A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes

• Sponsor: Helsinn Healthcare SA (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03151304
• Collaborator: (none)
• Enrollment: 64
• Locations: 25
• Arm: 1
• Actual Duration (Months): 42
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 2, two-stage study of the safety and efficacy of pracinostat in combination with azacitidine in patients with IPSS-R high and very high risk myelodysplastic syndrome (MDS) who are previously untreated with hypomethylating agents (HMAs). Enrollment in this study will be limited to high/very high risk MDS because this group represents the highest unmet need, with median survival of less than 18 months.

Stage 1a will be conducted as an open-label single arm in up to 40 subjects to assess if this regimen with a lower pracinostat dose results in a discontinuation rate that meets a predefined threshold and in efficacy that justifies expansion of enrollment into Stage 1b.

A discontinuation rate of approximately ≤10% in Stage 1a, a rate comparable to that observed with azacitidine alone in study MEI-003 (NCT01873703), supports expansion into Stage 1b.

Stage 1b will be conducted as expansion of stage 1a. Approximately 20 additional subjects will be enrolled. Study drugs should be continued until disease progression or intolerable toxicity. It is important to note that the median time to achieving a response with azacitidine alone is 4 to 5 months. Furthermore, the median time to achieving a Complete Response (CR) in study MEI-003 (NCT01873703) was 4 cycles. Therefore, early (<6 months) discontinuation of trial therapy for 'no response' should be avoided. The Medical Monitor should be contacted prior to discontinuing a subject from the study to discuss the rationale for discontinuation.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: Pracinostat; Drug: Azacitidine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Two-Stage, Open-LabelTwo-Stage, Open-Label
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Two-Stage, Open-Label Phase 2 Study of Pracinostat and Azacitidine in Patients With IPSS-R High and Very High Risk Myelodysplastic Syndromes Previously Untreated With Hypomethylating Agents
• Actual Study Start Date: Jun 1, 2017
• Actual Primary Completion Date: Dec 1, 2020
• Actual Study Completion Date: Dec 1, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Stage 1a and 1b open-label pracinostat plus azacitidine open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle

Drug: Pracinostat; 45 mg capsule; Other Names: SB939 ; Drug: Azacitidine; SC or IV injection

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [36 months]

   Percentage of subjects with confirmed complete remission (CR), partial remission (PR) and marrow CR, as per modified International Working Group (IWG) criteria: CR: Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood Hemoglobin (Hb) ≥11 g/dL; Platelets ≥100 × 10^9/L; Neutrophils ≥1.0 × 10^9/L; Blasts 0%. PR: All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by ≥ 50% over pre-treatment but still >5%; Cellularity and morphology not relevant Marrow CR: Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pre-treatment

Secondary Outcome Measures

1. Complete Response (CR) Rate [36 months]

   Percentage of subjects with confirmed CR (i.e., 2 CRs at least 28 days apart) as per modified IWG criteria: CR: Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood Hb ≥11 g/dL; Platelets ≥100 × 109/L; Neutrophils ≥1.0 × 109/L; Blasts 0%.

2. Overall Hematologic Improvement (HI) Response Rate [36 months]

   Percentage of subjects demonstrating major hematologic improvement according to modified IWG: Erythroid response (pre-treatment, <11 g/dL): Hb increase by ≥1.5 g/dL; Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pre-treatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hb of ≤9.0 g/dL pre-treatment will count in the RBC transfusion response evaluation. Platelet response (pre-treatment, <100 × 10^9/L): Absolute increase of ≥30 × 10^9/L for patients starting with >20 × 10^9/L platelets; Increase from <20 × 10^9/L to >20 × 10^9/L and by at least 100%. Neutrophil response (pre-treatment, <1.0 × 10^9/L): At least 100% increase and an absolute increase >0.5 × 10^9/L. Progression or relapse after HI: at least 1 of the following: At least 50% decrement from maximum response levels in granulocytes or platelets Reduction in Hb by≥1.5 g/dL Transfusion dependence

