reduction of at Least 4 Units of RBCs for at Least 8 Weeks [From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      A participant was considered as a RBC transfusion reduction responder if the participant had at least 4 units reduction in transfusion units over any consecutive 56 days period compared to the baseline transfusion units in 56 days.

    4. Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence for ≥ 84 Days [From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive "rolling" 84 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 84 days (i.e., day 1 to day 84, day 2 to day 85) were considered as a 84-day RBC transfusion independent responder.

    5. Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days [From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 84 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 84 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In case a participant had more than one ≥84 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis.

    6. Time to RBC Transfusion Independence for at Least 84 Days Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days [From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Time to RBC transfusion independence of ≥ 84 days was defined as the time between randomization and the date onset of transfusion independence was first observed (ie, Day 1 of 84 without any RBC transfusions).

    7. Percentage of Participants With an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria [From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Erythroid HI-E improvement was defined as a hemoglobin increase of ≥ 1.5 g/dL; or a reduction in units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a hemoglobin of ≤ 9.0 g/dL on treatment were counted in the RBC transfusion response evaluation.

    8. Percentage of Participants With a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria [From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      HI-P response was defined according to IWG 2006 criteria (Cheson, 2006) and as: 1. Absolute increase of ≥ 30 X 10^9/L for participants^ starting with > 20 X 10^9/L platelets; 2. Increase from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%. HI-P must have lasted at least 8 weeks.

    9. Percentage of Participants Who Achieved Platelet Transfusion Independence With a Duration of ≥ 8 Weeks (56 Days) [From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Platelet transfusion independence was defined as the absence of any platelet transfusion during any consecutive "rolling" 56 days during the treatment period, (ie, Day 1 to 56, Day 2 to 57, Days 3 to 58, etc.). Participants were considered platelet transfusion dependent at baseline if they had received ≥ 2 platelet transfusions during the 56 days immediately preceding randomization and had no consecutive 28-day period during which no platelet transfusions were administered.

    10. Time to Platelet Transfusion Independence [From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Time to platelet transfusion independence was defined as the time between randomization and the first documented date of onset of transfusion independence (ie, Day 1 of 56 without any platelet transfusions).

    11. Kaplan-Meier Estimate of Overall Survival (OS) [From randomization to death from any cause; up to the data cut-off of date of 25 January 2019; maximum follow-up time for all participants was 67.9 months for the oral azacitidine arm and 64.8 months for placebo arm]

      Overall survial was defined as the time from randomization to death from any cause, and was calculated using randomization date and date of death, or date of last follow-up for censored participants. All subjects were followed until drop out (withdrawal of consent from further data collection or lost to follow-up), death, or study closure. Participants who dropped out or were alive at study closure (or at the time of the interim analysis) had their OS times censored at the time of last contact, as appropriate. Overall survival was assessed as an interim analysis at the time of the primary analysis.

    12. Percentage of Participants With a Hematologic Response According to the 2006 IWG Criteria for MDS [Response was assessed every 3 cycles; up to the data cut-off date of 25 Jan 2019; median duration of exposure to oral azacitidine was 86.0 days and 119.0 days for placebo]

      Hematologic response was defined as: A complete response (CR): <5% myeloblasts, and normal maturation of all cell lines; Peripheral blood (PB) shows: hemoglobin >10 g/dL, neutrophils ≥1.0x10^9/L, platelets ≥100x10^9/dL, blasts (0%) Partial Response (PR): same as CR bone marrow (BM) shows blasts decreased by ≥ 50% over pre-treatment but still > 5%; Cellularity and morphology not relevant Marrow CR: BM: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatment PB Stable disease (SD): failure to achieve at least PR, but no evidence of progression for > 8 wks Failure: death during treatment or disease progression Disease Progression for those with: Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts 5%-10% blasts:≥ 50% increase to > 10% blasts 10%-20% blasts:≥ 50% increase to > 20% blasts 20%-30% blasts ≥ 50% increase to > 30% blasts Any of the following: ≥ 50% decrease from maximum remission/response in granulocytes or platelets

    13. Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML) [From randomization of study drug to the end up to final data cut-off date of 25 January 2019; maximum follow-up time was 67.9 months for azacitidine and 64.8 months for placebo group]

      Participants with a documented diagnosis of AML arising from previous MDS documented diagnosis.

    14. Time to Progression to Acute Myeloid Leukemia (AML) Among Participants Who Progressed to AML [From randomization of study drug to progression of AML; up to final data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Time to AML progression was defined as the time from the date of randomization until the date the subject has documented progression to AML. For participants who had progression to AML documented in MLL central lab report, the earliest sample collection date with the diagnosis of "s-AML arising from previous MDS" was used as the date to AML progression.

    15. Percentage of Participants With Significant Bleeding Events [From date of randomization until 28 days after the last dose of IP; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo]

      Clinically significant bleeding event was defined as: any intracranial or retroperitoneal bleed; bleeding requiring transfusions of > 2 units of blood/blood products; bleeding associated with a decrease in hemoglobin of > 2 g/dL; or bleeding from any site requiring transfusions of > 2 units of blood.

    16. Number of Participants With Treatment Emergent Adverse Events (TEAE) [From first dose of IP up to 28 days after the last dose of IP; up to data cut-off date of 25 Jan 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo]

      A TEAE was defined as an adverse event that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: Death; Life-threatening event; Any inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability or incapacity; Congenital anomaly or birth defect; Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.

    17. Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.

    18. Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.

    19. Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.

    20. Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.

    21. Mean Change From Baseline in the Anemia Subscale Within FACT-An Instrument at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.

    22. Mean Change From Baseline in the Fatigue-Related Subscale Within the FACT-An Instrument at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.

    23. Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale Within the FACT-An Instrument at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-G and FACT-An score are summed to form the FACT-An total score. The FACT-An Trial Outcome Index (TOI) consists of the summation of a "summary scale" and includes the Physical Well-being, (PWB; 7 items; score range, 0-28), the Functional Well-being (7 items; score range, 0-28) and the Anemia subscale consisting of 20 items on the same five-point scale, with 13 of them measuring fatigue related symptoms (FS) and seven measuring non-FS. The FACT-An TOI has been demonstrated to be a sensitive indicator of clinical outcomes in a number of diseases including MDS. The Fact-TOI score ranges from 0 to 136. Higher scores on all scales of the Fact-An and subscales on the FACT-TOI reflect better quality of life or fewer symptoms.

    24. Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale Within the FACT-An Instrument at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-An is a 47-item, cancer-specific questionnaire consisting of a core 27-item general questionnaire (i.e., the Functional Assessment of Cancer Therapy-General [FACT-G]) The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: Physical Well-being (PWB; 7 items; score range, 0-28), Social/Family Well-being (SWB; 7 items; score range, 0-28), Emotional Well-being (EWB; 6 items; score range, 0-24), and Functional Well-being (7 items; score range, 0-28). The FACT-G is a summation composed of a "summary scale" including the PWB, SWB, EWB and FWB. The FACT-G score range is from 0 to 108. For all summary scales including FACT-G, a higher score indicates better HRQoL or lower level of symptoms.

    25. Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6 [Baseline to Cycle 6 Day 1]

      The FACT-G and the anemia subscale (AnS) are summed to form the FACT-An total score and the total score ranges from 0 to 188. The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: Physical Well-being (PWB; 7 items; score range, 0-28), Social/Family Well-being (SWB; 7 items; score range, 0-28), Emotional Well-being (EWB; 6 items; score range, 0-24), and Functional Well-being (7 items; score range, 0-28). The AnS consists of 20 items on the same 5-point scale, with 13 of them measuring fatigue-related symptoms (FS) and 7 measuring non-FS. The AnS and FS scores can range from 0-80 and 0-52, respectively. For all domains and summary subscales, a higher score indicates better HRQoL or lower level of symptoms.

    26. Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    27. Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    28. Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    29. Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    30. Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    31. Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    32. Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    33. Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    34. Percentage of Participants With a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain Within the FACT-An Instrument at Cycle 6 [Cycle 6 Day 1]

      A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

    35. Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 [From Baseline to Cycle 2 Day 1 (C2D1)]

      The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.

    36. Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 [From Baseline to Cycle 3 Day 1 (C3D1)]

      The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.

    37. Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 [From Baseline to Cycle 4 Day 1 (C4D1)]

      The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.

    38. Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 [From Baseline to Cycle 5 Day 1 (C5D1)]

      The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.

    39. Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 [From Baseline to Cycle 6 Day 1 (C6 D1)]

      The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.

    40. Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 [From Baseline to Cycle 7 Day 1 (C7D1)]

      The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.

    41. Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 [From Baseline to End of Treatment]

      The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.

    42. Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level (EQ-5D-3L) Mobility Dimension Responses at Cycle 6 [From Baseline to Cycle 6 Day 1]

      The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.

    43. Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level of Self-Care Dimension Responses at Cycle 6 [From Baseline to Cycle 6 Day 1]

      The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.

    44. Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level Usual Activities Dimension Responses at Cycle 6 [From Baseline to Cycle 6 Day 1]

      TThe EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.

    45. Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level in the Pain/Discomfort Dimension Responses at Cycle 6 [From Baseline to Cycle 6 Day 1]

      The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.

    46. Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level in the Anxiety/Depression Dimension Responses at Cycle 6 [From Baseline to Cycle 6 Day 1]

      The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.

    47. Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized During the Treatment Period [From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo]

      The number of reasons for hospitalizations and hospital admissions during the treatment period were monitored and include those associated with: AEs, protocol-driven procedures, transfusions, non-protocol procedures, elective procedures or those associated with social, practical or technical reasons in the absence of AEs. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

    48. Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to Any Reason During the Treatment Period [From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo]

      The total number of days hospitalized due to any reason during the treatment period was monitored. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

    49. Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years [From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo]

      The number of days hospitalized per total patient years. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • 18 years or older

    • Have a documented diagnosis of MDS

    • Anemia that requires red blood cell transfusions

    • Thrombocytopenia (sustained for at least 21 days) within 14 days prior to randomization

    • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

    • Must agree to follow pregnancy precautions as required by protocol.

    • Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted

    Exclusion Criteria:

    • Secondary or hypoplastic MDS or other subtype with eligibility for treatment with immunotherapy

    • Prior treatment with azacitidine, decitabine, other hypomethylating agents and lenalidomide (for lenalidomide : unless the last dose received is >= 8 weeks prior to inclusion into the study).

