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Ofatumumab Added to Fludarabine-Cyclophosphamide vs Fludarabine-Cyclophosphamide Combination in Relapsed Subjects With Chronic Lymphocytic Leukemia

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT00824265
Collaborator
(none)
365
Enrollment
135
Locations
2
Arms
103.5
Actual Duration (Months)
2.7
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and efficacy of ofatumumab added to fludarabine-cyclophosphamide in patients with relapsed Chronic Lymphocytic Leukemia (CLL).

Condition or Disease Intervention/Treatment Phase
  • Drug: OFC Infusion
  • Drug: FC infusion
 Phase 3

Detailed Description

Fludarabine is currently approved for treatment of relapsed Chronic Lymphocytic Leukemia. Studies have shown that drugs in combination with fludarabine have shown more effectiveness than fludarabine alone. The addition of ofatumumab to fludarabine-cyclophosphamide combination offers potentially a more effective therapy, without additional toxicity.

The objective of this study was to determine the effect of ofatumumab added to fludarabine and cyclophosphamide in patients with Chronic Lymphocytic Leukemia who have responded previously to therapy but later develop progressive disease and require additional therapy.

Study Design

Study Type:
Interventional
Actual Enrollment :
365 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase III, Open Label, Randomized Trial of Ofatumumab Added to Fludarabine-Cyclophosphamide vs. Fludarabine-Cyclophosphamide Combination in Subjects With Relapsed Chronic Lymphocytic Leukemia
Actual Study Start Date :
Mar 12, 2009
Actual Primary Completion Date :
Dec 17, 2014
Actual Study Completion Date :
Oct 25, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ofatumumab, Fludarabine, Cyclophosphamide

Ofatumumab Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days, Fludarabine 25mg/m2 Days 1-3 every 28 days for 6 cycles, Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

Drug: OFC Infusion
Ofatumumab Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days, Fludarabine 25mg/m2 Days 1-3 every 28 days for 6 cycles, Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles
Active Comparator: Fludarabine, Cyclophosphamide

Fludarabine 25mg/m2 Days 1-3 every 28 days for 6 cycles, Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

Drug: FC infusion
Fludarabine 25mg/m2 Days 1-3 every 28 days for 6 cycles, Cyclophosphamide 250mg/m2 Days 1-3 every 28 days for 6 cycles

Outcome Measures

Primary Outcome Measures

  1. Progression-free Survival (PFS), as Assessed by the Independent Review Committee (IRC) [From randomization up to 5 years after last dose of study drug]

    PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression (progressive disease,PD) and the date of death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia (CLL).

Secondary Outcome Measures

  1. Overall Survival (OS) [From randomization up to 5 years after last dose of study drug]

    Overall survival is defined as the time from randomization to death due to any cause. Each participant was followed at the time when the last IRC-assessed PFS events occurred. Participants who had not died were censored at the date of last contact.

  2. Time to Response, as Assessed by the IRC [From randomization up to 5 years after last dose of study drug]

    Time to response is defined as the time from randomization to the first response. Complete Response/remission(CR) all the criteria at least 2 months after last treatment: no lymphadenopathy(Ly) > 1.5 cm/ hepatomegaly/spleenomegaly/constitutional symptoms; neutrophils >1500 per microliter(µL), platelets(PL) >100,000/µL, hemoglobin(Hb) >11 grams/deciliter(g/dL), lymphocytes(LC) <4000/µL, bone marrow(BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. Incomplete bone marrow recovery(CRi): CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. Partial Remission/response(PR): >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline(BL), Hb >11 g/dL or 50% improvement over BL. Nodular PR(nPR): persistent nodules BM.

  3. Duration of Response (DOR), as Assessed by the IRC [From time of initial response to disease progression or death, whichever came first (up to 5 years after the last dose of study drug)]

    DOR is defined as the time from the initial response (CR, CRi, nPR, or PR) to the first documented sign of PD or death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.

  4. Time to Progression, as Assessed by the IRC [From randomization up to 5 years after the last dose of study drug]

    Time to progression is defined as the time from the date of randomization to PD. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.

  5. Time to Next Therapy [From the start of study drug until the start of the next anti-CLL therapy (up to 5 years after the last dose of study drug)]

    Time to next therapy is defined as the time from randomization until the start of the next-line of treatment. Data are presented for participants who took anti-cancer therapies and participants in the ITT population.

  6. Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status [Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day1, follow up (FU) at 1Month (M) after study drug therapy, 3M, then every 3 month up to 5 year (up to 60 months)]

    The ECOG performance status scales and criteria are used by doctors and researchers to assess how a participant's disease is progressing, how the disease affects the daily living, and determines appropriate treatment and prognosis. ECOG performance status are measured at Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1 and Cycle 6 Day1. During follow period, 1 M after study drug therapy, then every 3 month up to 5 year (up to 60 months). Improvement is defined as a decrease from baseline by at least one step on the ECOG performance status scale (yes/no).

  7. Number of Participants With no B-Symptoms or at Least One B-symptoms Over the Time [Screening, Cycle1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and During at 1M after study drug therapy, 3M, then every 3 M up to 5 year (up to 60 months)]

    Participants with no B-symptoms (B-Sy) (no night sweat, no weight loss, no fever and no extreme fatigue) and at least one indicated B-sy(night sweats, weight loss, fever or extreme fatigue) were presented at Screening, Cycle 1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and during follow up period at 1 M after study drug therapy, then every 3 M up to 5 year (up to 60 months).

  8. Percentage of Participants With the Best Overall Response (OR), as Assessed by the IRC [From randomization up to 5 years after last dose of study drug]

    OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM.

  9. Percentage of Participants With the Best OR, as Assessed by the Investigator [From randomization up to 5 years after last dose of study drug]

    OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM. Responder = CR + CRi + NPR + PR

  10. Number of Participants Who Were Negative for Minimal Residual Disease (MRD) Assessed by IRC [From randomization up to 5 years after last dose of study drug]

    MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.

  11. Number of Participants Who Were Negative for MRD Assessed by Investigator [From randomization up to 5 years after last dose of study drug]

    MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.

  12. Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) [From first dose of study medication to 60 Days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)]

    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

  13. Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at Indicated Time Points [From start of study drug until 60 days after the last dose of study medication]

    Serum samples for analysis of HAHA were collected at Baseline (Screening), after 3 cycles were compelted, after 1 M and 6 M post last dose. All samples were first tested in a screening step; positive samples from the screening were further evaluated in a confirmation test. The confirmed positive samples were reported as HAHA-positive.

  14. Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) [From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)]

    AIHA is a condition where the body's immune system fails to recognize red blood cells as "self" and begins destroying these red blood cells. The number of participants experienced AIHA are presented.

  15. Number of Participants With Drug Related Infections Reported as AEs and SAEs of Maximum Severity of Grade 3 or Higher [From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)]

    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Maximum severity grades were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).

  16. Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression Adverse Events [From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)]

    Participants with at least one Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).

  17. Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study [From randomization up to 5 years after last dose of study drug]

    Participants who received no transfusion and at least one transfusion during the study are presented. Participants who took any blood products or blood supportive care product are included.

  18. Mean Level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM [Baseline, 1M and 6M follow up]

    Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. Blood samples were collected from each participant and IgA, IgG, and IgM were measured at Baseline, and 1M and 6M after last dose during follow up period.

  19. Change From Baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+ [Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three months up to 45 M during Follow-up Period]

    CD5+ and CD19+ cells were counted by flow cytometry at Screening (Baseline) on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during the treatment period and after last dose of study drug at 1 M and then every three month follow up up to 45 M. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. day 1 if available, otherwise, screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  20. Change From Baseline in Cell Counts, CD5- CD19+ [Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three month up to 45 M during Follow-up Period]

    CD5- CD19+ cells were counted by flow cytometry at Screening (baseline) at Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during treatment period and after last dose of study drug at 1 M and then every three month up to 45 M during follow up period. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. Day 1 if available otherwise screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  21. Prognostic and Biological Markers Correlating With Clinical Response [From randomization up to 5 years after last dose of study drug]

    Blood samples were collected for the assessment of the following prognostic markers at BL: immunoglobulin heavy chain variable region(IgVH) homology; Zeta-Chain-Associated Protein Kinase 70(ZAP70), VH3-21 usage; Cytogenetics (by fluorescent in situ hybridization [FISH]); beta 2 microglobulin. Cox-regression model was used to explore the relationship between progression-free survival and the following explanatory variables: treatment group, cytogenetics (analyzed by FISH included 6q-,11q-, +12q, 17p-, 13q-) , ZAP-70 (positive, negative or intermediate), VH3-21 usage (Yes and No), IgVH homology (>98%, 97%-98% and <97%), beta 2 microglobulin (>3500 microgram per liter [µg/L] and <=3500 µg/L). For each covariate, a hazard ratio <1 indicates a lower risk on the first effect tested compared with the other effects tested. Cytogenetics Group (based on >=20%)=cytogenetics (CY G).

  22. Changes in Patient Reported Outcome (PRO) Measures and Scores for European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Chronic Lymphocytic Leukaemia 16 Item Module (EORTC QLQ-CLL 16) [Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.]