3. Clinical Benefit Rate [36 months]

   Percentage of subjects with confirmed CR, PR, Marrow CR, and HI with clinical benefit rate, defines as rate of CR + PR + HI + Marrow CR. All subjects who achieve hematologic CR, PR, marrow CR, or hematologic improvement on the erythrocytic lineage per modified IWG response criteria will be considered responders

4. Rate of Cytogenetic CR [36 months]

   Percentage of subjects with confirmed CR by cytogenetic assessment. Complete cytogenetic response is defined per modified IWG response criteria: Complete: Disappearance of the chromosomal abnormality without appearance of new ones Partial: At least 50% reduction of the chromosomal abnormality

5. Duration of Response (DoR) [36 months]

   For subjects who have achieved CR, PR, Marrow CR, or HI, DoR is defined as the time from the initial determination of response to the time of disease progression or death on study, whichever occurs first.

6. Rate of Leukemic Transformation [6 months]

   Percentage of subjects with leukemic transformation at landmark time point of 6 months

7. Event-free Survival (EFS) [36 months]

   time from the first day of study drug administration (Day 1) to failure or death from any cause

8. Progression-free Survival (PFS) [36 months]

   time from the first day of study drug administration (Day 1) to disease recurrence or progression as defined by the IWG criteria, or death on study: Disease progression for subjects 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: At least 50% decrement from maximum remission/response in granulocytes or platelets Reduction in Hb by ≥2 g/dL Transfusion dependence

9. Overall Survival (OS) [form day 1 to death on study, assessed up to 36 months]

   time from the first day of study drug administration (Day 1) to death on study

10. Rate of Leukemic Transformation [12 months]

    Percentage of subjects with leukemic transformation at landmark time point of 12 months

11. Rate of Leukemic Transformation [18 months]

    Percentage of subjects with leukemic transformation at landmark time point of 18 months

12. Rate of Leukemic Transformation [24 months]

    Percentage of subjects with leukemic transformation at landmark time point of 24 months

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Female or male subjects ≥18 years-of-age.

2. Histologically or cytologically documented diagnosis of MDS according to the World Health Organization (WHO) classification (Vardiman 2009, Arber 2016) with >5% and <20% bone marrow blasts by morphology and a peripheral white blood cell (WBC) count of <20,000/μL

• If WBC ≥20,000/μL, cytoreduction with hydroxyurea is permitted prior to enrollment.

• chronic myelomonocytic leukemia CMML-1 and CMML-2 subtypes

1. Classified as high or very high risk according to the Revised International Prognostic Scoring System (IPSS-R) risk category. CMML-1 and CMML-2 subtypes will be considered high-risk MDS and will not require IPSS-r scoring

2. Bone marrow biopsy (BMBx) and/or aspirate within 28 days prior to first study treatment.

3. Clinical indication for treatment with azacitidine.

4. Previously untreated with HMAs (prior therapy with transfusions, hematopoietic growth factors, or immunosuppressive therapy is allowed).

1. subjects who require the start of an HMA (e.g., azacitidine) due to progressing MDS may receive up to 1 cycle of azacitidine within 30 days prior to planned first dose (Cycle 1 Day 1)

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

2. Adequate organ function as evidenced by:

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × the upper limit of normal (ULN).

• Total bilirubin ≤1.5 × ULN or total bilirubin of ≤2 mg/dL, whichever is higher. Total bilirubin < 3 x ULN for patients with Gilbert-Meulengracht Syndrome

• Serum creatinine <1.5 mg/dL, or creatinine clearance>40 mL/min.

• QTcF interval ≤450 msec using the mean of triplicate electrocardiograms (ECGs).

1. Female subjects of childbearing potential and male subjects with female partners of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 30 days following last dose. Female subjects of childbearing potential must not be breastfeeding, or planning to breastfeed, and must have a negative pregnancy test ≤7 days before first study drug administration.

Male subjects must also refrain from donating sperm during their participation in the study.

1. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care.

2. Have the willingness and ability to understand the nature of this study and to comply with the study and follow-up procedures.

Exclusion Criteria:

1. Bone marrow blasts ≥20%, indicating a diagnosis of acute myeloid leukemia (AML).

2. Received any of the following within the specified time frame prior to administration of study medication:

• Any investigational agent within 14 days or 5 half-lives prior to enrollment, whichever is longer.