    • Prior allogeneic or autologous stem cell transplant

    • Eligible for allogenic or autologous stem cell transplant

    • History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect

    • Thrombocytopenia secondary to other possible causes, including medication(s), congenital disorder(s), immune disorder(s), or microvascular disorder(s)

    • Use of cytotoxic, chemotherapeutic, targeted or investigational agents/therapies, thrombopoiesis-stimulating agents (TSAs), erythropoiesis-stimulating agents (ESAs) and other red blood cell hematopoietic growth factors, and within 28 days prior to randomization

    • Ongoing medically significant adverse events from previous treatment, regardless of the time period

    • Concurrent use of iron-chelating agents, (except for subjects on a stable or decreasing dose for at least 8 weeks (56 days) prior to randomization), corticosteroid (except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS)

    • Prior history of cancer, other than MDS, unless the subject has been free of the disease for ≥ 3 years. (Basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, and incidental histologic finding of prostate cancer) (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system is allowed)

    • Significant active cardiac disease within the previous 6 months

    • Uncontrolled systemic fungal, bacterial, or viral infection

    • Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection

    • Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding

    • Abnormal coagulation parameters

    • Abnormal liver function test results

    • Abnormal kidney function test results

    • Known or suspected hypersensitivity to azacitidine or mannitol

    • Any significant medical condition, laboratory abnormality, or psychiatric illness

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Alta Bates Comprehensive Cancer Center Berkeley California United States 94704
    2 Tower Hematology/Oncology Medical Group and Tower Cancer Research Found Beverly Hills California United States 90211
    3 City of Hope Duarte California United States 91010-301
    4 California Cancer Associates for Research and Excellence cCARE Escondido California United States 92025
    5 Marin Oncology Associates Greenbrae California United States 94904-2007
    6 UCSD-Thornton Hospital La Jolla California United States 92093-0943
    7 University of Southern California Norris Cancer Center Los Angeles California United States 90033
    8 Yale Cancer Center New Haven Connecticut United States 06519
    9 University of Florida Health Cancer Center at Orlando Health Orlando Florida United States 32806
    10 Phoebe Cancer Center of Phoebe Putney Memorial Hospital Albany Georgia United States 31701
    11 Robert H Lurie Comprehensive Cancer Center NW Univ Chicago Illinois United States 60611
    12 University of Illinois at Chicago Chicago Illinois United States 60612
    13 University of Chicago Medical Center Chicago Illinois United States 60637
    14 Loyola University Chicago Maywood Illinois United States 60153
    15 University of Kansas Medical Center Kansas City Kansas United States 66160-7233
    16 University of Louisville, J.G. Brown Cancer Center Louisville Kentucky United States 40202
    17 Hematology and Oncology Specialists, LLC Metairie Louisiana United States 70006
    18 Johns Hopkins Medicine Baltimore Maryland United States 21231
    19 UMASS Memorial Hospital Worcester Massachusetts United States 01655
    20 Mayo Clinic Rochester Minnesota United States 55905
    21 Jackson Oncology Associates PLLC Jackson Mississippi United States 39202
    22 Saint Luke's Cancer Institute Kansas City Missouri United States 64111
    23 Kansas City VA Medical Center University of Kansas Medical Center Kansas City Missouri United States 64128
    24 University of Nebraska Medical Center Omaha Nebraska United States 68198-6805
    25 Weill Cornell Medical College - New York - Presbyterian Hospital New York New York United States 10021
    26 Icahn School of Medicine at Mount Sinai Medical Center New York New York United States 10029
    27 Levine Cancer Institute Charlotte North Carolina United States 28204
    28 Eastern Institute of Medical Sciences Greenville North Carolina United States 27834
    29 University Hospitals of Cleveland Case Medical Center Cleveland Ohio United States 44106-5000
    30 Ohio State University Medical Center Columbus Ohio United States 43210
    31 Kaiser Permanente Northwest Oncology Hematology Portland Oregon United States 97227
    32 University of Pennsylvania Philadelphia Pennsylvania United States 19104
    33 Western Pennsylvania Cancer Institute Pittsburgh Pennsylvania United States 15224
    34 Brooke Army Medical Center Francis Street Medical Center Fort Sam Houston Texas United States 78235-8200
    35 MD Anderson Cancer Center The University of Texas Houston Texas United States 77030
    36 Michael Debakey VA Medical Center Houston Texas United States 77030
    37 Millenium Oncology Houston Texas United States 77090
    38 VA Commonwealth University Massey Cancer Center Richmond Virginia United States 23298-0037
    39 Fred Hutchinson Cancer Research Center Seattle Washington United States 98109-4417
    40 Waukesha Memorial Hospital Waukesha Wisconsin United States 53188-5099
    41 Canberra Hospital Garran Australian Capital Territory Australia 2605
    42 Royal Adelaide Hospital Adelaide South Australia Australia SA 5000
    43 Monash Medical Centre Clayton Victoria Australia 3168
    44 Frankston Hospital Frankston Victoria Australia 3199
    45 Royal Prince Alfred Hospital, Sydney Cancer Centre Camperdown Australia 2050
    46 The Northern Hospital Epping, VIC Australia 3076
    47 St Vincent's Hospital Melbourne Fitzroy Australia 3065
    48 St George Hospital Kogarah Australia 2217
    49 Cabrini Hospital Malvern Australia 3144
    50 Local Institution - 130 Malvern Australia 3144
    51 Haematoloy and Oncology Clinics of Australia Milton, Brisbane Australia 4064
    52 Calvary Mater New Castle Waratah Australia NSW
    53 Princess Alexandra Hospital Woolloongabba Australia QLD 4102
    54 Algemeen Ziekenhuis Klina Brasschaat Belgium 2930
    55 AZ St-Jan Brugge Oostende AV Brugge Belgium 8000
    56 Grand Hopital de Charleroi Charleroi Belgium 6000
    57 UZ Leuven Leuven Belgium 3000
    58 Universidade Federal do Ceara Fortaleza Ceará Brazil 60430370
    59 Hospital de Clínicas de Porto Alegre Porto Alegre Rio Grande Do Sul Brazil 90035-903
    60 Hospital Erasto Gaertner Curitiba Brazil 81520-060
    61 MS INCA HC I Hospital do Cancer I Rio De Janeiro Brazil 20231-130
    62 Hospital Albert Einstein Sociedade Beneficente Israelita Brasileira Sao Paulo Brazil 05651-901
    63 University of Alberta Hospital Adult Hematology Research Edmonton Alberta Canada T6G 2B7
    64 Vancouver General Hospital Vancouver British Columbia Canada V5Z 1M9
    65 Royal Victoria Hospital, Barrie Barrie Ontario Canada LYM6M2
    66 Juravinski Cancer Centre Hamilton Ontario Canada L8V 5C2
    67 Local Institution - 180 Hamilton Ontario Canada L8V 5C2
    68 Local Institution - 179 Toronto Ontario Canada M4N 3M5
    69 Sunnybrook Health Sciences Centre Toronto Ontario Canada M4N 3M5
    70 Princess Margaret Hospital University Health Network Toronto Ontario Canada M5G 2M9
    71 Local Institution - 181 Montreal Quebec Canada H2W 1S6
    72 McGill University, Dept. Oncology Clinical Research Program Montreal Quebec Canada H2W 1S6
    73 Hopital du Sacre-Coeur de Montreal Montreal Quebec Canada H4J 1C5
    74 Fakultni nemocnice Brno Brno Czechia 625 00
    75 Local Institution - 230 Hradec Králové Czechia 500 05
    76 University Hospital Hradec Kralove Hradec Králové Czechia 500 05
    77 University Hospital Olomouc Olomouc Czechia 77520
    78 Vseobecna Fakultni Nemocnice v Praze Praha Czechia 128 08
    79 Ustav hematologie a krevni transfuze Praha Czechia 128 20
    80 Aarhus University Hospital Aarhus Denmark 8000
    81 Onk.Dep., Odense Universitets hospital Odense C Denmark 5000
    82 Roskilde Hospital Roskilde Denmark DK-4000
    83 Helsinki University Central Hospital Helsinki Finland 00029 HUS
    84 Turku University Hospital Turku Finland 20521
    85 CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang Lille France 59037
    86 Local Institution - 305 Lille France 59037
    87 Institute Paoli-Calmettes Service Haematology Marseille Cedex 9 France 13009
    88 CHU Nantes Hotel Dieu Nantes France 44093
    89 Hospital Saint Louis Paris France 7575
    90 Local Institution - 308 Paris France 7575