    The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales - fatigue (2 items), treatment side effects ([TSE], 4 items), disease symptoms (disease effects scale [DES], 4 items), and infection scale [IS] (4 items) - and single item scales (social activities [Social Problems (SP) Scale] and future health worries[Future Health (FH) Scale].). These are measured on a four point scale where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 - 100, where 0 =no symptoms or problems and 100 = a severe symptoms or problems. EORTC QLQ-CLL16 was assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value was obtained at randomization.

  23. Change From Baseline in Patient Reported Outcome (PRO) as Assessed by EuroQoL Five-Dimension (EQ-5D) Score at Indicated Visit [Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.]

    EQ-5D is comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score. The utility score measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = unable, or extreme problems). Responses are typically converted into health utilities or valuations on a scale ranging from 0 (death) to 1 (perfect health). The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A Negative health status describes health state worse than death.Baseline is the most recent, non-missing value prior to or on the first study drug dose date.

  24. Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score [Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.]

    EORTC QLQ-C30, a self-reported, cancer-specific instrument assessing 15 domains: physical, role, emotional, cognitive and social functioning, pain,fatigue, nausea and vomiting, insomnia, loss of appetite, constipation, diarrhea, and dyspnea, financial difficulties and a global health status/quality of life (QOF). Functional and symptoms scales were measured on four point Likert scale where 1 = not at all and 4 = very much. Pat. assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Clinically meaningful changes or minimally important differences (MIDs)have been previously established for the EORTC QLQ C30, and categorized as 'small' if the mean change in scores is 5-10 points, 'moderate' if 10-20 points, and 'large' if >20points.

  25. Mean of Health Change Questionnaire (HCQ) [Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.]

    The HCQ consists of a single question in which the participant is asked if he/she has experienced any change in his/her health overall since beginning the study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for 'my health is a great deal better' to 9 for 'my health is a great deal worse' since the beginning of the study. Lower scores represent better conditions.

  26. Mean Area Under the Time-concentration Curve (AUC) Curve Over the Dosing Interval (AUC[0-tau]) of Ofatumumab [Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5,6]

    Area under the time-concentration curve (AUC) over the dosing interval (AUC[0-tau]) was evaluated. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).

  27. Maximum Concentration (Cmax) and Observed Drug Concentration Prior to the Next Dose (Ctrough) of Ofatumumab [Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5]

    Blood samples were collected to assess the plasma concentration of ofatumumab.Cmax and Ctrough were determined. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).

  28. Time of Occurrence of Cmax (Tmax) of Ofatumumab [Cycle 1 Week 1, Cycle 1 Week 2, Cycle 4]

    Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4.

Eligibility Criteria

Criteria

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

  • confirmed and active CLL requiring treatment

  • at least one previous treatment for CLL and having achieved a complete or partial remission/response but after a period of 6 or more months, shows evidence of disease progression

  • fully active at a minimum or fully capable of selfcare and up and about more than 50% of waking hours

  • age 18yrs or older

  • signed written informed consent

Key Exclusion Criteria:

  • diagnosis of refractory CLL (failure to achieve a complete or partial remission/response or disease progression within 6 months of last anti-CLL treatment

  • abnormal/inadequate blood values, liver and kidney function

  • certain heart problems, serious significant diseases, AIHA, other current cancers or within the last 5 years

  • active or chronic infections

  • use of drugs to suppress allergic or inflammatory responses (glucocorticoids)

  • CLL transformation

  • CLL central nervous system involvement

  • current participation in other clinical study

  • inability to comply with the protocol activities

  • lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception

Contacts and Locations

Locations

Site City State Country Postal Code
1 Novartis Investigative Site Boca Raton Florida United States 33486
2 Novartis Investigative Site Chicago Illinois United States 60612-3833
3 Novartis Investigative Site Clinton Maryland United States 20735
4 Novartis Investigative Site Kansas City Missouri United States 64128
5 Novartis Investigative Site Saint Louis Missouri United States 63110
6 Novartis Investigative Site Memphis Tennessee United States 38120
7 Novartis Investigative Site Brasilia Goiás Brazil 70390-150
8 Novartis Investigative Site Porto Alegre Rio Grande Do Sul Brazil 90610000
9 Novartis Investigative Site Sao Paulo São Paulo Brazil 05403-000
10 Novartis Investigational Site Porto Alegre Brazil 91350
11 Novartis Investigative Site Rio de Janeiro Brazil 20211-030
12 Novartis Investigation Site Rio de Janeiro Brazil 20230-130
13 Novartis Investigative Site Rio de Janeiro Brazil 21941-913
14 Novartis Investigational Site Sao Paulo Brazil 03102-002
15 Novartis Investigative Site Pleven Bulgaria 5800
16 Novartis Investigative Site Plovdiv Bulgaria 4000
17 Novartis Investigative Site Sofia Bulgaria 1233
18 Novartis Investigational Site Sofia Bulgaria 1407
19 Novartis Investigational Site Sofia Bulgaria 1606
20 Novartis Investigative Site Sofia Bulgaria
21 Novartis Investigative Site Varna Bulgaria 9010
22 Novartis Investigative Site New Westminster British Columbia Canada V3L 3W4
23 Novartis Investigative Site Kitchener Ontario Canada N2G 1G3
24 Novartis Investigative Site Newmarket Ontario Canada L3Y 2P9
25 Novartis Investigative Site Ottawa Ontario Canada K1H 8L6
26 Novartis Investigative Site Greenfield Park Quebec Canada J4V 2H1
27 Novartis Investigative Site Montreal Quebec Canada H1T 2M4
28 Novartis Investigative Site Sherbrooke Quebec Canada J1H 5N4
29 Novartis Investigative Site Saskatoon Saskatchewan Canada S7N 4H4
30 Novartis Investigative Site Karlsruhe Baden-Wuerttemberg Germany 76137
31 Novartis Investigative Site Stuttgart Baden-Wuerttemberg Germany 70190
32 Novartis Investigative Site Stuttgart Baden-Wuerttemberg Germany 70376
33 Novartis Investigative Site Villingen-Schwenningen Baden-Wuerttemberg Germany 78052
34 Novartis Investigative Site Muenchen Bayern Germany 81241
35 Novartis Investigative Site Frankfurt Hessen Germany 65929
36 Novartis Investigative Site Kassel Hessen Germany 34119
37 Novartis Investigative Site Hannover Niedersachsen Germany 30625
38 Novartis Investigative Site Lehrte Niedersachsen Germany 31275
39 Novartis Investigative Site Essen Nordrhein-Westfalen Germany 45122
40 Novartis Investigative Site Moenchengladbach-Rheydt Nordrhein-Westfalen Germany 41239
41 Novartis Investigative Site Muenster Nordrhein-Westfalen Germany 48149
42 Novartis Investigative Site Saarbruecken Saarland Germany 66113
43 Novartis Investigative Site Dresden Sachsen Germany 01307
44 Novartis Investigational Site Hamburg Germany 22767
45 Novartis Investigational Site Lubeck Germany 23562
46 Novartis Investigative Site Athens, Greece 11 527
47 Novartis Investigative Site Athens Greece 11527
48 Novartis Investigative Site Thessaloniki Greece 564 29
49 Novartis Investigative Site Thessaloniki Greece 57010
50 Novartis Investigative Site Bangalore India 560029
51 Novartis Investigative Site Mumbai India 400012
52 Novartis Investigative Site Mumbai India 400014
53 Novartis Investigative Site New Delhi India 110029
54 Novartis Investigative Site Pune India 411001
55 Novartis Investigative Site Vadodara India 390007
56 Novartis Investigative Site Potenza Basilicata Italy 85100
57 Novartis Investigative Site Roma Lazio Italy 00041
58 Novartis Investigative Site Roma Lazio Italy 00161
59 Novartis Investigative Site Genova Liguria Italy 16132
60 Novartis Investigative Site Pavia Lombardia Italy 27100
61 Novartis Investigative Site Ascoli Piceno Marche Italy 63100
62 Novartis Investigative Site Alessandria Piemonte Italy 15100
63 Novartis Investigative Site Novara Piemonte Italy 28100
64 Novartis Investigative Site Catania Sicilia Italy 95124
65 Novartis Investigative Site Palermo Sicilia Italy 90146
66 Novartis Investigative Site Guadalajara Jalisco Mexico 44280
67 Novartis Investigative Site Monterrey Nuevo León Mexico 64460
68 Novartis Investigative Site Monterrey Nuevo León Mexico 64710
69 Novartis Investigative Site Mexico City Mexico CP 14080
70 Novartis Investigative Site Amersfoort Netherlands 3818 ES
71 Novartis Investigative Site Den Haag Netherlands 2545 CH
72 Novartis Investigative Site Nijmegen Netherlands 6525 GA
73 Novartis Investigative Site Rotterdam Netherlands 3015 CE
74 Novartis Investigative Site Rotterdam Netherlands 3075 EA
75 Novartis Investigative Site Bialystok Poland 15-276
76 Novartis Investigative Site Chorzow Poland 41-500
77 Novartis Investigative Site Krakow Poland 31-501
78 Novartis Investigative Site Lodz Poland 93-510
79 Novartis Investigative Site Opole Poland 45-372
80 Novartis Investigative Site Slupsk Poland 76-200
81 Novartis Investigative Site Szczecin Poland 71-242
82 Novartis Investigative Site Warszawa Poland 02-507
83 Novartis Investigative Site Warszawa Poland 02-776
84 Novartis Investigative Site Warszawa Poland 02-781
85 Novartis Investigative Site Wroclaw Poland 50-367
86 Novartis Investigative Site Bucharest Romania 022328
87 Novartis Investigative Site Bucharest Romania 050098
88 Iasi Romania 300328
89 Novartis Investigative Site Iasi Romania 700483
90 Novartis Investigative Site Kazan Russian Federation 420029
91 Novartis Investigative Site Moscow Russian Federation 115478
92 Novartis Investigative Site Moscow Russian Federation 125101
93 Novartis Investigative Site Moscow Russian Federation 125167
94 Novartis Investigative Site Novosibirsk Russian Federation 630087
95 Novartis Investigative Site St'Petersburg Russian Federation 191024
96 Novartis Investigative Site St. Petersburg Russian Federation 197 089
97 Novartis Investigative Site Barcelona Spain 08003
98 Novartis Investigative Site Barcelona Spain 08025
99 Novartis Investigative Site Barcelona Spain 08916
100 Novartis Investigative Site Madrid Spain 28006
101 Novartis Investigative Site Madrid Spain 28040
102 Novartis Investigative Site Madrid Spain 28046
103 Novartis Investigative Site Salamanca Spain 37007
104 Novartis Investigative Site Sevilla Spain 41014
105 Novartis Investigative Site Taichung Taiwan 404
106 Novartis Investigative Site Taipei city Taiwan 100
107 Novartis Investigative Site Taipei Taiwan 112
108 Novartis Investigational Site Taipei Taiwan 404
109 Novartis Investigative Site Bangkok Thailand 10330
110 Novartis Investigative Site Bangkok Thailand 10400
111 Novartis Investigative Site Bangkok Thailand 10700
112 Novartis Investigative Site Cherkasy Ukraine 18009
113 Novartis Investigative Site Dnipropetrovsk Ukraine 49102
114 Novartis Investigative Site Kharkiv Ukraine 61070
115 Novartis Investigative Site Khmelnytskyi Ukraine 29000
116 Novartis Investigative Site Kyiv Ukraine 03022
117 Novartis Investigative Site Kyiv Ukraine 04112
118 Novartis Investigative Site Lviv Ukraine 79044
119 Novartis Investigative Site Makiivka Ukraine 86132
120 Novartis Investigational Site Simferopil Ukraine 95023
121 Novartis Investigative Site Vinnitsa Ukraine 21018
122 Novartis Investigational Site Zhytomyr Ukraine 10002
123 Novartis Investigative Site Birmingham United Kingdom B9 5SS
124 Novartis Investigative Site Bradford United Kingdom BD96RJ
125 Novartis Investigative Site Burton on Trent United Kingdom DE13 0RB
126 Novartis Investigative Site Cottingham United Kingdom HU16 5JQ
127 Novartis Investigative Site Dudley United Kingdom DY1 2HQ
128 Novartis Investigative Site Glasgow United Kingdom G12 OYN
129 Novartis Investigative Site Leicester United Kingdom LE1 5WW
130 Novartis Investigative Site London United Kingdom SE5 9RS
131 Novartis Investigative Site Manchester United Kingdom M13 9WL
132 Novartis Investigative Site Sutton United Kingdom SM5 1AA
133 Novartis Investigative Site Swindon United Kingdom SN3 6BB
134 Novartis Investigative Site Truro United Kingdom TR1 3LJ
135 Novartis Investigative Site Uxbridge United Kingdom UB8 3NN