• Hydroxyurea within 48 hours prior to first day of study treatment.

• Hematopoietic growth factors: erythropoietin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), or thrombopoietin receptor agonists at least 7 days (14 days for Aranesp), prior to study enrollment.

• Major surgery within 28 days prior to first study treatment.

1. Subjects who have not recovered from side effects of previous therapy.

2. Cardiopulmonary function criteria:

• Current unstable arrhythmia requiring treatment.

• History of symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV).

• History of myocardial infarction, pulmonary embolism or cerebrovascular accident within 6 months of enrollment.

• Current unstable angina.

1. Prior treatment for MDS with histone deacetylase (HDAC) inhibitors Zolinza (vorinostat), Belenodaq (belinostat), Farydak (panobinostat), Istodax (romidepsin/depsipetide), or investigational agent with significant action as an HDAC inhibitor.

2. Clinical evidence of central nervous system involvement.

3. Subjects with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).

4. Uncontrolled infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C.

5. Life-threatening illness unrelated to cancer or any serious medical or psychiatric illness that could, in the Investigator's opinion, potentially interfere with participation in this study.

6. Presence of a malignant disease within the last 12 months, with the exception of adequately treated in-situ carcinomas, basal or squamous cell carcinoma, non-melanomatous skin cancer, or malignancies treated with curative intent and no evidence of active disease in prior 12 months and felt to be low risk for recurrence. Other malignancies may be considered after consultation with the Medical Monitor

7. An unwillingness or inability (including breastfeeding women, prohibited concomitant medications, uncontrolled infections, psychological, familial, sociological, or geographical conditions) to comply with study and/or follow-up procedures as outlined in the protocol

8. Known hypersensitivity to any components of pracinostat, azacitidine or mannitol

9. Current smoking or vaporizing of tobacco or cannabis-related products (use of patches, chewing tobacco, or nicotine gum is permitted). Subjects who stopped smoking at least 8 days prior to first pracinostat dosing can be, provided they refrain from smoking during the whole study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Scripps Cancer Center-Mercy	San Diego	California	United States	92103
3	Georgia Cancer Center at Augusta University	Augusta	Georgia	United States	30912
4	georgia cancer Center	Augusta	Georgia	United States	30912
5	Pontchartrain cancer Center	Covington	Louisiana	United States	70433
6	RCCA MD LLC (The Center for Cancer and Blood Disorders)	Bethesda	Maryland	United States	20817
7	Michigan Center of Medical Research	Farmington Hills	Michigan	United States	48334
8	Michigan State University, Breslin Cancer Center	Lansing	Michigan	United States	48910
9	university of minnesota medical Center, Fairview	Minneapolis	Minnesota	United States	55455
10	Mercy Medical Research Institute	Springfield	Missouri	United States	65807
11	New Mexico Cancer care Alliance	Albuquerque	New Mexico	United States	87131
12	University of Rochester Medical Center	Rochester	New York	United States	14642
13	Stony Brook University	Stony Brook	New York	United States	11794
14	Duke University Medical Center	Durham	North Carolina	United States	27710
15	Southeastern Medical Oncology Center	Goldsboro	North Carolina	United States	27534
16	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
17	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
18	Cancer Centers of Southwest Oklahoma	Lawton	Oklahoma	United States	73501
19	Oklahoma Cancer Specialists and Research Institute	Tulsa	Oklahoma	United States	74146
20	Providence Portland Medical center	Portland	Oregon	United States	97213
21	UT Southwestern Medical Center	Dallas	Texas	United States	75390
22	UVA Health System Division of Hematology & Oncology	Charlottesville	Virginia	United States	22908
23	Swedish Cancer Institute	Seattle	Washington	United States	98104
24	Universityof Wisconsin Clinical Science Center	Madison	Wisconsin	United States	53792
25	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Helsinn Healthcare SA

Investigators

• Study Director: Richard Ghalie, MD, MEI Pharma
• Study Chair: Ehab Atallah, MD, Medical College of Wisconsin adn Froedtert Hospital

Study Documents (Full-Text)

• Study Protocol - Jun 25, 2018
• Statistical Analysis Plan - Aug 28, 2020

More Information

Publications

None provided.