    91 Centre Hospitalier Lyon Sud Pierre-Bénite Cedex France 69495
    92 CHRU Hôpital de Pontchaillou Rennes Cedex France 35033
    93 Centre Henri Becquerel Rouen Cedex France 76038
    94 Hopital Civil de Strasbourg Strasbourg France 67091
    95 Institut Universitaire du Cancer de Toulouse - Oncopole Toulouse Cedex 9 France 31059
    96 Local Institution - 300 Toulouse Cedex 9 France 31059
    97 Hopital Bretonneau Tours France 37044
    98 Gemeinschaftspraxis Haematologie-Onkologie Dresden Germany 01307
    99 Local Institution - 350 Dresden Germany 01307
    100 Universitatsklinikum Carl Gustav Carus Dresden Germany 01307
    101 Local Institution - 359 Duesseldorf Germany 40479
    102 Marien Hospital Duesseldorf Germany 40479
    103 Universitatsklinkikum DusseldorfKlinik fur Hamatologie, Onkologie und klin. Immunoligie Dusseldorf Germany 40225
    104 Asklepios Klinik St. Georg Hamburg Germany D-20099
    105 Universitatsklinikum Schleswig-Holstein Keil Germany 24105
    106 Universitatsklinikum Leipzig Leipzig Germany 04103
    107 TU München - Klinikum rechts der Isar München Germany 81675
    108 University Hospital Tubingen Tubingen Germany 72076
    109 Universitatsklinikum Ulm Ulm Germany 89081
    110 Democritus University of Thrace Alexandroupolis Greece 68100
    111 Evangelismos General Hospital of Athens Athens Greece 10676
    112 Laiko General Hospital Athens Greece 11527
    113 Attikon General University Hospital of Athens Athens Greece 124 62
    114 University General Hospital of Heraklion Heraklion Greece 711 10
    115 University of Patras Patras Greece 26500
    116 Rambam Medical Center Haifa Israel 31096
    117 Rabin Medical Center Petach Tikva Israel 49100
    118 Sheba Medical Center Tel Hashomer Israel 52621
    119 Tel-Aviv Sourasky Medical Center Tel-Aviv Israel 64239
    120 Az. Osp. SS.Antonio e Biagio - SC Ematologia Alessandria Italy 15121
    121 Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari Bari Italy 70124
    122 Policlinico S. Orsola Malpighi Bologna Italy 40138
    123 U.O. Ematologia. Ospedale Oncologico di Riferimento Regionale Armando Businco Cagliari Italy 09121
    124 Azienda Ospedaliero Universitaria Careggi Firenze Italy 50129
    125 AUSL LE1 - Vito Fazzii Hospital Medical Oncology Department Lecce Italy 73100
    126 Local Institution - 479 Lecce Italy 73100
    127 Local Institution - 488 Milano Italy 20122
    128 Opsedale Maggiore Policlinico and University Milano Italy 20122
    129 IRCCS - Istituo Clinico Humanitas - Humanitas Cancer Center Milan Italy 20089
    130 A.O.U. Maggiore della Carità Novara Italy 28100
    131 Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello Palermo Italy 90146
    132 Fondazione IRCCS Policlinico San Matteo Pavia Italy 27100
    133 Local Institution - 495 Pavia Italy 27100
    134 Ospedale S. Chiara Pisa Italy 56126
    135 Azienda Ospedaliera "Bianchi-Melacrino-Morelli" Reggio Calabria Italy 89100
    136 Local Institution - 485 Reggio Calabria Italy 89133
    137 IRCCS Centro di Riferimento Oncologico di Basilicata Rionero in Vulture Italy 85028
    138 Fondazione PTV Policlinico Tor Vergata Roma Italy 00133
    139 Policlinico Umberto I Roma Italy 00161
    140 Policlinico Universitario "A. Gemelli" Roma Italy 00168
    141 AO Santa Maria Terni Italy 05100
    142 Azienda Ospedaliera San Giovanni Battista Torino Italy 10126
    143 Ospedale Umberto I Torrette Di Ancona Italy 60020
    144 Policlinico Univeristario di Udine Udine Italy 33100
    145 Ospedale dell Angelo di Mestre Venezia - Mestre Italy 30174
    146 Inje University Busan Paik Hospital Busan Korea, Republic of 614-735
    147 Kyungpook National University Hospital Daegu Korea, Republic of 700-721
    148 Severance Hospital, Yonsei University Health System Seoul Korea, Republic of 120-752
    149 Samsung Medical Center Seoul Korea, Republic of 135-710
    150 Seoul St Marys Hospital College of Medicine The Catholic University of Korea Seoul Korea, Republic of 137-701
    151 Hospital Angeles Lomas - Consultorio 830 Huixquilucan de Degollado Mexico 52763
    152 Hospital Universitario "Dr. Jose E. Gonzalez" Monterrey Mexico 64460
    153 Local Institution - 828 Monterrey Mexico 64460
    154 AVIX Investigacion Clinica Monterrey Mexico 64710
    155 Instituto Nacional de Cancerologia Tlalpan Mexico 14080
    156 VU University Medical Center Amsterdam Netherlands 1081 HV
    157 Universitair Medisch Centrum Groningen Groningen Netherlands 9713 GZ
    158 UMC St Radboud Nijmegen Netherlands 6500 HB
    159 Erasmus Medical Center Rotterdam Netherlands 3075 EA
    160 Helse Forde HF Central hospital Førde Norway 6807
    161 Oslo University Hospital, Rikshospitalet HF Oslo Norway N-0027
    162 Szpital Uniwersytecki nr 2 im dr. Jana Biziela Bydgoszcz Poland 85-168
    163 Uniwersyteckie Centrum Kliniczne Gdansk Poland 80-952
    164 Uniwersytet Jagiellonski Collegium Medicum Krakow Poland 31-501
    165 Wojewodzki Szpital Specjalistyczny im. M. Kopernika w Lodzi Lodz Poland 93-510
    166 Local Institution - 580 Torun Poland 87-100
    167 Specjalistyczny Szpital Miejski im. M. Kopernika w Toruniu Torun Poland 87-100
    168 Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie Warszawa Poland 02-097
    169 Instytut Hematologii i Transfuzjologii, Klinika Hematologii Warszawa Poland 02-776
    170 Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie Wroclaw Poland 50-367
    171 ULSBA (Unidade Local de Saúde do Baixo Alentejo, EPE) - Hospital de Beja Beja Portugal 7801-849
    172 Hospital Universitario de Coimbra Coimbra Portugal 3000-075
    173 Instituto Portugues de Oncologia de Lisboa Lisboa Portugal 1099-023
    174 Centro Hospitalar de Lisboa Central - Hospital de Santo António dos Capuchos Lisboa Portugal 1150-314
    175 Instituto Portugues de Oncologia do Porto Porto Portugal 4200-072
    176 Hospital Universitari Germans Trias i Pujol Badalona (Barcelona) Spain 8916
    177 Hospital de la Santa Creu i Sant Pau Barcelona Spain 08025
    178 Hospital Universitario Vall D Hebron Barcelona Spain 8035
    179 Complejo Hospitalario Universitario de Granada Granada Spain 18014
    180 Hospital General Universitario Gregorio Maranon Madrid Spain 28009
    181 Hospital Ramon y Cajal Madrid Spain 28034
    182 Hospital Universitario La Paz Madrid Spain 28046
    183 Hospital Universitario Virgen de la Victoria Malaga Spain 29010
    184 Hospital Central de Asturias Oviedo Spain 33006
    185 Hospital Universitario de Salamanca Salamanca Spain 37007
    186 Hospital Universitario Virgen del Rocio Seville Spain 41013
    187 Hospital Txagorritxu - Hospital Universitario de Álava Vitoria-Gasteiz, Álava Spain 1009
    188 SU/Sahlgrenska, Section of Haematology and Coagulation Goeteborg Sweden 413 45
    189 University Hospital in Lund Lund Sweden 22185
    190 Local Institution - 652 Lund Sweden 222 41
    191 Karolinska Universitetssjukhuset - Huddinge Stockholm Sweden 14186
    192 Baskent University Medical Faculty Adana Practice and Research Center Adana Turkey 01250
    193 Antalya Egitim Arastirma Antalya Turkey 07100
    194 Istanbul University Cerrahpasa Istanbul Turkey 34098
    195 Istanbul University Faculty of Medicine Istanbul Turkey 34390
    196 Mersin University Medical Faculty Mersin Turkey 33343
    197 Karadeniz Teknik Universitesi Tip Fakultesi Farabi Hastanesi Trabzon Turkey 61080
    198 Local Institution - 685 Oxford Oxfordshire United Kingdom OX3 9DU
    199 Aberdeen Royal Infirmary Aberdeen United Kingdom AB25 2ZN
    200 Birmingham Heartlands Hospital Birmingham United Kingdom B9 5SS
    201 Bristol Haematology and Oncology Centre Bristol United Kingdom BS2 8ED
    202 Addenbrookes Hospital Cambridge United Kingdom CB2 0QQ
    203 University Hospital of Wales - Cardiff Cardiff United Kingdom CF14 4XW
    204 Northwick Park Hospital Harrow Middlesex United Kingdom HA1 3UJ
    205 Queens Centre for Oncology & Haematology Hull United Kingdom HU16 5JQ
    206 Leicester Royal Infirmary Leicester United Kingdom LE1 5WW
    207 Royal Liverpool University Hospital, Prescot Street Liverpool United Kingdom L7 8XP
    208 Barts and The London NHS Trust London United Kingdom EC1A 7BE
    209 Guy's and St Thomas' Hospital - London London United Kingdom SE1 9RT
    210 Manchester Royal Infirmary Manchester United Kingdom M13 9WL
    211 Nottingham City Hospital - Dept of Haematology Nottingham United Kingdom NG5 1PB
    212 John Radcliffe Hospital Oxford United Kingdom OX3 9DU
    213 Kings Mill Hospital Sutton in Ashfield United Kingdom NG17 4SL
    214 New Cross Hospital Wolverhampton United Kingdom WV10 0QP