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00824265
Other Study ID Numbers:
  • 110913
First Posted:
Jan 16, 2009
Last Update Posted:
Jun 18, 2020
Last Verified:
Jun 1, 2020
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
Relapsed
Oncology
Safety
Chronic Lymphocytic Leukemia
Ofatumumab
Efficacy
Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell

Study Results

Participant Flow

Recruitment Details Participants (par) were screened within 14 days prior to the start of study drug administration to determine eligibility.
Pre-assignment Detail Eligible par were stratified by Stage (Binet A vs. B vs. C) and number of prior therapies (1-2 vs. ≥3). Par in each stratum were then centrally randomized in a 1:1 ratio to recive intravenous (IV) fludarabine and cyclophosphamide in combination with ofatumumab or IV fludarabine and cyclophosphamide alone.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Period Title: Treatment Phase
STARTED 183 182
COMPLETED 119 102
NOT COMPLETED 64 80
Period Title: Treatment Phase
STARTED 172 160
COMPLETED 154 129
NOT COMPLETED 18 31
Period Title: Treatment Phase
STARTED 96 89
COMPLETED 87 73
NOT COMPLETED 9 16

Baseline Characteristics

Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects Total
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Total of all reporting groups
Overall Participants 183 182 365
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
61.4
(8.82)
61.6
(10.21)
61.5
(9.53)
Sex: Female, Male (Count of Participants)
Female
79
43.2%
66
36.3%
145
39.7%
Male
104
56.8%
116
63.7%
220
60.3%
Race/Ethnicity, Customized (Count of Participants)
African American/African Heritage
3
1.6%
5
2.7%
8
2.2%
American Indian or Alaska Native
3
1.6%
1
0.5%
4
1.1%
Asian - Central/South Asian Heritage
13
7.1%
16
8.8%
29
7.9%
Asian - East Asian Heritage
3
1.6%
3
1.6%
6
1.6%
Asian - South East Asian Heritage
3
1.6%
3
1.6%
6
1.6%
White - Arabic/North African Heritage
0
0%
1
0.5%
1
0.3%
White - White/Caucasian/European Heritage
158
86.3%
153
84.1%
311
85.2%

Outcome Measures

1. Primary Outcome
Title Progression-free Survival (PFS), as Assessed by the Independent Review Committee (IRC)
Description PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression (progressive disease,PD) and the date of death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia (CLL).
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
Intent-to-Treat (ITT) Population: all participants randomized and received study drug.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Median (95% Confidence Interval) [Months]
28.94
18.83
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.0032
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.51 to 0.88
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Overall Survival (OS)
Description Overall survival is defined as the time from randomization to death due to any cause. Each participant was followed at the time when the last IRC-assessed PFS events occurred. Participants who had not died were censored at the date of last contact.
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
ITT Population.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Median (95% Confidence Interval) [Months]
62.65
46.23
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.1427
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.59 to 1.09
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Time to Response, as Assessed by the IRC
Description Time to response is defined as the time from randomization to the first response. Complete Response/remission(CR) all the criteria at least 2 months after last treatment: no lymphadenopathy(Ly) > 1.5 cm/ hepatomegaly/spleenomegaly/constitutional symptoms; neutrophils >1500 per microliter(µL), platelets(PL) >100,000/µL, hemoglobin(Hb) >11 grams/deciliter(g/dL), lymphocytes(LC) <4000/µL, bone marrow(BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. Incomplete bone marrow recovery(CRi): CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. Partial Remission/response(PR): >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline(BL), Hb >11 g/dL or 50% improvement over BL. Nodular PR(nPR): persistent nodules BM.
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
ITT Population. Participants with unknown or missing responses were considered as non-responders. Only responders were included in the analysis.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 152 123
Median (95% Confidence Interval) [Months]
0.99
0.99
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.4490
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.08
Confidence Interval (2-Sided) 95%
0.85 to 1.37
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Duration of Response (DOR), as Assessed by the IRC
Description DOR is defined as the time from the initial response (CR, CRi, nPR, or PR) to the first documented sign of PD or death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.
Time Frame From time of initial response to disease progression or death, whichever came first (up to 5 years after the last dose of study drug)

Outcome Measure Data

Analysis Population Description
ITT Population. Par with unknown or missing responses were considered as non-responders, only responders were included in this analysis.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 152 123
Median (95% Confidence Interval) [Months]
29.63
24.90
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.0878
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.56 to 1.05
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title Time to Progression, as Assessed by the IRC
Description Time to progression is defined as the time from the date of randomization to PD. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.
Time Frame From randomization up to 5 years after the last dose of study drug

Outcome Measure Data

Analysis Population Description
ITT Population.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Median (95% Confidence Interval) [Months]
42.12
26.78
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.0036
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.45 to 0.87
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title Time to Next Therapy
Description Time to next therapy is defined as the time from randomization until the start of the next-line of treatment. Data are presented for participants who took anti-cancer therapies and participants in the ITT population.
Time Frame From the start of study drug until the start of the next anti-CLL therapy (up to 5 years after the last dose of study drug)