• Responsible Party: Helsinn Healthcare SA
• ClinicalTrials.gov Identifier: NCT03151304
• Other Study ID Numbers: MEI-011
• First Posted: May 12, 2017
• Last Update Posted: Mar 2, 2022
• Last Verified: Feb 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Helsinn Healthcare SA: MDS
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Azacitidine

Study Results

Participant Flow

Pre-assignment Detail	Stage 1 was to be conducted in 20-40 evaluable subjects to assess if the pracinostat dose regimen resulted in a discontinuation rate that met a predefined threshold, and the observed efficacy justified expansion of enrollment in Stage 1b. Stage 1b was conducted to achieve a planned total enrollment of 60 subjects evaluable for efficacy, inclusive of Stage 1 and Stage 1b enrollment.

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Period Title: Overall Study
STARTED	64
COMPLETED	0
NOT COMPLETED	64

Baseline Characteristics

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Overall Participants	64
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.8 (8.59)
Sex: Female, Male (Count of Participants)
Female	43 67.2%
Male	21 32.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 4.7%
Not Hispanic or Latino	57 89.1%
Unknown or Not Reported	4 6.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 4.7%
White	57 89.1%
More than one race	0 0%
Unknown or Not Reported	3 4.7%
Region of Enrollment (participants) [Number]
United States	64 100%
Body Mass Index (BMI) (Kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg/m^2]	30.53 (5.88)

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Percentage of subjects with confirmed complete remission (CR), partial remission (PR) and marrow CR, as per modified International Working Group (IWG) criteria: CR: Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood Hemoglobin (Hb) ≥11 g/dL; Platelets ≥100 × 10^9/L; Neutrophils ≥1.0 × 10^9/L; Blasts 0%. PR: All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by ≥ 50% over pre-treatment but still >5%; Cellularity and morphology not relevant Marrow CR: Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pre-treatment
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	64
Number (95% Confidence Interval) [percentage of subjects]	35.9

2. Secondary Outcome

Title	Complete Response (CR) Rate
Description	Percentage of subjects with confirmed CR (i.e., 2 CRs at least 28 days apart) as per modified IWG criteria: CR: Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood Hb ≥11 g/dL; Platelets ≥100 × 109/L; Neutrophils ≥1.0 × 109/L; Blasts 0%.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	64
Number (95% Confidence Interval) [percentage of subjects with CR]	35.9

3. Secondary Outcome

Title	Overall Hematologic Improvement (HI) Response Rate
Description	Percentage of subjects demonstrating major hematologic improvement according to modified IWG: Erythroid response (pre-treatment, <11 g/dL): Hb increase by ≥1.5 g/dL; Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pre-treatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hb of ≤9.0 g/dL pre-treatment will count in the RBC transfusion response evaluation. Platelet response (pre-treatment, <100 × 10^9/L): Absolute increase of ≥30 × 10^9/L for patients starting with >20 × 10^9/L platelets; Increase from <20 × 10^9/L to >20 × 10^9/L and by at least 100%. Neutrophil response (pre-treatment, <1.0 × 10^9/L): At least 100% increase and an absolute increase >0.5 × 10^9/L. Progression or relapse after HI: at least 1 of the following: At least 50% decrement from maximum response levels in granulocytes or platelets Reduction in Hb by≥1.5 g/dL Transfusion dependence
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	63
Number (95% Confidence Interval) [percentage of subjects with HI]	71.4

4. Secondary Outcome

Title	Clinical Benefit Rate
Description	Percentage of subjects with confirmed CR, PR, Marrow CR, and HI with clinical benefit rate, defines as rate of CR + PR + HI + Marrow CR. All subjects who achieve hematologic CR, PR, marrow CR, or hematologic improvement on the erythrocytic lineage per modified IWG response criteria will be considered responders
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	64
Number (95% Confidence Interval) [percentage of subjects with benefit rate]	78.1