    Sponsors and Collaborators

    • Celgene

    Investigators

    • Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT01566695
    Other Study ID Numbers:
    • AZA-MDS-003
    • 2012-002471-34
    First Posted:
    Mar 29, 2012
    Last Update Posted:
    Aug 2, 2022
    Last Verified:
    Jul 1, 2022
    Additional relevant MeSH terms:
    Preleukemia
    Myelodysplastic Syndromes
    Thrombocytopenia
    Syndrome
    Azacitidine

    Study Results

    Participant Flow

    Recruitment Details Participants were randomized at 101 sites globally. The sites were located in: Europe (76), North America (13), Asia/Pacific (10), and Latin America (2). Results are reported as of the data cut-off date of 25 January 2019.
    Pre-assignment Detail Participants were stratified by: average baseline (BL) Red Blood Cell (RBC) transfusion requirement (≤ 4 units versus > 4 units of RBC per 28 days), BL platelet transfusion status (dependent or independent), country of enrollment and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 to 1 versus 2).
    Arm/Group Title Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Period Title: Overall Study
    STARTED 107 109
    COMPLETED 12 10
    NOT COMPLETED 95 99

    Baseline Characteristics

    Arm/Group Title Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care Total
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections. Total of all reporting groups
    Overall Participants 107 109 216
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    73.0
    (9.23)
    73.1
    (8.36)
    73.0
    (8.78)
    Sex: Female, Male (Count of Participants)
    Female
    28
    26.2%
    30
    27.5%
    58
    26.9%
    Male
    79
    73.8%
    79
    72.5%
    158
    73.1%
    Race/Ethnicity, Customized (Count of Participants)
    White
    96
    89.7%
    99
    90.8%
    195
    90.3%
    Black or African American
    1
    0.9%
    0
    0%
    1
    0.5%
    Asian
    2
    1.9%
    3
    2.8%
    5
    2.3%
    Native Hawaiian or Other Pacific Islanders
    0
    0%
    0
    0%
    0
    0%
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Japanese
    0
    0%
    0
    0%
    0
    0%
    Other
    8
    7.5%
    7
    6.4%
    15
    6.9%
    Race/Ethnicity, Customized (Count of Participants)
    Hispanic or Latino
    4
    3.7%
    9
    8.3%
    13
    6%
    Not Hispanic or Latino
    91
    85%
    93
    85.3%
    184
    85.2%
    Not Reported
    12
    11.2%
    7
    6.4%
    19
    8.8%
    Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification (Count of Participants)
    RA = Refractory Anemia
    4
    3.7%
    3
    2.8%
    7
    3.2%
    RN = Refractory Neutropenia
    0
    0%
    0
    0%
    0
    0%
    RT = Refractory Thrombocytopenia
    1
    0.9%
    0
    0%
    1
    0.5%
    RARS = RA with Ringed Sideroblasts
    3
    2.8%
    2
    1.8%
    5
    2.3%
    RCMD = R Cytopenia w/ Multilineage Dysplasia
    80
    74.8%
    73
    67%
    153
    70.8%
    RAEB-1 RA with Excess Blasts - 1
    17
    15.9%
    29
    26.6%
    46
    21.3%
    RAEB-2 RA with Excess Blasts - 2
    0
    0%
    0
    0%
    0
    0%
    MDS-U (MDS-unclassified)
    2
    1.9%
    2
    1.8%
    4
    1.9%
    del (5q) MDS Associated with Isolated del 5q
    0
    0%
    0
    0%
    0
    0%
    International Prognostic Scoring System (IPSS) (Count of Participants)
    Low
    0
    0%
    0
    0%
    0
    0%
    Intermediate 1 (0..5-1.0)
    106
    99.1%
    109
    100%
    215
    99.5%
    Intermediate 2 (1.5-2.0)
    1
    0.9%
    0
    0%
    1
    0.5%
    High
    0
    0%
    0
    0%
    0
    0%
    Average Red Blood Cell Transfusion Requirement (units per 28 days) (units per 28 days) [Median (Full Range) ]
    Median (Full Range) [units per 28 days]
    3.33
    3.33
    3.33
    Hemoglobin (g/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [g/dL]
    8.22
    (0.988)
    8.04
    (0.960)
    8.13
    (0.976)
    Platelet Count (10^9 cells/L) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [10^9 cells/L]
    27.0
    (15.97)
    27.9
    (18.11)
    27.5
    (17.05)
    Platelet Transfusion Status (Count of Participants)
    Dependent
    30
    28%
    35
    32.1%
    65
    30.1%
    Independent
    77
    72%
    74
    67.9%
    151
    69.9%
    Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
    Grade 0-1
    91
    85%
    94
    86.2%
    185
    85.6%
    Grade 2
    16
    15%
    15
    13.8%
    31
    14.4%
    Grade 3
    0
    0%
    0
    0%
    0
    0%
    Grade 4
    0
    0%
    0
    0%
    0
    0%
    Grade 5
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days
    Description RBC transfusion (tfx) independence was defined as the absence of any RBC transfusion during any consecutive "rolling" 56 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 56 days (i.e., day 1 to day 56, day 2 to day 57) were considered as a 56-day RBC transfusion independent responder.
    Time Frame Each participant was assessed for at least 56 days or more; from the date of randomization of study drug up to the data cut-off date of 25 January 2019, approximately 5 months.

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all participants who were randomized, regardless of whether they received treatment or not.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Number (95% Confidence Interval) [Percentage of Participants]
    30.8
    28.8%
    11.9
    10.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0005
    Comments 2 sided
    Method Stratified Mantel-Haenszel Chi-squared
    Comments Stratified by average baseline (BL) RBC tfx needs: ≤4 units versus >4 units; BL platelet tfx status: dependent or independent and ECOG PS: 0 to 1 vs 2
    Method of Estimation Estimation Parameter Rate Difference
    Estimated Value 18.9
    Confidence Interval (2-Sided) 95%
    8.3 to 29.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days
    Description Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 56 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 56 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In the event a participant had more than one ≥56 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis. Participants who maintained RBC TI through the end of the treatment period were censored at the date of treatment discontinuation, death, or 1 day before the start of the subsequent MDS treatment (if any), whichever occurred first, or the particiapnts latest available assessment date in the database if the treatment was still on-going.
    Time Frame From the date of randomization of study drug up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat population. Participants who achieved RBC transfusion independence of ≥ 56 days on treatment.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 33 13
    Median (95% Confidence Interval) [months]
    11.1
    12.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7547
    Comments
    Method Two-sided Unstratified Log Rank Test
    Comments
    3. Secondary Outcome
    Title Time to RBC Transfusion Independence for at Least 56 Days Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days
    Description Time to RBC transfusion independence of ≥ 56 days was defined as the time between randomization and the date onset of transfusion independence was first observed (ie, Day 1 of 56 without any RBC transfusions).
    Time Frame From the date of randomization of study drug up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a 56-day TI response. Responders in the intent to treat population.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 33 13
    Median (Full Range) [Months]
    2.37
    2.04
    4. Secondary Outcome
    Title Duration of RBC Transfusion Reduction for Participants Who Achieved RBC Transfusion Reduction of at Least 4 Units of RBCs for at Least 8 Weeks
    Description A participant was considered as a RBC transfusion reduction responder if the participant had at least 4 units reduction in transfusion units over any consecutive 56 days period compared to the baseline transfusion units in 56 days.
    Time Frame From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat population; includes participants who achieved RBC transfusion reduction of at least 4 units for at least 8 weeks.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 45 34
    Median (95% Confidence Interval) [months]
    10.0
    2.3
    5. Secondary Outcome
    Title Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence for ≥ 84 Days
    Description RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive "rolling" 84 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 84 days (i.e., day 1 to day 84, day 2 to day 85) were considered as a 84-day RBC transfusion independent responder.
    Time Frame From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The ITT population includes all participants who were randomized, regardless of whether they received treatment or not.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Number (95% Confidence Interval) [Percentage of Participants]
    28.0
    26.2%
    6.4
    5.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments 2 sided
    Method Stratified Mantel-Haenszel; Chi-squared
    Comments Stratified by average BL RBC tfx needs: ≤4 units versus >4 units; BL platelet tfx status: dependent or independent and ECOG PS: 0 to 1 vs 2
    Method of Estimation Estimation Parameter Rate Difference
    Estimated Value 21.6
    Confidence Interval (2-Sided) 95%
    11.9 to 31.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days
    Description Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 84 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 84 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In case a participant had more than one ≥84 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis.
    Time Frame From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat population. Participants who achieved RBC transfusion independence for at least 84 days on treatment.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 30 7
    Median (95% Confidence Interval) [months]
    11.1
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4347
    Comments
    Method Two-Sided Unstratified Log Rank Test
    Comments
    7. Secondary Outcome
    Title Time to RBC Transfusion Independence for at Least 84 Days Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days
    Description Time to RBC transfusion independence of ≥ 84 days was defined as the time between randomization and the date onset of transfusion independence was first observed (ie, Day 1 of 84 without any RBC transfusions).
    Time Frame From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a 84-day TI response. Responders in the intent to treat population.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 30 7
    Median (Full Range) [Months]
    2.64
    4.01
    8. Secondary Outcome
    Title Percentage of Participants With an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria
    Description Erythroid HI-E improvement was defined as a hemoglobin increase of ≥ 1.5 g/dL; or a reduction in units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a hemoglobin of ≤ 9.0 g/dL on treatment were counted in the RBC transfusion response evaluation.
    Time Frame From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all participants who were randomized, regardless of whether they received treatment or not.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    HI-E Response
    43.0
    40.2%
    32.1
    29.4%
    ≥ 1.5 g/dL Hemoglobin Increase
    23.4
    21.9%
    5.5
    5%
    RBC Transfusion Reduction
    42.1
    39.3%
    31.2
    28.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments HI-E
    Statistical Test of Hypothesis p-Value 0.1467
    Comments
    Method Stratified Mantel-Haenszel. Chi-squared
    Comments Stratified by average BL RBC tfx needs: ≤4 units versus >4 units; BL platelet tfx status: dependent or independent and ECOG PS: 0 to 1 vs 2
    Method of Estimation Estimation Parameter Rate Difference
    Estimated Value 10.9
    Confidence Interval (2-Sided) 95%
    -2.0 to 23.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments ≥ 1.5 g/dL Hemoglobin Increase
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method Stratified Mantel-Haenszel. Chi-squared
    Comments Stratified by average BL RBC tfx needs: ≤4 units versus >4 units; BL platelet tfx status: dependent or independent and ECOG PS: 0 to 1 vs 2
    Method of Estimation Estimation Parameter Rate Diffrence
    Estimated Value 17.9
    Confidence Interval (2-Sided) 95%
    8.8 to 26.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments RBC Transfusion Reduction
    Statistical Test of Hypothesis p-Value 0.1431
    Comments
    Method Stratified Mantel-Haenszel. Chi-squared
    Comments Stratified by average BL RBC tfx needs: ≤4 units versus >4 units; BL platelet tfx status: dependent or independent and ECOG PS: 0 to 1 vs 2
    Method of Estimation Estimation Parameter Rate Difference
    Estimated Value 10.9
    Confidence Interval (2-Sided) 95%
    -1.9 to 23.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Percentage of Participants With a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria
    Description HI-P response was defined according to IWG 2006 criteria (Cheson, 2006) and as: 1. Absolute increase of ≥ 30 X 10^9/L for participants^ starting with > 20 X 10^9/L platelets; 2. Increase from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%. HI-P must have lasted at least 8 weeks.
    Time Frame From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The ITT population included all participants who were randomized, regardless of whether they received treatment or not.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Number (95% Confidence Interval) [Percentage of Participants]
    24.3
    22.7%
    7.3
    6.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0007
    Comments
    Method Stratified Mantel-Haenszel. Chi-squared
    Comments Stratified by average BL RBC tfx needs: ≤4 units versus >4 units; BL platelet tfx status: dependent or independent and ECOG PS: 0 to 1 vs 2
    Method of Estimation Estimation Parameter Rate Difference
    Estimated Value 17.0
    Confidence Interval (2-Sided) 95%
    7.5 to 26.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Percentage of Participants Who Achieved Platelet Transfusion Independence With a Duration of ≥ 8 Weeks (56 Days)
    Description Platelet transfusion independence was defined as the absence of any platelet transfusion during any consecutive "rolling" 56 days during the treatment period, (ie, Day 1 to 56, Day 2 to 57, Days 3 to 58, etc.). Participants were considered platelet transfusion dependent at baseline if they had received ≥ 2 platelet transfusions during the 56 days immediately preceding randomization and had no consecutive 28-day period during which no platelet transfusions were administered.
    Time Frame From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    ITT population; includes participants were were platelet transfusion dependent.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 30 35
    Number [Percentage Participants]
    16.7
    15.6%
    14.3
    13.1%
    11. Secondary Outcome
    Title Time to Platelet Transfusion Independence
    Description Time to platelet transfusion independence was defined as the time between randomization and the first documented date of onset of transfusion independence (ie, Day 1 of 56 without any platelet transfusions).
    Time Frame From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat population; includes participants who achieved platelet transfusion independence for at least 56 days.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 5 5
    Median (Full Range) [Months]
    2.04
    1.48
    12. Secondary Outcome
    Title Kaplan-Meier Estimate of Overall Survival (OS)
    Description Overall survial was defined as the time from randomization to death from any cause, and was calculated using randomization date and date of death, or date of last follow-up for censored participants. All subjects were followed until drop out (withdrawal of consent from further data collection or lost to follow-up), death, or study closure. Participants who dropped out or were alive at study closure (or at the time of the interim analysis) had their OS times censored at the time of last contact, as appropriate. Overall survival was assessed as an interim analysis at the time of the primary analysis.
    Time Frame From randomization to death from any cause; up to the data cut-off of date of 25 January 2019; maximum follow-up time for all participants was 67.9 months for the oral azacitidine arm and 64.8 months for placebo arm