Outcome Measure Data

Analysis Population Description
ITT Population
Arm/Group Title Ofatumumab+Fludarabine+Cyclophosphamide_anti-CLL Therapies Fludarabine+Cyclophosphamide_anti-CLL Therapies Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 74 67 183 182
Median (95% Confidence Interval) [Months]
29.68
21.03
52.96
40.08
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments Participants in the ITT population
Statistical Test of Hypothesis p-Value 0.1143
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.55 to 1.08
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments Participants who took anti-cancer therapies
Statistical Test of Hypothesis p-Value 0.0109
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.48 to 0.94
Parameter Dispersion Type:
Value:
Estimation Comments
7. Secondary Outcome
Title Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status
Description The ECOG performance status scales and criteria are used by doctors and researchers to assess how a participant's disease is progressing, how the disease affects the daily living, and determines appropriate treatment and prognosis. ECOG performance status are measured at Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1 and Cycle 6 Day1. During follow period, 1 M after study drug therapy, then every 3 month up to 5 year (up to 60 months). Improvement is defined as a decrease from baseline by at least one step on the ECOG performance status scale (yes/no).
Time Frame Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day1, follow up (FU) at 1Month (M) after study drug therapy, 3M, then every 3 month up to 5 year (up to 60 months)

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Cycle 2 Day 1
15
8.2%
13
7.1%
Cycle 3 Day 1
16
8.7%
13
7.1%
Cycle 4 Day 1
19
10.4%
13
7.1%
Cycle 5 Day 1
20
10.9%
15
8.2%
Cycle 6 Day 1
26
14.2%
16
8.8%
1 M, FU
31
16.9%
22
12.1%
3 M, FU
31
16.9%
21
11.5%
6 M, FU
30
16.4%
18
9.9%
9 M, FU
31
16.9%
23
12.6%
12 M, FU
30
16.4%
20
11%
15 M, FU
23
12.6%
18
9.9%
18 M, FU
23
12.6%
18
9.9%
21 M, FU
22
12%
16
8.8%
24 M, FU
20
10.9%
15
8.2%
27 M, FU
15
8.2%
13
7.1%
30 M, FU
14
7.7%
8
4.4%
33 M, FU
15
8.2%
7
3.8%
36 M, FU
12
6.6%
7
3.8%
39 M, FU
12
6.6%
7
3.8%
42 M, FU
11
6%
6
3.3%
45 M, FU
8
4.4%
4
2.2%
48 M, FU
8
4.4%
2
1.1%
51 M, FU
7
3.8%
3
1.6%
54 M, FU
7
3.8%
2
1.1%
57 M, FU
3
1.6%
3
1.6%
60 M, FU
3
1.6%
3
1.6%
8. Secondary Outcome
Title Number of Participants With no B-Symptoms or at Least One B-symptoms Over the Time
Description Participants with no B-symptoms (B-Sy) (no night sweat, no weight loss, no fever and no extreme fatigue) and at least one indicated B-sy(night sweats, weight loss, fever or extreme fatigue) were presented at Screening, Cycle 1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and during follow up period at 1 M after study drug therapy, then every 3 M up to 5 year (up to 60 months).
Time Frame Screening, Cycle1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and During at 1M after study drug therapy, 3M, then every 3 M up to 5 year (up to 60 months)

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Screening, no B-sy
63
34.4%
59
32.4%
Screening, one B-sy
120
65.6%
121
66.5%
Cycle 1 Day 1, no B-sy
64
35%
68
37.4%
Cycle 1 Day 1, one B-sy
115
62.8%
111
61%
Cycle 2 Day 1,no B-sy
116
63.4%
108
59.3%
Cycle 2 Day 1, one B-sy
52
28.4%
62
34.1%
Cycle 3 Day 1, no B-sy
131
71.6%
116
63.7%
Cycle 3 Day 1, one B-sy
34
18.6%
40
22%
Cycle 4 Day 1, no B-sy
129
70.5%
107
58.8%
Cycle 4 Day 1, one B-sy
25
13.7%
25
13.7%
Cycle 5 Day 1, no B-sy
120
65.6%
97
53.3%
Cycle 5 Day 1, one B-sy
14
7.7%
21
11.5%
Cycle 6 Day 1, no B-sy
111
60.7%
82
45.1%
Cycle 6 Day 1, one B-sy
9
4.9%
13
7.1%
1 M, FU, no B-sy
141
77%
116
63.7%
1 M, FU, one B-sy
20
10.9%
29
15.9%
3 M, FU, no B-sy
136
74.3%
105
57.7%
3 M, FU, one B-sy
17
9.3%
14
7.7%
6 M, FU, no B-sy
123
67.2%
96
52.7%
6 M, FU, one B-sy
15
8.2%
11
6%
9 M, FU, no B-sy
116
63.4%
87
47.8%
9 M, FU, one B-sy
13
7.1%
9
4.9%
12 M, FU, no B-sy
108
59%
74
40.7%
12 M, FU, one B-sy
11
6%
13
7.1%
15 M, FU, no B-sy
98
53.6%
63
34.6%
15 M, FU, one B-sy
5
2.7%
8
4.4%
18 M, FU, no B-sy
93
50.8%
58
31.9%
18 M, FU, one B-sy
5
2.7%
6
3.3%
21 M, FU, no B-sy
87
47.5%
55
30.2%
21 M, FU, one B-sy
7
3.8%
5
2.7%
24 M, FU, no B-sy
79
43.2%
48
26.4%
24 M, FU, one B-sy
1
0.5%
4
2.2%
27 M, FU, no B-sy
71
38.8%
41
22.5%
27 M, FU, one B-syn
4
2.2%
3
1.6%
30 M, FU, no B-sy
68
37.2%
33
18.1%
30 M, FU, one B-sy
2
1.1%
2
1.1%
33 M, FU, no B-sy
63
34.4%
27
14.8%
33 M, FU, one B-sy
3
1.6%
2
1.1%
36 M, FU, no B-sy
56
30.6%
23
12.6%
36 M, FU, one B-sy
2
1.1%
0
0%
39 M, FU, no B-sy
49
26.8%
18
9.9%
39 M, FU, one B-sy
3
1.6%
0
0%
42 M, FU, no B-sy
45
24.6%
16
8.8%
42 M, FU, one B-sy
0
0%
0
0%
45 M, FU, no B-sy
41
22.4%
14
7.7%
45 M, FU, one B-sy
0
0%
1
0.5%
48 M, FU, no B-sy
36
19.7%
13
7.1%
48 M, FU, one B-sy
1
0.5%
0
0%
51 M, FU, no B-sy
32
17.5%
11
6%
51 M, FU, one B-sy
0
0%
1
0.5%
54 M, FU, no B-sy
30
16.4%
10
5.5%
54 M, FU, one B-sy
0
0%
0
0%
57 M, FU, no B-sy
26
14.2%
9
4.9%
57 M, FU, one B-sy
0
0%
0
0%
60 M, FU, no B-sy
24
13.1%
9
4.9%
60 M, FU, one B-sy
1
0.5%
0
0%
9. Secondary Outcome
Title Percentage of Participants With the Best Overall Response (OR), as Assessed by the IRC
Description OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM.
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
ITT Population
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
CR
27
14.8%
7
3.8%
CRi
2
1.1%
1
0.5%
nPR
0
0%
0
0%
PR
55
30.1%
59
32.4%
Stable disease
11
6%
28
15.4%
Progressive Disease
0
0%
0
0%
Not Evaluable
4
2.2%
2
1.1%
Missing
1
0.5%
2
1.1%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.0003
Comments
Method Cochran-Mantel-Haenszel
Comments
10. Secondary Outcome
Title Percentage of Participants With the Best OR, as Assessed by the Investigator
Description OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM. Responder = CR + CRi + NPR + PR
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
ITT Population
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
CR
45
24.6%
24
13.2%
CRi
12
6.6%
4
2.2%
nPR
2
1.1%
8
4.4%
PR
107
58.5%
113
62.1%
Stable disease
9
4.9%
21
11.5%
Progressive Disease
0
0%
3
1.6%
Missing
8
4.4%
9
4.9%
Responder
166
90.7%
149
81.9%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects, Fludarabine + Cyclophosphamide_ ITT Subjects
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.0166
Comments
Method Cochran-Mantel-Haenszel
Comments
11. Secondary Outcome
Title Number of Participants Who Were Negative for Minimal Residual Disease (MRD) Assessed by IRC
Description MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Screening
0
0%
0
0%
Cycle 1 Day 1
0
0%
3 M, FU
21
11.5%
7
3.8%
6 M, FU
25
13.7%
6
3.3%
9 M, FU
20
10.9%
4
2.2%
12 M, FU
16
8.7%
1
0.5%
15 M, FU
14
7.7%
1
0.5%
18 M, FU
12
6.6%
1
0.5%
21 M, FU
9
4.9%
1
0.5%
24 M, FU
8
4.4%
1
0.5%
27 M, FU
8
4.4%
0
0%
30 M, FU
8
4.4%
2
1.1%
33 M, FU
3
1.6%
1
0.5%
36 M, FU
5
2.7%
1
0.5%
39 M, FU
2
1.1%
1
0.5%
42 M, FU
2
1.1%
45 M, FU
1
0.5%
1
0.5%
48 M, FU
2
1.1%
1
0.5%
51 M, FU
2
1.1%
1
0.5%
54 M, FU
2
1.1%
1
0.5%
12. Secondary Outcome
Title Number of Participants Who Were Negative for MRD Assessed by Investigator
Description MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Screening
0
0%
1
0.5%
3 M, FU
39
21.3%
15
8.2%
6 M, FU
48
26.2%
11
6%
9 M, FU
35
19.1%
6
3.3%
12 M, FU
31
16.9%
3
1.6%
15 M, FU
23
12.6%
2
1.1%
18 M, FU
20
10.9%
2
1.1%
21 M, FU
16
8.7%
3
1.6%
24 M, FU
13
7.1%
2
1.1%
27 M, FU
14
7.7%
1
0.5%
30 M, FU
12
6.6%
3
1.6%
33 M, FU
8
4.4%
2
1.1%
36 M, FU
9
4.9%
2
1.1%
39 M, FU
6
3.3%
2
1.1%
42 M, FU
7
3.8%
1
0.5%
45 M, FU
6
3.3%
2
1.1%
48 M, FU
6
3.3%
2
1.1%
51 M, FU
5
2.7%
1
0.5%
54 M, FU
4
2.2%
2
1.1%
57 M, FU
3
1.6%
2
1.1%
60 M, FU
3
1.6%
2
1.1%
13. Secondary Outcome
Title Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
Description An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
Time Frame From first dose of study medication to 60 Days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)