5. Secondary Outcome

Title	Rate of Cytogenetic CR
Description	Percentage of subjects with confirmed CR by cytogenetic assessment. Complete cytogenetic response is defined per modified IWG response criteria: Complete: Disappearance of the chromosomal abnormality without appearance of new ones Partial: At least 50% reduction of the chromosomal abnormality
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	64
Number (95% Confidence Interval) [percentage of subjects with cCR]	46.9

6. Secondary Outcome

Title	Duration of Response (DoR)
Description	For subjects who have achieved CR, PR, Marrow CR, or HI, DoR is defined as the time from the initial determination of response to the time of disease progression or death on study, whichever occurs first.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	59
Median (95% Confidence Interval) [months]	15.67

7. Secondary Outcome

Title	Rate of Leukemic Transformation
Description	Percentage of subjects with leukemic transformation at landmark time point of 6 months
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	59
Number (95% Confidence Interval) [percentage of subjects]	5.4

8. Secondary Outcome

Title	Event-free Survival (EFS)
Description	time from the first day of study drug administration (Day 1) to failure or death from any cause
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	59
Median (95% Confidence Interval) [months]	17.05

9. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	time from the first day of study drug administration (Day 1) to disease recurrence or progression as defined by the IWG criteria, or death on study: Disease progression for subjects 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: At least 50% decrement from maximum remission/response in granulocytes or platelets Reduction in Hb by ≥2 g/dL Transfusion dependence
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	64
Median (95% Confidence Interval) [months]	16.43

10. Secondary Outcome

Title	Overall Survival (OS)
Description	time from the first day of study drug administration (Day 1) to death on study
Time Frame	form day 1 to death on study, assessed up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	64
Median (95% Confidence Interval) [months]	23.56

11. Secondary Outcome

Title	Rate of Leukemic Transformation
Description	Percentage of subjects with leukemic transformation at landmark time point of 12 months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	59
Number (95% Confidence Interval) [percentage of subjects]	9.5

12. Secondary Outcome

Title	Rate of Leukemic Transformation
Description	Percentage of subjects with leukemic transformation at landmark time point of 18 months
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	59
Number (95% Confidence Interval) [percentage of subjects]	13.8

13. Secondary Outcome

Title	Rate of Leukemic Transformation
Description	Percentage of subjects with leukemic transformation at landmark time point of 24 months
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
Measure Participants	59
Number (95% Confidence Interval) [percentage of subjects]	21.6