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    13. Secondary Outcome
    Title Percentage of Participants With a Hematologic Response According to the 2006 IWG Criteria for MDS
    Description Hematologic response was defined as: A complete response (CR): <5% myeloblasts, and normal maturation of all cell lines; Peripheral blood (PB) shows: hemoglobin >10 g/dL, neutrophils ≥1.0x10^9/L, platelets ≥100x10^9/dL, blasts (0%) Partial Response (PR): same as CR bone marrow (BM) shows blasts decreased by ≥ 50% over pre-treatment but still > 5%; Cellularity and morphology not relevant Marrow CR: BM: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatment PB Stable disease (SD): failure to achieve at least PR, but no evidence of progression for > 8 wks Failure: death during treatment or disease progression Disease Progression for those with: Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts 5%-10% blasts:≥ 50% increase to > 10% blasts 10%-20% blasts:≥ 50% increase to > 20% blasts 20%-30% blasts ≥ 50% increase to > 30% blasts Any of the following: ≥ 50% decrease from maximum remission/response in granulocytes or platelets
    Time Frame Response was assessed every 3 cycles; up to the data cut-off date of 25 Jan 2019; median duration of exposure to oral azacitidine was 86.0 days and 119.0 days for placebo

    Outcome Measure Data

    Analysis Population Description
    Population includes participants with a CR, PR and mCR who had baseline bone marrow blasts > 5%. ITT population.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Complete Response (CR)
    7.7
    7.2%
    0
    0%
    Partial Response
    0
    0%
    0
    0%
    Marrow CR
    23.1
    21.6%
    4.2
    3.9%
    Stable Disease (SD)
    2.8
    2.6%
    30.3
    27.8%
    Disease Progression
    62.6
    58.5%
    46.8
    42.9%
    Failure due to Death
    0.9
    0.8%
    0.9
    0.8%
    14. Secondary Outcome
    Title Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)
    Description Participants with a documented diagnosis of AML arising from previous MDS documented diagnosis.
    Time Frame From randomization of study drug to the end up to final data cut-off date of 25 January 2019; maximum follow-up time was 67.9 months for azacitidine and 64.8 months for placebo group

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all participants who were randomized, regardless of whether they received treatment or not.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Number [Percentage of Participants]
    7.5
    7%
    16.5
    15.1%
    15. Secondary Outcome
    Title Time to Progression to Acute Myeloid Leukemia (AML) Among Participants Who Progressed to AML
    Description Time to AML progression was defined as the time from the date of randomization until the date the subject has documented progression to AML. For participants who had progression to AML documented in MLL central lab report, the earliest sample collection date with the diagnosis of "s-AML arising from previous MDS" was used as the date to AML progression.
    Time Frame From randomization of study drug to progression of AML; up to final data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population who progressed to AML.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 8 18
    Median (Full Range) [Months]
    17.94
    9.91
    16. Secondary Outcome
    Title Percentage of Participants With Significant Bleeding Events
    Description Clinically significant bleeding event was defined as: any intracranial or retroperitoneal bleed; bleeding requiring transfusions of > 2 units of blood/blood products; bleeding associated with a decrease in hemoglobin of > 2 g/dL; or bleeding from any site requiring transfusions of > 2 units of blood.
    Time Frame From date of randomization until 28 days after the last dose of IP; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all participants who were randomized, regardless of whether they received treatment or not.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Number [Percentage of Participants]
    8.4
    7.9%
    9.2
    8.4%
    17. Secondary Outcome
    Title Number of Participants With Treatment Emergent Adverse Events (TEAE)
    Description A TEAE was defined as an adverse event that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: Death; Life-threatening event; Any inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability or incapacity; Congenital anomaly or birth defect; Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.
    Time Frame From first dose of IP up to 28 days after the last dose of IP; up to data cut-off date of 25 Jan 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The safety population includes all randomized participants who received at least one dose of study drug.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    ≥ 1 TEAE
    107
    100%
    108
    99.1%
    ≥ 1 TEAE Related to Study Drug
    102
    95.3%
    54
    49.5%
    ≥ 1 Serious TEAE
    79
    73.8%
    69
    63.3%
    ≥ 1 Serious TEAE Related to Study Drug
    37
    34.6%
    8
    7.3%
    ≥ 1 Grade (GR) 3-4 TEAE
    96
    89.7%
    80
    73.4%
    ≥ 1 Grade 3-4 TEAE Related to Study Drug
    73
    68.2%
    19
    17.4%
    ≥ 1 Grade (GR) 3-4 Serious TEAE
    75
    70.1%
    56
    51.4%
    ≥ 1 GR 3-4 Serious TEAE Related to Study Drug
    37
    34.6%
    5
    4.6%
    ≥ 1 TEAE Leading to Death
    25
    23.4%
    14
    12.8%
    ≥ 1 TEAE Related to Study Drug Leading to Death
    9
    8.4%
    2
    1.8%
    ≥ 1 TEAE Leading to Dose Reduction
    31
    29%
    4
    3.7%
    ≥ 1 TEAE Leading to Dose Interruption
    66
    61.7%
    40
    36.7%
    ≥ 1 TEAE Leading to Dose Interruption/Reduction
    29
    27.1%
    2
    1.8%
    ≥ 1 TEAE Leading to Treatment Discontinuation
    32
    29.9%
    31
    28.4%
    18. Secondary Outcome
    Title Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6
    Description The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    0.2
    (4.12)
    -0.8
    (3.91)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.214
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    19. Secondary Outcome
    Title Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6
    Description The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    -0.4
    (3.96)
    -1.1
    (4.69)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.446
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    20. Secondary Outcome
    Title Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6
    Description The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    1.3
    (4.33)
    0.2
    (4.35)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.248
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    21. Secondary Outcome
    Title Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6
    Description The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The FACT-Anemia evaluable population was defined as all ITT participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    0.5
    (3.95)
    -1.2
    (4.45)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.058
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    22. Secondary Outcome
    Title Mean Change From Baseline in the Anemia Subscale Within FACT-An Instrument at Cycle 6
    Description The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    2.9
    (11.81)
    -0.6
    (10.39)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.130
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    23. Secondary Outcome
    Title Mean Change From Baseline in the Fatigue-Related Subscale Within the FACT-An Instrument at Cycle 6
    Description The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    2.1
    (8.74)
    -0.6
    (7.84)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.123
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    24. Secondary Outcome
    Title Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale Within the FACT-An Instrument at Cycle 6
    Description The FACT-G and FACT-An score are summed to form the FACT-An total score. The FACT-An Trial Outcome Index (TOI) consists of the summation of a "summary scale" and includes the Physical Well-being, (PWB; 7 items; score range, 0-28), the Functional Well-being (7 items; score range, 0-28) and the Anemia subscale consisting of 20 items on the same five-point scale, with 13 of them measuring fatigue related symptoms (FS) and seven measuring non-FS. The FACT-An TOI has been demonstrated to be a sensitive indicator of clinical outcomes in a number of diseases including MDS. The Fact-TOI score ranges from 0 to 136. Higher scores on all scales of the Fact-An and subscales on the FACT-TOI reflect better quality of life or fewer symptoms.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    3.7
    (17.29)
    -2.7
    (15.45)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.069
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    25. Secondary Outcome
    Title Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale Within the FACT-An Instrument at Cycle 6
    Description The FACT-An is a 47-item, cancer-specific questionnaire consisting of a core 27-item general questionnaire (i.e., the Functional Assessment of Cancer Therapy-General [FACT-G]) The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: Physical Well-being (PWB; 7 items; score range, 0-28), Social/Family Well-being (SWB; 7 items; score range, 0-28), Emotional Well-being (EWB; 6 items; score range, 0-24), and Functional Well-being (7 items; score range, 0-28). The FACT-G is a summation composed of a "summary scale" including the PWB, SWB, EWB and FWB. The FACT-G score range is from 0 to 108. For all summary scales including FACT-G, a higher score indicates better HRQoL or lower level of symptoms.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    1.6
    (12.00)
    -2.9
    (12.11)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.078
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    26. Secondary Outcome
    Title Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6
    Description The FACT-G and the anemia subscale (AnS) are summed to form the FACT-An total score and the total score ranges from 0 to 188. The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: Physical Well-being (PWB; 7 items; score range, 0-28), Social/Family Well-being (SWB; 7 items; score range, 0-28), Emotional Well-being (EWB; 6 items; score range, 0-24), and Functional Well-being (7 items; score range, 0-28). The AnS consists of 20 items on the same 5-point scale, with 13 of them measuring fatigue-related symptoms (FS) and 7 measuring non-FS. The AnS and FS scores can range from 0-80 and 0-52, respectively. For all domains and summary subscales, a higher score indicates better HRQoL or lower level of symptoms.
    Time Frame Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 42 49
    Mean (Standard Deviation) [Units on a Scale]
    4.5
    (21.88)
    -3.5
    (20.62)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.073
    Comments
    Method t-test, 2 sided
    Comments The p-value was calculated based on a pooled 2-sample, 2-sided t-test for the difference in mean change from baseline between treatment groups.
    27. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    17.3
    16.2%
    13.7
    12.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.560
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Raatio
    Estimated Value 0.77
    Confidence Interval (2-Sided) 95%
    0.54 to 1.30
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    28. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    11.1
    10.4%
    14.7
    13.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.480
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Raatio
    Estimated Value 0.72
    Confidence Interval (2-Sided) 95%
    0.29 to 1.78
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    29. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    23.5
    22%
    15.8
    14.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.197
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Ratio
    Estimated Value 1.67
    Confidence Interval (2-Sided) 95%
    0.76 to 3.65
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    30. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    14.8
    13.8%
    8.4
    7.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.121
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Ratio
    Estimated Value 2.14
    Confidence Interval (2-Sided) 95%
    0.82 to 5.57
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    31. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    27.2
    25.4%
    15.8
    14.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.075
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Ratio
    Estimated Value 2.00
    Confidence Interval (2-Sided) 95%
    0.93 to 4.30
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    32. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    27.2
    25.4%
    18.9
    17.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.222
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Ratio
    Estimated Value 1.58
    Confidence Interval (2-Sided) 95%
    0.76 to 3.29
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    33. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    19.8
    18.5%
    12.6
    11.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.249
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Ratio
    Estimated Value 1.65
    Confidence Interval (2-Sided) 95%
    0.71 to 3.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    34. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score baseline visit and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    23.5
    22%
    13.7
    12.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.082
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Ratio
    Estimated Value 2.03
    Confidence Interval (2-Sided) 95%
    0.92 to 4.48
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    35. Secondary Outcome
    Title Percentage of Participants With a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain Within the FACT-An Instrument at Cycle 6
    Description A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    Time Frame Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    Health Related Quality of Life (HR-QoL) evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score at C1D1 and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Number [Percentage of Participants]
    19.8
    18.5%
    11.6
    10.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.153
    Comments
    Method Cochran-Mantel-Haenszel
    Comments The p-value was calculated based on the CMH tests for comparing the odds of experiencing CMI between CC-486 versus placebo.
    Method of Estimation Estimation Parameter Common Odds Ratio
    Estimated Value 1.86
    Confidence Interval (2-Sided) 95%
    0.79 to 4.34
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical Analysis The common odds ratio and the 95% confidence interval (CI) were calculated using CMH tests, stratified by randomization stratification factors, to compare the odds of experiencing clinically meaningful improvement between CC-486 and placebo.
    36. Secondary Outcome
    Title Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5
    Description The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    Time Frame From Baseline to Cycle 2 Day 1 (C2D1)