Outcome Measure Data

Analysis Population Description
Safety Population: Participants who received at least one dose of a study drug.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 181 178
AE
170
92.9%
153
84.1%
SAE
108
59%
86
47.3%
14. Secondary Outcome
Title Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at Indicated Time Points
Description Serum samples for analysis of HAHA were collected at Baseline (Screening), after 3 cycles were compelted, after 1 M and 6 M post last dose. All samples were first tested in a screening step; positive samples from the screening were further evaluated in a confirmation test. The confirmed positive samples were reported as HAHA-positive.
Time Frame From start of study drug until 60 days after the last dose of study medication

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles)
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 181 178
Screening Visit, n= 179,177
8
4.4%
1
0.5%
Cycle 4 Day 1, n= 151,130
0
0%
2
1.1%
1 M, FU, n= 148,132
0
0%
2
1.1%
3 M, FU, n= 0,1
0
0%
6 M, FU, n= 130, 99
2
1.1%
0
0%
9 M, FU, n= 0, 2
0
0%
30 M, FU, n= 2, 0
0
0%
15. Secondary Outcome
Title Number of Participants With Autoimmune Hemolytic Anaemia (AIHA)
Description AIHA is a condition where the body's immune system fails to recognize red blood cells as "self" and begins destroying these red blood cells. The number of participants experienced AIHA are presented.
Time Frame From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)

Outcome Measure Data

Analysis Population Description
Safety Population
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 181 178
Number [Participants]
3
1.6%
2
1.1%
16. Secondary Outcome
Title Number of Participants With Drug Related Infections Reported as AEs and SAEs of Maximum Severity of Grade 3 or Higher
Description An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Maximum severity grades were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).
Time Frame From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)

Outcome Measure Data

Analysis Population Description
Safety Population
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 181 178
AE
19
10.4%
11
6%
SAE
25
13.7%
21
11.5%
17. Secondary Outcome
Title Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression Adverse Events
Description Participants with at least one Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).
Time Frame From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)

Outcome Measure Data

Analysis Population Description
Safety Population
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 181 178
Number [Participants]
126
68.9%
118
64.8%
18. Secondary Outcome
Title Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study
Description Participants who received no transfusion and at least one transfusion during the study are presented. Participants who took any blood products or blood supportive care product are included.
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
Safety Population
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 181 178
At least one transfusion
125
68.3%
99
54.4%
No transfusions
56
30.6%
79
43.4%
19. Secondary Outcome
Title Mean Level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM
Description Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. Blood samples were collected from each participant and IgA, IgG, and IgM were measured at Baseline, and 1M and 6M after last dose during follow up period.
Time Frame Baseline, 1M and 6M follow up

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 181 178
Cycle 1 Day 1, IgA
1.0
(0.74)
0.9
(0.68)
Cycle 1 Day 1, IgG
8.7
(5.22)
8.2
(3.86)
Cycle 1 Day 1, IgM
0.6
(1.36)
0.8
(1.77)
1 M, FU, IgA
1.0
(0.79)
1.0
(0.77)
1 M, FU, IgG
7.9
(4.05)
7.9
(3.38)
1 M, FU, IgM
0.5
(1.16)
0.8
(1.88)
6 M, FU, IgA
1.0
(0.77)
1.0
(0.76)
6 M, FU, IgG
7.8
(3.97)
8.9
(4.31)
6 M, FU, IgM
0.4
(0.50)
1.1
(1.98)
9 M, FU, IgA
0.9
(NA)
0.9
(0.21)
9 M, FU, IgG
15.2
(NA)
8.8
(6.87)
9 M, FU, IgM
0.8
(NA)
0.2
(0.04)
18 M, FU, IgA
2.4
(NA)
18 M, FU, IgG
9.1
(NA)
18 M, FU, IgM
1.0
(NA)
30 M, FU, IgA
1.3
(1.17)
30 M, FU, IgG
4.7
(0.33)
30 M, FU, IgM
0.4
(0.26)
20. Secondary Outcome
Title Change From Baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+
Description CD5+ and CD19+ cells were counted by flow cytometry at Screening (Baseline) on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during the treatment period and after last dose of study drug at 1 M and then every three month follow up up to 45 M. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. day 1 if available, otherwise, screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three months up to 45 M during Follow-up Period

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Cycle 1 Day 1
43180.6
(48784.64)
53208.7
(70944.56)
Cycle 1 Day 15
2656.9
(6418.02)
9244.0
(19610.62)
Cycle 2 Day 1
2057.4
(5525.72)
10318.8
(21453.15)
Cycle 2 Day 15
513.7
(1717.65)
6874.4
(20632.64)
Cycle 3 Day 1
790.0
(2953.42)
6423.6
(19725.57)
Cycle 4 Day 1
402.1
(1768.74)
2643.2
(8092.22)
Cycle 5 Day 1
142.6
(472.24)
2838.6
(8314.08)
Cycle 6 Day 1
109.8
(398.77)
3862.7
(13312.14)
1 M, FU
163.5
(685.41)
5514.3
(17369.97)
3 M, FU
671.3
(2786.99)
2604.9
(9229.90)
6 M, FU
1591.6
(8857.22)
2275.6
(5118.00)
9 M, FU
910.5
(2495.85)
3408.4
(7438.45)
12 M, FU
2303.2
(6675.70)
2876.5
(6252.53)
15 M, FU
3325.8
(8006.48)
3072.7
(9038.23)
18 M, FU
1607.5
(2935.82)
4549.8
(8839.23)
21 M, FU
3830.8
(8989.02)
5236.9
(10537.31)
24 M, FU
1244.6
(1300.01)
7843.3
(11897.55)
27 M, FU
1877.4
(2117.84)
6128.0
(9161.38)
30 M, FU
5029.7
(8266.90)
6515.5
(5916.36)
33 M, FU
14166.8
(20166.09)
5208.0
(NA)
36 M, FU
1187.0
(1407.79)
8184.0
(NA)
39 M, FU
557.0
(NA)
42 M, FU
1640.0
(NA)
45 M, FU
4689.0
(1493.41)
48 M FU
27755.0
(NA)
29155.0
(NA)
54 M FU
189849.0
(NA)
21. Secondary Outcome
Title Change From Baseline in Cell Counts, CD5- CD19+
Description CD5- CD19+ cells were counted by flow cytometry at Screening (baseline) at Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during treatment period and after last dose of study drug at 1 M and then every three month up to 45 M during follow up period. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. Day 1 if available otherwise screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three month up to 45 M during Follow-up Period