Adverse Events

Time Frame	All AEs regardless of seriousness or relationship to pracinostat or azacitidine, from the start of study drug treatment until 30 calendar days after discontinuation or completion of treatment as defined by the clinical study for that subject, have been recorded.
Arm/Group Title	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
Arm/Group Description	open-label single arm pracinostat plus azacitidine. Pracinostat: 45 mg administered orally 3 days each week for 3 consecutive weeks, followed by 1 week of rest, in 28-day cycles. In later cycles (i.e., after Cycle 4), pracinostat dose reduction to 45 mg orally 3 days each week × 2 weeks (instead of 3 weeks) or dose interruption is allowed to manage toxicity such as fatigue, gastrointestinal toxicity, or myelosuppression. Azacitidine: 75 mg/m2 for 7 days of each 28-day cycle. Administration will occur by subcutaneous (SC) injection, or IV infusion if SC injections are not tolerated, on one of two schedules: Schedule 1 - daily therapy on Days 1 through 7 Schedule 2 - 5-2-2 schedule in which subjects receive azacitidine for 5 consecutive days (Days 1 through 5) with rest on Days 6 and 7, and resume azacitidine dosing the first two days of the next week (Days 8 and 9) of each 28-day cycle Pracinostat: 45 mg capsule Azacitidine: SC or IV injection
All Cause Mortality
	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
	Affected / at Risk (%)	# Events
Total	5/64 (7.8%)
Serious Adverse Events
	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
	Affected / at Risk (%)	# Events
Total	45/64 (70.3%)
Blood and lymphatic system disorders
Febrile neutropenia	17/64 (26.6%)
Pancytopenia	2/64 (3.1%)
Thrombocytopenia	2/64 (3.1%)
Anaemia	5/64 (7.8%)
Cardiac disorders
Acute coronary syndrome	1/64 (1.6%)
Acute myocardial infarction	1/64 (1.6%)
Atrial fibrillation	1/64 (1.6%)
Cardiac failure	1/64 (1.6%)
Cardiac failure congestive	1/64 (1.6%)
Pericardial effusion	1/64 (1.6%)
Pericarditis	2/64 (3.1%)
Sinus tachycardia	1/64 (1.6%)
Gastrointestinal disorders
Anal fissure	1/64 (1.6%)
Ascites	1/64 (1.6%)
Dysphagia	1/64 (1.6%)
Gastrointestinal haemorrhage	1/64 (1.6%)
Haemorrhoidal haemorrhage	1/64 (1.6%)
Large intestine perforation	1/64 (1.6%)
Nausea	1/64 (1.6%)
Proctitis	1/64 (1.6%)
Rectal ulcer	1/64 (1.6%)
Stomatitis	1/64 (1.6%)
Upper gastrointestinal haemorrhage	1/64 (1.6%)
Vomiting	1/64 (1.6%)
General disorders
Asthenia	2/64 (3.1%)
Malaise	1/64 (1.6%)
Pyrexia	1/64 (1.6%)
Infections and infestations
Abscess limb	1/64 (1.6%)
Anal abscess	1/64 (1.6%)
Cellulitis	1/64 (1.6%)
Clostridial sepsis	1/64 (1.6%)
Clostridium difficile colitis	1/64 (1.6%)
Escherichia sepsis	1/64 (1.6%)
Fungal oesophagitis	1/64 (1.6%)
Influenza	1/64 (1.6%)
Lung infection	3/64 (4.7%)
Perirectal abscess	1/64 (1.6%)
Pneumonia	6/64 (9.4%)
Pseudomonal sepsis	1/64 (1.6%)
Respiratory tract infection viral	1/64 (1.6%)
Sepsis	5/64 (7.8%)
Sialoadenitis	1/64 (1.6%)
Staphylococcal infection	1/64 (1.6%)
Staphylococcal sepsis	1/64 (1.6%)
Streptococcal sepsis	1/64 (1.6%)
Vascular access site infection	1/64 (1.6%)
Injury, poisoning and procedural complications
Fall	1/64 (1.6%)
Laceration	1/64 (1.6%)
Spinal compression fracture	1/64 (1.6%)
Investigations
Electrocardiogram qt prolonged	1/64 (1.6%)
Neutrophil count decreased	1/64 (1.6%)
Metabolism and nutrition disorders
Dehydration	1/64 (1.6%)
Hypercalcaemia	1/64 (1.6%)
Hyperinsulinaemic hypoglycaemia	1/64 (1.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/64 (1.6%)
Nervous system disorders
Presyncope	2/64 (3.1%)