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score baseline visit and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    2.5
    2.3%
    10.5
    9.6%
    No Change
    30.9
    28.9%
    49.5
    45.4%
    Worsened by 1 Level
    25.9
    24.2%
    23.2
    21.3%
    Worsened by 2 Levels
    23.5
    22%
    6.3
    5.8%
    Missing
    17.3
    16.2%
    10.5
    9.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Fisher Exact
    Comments
    37. Secondary Outcome
    Title Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5
    Description The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    Time Frame From Baseline to Cycle 3 Day 1 (C3D1)

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score baseline visit and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    7.4
    6.9%
    10.5
    9.6%
    No Change
    24.7
    23.1%
    41.1
    37.7%
    Worsened by 1 Level
    16.0
    15%
    18.9
    17.3%
    Worsened by 2 Levels
    23.5
    22%
    13.7
    12.6%
    Missing
    28.4
    26.5%
    15.8
    14.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.046
    Comments
    Method Fisher Exact
    Comments
    38. Secondary Outcome
    Title Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5
    Description The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    Time Frame From Baseline to Cycle 4 Day 1 (C4D1)

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score baseline visit and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    2.5
    2.3%
    9.5
    8.7%
    No Change
    32.1
    30%
    37.9
    34.8%
    Worsened by 1 Level
    16.0
    15%
    14.7
    13.5%
    Worsened by 2 Levels
    14.8
    13.8%
    6.3
    5.8%
    Missing
    34.6
    32.3%
    31.6
    29%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.134
    Comments
    Method Fisher Exact
    Comments
    39. Secondary Outcome
    Title Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5
    Description The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    Time Frame From Baseline to Cycle 5 Day 1 (C5D1)

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score baseline visit and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    2.5
    2.3%
    7.4
    6.8%
    No Change
    25.9
    24.2%
    34.7
    31.8%
    Worsened by 1 Level
    13.6
    12.7%
    12.6
    11.6%
    Worsened by 2 Levels
    8.6
    8%
    5.3
    4.9%
    Missing
    49.4
    46.2%
    40.0
    36.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.324
    Comments
    Method Fisher Exact
    Comments
    40. Secondary Outcome
    Title Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5
    Description The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    Time Frame From Baseline to Cycle 6 Day 1 (C6 D1)

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score baseline visit and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    1.2
    1.1%
    4.2
    3.9%
    No Change
    25.9
    24.2%
    27.4
    25.1%
    Worsened by 1 Level
    9.9
    9.3%
    12.6
    11.6%
    Worsened by 2 Levels
    14.8
    13.8%
    7.4
    6.8%
    Missing
    48.1
    45%
    48.4
    44.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.442
    Comments
    Method Fisher Exact
    Comments
    41. Secondary Outcome
    Title Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5
    Description The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    Time Frame From Baseline to Cycle 7 Day 1 (C7D1)

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score baseline visit and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    1.2
    1.1%
    1.1
    1%
    No Change
    25.9
    24.2%
    21.1
    19.4%
    Worsened by 1 Level
    11.1
    10.4%
    3.2
    2.9%
    Worsened by 2 Levels
    7.4
    6.9%
    3.2
    2.9%
    Missing
    54.3
    50.7%
    71.6
    65.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.063
    Comments
    Method Fisher Exact
    Comments
    42. Secondary Outcome
    Title Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5
    Description The distribution (frequency and percentage) of the observed responses (i.e., "Not at all (0)," "A little bit (1)," "Somewhat (2)," "Quite a bit (3)," "Very much (4)," and missing) to Item GP-5 ("I am bothered by side effects of treatment" in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    Time Frame From Baseline to End of Treatment

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a non-missing FACT-An Trial Outcome Index (TOI) score baseline visit and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    2.5
    2.3%
    6.3
    5.8%
    No Change
    14.8
    13.8%
    25.3
    23.2%
    Worsened by 1 Level
    9.9
    9.3%
    8.4
    7.7%
    Worsened by 2 Levels
    9.9
    9.3%
    12.6
    11.6%
    Missing
    63.0
    58.9%
    47.4
    43.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.198
    Comments
    Method Fisher Exact
    Comments
    43. Secondary Outcome
    Title Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level (EQ-5D-3L) Mobility Dimension Responses at Cycle 6
    Description The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    Time Frame From Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a EQ-5D-3L health utility at baseline and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    8.6
    8%
    8.4
    7.7%
    No Change
    35.8
    33.5%
    33.7
    30.9%
    Worsened
    7.4
    6.9%
    9.5
    8.7%
    Missing
    48.1
    45%
    48.4
    44.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.972
    Comments
    Method Fisher Exact
    Comments
    44. Secondary Outcome
    Title Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level of Self-Care Dimension Responses at Cycle 6
    Description The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    Time Frame From Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a EQ-5D-3L health utility at baseline and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    2.5
    2.3%
    4.2
    3.9%
    No Change
    42.0
    39.3%
    44.2
    40.6%
    Worsened
    7.4
    6.9%
    3.2
    2.9%
    Missing
    48.1
    45%
    48.4
    44.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.601
    Comments
    Method Fisher Exact
    Comments
    45. Secondary Outcome
    Title Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level Usual Activities Dimension Responses at Cycle 6
    Description TThe EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    Time Frame From Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a EQ-5D-3L health utility at baseline and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    11.1
    10.4%
    3.2
    2.9%
    No Change
    28.4
    26.5%
    41.1
    37.7%
    Worsened
    12.3
    11.5%
    7.4
    6.8%
    Missing
    48.1
    45%
    48.4
    44.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.070
    Comments
    Method Fisher Exact
    Comments
    46. Secondary Outcome
    Title Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level in the Pain/Discomfort Dimension Responses at Cycle 6
    Description The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    Time Frame From Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a EQ-5D-3L health utility at baseline and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    13.6
    12.7%
    8.4
    7.7%
    No Change
    33.3
    31.1%
    32.6
    29.9%
    Worsened
    4.9
    4.6%
    10.5
    9.6%
    Missing
    48.1
    45%
    48.4
    44.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.436
    Comments
    Method Fisher Exact
    Comments
    47. Secondary Outcome
    Title Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level in the Anxiety/Depression Dimension Responses at Cycle 6
    Description The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    Time Frame From Baseline to Cycle 6 Day 1

    Outcome Measure Data

    Analysis Population Description
    The HRQoL evaluable population was defined as participants with a EQ-5D-3L health utility at baseline and at least one post-baseline assessment visit.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 81 95
    Improved
    4.9
    4.6%
    7.4
    6.8%
    No Change
    35.8
    33.5%
    37.9
    34.8%
    Worsened
    11.1
    10.4%
    6.3
    5.8%
    Missing
    48.1
    45%
    48.4
    44.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Oral Azacitidine and Best Supportive Care, Placebo Plus Best Supportive Care
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.683
    Comments
    Method Fisher Exact
    Comments
    48. Secondary Outcome
    Title Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized During the Treatment Period
    Description The number of reasons for hospitalizations and hospital admissions during the treatment period were monitored and include those associated with: AEs, protocol-driven procedures, transfusions, non-protocol procedures, elective procedures or those associated with social, practical or technical reasons in the absence of AEs. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
    Time Frame From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The safety population includes all randomized participants who received at least one dose of study drug.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Adverse Events
    79
    73.8%
    65
    59.6%
    Protocol Driven Procedures
    2
    1.9%
    7
    6.4%
    Non-Protocol Driven Procedures
    9
    8.4%
    19
    17.4%
    Transfusion
    32
    29.9%
    33
    30.3%
    Procedure Planned Prior to Signing Consent
    0
    0%
    4
    3.7%
    Elective Procedures
    4
    3.7%
    10
    9.2%
    Social, Technical or Practical Reason except AEs
    4
    3.7%
    6
    5.5%
    49. Secondary Outcome
    Title Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to Any Reason During the Treatment Period
    Description The total number of days hospitalized due to any reason during the treatment period was monitored. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
    Time Frame From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The safety population includes all randomized participants who received at least one dose of study drug.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Number [Days]
    3513
    2688
    50. Secondary Outcome
    Title Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years
    Description The number of days hospitalized per total patient years. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
    Time Frame From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo

    Outcome Measure Data

    Analysis Population Description
    The safety population includes all randomized participants who received at least one dose of study drug.
    Arm/Group Title Oral Azacitidine and Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily on days 1 to 21 of each 28-day treatment cycle and BSC included and was not limited to pRBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Measure Participants 107 109
    Number [Days Per Total Patient Years]
    41.44
    40.53

    Adverse Events

    Time Frame Treatment Emergent AEs were monitored from randomization date up to 28 days after the last dose of IP;; up to data cut-off date of 25 Jan 2019; up to 69 months.
    Adverse Event Reporting Description Median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo
    Arm/Group Title Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Arm/Group Description Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections. Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    All Cause Mortality
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 69/107 (64.5%) 71/109 (65.1%)
    Serious Adverse Events
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 79/107 (73.8%) 69/109 (63.3%)
    Blood and lymphatic system disorders
    Anaemia 5/107 (4.7%) 5/109 (4.6%)
    Bone marrow failure 2/107 (1.9%) 0/109 (0%)
    Febrile neutropenia 29/107 (27.1%) 9/109 (8.3%)
    Haemolytic anaemia 1/107 (0.9%) 0/109 (0%)
    Haemorrhagic anaemia 1/107 (0.9%) 0/109 (0%)
    Neutropenia 2/107 (1.9%) 1/109 (0.9%)
    Pancytopenia 1/107 (0.9%) 0/109 (0%)
    Thrombocytopenia 4/107 (3.7%) 1/109 (0.9%)
    Cardiac disorders
    Acute myocardial infarction 1/107 (0.9%) 0/109 (0%)
    Angina pectoris 0/107 (0%) 1/109 (0.9%)
    Angina unstable 1/107 (0.9%) 0/109 (0%)
    Atrial fibrillation 1/107 (0.9%) 2/109 (1.8%)
    Atrioventricular block first degree 0/107 (0%) 1/109 (0.9%)
    Cardiac arrest 0/107 (0%) 1/109 (0.9%)
    Cardiac failure 2/107 (1.9%) 2/109 (1.8%)
    Cardiac failure congestive 3/107 (2.8%) 0/109 (0%)
    Cardio-respiratory arrest 0/107 (0%) 1/109 (0.9%)
    Cardiogenic shock 1/107 (0.9%) 0/109 (0%)
    Long QT syndrome 0/107 (0%) 1/109 (0.9%)
    Myocardial infarction 1/107 (0.9%) 2/109 (1.8%)
    Tachyarrhythmia 2/107 (1.9%) 0/109 (0%)
    Ventricular tachycardia 0/107 (0%) 1/109 (0.9%)
    Gastrointestinal disorders
    Abdominal pain 3/107 (2.8%) 0/109 (0%)
    Abdominal pain upper 1/107 (0.9%) 0/109 (0%)
    Colitis 0/107 (0%) 1/109 (0.9%)
    Constipation 1/107 (0.9%) 0/109 (0%)
    Diarrhoea 3/107 (2.8%) 0/109 (0%)
    Gastritis 1/107 (0.9%) 0/109 (0%)
    Gastrointestinal haemorrhage 1/107 (0.9%) 2/109 (1.8%)
    Haemorrhoidal haemorrhage 0/107 (0%) 1/109 (0.9%)
    Intestinal obstruction 1/107 (0.9%) 0/109 (0%)
    Intestinal perforation 1/107 (0.9%) 0/109 (0%)
    Intra-abdominal haemorrhage 1/107 (0.9%) 0/109 (0%)
    Melaena 0/107 (0%) 2/109 (1.8%)
    Nausea 2/107 (1.9%) 0/109 (0%)
    Neutropenic colitis 1/107 (0.9%) 0/109 (0%)
    Oesophageal achalasia 1/107 (0.9%) 0/109 (0%)
    Oral mucosal blistering 1/107 (0.9%) 0/109 (0%)
    Rectal haemorrhage 1/107 (0.9%) 1/109 (0.9%)
    Upper gastrointestinal haemorrhage 0/107 (0%) 1/109 (0.9%)
    Vomiting 1/107 (0.9%) 0/109 (0%)
    General disorders
    Fatigue 0/107 (0%) 1/109 (0.9%)
    Gait disturbance 1/107 (0.9%) 0/109 (0%)
    General physical health deterioration 3/107 (2.8%) 1/109 (0.9%)
    Hypothermia 1/107 (0.9%) 0/109 (0%)
    Multiple organ dysfunction syndrome 2/107 (1.9%) 0/109 (0%)
    Pyrexia 8/107 (7.5%) 4/109 (3.7%)
    Sudden death 0/107 (0%) 1/109 (0.9%)
    Hepatobiliary disorders
    Biliary colic 0/107 (0%) 1/109 (0.9%)
    Cholecystitis 2/107 (1.9%) 1/109 (0.9%)
    Hyperbilirubinaemia 2/107 (1.9%) 0/109 (0%)
    Infections and infestations
    Abscess limb 1/107 (0.9%) 0/109 (0%)
    Arteriovenous fistula site infection 1/107 (0.9%) 0/109 (0%)
    Atypical pneumonia 2/107 (1.9%) 0/109 (0%)
    Bacteraemia 0/107 (0%) 2/109 (1.8%)
    Bronchitis 0/107 (0%) 1/109 (0.9%)
    Bronchopulmonary aspergillosis 2/107 (1.9%) 0/109 (0%)
    Cellulitis 1/107 (0.9%) 0/109 (0%)
    Clostridium difficile colitis 0/107 (0%) 1/109 (0.9%)
    Corona virus infection 1/107 (0.9%) 0/109 (0%)
    Cystitis escherichia 0/107 (0%) 1/109 (0.9%)
    Device related infection 1/107 (0.9%) 0/109 (0%)
    Diverticulitis 0/107 (0%) 1/109 (0.9%)
    Epididymitis 1/107 (0.9%) 0/109 (0%)
    Escherichia sepsis 1/107 (0.9%) 0/109 (0%)
    Febrile infection 1/107 (0.9%) 1/109 (0.9%)
    Gastroenteritis 1/107 (0.9%) 0/109 (0%)
    Gastroenteritis clostridial 0/107 (0%) 1/109 (0.9%)
    Groin abscess 1/107 (0.9%) 0/109 (0%)
    Haemophilus infection 0/107 (0%) 1/109 (0.9%)
    Infection 0/107 (0%) 1/109 (0.9%)
    Influenza 1/107 (0.9%) 0/109 (0%)
    Klebsiella infection 1/107 (0.9%) 0/109 (0%)
    Klebsiella sepsis 1/107 (0.9%) 0/109 (0%)
    Lower respiratory tract infection 1/107 (0.9%) 4/109 (3.7%)
    Lung infection 3/107 (2.8%) 0/109 (0%)
    Lymph gland infection 0/107 (0%) 1/109 (0.9%)
    Meningitis 1/107 (0.9%) 0/109 (0%)
    Meningitis bacterial 1/107 (0.9%) 0/109 (0%)
    Myringitis 1/107 (0.9%) 0/109 (0%)
    Neutropenic sepsis 5/107 (4.7%) 1/109 (0.9%)
    Pharyngeal abscess 0/107 (0%) 1/109 (0.9%)
    Pharyngitis 0/107 (0%) 2/109 (1.8%)
    Pneumonia 10/107 (9.3%) 12/109 (11%)
    Pneumonia fungal 1/107 (0.9%) 0/109 (0%)
    Pneumonia pneumococcal 1/107 (0.9%) 0/109 (0%)
    Prostatic abscess 0/107 (0%) 1/109 (0.9%)
    Pseudomonal sepsis 1/107 (0.9%) 0/109 (0%)
    Pulmonary mycosis 1/107 (0.9%) 0/109 (0%)
    Respiratory tract infection 1/107 (0.9%) 1/109 (0.9%)
    Respiratory tract infection bacterial 0/107 (0%) 1/109 (0.9%)
    Sepsis 8/107 (7.5%) 3/109 (2.8%)
    Septic shock 6/107 (5.6%) 3/109 (2.8%)
    Skin infection 1/107 (0.9%) 0/109 (0%)
    Staphylococcal infection 1/107 (0.9%) 1/109 (0.9%)
    Staphylococcal sepsis 0/107 (0%) 1/109 (0.9%)
    Tooth abscess 0/107 (0%) 1/109 (0.9%)
    Upper respiratory tract infection 3/107 (2.8%) 1/109 (0.9%)
    Urinary tract infection 2/107 (1.9%) 1/109 (0.9%)
    Urinary tract infection bacterial 1/107 (0.9%) 1/109 (0.9%)
    Viral sepsis 1/107 (0.9%) 0/109 (0%)
    Injury, poisoning and procedural complications
    Arteriovenous fistula site haemorrhage 0/107 (0%) 1/109 (0.9%)
    Cystitis radiation 0/107 (0%) 1/109 (0.9%)
    Fall 4/107 (3.7%) 0/109 (0%)
    Febrile nonhaemolytic transfusion reaction 1/107 (0.9%) 0/109 (0%)
    Head injury 1/107 (0.9%) 0/109 (0%)
    Hip fracture 1/107 (0.9%) 0/109 (0%)
    Periorbital haematoma 1/107 (0.9%) 0/109 (0%)
    Subdural haematoma 2/107 (1.9%) 0/109 (0%)
    Subdural haemorrhage 1/107 (0.9%) 0/109 (0%)
    Transfusion reaction 0/107 (0%) 1/109 (0.9%)
    Upper limb fracture 1/107 (0.9%) 0/109 (0%)
    Investigations
    Gamma-glutamyltransferase increased 0/107 (0%) 1/109 (0.9%)
    Weight decreased 1/107 (0.9%) 0/109 (0%)
    Metabolism and nutrition disorders
    Dehydration 1/107 (0.9%) 1/109 (0.9%)
    Diabetes mellitus 0/107 (0%) 1/109 (0.9%)