Outcome Measure Data

Analysis Population Description
Safety Population
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 181 178
Screening
4817.8
(20948.17)
6959.1
(39980.14)
Cycle 1 Day 1
5996.7
(22331.29)
2041.3
(4418.63)
Cycle 1 Day 15
239.0
(1052.19)
351.7
(1377.56)
Cycle 2 Day 1
115.4
(403.09)
465.7
(1610.05)
Cycle 2 Day 15
35.6
(133.75)
331.3
(1177.18)
Cycle 3 Day 1
39.5
(144.64)
179.7
(520.63)
Cycle 4 Day 1
25.7
(92.88)
95.3
(369.19)
Cycle 5 Day 1
15.9
(77.11)
195.5
(945.34)
Cycle 6 Day 1
10.0
(29.85)
649.7
(3606.28)
1 M, FU
7.5
(19.54)
863.8
(5001.84)
3 M, FU
40.1
(238.18)
172.0
(681.28)
6 M, FU
21.2
(58.16)
50.7
(49.13)
9 M, FU
85.7
(359.01)
92.0
(101.16)
12 M, FU
89.9
(226.06)
220.1
(698.57)
15 M, FU
67.3
(59.52)
94.6
(70.17)
18 M, FU
126.1
(188.25)
92.3
(69.14)
21 M, FU
375.5
(1307.35)
108.3
(95.86)
24 M, FU
74.0
(57.46)
104.5
(70.46)
27 M, FU
73.9
(60.40)
187.5
(200.85)
30 M, FU
74.2
(58.82)
129.5
(5303)
33 M, FU
41.8
(40.13)
1003.0
(NA)
36 M, FU
107.3
(86.75)
1506.0
(NA)
39 M, FU
13.0
(NA)
42 M, FU
13.0
(NA)
45 M, FU
166.5
(222.74)
48 M, FU
6528.0
(NA)
28.0
(NA)
54 M, FU
690.0
(NA)
22. Secondary Outcome
Title Prognostic and Biological Markers Correlating With Clinical Response
Description Blood samples were collected for the assessment of the following prognostic markers at BL: immunoglobulin heavy chain variable region(IgVH) homology; Zeta-Chain-Associated Protein Kinase 70(ZAP70), VH3-21 usage; Cytogenetics (by fluorescent in situ hybridization [FISH]); beta 2 microglobulin. Cox-regression model was used to explore the relationship between progression-free survival and the following explanatory variables: treatment group, cytogenetics (analyzed by FISH included 6q-,11q-, +12q, 17p-, 13q-) , ZAP-70 (positive, negative or intermediate), VH3-21 usage (Yes and No), IgVH homology (>98%, 97%-98% and <97%), beta 2 microglobulin (>3500 microgram per liter [µg/L] and <=3500 µg/L). For each covariate, a hazard ratio <1 indicates a lower risk on the first effect tested compared with the other effects tested. Cytogenetics Group (based on >=20%)=cytogenetics (CY G).
Time Frame From randomization up to 5 years after last dose of study drug

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
B2 Microglobulin G 1: > 3500 microgram/liter (μg/L
79
43.2%
78
42.9%
B2 Microglobulin G 1: <= 3500 ug/L
22
12%
26
14.3%
CY G 1: 11q-
29
15.8%
19
10.4%
CY G 1: 17p-
6
3.3%
9
4.9%
CY G 1: 6q- or +12q or 13q-
38
20.8%
48
26.4%
CY G 1: no aberration
27
14.8%
27
14.8%
VH3-21 Usage Flag: Yes
6
3.3%
4
2.2%
VH3-21 Usage Flag: No
93
50.8%
96
52.7%
IgVH Homology, <97%
13
7.1%
15
8.2%
IgVH Homology, 97%-98%
5
2.7%
7
3.8%
IgVH Homology, >98%
80
43.7%
78
42.9%
ZAP70 G 1, Negative
14
7.7%
13
7.1%
ZAP70 G 1, Intermediate
27
14.8%
23
12.6%
ZAP70, G1 Positive
60
32.8%
65
35.7%
23. Secondary Outcome
Title Changes in Patient Reported Outcome (PRO) Measures and Scores for European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Chronic Lymphocytic Leukaemia 16 Item Module (EORTC QLQ-CLL 16)
Description The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales - fatigue (2 items), treatment side effects ([TSE], 4 items), disease symptoms (disease effects scale [DES], 4 items), and infection scale [IS] (4 items) - and single item scales (social activities [Social Problems (SP) Scale] and future health worries[Future Health (FH) Scale].). These are measured on a four point scale where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 - 100, where 0 =no symptoms or problems and 100 = a severe symptoms or problems. EORTC QLQ-CLL16 was assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value was obtained at randomization.
Time Frame Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.