Syncope	1/64 (1.6%)
Psychiatric disorders
Mania	1/64 (1.6%)
Mental disorder	1/64 (1.6%)
Renal and urinary disorders
Acute kidney injury	1/64 (1.6%)
Haematuria	1/64 (1.6%)
Renal failure	1/64 (1.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/64 (3.1%)
Epistaxis	2/64 (3.1%)
Pleural effusion	2/64 (3.1%)
Pulmonary embolism	1/64 (1.6%)
Pulmonary oedema	1/64 (1.6%)
Respiratory distress	1/64 (1.6%)
Respiratory failure	1/64 (1.6%)
Vascular disorders
Deep vein thrombosis	1/64 (1.6%)
Orthostatic hypotension	1/64 (1.6%)
Other (Not Including Serious) Adverse Events
	Stage 1a and 1b Open-label Pracinostat Plus Azacitidine
	Affected / at Risk (%)	# Events
Total	64/64 (100%)
Blood and lymphatic system disorders
Anaemia	31/64 (48.4%)
Febrile neutropenia	23/64 (35.9%)
Leukopenia	7/64 (10.9%)
Neutropenia	9/64 (14.1%)
Pancytopenia	5/64 (7.8%)
Thrombocytopenia	18/64 (28.1%)
Cardiac disorders
Tachycardia	7/64 (10.9%)
Ear and labyrinth disorders
Ear pain	4/64 (6.3%)
Eye disorders
Dry eye	4/64 (6.3%)
Gastrointestinal disorders
Abdominal pain	7/64 (10.9%)
Constipation	33/64 (51.6%)
Diarrhoea	21/64 (32.8%)
Dry mouth	7/64 (10.9%)
Dyspepsia	6/64 (9.4%)
Dysphagia	5/64 (7.8%)
Nausea	34/64 (53.1%)
Oral pain	5/64 (7.8%)
Proctalgia	4/64 (6.3%)
Tongue discolouration	14/64 (21.9%)
Vomiting	16/64 (25%)
General disorders
Asthenia	6/64 (9.4%)
Chest pain	5/64 (7.8%)
Chills	9/64 (14.1%)
Fatigue	29/64 (45.3%)
Injection site reaction	7/64 (10.9%)
Oedema peripheral	23/64 (35.9%)
Pyrexia	12/64 (18.8%)
Infections and infestations
Lung infection	4/64 (6.3%)
Pneumonia	8/64 (12.5%)
Sepsis	6/64 (9.4%)
Sinusitis	4/64 (6.3%)
Upper respiratory tract infection	5/64 (7.8%)
Urinary tract infection	4/64 (6.3%)
Injury, poisoning and procedural complications
Contusion	10/64 (15.6%)
Fall	10/64 (15.6%)
Investigations
Blood alkaline phosphatase increased	4/64 (6.3%)
Blood creatinine increased	8/64 (12.5%)
International normalised ratio increased	5/64 (7.8%)
Lymphocyte count decreased	5/64 (7.8%)
Neutrophil count decreased	34/64 (53.1%)
Weight decreased	7/64 (10.9%)
White blood cell count decreased	14/64 (21.9%)
Metabolism and nutrition disorders
Decreased appetite	26/64 (40.6%)
Dehydration	10/64 (15.6%)
Hyperglycaemia	8/64 (12.5%)
Hypoalbuminaemia	18/64 (28.1%)
Hypocalcaemia	9/64 (14.1%)
Hypoglycaemia	4/64 (6.3%)
Hypokalaemia	16/64 (25%)
Hyponatraemia	13/64 (20.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/64 (20.3%)
Arthritis	4/64 (6.3%)
Back pain	8/64 (12.5%)
Muscle spasms	4/64 (6.3%)
Muscular weakness	4/64 (6.3%)
Musculoskeletal pain	4/64 (6.3%)
Myalgia	6/64 (9.4%)
Neck pain	5/64 (7.8%)
Pain in extremity	9/64 (14.1%)
Nervous system disorders
Dizziness	19/64 (29.7%)
Dysgeusia	7/64 (10.9%)
Headache	8/64 (12.5%)
Presyncope	4/64 (6.3%)
Syncope	4/64 (6.3%)
Tremor	7/64 (10.9%)
Psychiatric disorders
Anxiety	10/64 (15.6%)
Confusional state	4/64 (6.3%)
Insomnia	12/64 (18.8%)
Renal and urinary disorders
Acute kidney injury	9/64 (14.1%)
Pollakiuria	4/64 (6.3%)
Urinary retention	6/64 (9.4%)
Respiratory, thoracic and mediastinal disorders
Cough	15/64 (23.4%)
Dyspnoea	20/64 (31.3%)
Dyspnoea exertional	5/64 (7.8%)
Epistaxis	9/64 (14.1%)
Hypoxia	5/64 (7.8%)
Nasal congestion	4/64 (6.3%)
Oropharyngeal pain	8/64 (12.5%)
Pleural effusion	7/64 (10.9%)
Rhinorrhoea	4/64 (6.3%)
Skin and subcutaneous tissue disorders
Alopecia	10/64 (15.6%)
Papule	5/64 (7.8%)
Pruritus	6/64 (9.4%)
Rash	11/64 (17.2%)
Rash maculo-papular	10/64 (15.6%)
Vascular disorders
Hypertension	8/64 (12.5%)
Hypotension	15/64 (23.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.