    Diabetes mellitus inadequate control 1/107 (0.9%) 0/109 (0%)
    Diabetic metabolic decompensation 1/107 (0.9%) 0/109 (0%)
    Hyperkalaemia 1/107 (0.9%) 0/109 (0%)
    Hypoglycaemia 1/107 (0.9%) 0/109 (0%)
    Hyponatraemia 0/107 (0%) 1/109 (0.9%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/107 (0.9%) 0/109 (0%)
    Muscular weakness 1/107 (0.9%) 0/109 (0%)
    Polychondritis 1/107 (0.9%) 0/109 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 1/107 (0.9%) 2/109 (1.8%)
    Basal cell carcinoma 0/107 (0%) 1/109 (0.9%)
    Bone neoplasm 1/107 (0.9%) 0/109 (0%)
    Bowen's disease 1/107 (0.9%) 0/109 (0%)
    Carcinoma in situ of skin 0/107 (0%) 1/109 (0.9%)
    Central nervous system leukaemia 0/107 (0%) 1/109 (0.9%)
    Chronic myelomonocytic leukaemia 0/107 (0%) 1/109 (0.9%)
    Colon adenoma 1/107 (0.9%) 0/109 (0%)
    Colon cancer 0/107 (0%) 1/109 (0.9%)
    Malignant neoplasm of unknown primary site 0/107 (0%) 1/109 (0.9%)
    Mantle cell lymphoma recurrent 1/107 (0.9%) 0/109 (0%)
    Myelodysplastic syndrome 0/107 (0%) 3/109 (2.8%)
    Refractory anaemia with an excess of blasts 0/107 (0%) 1/109 (0.9%)
    Spinal cord neoplasm 1/107 (0.9%) 0/109 (0%)
    Squamous cell carcinoma of skin 0/107 (0%) 1/109 (0.9%)
    Transformation to acute myeloid leukaemia 0/107 (0%) 6/109 (5.5%)
    Nervous system disorders
    Central nervous system lesion 1/107 (0.9%) 0/109 (0%)
    Cerebral haemorrhage 0/107 (0%) 1/109 (0.9%)
    Epilepsy 1/107 (0.9%) 0/109 (0%)
    Generalised tonic-clonic seizure 1/107 (0.9%) 0/109 (0%)
    Guillain-Barre syndrome 0/107 (0%) 1/109 (0.9%)
    Haemorrhage intracranial 2/107 (1.9%) 0/109 (0%)
    IIIrd nerve paresis 0/107 (0%) 1/109 (0.9%)
    Lethargy 1/107 (0.9%) 0/109 (0%)
    Presyncope 0/107 (0%) 1/109 (0.9%)
    Sciatica 0/107 (0%) 1/109 (0.9%)
    Status epilepticus 1/107 (0.9%) 0/109 (0%)
    Syncope 1/107 (0.9%) 0/109 (0%)
    Transient ischaemic attack 1/107 (0.9%) 1/109 (0.9%)
    Psychiatric disorders
    Bipolar disorder 0/107 (0%) 1/109 (0.9%)
    Confusional state 0/107 (0%) 2/109 (1.8%)
    Renal and urinary disorders
    Acute kidney injury 2/107 (1.9%) 3/109 (2.8%)
    Chronic kidney disease 1/107 (0.9%) 0/109 (0%)
    Haematuria 0/107 (0%) 1/109 (0.9%)
    Prerenal failure 1/107 (0.9%) 0/109 (0%)
    Renal colic 1/107 (0.9%) 0/109 (0%)
    Renal failure 2/107 (1.9%) 0/109 (0%)
    Urinary retention 1/107 (0.9%) 1/109 (0.9%)
    Urinary tract obstruction 0/107 (0%) 1/109 (0.9%)
    Reproductive system and breast disorders
    Prostatitis 1/107 (0.9%) 0/109 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 1/107 (0.9%) 0/109 (0%)
    Epistaxis 2/107 (1.9%) 1/109 (0.9%)
    Haemoptysis 0/107 (0%) 1/109 (0.9%)
    Laryngeal oedema 0/107 (0%) 1/109 (0.9%)
    Pleural effusion 1/107 (0.9%) 1/109 (0.9%)
    Pleurisy 1/107 (0.9%) 0/109 (0%)
    Pleuritic pain 0/107 (0%) 1/109 (0.9%)
    Pneumonia aspiration 1/107 (0.9%) 0/109 (0%)
    Pulmonary embolism 1/107 (0.9%) 0/109 (0%)
    Pulmonary oedema 0/107 (0%) 2/109 (1.8%)
    Respiratory failure 1/107 (0.9%) 0/109 (0%)
    Skin and subcutaneous tissue disorders
    Hypersensitivity vasculitis 1/107 (0.9%) 0/109 (0%)
    Rash 1/107 (0.9%) 0/109 (0%)
    Rash generalised 1/107 (0.9%) 0/109 (0%)
    Vascular disorders
    Arteritis 0/107 (0%) 1/109 (0.9%)
    Haematoma 1/107 (0.9%) 0/109 (0%)
    Polyarteritis nodosa 0/107 (0%) 1/109 (0.9%)
    Shock haemorrhagic 1/107 (0.9%) 0/109 (0%)
    Other (Not Including Serious) Adverse Events
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 107/107 (100%) 104/109 (95.4%)
    Blood and lymphatic system disorders
    Anaemia 19/107 (17.8%) 17/109 (15.6%)
    Leukopenia 10/107 (9.3%) 0/109 (0%)
    Neutropenia 52/107 (48.6%) 15/109 (13.8%)
    Thrombocytopenia 29/107 (27.1%) 18/109 (16.5%)
    Gastrointestinal disorders
    Abdominal pain 14/107 (13.1%) 14/109 (12.8%)
    Constipation 50/107 (46.7%) 24/109 (22%)
    Diarrhoea 73/107 (68.2%) 25/109 (22.9%)
    Gastrooesophageal reflux disease 6/107 (5.6%) 0/109 (0%)
    Gingival bleeding 7/107 (6.5%) 0/109 (0%)
    Haemorrhoids 0/107 (0%) 6/109 (5.5%)
    Mouth haemorrhage 10/107 (9.3%) 7/109 (6.4%)
    Nausea 81/107 (75.7%) 25/109 (22.9%)
    Rectal haemorrhage 0/107 (0%) 8/109 (7.3%)
    Vomiting 67/107 (62.6%) 10/109 (9.2%)
    General disorders
    Asthenia 25/107 (23.4%) 20/109 (18.3%)
    Fatigue 23/107 (21.5%) 22/109 (20.2%)
    Oedema peripheral 29/107 (27.1%) 17/109 (15.6%)
    Pyrexia 30/107 (28%) 15/109 (13.8%)
    Infections and infestations
    Cellulitis 6/107 (5.6%) 0/109 (0%)
    Oral herpes 6/107 (5.6%) 0/109 (0%)
    Pneumonia 7/107 (6.5%) 0/109 (0%)
    Upper respiratory tract infection 7/107 (6.5%) 0/109 (0%)
    Urinary tract infection 12/107 (11.2%) 0/109 (0%)
    Injury, poisoning and procedural complications
    Contusion 15/107 (14%) 0/109 (0%)
    Investigations
    Alanine aminotransferase increased 9/107 (8.4%) 6/109 (5.5%)
    Serum ferritin increased 6/107 (5.6%) 0/109 (0%)
    Weight decreased 10/107 (9.3%) 0/109 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 27/107 (25.2%) 10/109 (9.2%)
    Hyperglycaemia 6/107 (5.6%) 0/109 (0%)
    Hypokalaemia 12/107 (11.2%) 10/109 (9.2%)
    Hypomagnesaemia 10/107 (9.3%) 0/109 (0%)
    Iron overload 6/107 (5.6%) 11/109 (10.1%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 9/107 (8.4%) 11/109 (10.1%)
    Back pain 13/107 (12.1%) 13/109 (11.9%)
    Pain in extremity 7/107 (6.5%) 0/109 (0%)
    Nervous system disorders
    Dizziness 8/107 (7.5%) 9/109 (8.3%)
    Psychiatric disorders
    Anxiety 9/107 (8.4%) 0/109 (0%)
    Confusional state 6/107 (5.6%) 0/109 (0%)
    Depression 6/107 (5.6%) 0/109 (0%)
    Insomnia 10/107 (9.3%) 6/109 (5.5%)
    Renal and urinary disorders
    Haematuria 0/107 (0%) 6/109 (5.5%)
    Respiratory, thoracic and mediastinal disorders
    Cough 16/107 (15%) 15/109 (13.8%)
    Dyspnoea 13/107 (12.1%) 15/109 (13.8%)
    Epistaxis 28/107 (26.2%) 21/109 (19.3%)
    Skin and subcutaneous tissue disorders
    Ecchymosis 6/107 (5.6%) 10/109 (9.2%)
    Petechiae 21/107 (19.6%) 20/109 (18.3%)
    Pruritus 0/107 (0%) 6/109 (5.5%)
    Vascular disorders
    Haematoma 10/107 (9.3%) 11/109 (10.1%)
    Hypertension 0/107 (0%) 6/109 (5.5%)
    Hypotension 6/107 (5.6%) 0/109 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Results from a center cannot be submitted for publication before results of multicenter study are published unless it is > 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 additional days. Investigator must delete confidential information before submission and defer publication to permit patent applications.

    Results Point of Contact

    Name/Title Anne McClain, Senior Manager
    Organization Celgene Corporation
    Phone 888-260-1599
    Email ClinicalTrialDisclosure@Celgene.com
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT01566695
    Other Study ID Numbers:
    • AZA-MDS-003
    • 2012-002471-34
    First Posted:
    Mar 29, 2012
    Last Update Posted:
    Aug 2, 2022
    Last Verified:
    Jul 1, 2022