Outcome Measure Data

Analysis Population Description
Participants
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
DES, Cycle 4 Day 1
-8.5
(18.08)
-9.0
(17.16)
DES, 1 M, FU
-9.7
(19.18)
-9.8
(19.89)
DES, 3 M, FU
-8.2
(19.48)
-10.9
(19.07)
DES, 6 M, FU
-9.8
(17.99)
-11.6
(18.05)
DES, 9 M, FU
-8.2
(20.70)
-12.0
(17.04)
DES. 12 M, FU
-10.1
(18.64)
-10.2
(16.09)
DES, 15 M, FU
-8.6
(18.08)
-10.2
(16.91)
DES, 18 M, FU
-8.5
(18.53)
-11.6
(18.79)
DES, 21 M, FU
-8.2
(18.48)
-11.3
(17.60)
DES, 24 M, FU
-7.1
(19.93)
-13.6
(16.18)
Fatigue Scale (FS), Cycle 4 Day 1
-7.0
(22.57)
-7.1
(24.16)
FS, 1 M, FU
-5.4
(29.16)
-6.2
(28.74)
FS, 3 M, FU
-4.4
(26.30)
-8.3
(30.14)
FS, 6 M, FU
-7.1
(25.94)
-12.0
(25.98)
FS, 9 M, FU
-6.2
(27.08)
-10.6
(26.95)
FS. 12 M, FU
-7.3
(27.26)
-8.1
(25.75)
FS, 15 M, FU
-7.6
(22.57)
-9.9
(24.04)
FS, 18 M, FU
-7.0
(23.03)
-3.7
(33.34)
FS, 21 M, FU
-10.3
(24.28)
-8.2
(27.27)
FS, 24 M, FU
-8.7
(24.19)
-8.7
(25.48)
FH, Cycle 4 Day 1
-11.8
(32.89)
-10.6
(27.76)
FH, 1 M, FU
-15.3
(35.04)
-11.9
(29.56)
FH, 3 M, FU
-14.3
(33.96)
-14.0
(32.06)
FH, 6 M, FU
-13.4
(33.98)
-17.7
(30.57)
FH, 9 M, FU
-15.6
(33.65)
-13.2
(34.43)
FH. 12 M, FU
-14.1
(32.80)
-14.9
(33.63)
FH, 15 M, FU
-14.6
(29.14)
-14.2
(34.13)
FH, 18 M, FU
-15.9
(31.69)
-18.4
(33.72)
FH, 21 M, FU
-16.9
(28.70)
-15.4
(29.12)
FH, 24 M, FU
-21.0
(29.58)
-17.7
(30.51)
IS, Cycle 4 Day 1
0.5
(17.65)
-1.4
(18.23)
IS, 1 M, FU
2.9
(22.79)
2.7
(24.06)
IS, 3 M, FU
0.8
(19.42)
0.8
(20.99)
IS, 6 M, FU
-1.2
(18.46)
-0.9
(20.40)
IS, 9 M, FU
-1.4
(18.81)
1.4
(22.45)
IS. 12 M, FU
0.4
(19.22)
2.1
(20.92)
IS, 15 M, FU
0.5
(17.56)
0.3
(18.79)
IS, 18 M, FU
-2.0
(16.04)
0.9
(19.04)
IS, 21 M, FU
-2.5
(18.13)
2.5
(22.09)
IS, 24 M, FU
-0.5
(18.85)
0.5
(21.34)
SP Scale Cycle 4 Day 1
1.9
(25.44)
0.3
(26.94)
SP Scale, 1 M, FU
3.2
(34.51)
0.0
(35.22)
SP Scale, 3 M, FU
-1.9
(33.04)
-4.3
(35.75)
SP Scale, 6 M, FU
-5.6
(31.73)
-10.9
(30.56)
SP Scale, 9 M, FU
-5.0
(30.15)
-11.0
(31.45)
SP Scale. 12 M, FU
-7.2
(31.06)
-7.6
(34.47)
SP Scale, 15 M, FU
-6.7
(30.21)
-13.7
(30.05)
SP Scale, 18 M, FU
-7.1
(31.57)
-8.5
(40.40)
SP Scale, 21 M, FU
-8.1
(31.07)
-7.5
(37.92)
SP Scale, 24 M, FU
-11.8
(24.27)
-8.7
(36.15)
TSE, Cycle 4 Day 1
-4.7
(16.15)
-4.0
(16.78)
TSE, 1 M, FU
-5.0
(18.09)
-3.2
(19.08)
TSE, 3 M, FU
-3.7
(19.41)
-4.3
(17.03)
TSE, 6 M, FU
-6.0
(15.25)
-4.8
(16.96)
TSE, 9 M, FU
-4.3
(17.22)
-5.1
(16.38)
TSE. 12 M, FU
-5.2
(16.44)
-3.2
(13.94)
TSE, 15 M, FU
-4.0
(14.92)
-4.2
(13.73)
TSE, 18 M, FU
-4.4
(17.10)
-3.6
(19.18)
TSE, 21 M, FU
-4.7
(16.63)
-4.0
(15.91)
TSE, 24 M, FU
-5.4
(17.52)
-6.5
(14.12)
24. Secondary Outcome
Title Change From Baseline in Patient Reported Outcome (PRO) as Assessed by EuroQoL Five-Dimension (EQ-5D) Score at Indicated Visit
Description EQ-5D is comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score. The utility score measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = unable, or extreme problems). Responses are typically converted into health utilities or valuations on a scale ranging from 0 (death) to 1 (perfect health). The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A Negative health status describes health state worse than death.Baseline is the most recent, non-missing value prior to or on the first study drug dose date.
Time Frame Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
UT, Cycle 4 Day 1
0.0
(0.27)
0.0
(0.21)
UT, 1 M, FU
0.1
(0.22)
0.0
(0.28)
UT, 3 M, FU
0.0
(0.27)
0.1
(0.23)
UT, 6 M, FU
0.1
(0.24)
0.1
(0.24)
UT, 9 M, FU
0.1
(0.26)
0.1
(0.24)
UT. 12 M, FU
0.1
(0.21)
0.1
(0.22)
UT, 15 M, FU
0.0
(0.23)
0.1
(0.24)
UT, 18 M, FU
0.1
(0.21)
0.0
(0.34)
UT, 21 M, FU
0.1
(0.21)
0.1
(0.26)
UT, 24 M, FU
0.1
(0.19)
0.1
(0.28)
VAS Cycle 4 Day 1
6.1
(17.68)
5.6
(17.64)
VAS, 1 M, FU
5.6
(20.73)
5.9
(22.83)
VAS, 3 M, FU
5.7
(19.92)
9.6
(20.88)
VAS, 6 M, FU
8.2
(18.84)
11.1
(19.08)
VAS, 9 M, FU
8.1
(18.33)
11.9
(20.59)
VAS. 12 M, FU
7.0
(21.93)
10.3
(21.21)
VAS, 15 M, FU
8.0
(17.52)
13.1
(21.06)
VAS, 18 M, FU
9.4
(17.86)
11.1
(25.40)
VAS, 21 M, FU
8.1
(16.42)
11.3
(24.16)
VAS, 24 M, FU
8.8
(19.50)
15.2
(21.88)
25. Secondary Outcome
Title Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
Description EORTC QLQ-C30, a self-reported, cancer-specific instrument assessing 15 domains: physical, role, emotional, cognitive and social functioning, pain,fatigue, nausea and vomiting, insomnia, loss of appetite, constipation, diarrhea, and dyspnea, financial difficulties and a global health status/quality of life (QOF). Functional and symptoms scales were measured on four point Likert scale where 1 = not at all and 4 = very much. Pat. assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Clinically meaningful changes or minimally important differences (MIDs)have been previously established for the EORTC QLQ C30, and categorized as 'small' if the mean change in scores is 5-10 points, 'moderate' if 10-20 points, and 'large' if >20points.
Time Frame Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Appetite Loss, Cycle 4 Day 1
0.5
(25.60)
-1.9
(26.65)
Appetite Loss, 1 M, FU
-0.2
(26.14)
-3.9
(28.52)
Appetite Loss, 3 M, FU
-0.7
(26.77)
-7.4
(28.22)
Appetite Loss, 6 M, FU
-6.0
(23.00)
-12.4
(26.05)
Appetite Loss, 9 M, FU
-3.9
(20.38)
-9.6
(25.25)
Appetite Loss. 12 M, FU
-4.0
(22.76)
-6.0
(27.59)
Appetite Loss, 15 M, FU
-3.8
(23.13)
-9.4
(28.19)
Appetite Loss, 18 M, FU
-7.9
(20.11)
-9.4
(30.12)
Appetite Loss, 21 M, FU
-3.4
(20.36)
-7.7
(27.70)
Appetite Loss, 24 M, FU
-3.9
(22.53)
-12.5
(29.68)
Cognitive Functioning, Cycle 4 Day 1
3.4
(18.25)
2.5
(18.39)
Cognitive Functioning, 1 M, FU
-0.4
(18.40)
3.0
(19.87)
Cognitive Functioning, 3 M, FU
0.0
(18.74)
2.3
(21.69)
Cognitive Functioning, 6 M, FU
1.7
(18.95)
2.7
(20.99)
Cognitive Functioning, 9 M, FU
-0.6
(20.58)
2.4
(19.61)
Cognitive Functioning. 12 M, FU
-2.1
(19.17)
-1.8
(21.36)
Cognitive Functioning, 15 M, FU
-1.0
(17.97)
0.3
(20.58)
Cognitive Functioning, 18 M, FU
-0.9
(20.00)
-0.3
(22.67)
Cognitive Functioning, 21 M, FU
-1.9
(21.65)
-1.9
(21.84)
Cognitive Functioning, 24 M, FU
1.0
(20.83)
-1.3
(21.25)
Constipation, Cycle 4 Day 1
2.1
(21.46)
0.8
(18.60)
Constipation, 1 M, FU
-0.7
(19.02)
0.3
(18.92)
Constipation, 3 M, FU
-2.1
(19.33)
-0.9
(20.01)
Constipation, 6 M, FU
-3.5
(19.32)
0.3
(18.22)
Constipation, 9 M, FU
-1.2
(19.71)
0.4
(18.18)
Constipation. 12 M, FU
-0.0
(23.13)
0.4
(19.24)
Constipation, 15 M, FU
-1.7
(21.29)
-3.8
(20.11)
Constipation, 18 M, FU
-0.4
(21.49)
-1.1
(24.32)
Constipation, 21 M, FU
-1.9
(22.93)
-3.8
(23.26)
Constipation, 24 M, FU
0.0
(21.23)
-3.3
(21.56)
Diarrhoea, Cycle 4 Day 1
0.2
(19.72)
-2.4
(17.54)
Diarrhoea, 1 M, FU
-3.5
(20.87)
0.8
(21.28)
Diarrhoea, 3 M, FU
1.6
(22.49)
1.5
(20.98)
Diarrhoea, 6 M, FU
0.0
(20.38)
-3.1
(16.64)
Diarrhoea, 9 M, FU
0.3
(20.56)
-2.7
(17.97)
Diarrhoea. 12 M, FU
-3.4
(15.75)
-2.2
(19.12)
Diarrhoea, 15 M, FU
-1.7
(19.57)
-4.4
(20.62)
Diarrhoea, 18 M, FU
-1.9
(17.67)
-1.1
(17.18)
Diarrhoea, 21 M, FU
-2.3
(18.88)
0.6
(21.17)
Diarrhoea, 24 M, FU
-2.9
(17.02)
-0.7
(20.75)
Dyspnoea Cycle 4 Day 1
-4.6
(22.85)
-4.6
(23.41)
Dyspnoea, 1 M, FU
-1.0
(26.60)
-2.8
(25.67)
Dyspnoea, 3 M, FU
-3.1
(26.40)
-1.5
(25.53)
Dyspnoea, 6 M, FU
-2.7
(21.92)
-7.2
(24.17)
Dyspnoea, 9 M, FU
-2.7
(26.03)
-6.4
(23.55)
Dyspnoea. 12 M, FU
-3.4
(24.52)
-4.1
(22.87)
Dyspnoea, 15 M, FU
-2.5
(20.77)
-2.2
(26.66)
Dyspnoea, 18 M, FU
-3.0
(24.81)
-2.8
(29.22)
Dyspnoea, 21 M, FU
-3.4
(24.92)
-1.9
(21.30)
Dyspnoea, 24 M, FU
-2.4
(26.39)
-4.8
(24.53)
Emotional Functioning Cycle 4 Day 1
4.4
(17.91)
5.4
(19.59)
Emotional Functioning, 1 M, FU
5.4
(20.26)
7.2
(24.08)
Emotional Functioning, 3 M, FU
5.7
(20.93)
7.8
(20.90)
Emotional Functioning, 6 M, FU
4.8
(22.57)
8.9
(22.34)
Emotional Functioning, 9 M
3.4
(22.95)
6.7
(18.52)
Emotional Functioning. 12 M, FU
3.9
(22.11)
8.0
(21.92)
Emotional Functioning, 15 M, FU
5.1
(21.54)
6.5
(21.15)
Emotional Functioning, 18 M, FU
5.1
(22.94)
6.5
(26.35)
Emotional Functioning, 21 M, FU
5.3
(22.43)
7.7
(23.56)
Emotional Functioning, 24 M, FU
7.1
(23.02)
7.1
(26.16)
Fatigue Cycle 4 Day 1
-4.3
(21.37)
-6.3
(22.66)
Fatigue, 1 M, FU
-7.4
(25.16)
-4.5
(28.64)
Fatigue, 3 M, FU
-5.4
(24.01)
-9.3
(27.83)
Fatigue, 6 M, FU
-8.2
(23.64)
-12.2
(22.43)
Fatigue, 9 M, FU
-8.8
(23.80)
-9.8
(24.56)
Fatigue. 12 M, FU
-6.8
(25.28)
-10.3
(23.44)
Fatigue, 15 M, FU
-7.6
(19.83)
-8.9
(27.61)
Fatigue, 18 M, FU
-7.0
(22.25)
-6.1
(30.15)
Fatigue, 21 M, FU
-9.6
(20.44)
-9.1
(25.34)
Fatigue, 24 M, FU
-9.1
(23.01)
-11.7
(25.30)
Financial Difficulties Cycle 4 Day 1
-4.5
(23.98)
-6.1
(29.93)
Financial Difficulties, 1 M, FU
-5.9
(26.57)
-5.2
(26.07)
Financial Difficulties, 3 M, FU
-4.1
(28.30)
-9.0
(29.40)
Financial Difficulties, 6 M, FU
-5.8
(24.61)
-8.8
(26.89)
Financial Difficulties, 9 M, FU
-6.1
(27.54)
-8.7
(27.44)
Financial Difficulties. 12 M, FU
-6.4
(24.93)
-9.6
(28.71)
Financial Difficulties, 15 M, FU
-8.3
(23.69)
-9.7
(27.91)
Financial Difficulties, 18 M, FU
-4.1
(24.39)
-12.2
(30.04)
Financial Difficulties, 21 M, FU,
-10.6
(22.34)
-11.1
(28.02)
Financial Difficulties, 24 M, FU
-6.2
(24.93)
-12.0
(27.57)
Nausea and Vomiting Cycle 4 Day 1
2.0
(16.06)
3.7
(18.37)
Nausea and Vomiting, 1 M, FU
1.0
(14.85)
0.1
(19.22)
Nausea and Vomiting, 3 M, FU
0.1
(15.90)
-2.9
(14.49)
Nausea and Vomiting, 6 M, FU
-2.8
(13.12)
-2.5
(14.36)
Nausea and Vomiting, 9 M, FU
-1.3
(13.81)
-1.2
(15.08)
Nausea and Vomiting. 12 M, FU
-2.9
(13.52)
-1.8
(12.35)
Nausea and Vomiting, 15 M, FU
-3.3
(11.45)
-2.7
(11.76)
Nausea and Vomiting, 18 M, FU
-3.3
(12.03)
-2.5
(10.02)
Nausea and Vomiting, 21 M, FU
-4.0
(13.37)
1.3
(11.72)
Nausea and Vomiting, 24 M, FU
-2.4
(13.69)
-0.3
(11.90)
Pain Cycle 4 Day 1
-3.6
(20.64)
-4.2
(20.43)
Pain, 1 M, FU
-2.8
(23.02)
-5.5
(22.31)
Pain, 3 M, FU
-3.8
(25.13)
-2.1
(24.44)
Pain, 6 M, FU
-5.3
(23.54)
-6.6
(20.59)
Pain, 9 M, FU
-4.2
(23.86)
-4.8
(22.12)
Pain. 12 M, FU
-3.5
(24.43)
-3.7
(21.01)
Pain, 15 M, FU
-2.9
(23.08)
-3.5
(22.00)
Pain, 18 M, FU
-3.3
(19.39)
0.5
(28.05)
Pain, 21 M, FU
-5.9
(19.74)
-0.9
(25.82)
Pain, 24 M, FU
-1.7
(23.25)
-3.0
(24.67)
Physical Functioning Cycle 4 Day 1
1.2
(14.50)
0.6
(16.81)
Physical Functioning, 1 M, FU
0.4
(19.52)
-0.7
(21.15)
Physical Functioning, 3 M, FU
0.9
(18.66)
0.9
(19.68)
Physical Functioning, 6 M, FU
3.2
(16.41)
5.7
(17.01)
Physical Functioning, 9 M, FU
3.9
(17.30)
6.2
(17.25)
Physical Functioning. 12 M, FU
2.4
(17.98)
3.5
(17.52)
Physical Functioning, 15 M, FU
3.8
(14.65)
2.7
(18.46)
Physical Functioning, 18 M, FU
4.1
(16.65)
0.1
(22.09)
Physical Functioning, 21 M, FU
4.7
(17.14)
2.1
(18.88)
Physical Functioning, 24 M, FU
5.3
(17.44)
3.7
(20.57)
Global Health Status Cycle 4 Day 1
6.4
(23.46)
6.8
(17.54)
Global Health Status, 1 M, FU
6.5
(24.23)
6.9
(26.32)
Global Health Status, 3 M, FU
5.0
(21.45)
12.3
(21.15)
Global Health Status, 6 M, FU
7.5
(21.57)
13.7
(23.01)
Global Health Status, 9 M, FU
7.6
(23.24)
11.7
(22.35)
Global Health Status. 12 M, FU
7.6
(23.64)
12.2
(21.77)
Global Health Status, 15 M, FU
7.6
(20.40)
12.7
(22.29)
Global Health Status, 18 M, FU
9.2
(23.03)
10.4
(27.00)
Global Health Status, 21 M, FU
10.8
(20.26)
12.7
(21.53)
Global Health Status, 24 M, FU
12.1
(24.28)
12.3
(24.31)
Role Functioning Cycle 4 Day 1
1.4
(23.27)
0.1
(24.83)
Role Functioning, 1 M, FU
-0.1
(25.83)
-0.7
(27.53)
Role Functioning, 3 M, FU
0.5
(25.19)
0.9
(28.94)
Role Functioning, 6 M, FU
4.3
(25.49)
5.5
(26.54)
Role Functioning, 9 M, FU
4.1
(26.21)
6.2
(25.60)
Role Functioning. 12 M, FU
2.1
(26.46)
3.9
(24.78)
Role Functioning, 15 M, FU
3.8
(24.84)
1.9
(25.13)
Role Functioning, 18 M, FU
7.0
(24.09)
-0.0
(28.95)
Role Functioning, 21 M, FU
5.3
(22.82)
2.6
(26.74)
Role Functioning, 24 M, FU
5.8
(25.54)
3.7
(30.10)
Social Functioning Cycle 4 Day 1
3.1
(20.30)
-0.9
(23.50)
Social Functioning, 1 M, FU
0.4
(25.98)
0.8
(27.93)
Social Functioning, 3 M, FU
0.8
(23.76)
4.3
(26.29)
Social Functioning, 6 M, FU
3.4
(22.04)
6.1
(26.24)
Social Functioning, 9 M, FU
2.3
(21.84)
4.2
(25.46)
Social Functioning. 12 M, FU
3.0
(23.04)
3.3
(21.95)
Social Functioning, 15 M, FU
6.2
(18.30)
1.6
(27.61)
Social Functioning, 18 M, FU
6.5
(19.78)
2.7
(29.69)
Social Functioning, 21 M, FU
6.6
(18.83)
4.5
(24.72)
Social Functioning, 24 M, FU
7.9
(19.60)
7.7
(24.56)
Insomnia Cycle 4 Day 1
-3.1
(26.07)
-8.7
(26.94)
Insomnia, 1 M, FU
-5.9
(29.04)
-11.1
(27.78)
Insomnia, 3 M, FU
-6.2
(29.64)
-13.3
(28.07)
Insomnia, 6 M, FU
-5.2
(26.18)
-17.0
(25.88)
Insomnia, 9 M, FU
-3.0
(30.53)
-13.2
(31.04)
Insomnia. 12 M, FU
-6.9
(25.91)
-10.5
(29.33)
Insomnia, 15 M, FU
-5.9
(29.02)
-17.5
(26.52)
Insomnia, 18 M, FU
-7.5
(28.32)
-15.3
(28.58)
Insomnia, 21 M, FU
-8.5
(25.15)
-10.3
(34.64)
Insomnia, 24 M, FU
-1.5
(33.30)
-13.6
(35.95)
26. Secondary Outcome
Title Mean of Health Change Questionnaire (HCQ)
Description The HCQ consists of a single question in which the participant is asked if he/she has experienced any change in his/her health overall since beginning the study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for 'my health is a great deal better' to 9 for 'my health is a great deal worse' since the beginning of the study. Lower scores represent better conditions.
Time Frame Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.

Outcome Measure Data

Analysis Population Description
ITT Population. Only those participants available at the specified time points were analyzed.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183 182
Cycle 4 Day 1
2.6
(1.62)
2.8
(1.59)
1 M, FU
3.0
(2.05)
3.2
(2.30)
3 M, FU
3.0
(2.11)
2.8
(1.86)
6 M, FU
2.6
(1.76)
2.6
(1.82)
9 M, FU
2.5
(1.78)
2.4
(1.57)
12 M, FU
2.5
(1.80)
2.5
(1.78)
15 M, FU
2.2
(1.57)
2.3
(1.68)
18 M, FU
2.4
(1.67)
2.7
(2.01)
21 M, FU
2.3
(1.50)
2.3
(1.52)
24 M, FU
2.3
(1.76)
2.6
(1.89)
27. Secondary Outcome
Title Mean Area Under the Time-concentration Curve (AUC) Curve Over the Dosing Interval (AUC[0-tau]) of Ofatumumab
Description Area under the time-concentration curve (AUC) over the dosing interval (AUC[0-tau]) was evaluated. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).
Time Frame Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5,6

Outcome Measure Data

Analysis Population Description
PK Population: Participants for whom a pharmacokinetic sample was obtained were analyzed, only participants available at the specified time points were analyzed(represented by n=X in the category titles)
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183
cycle 1, week 1
3554.910
cycle 1, week 2
34109.67
cycle 2
67069.79
cycle 3
84620.05
cycle 4
89091.35
cycle 5
96829.23
cycle 6
104798.0
28. Secondary Outcome
Title Maximum Concentration (Cmax) and Observed Drug Concentration Prior to the Next Dose (Ctrough) of Ofatumumab
Description Blood samples were collected to assess the plasma concentration of ofatumumab.Cmax and Ctrough were determined. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).
Time Frame Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5

Outcome Measure Data

Analysis Population Description
PK Population: Participants for whom a pharmacokinetic sample was obtained were analyzed, only participants available at the specified time points were analyzed(represented by n=X in the category titles)
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183
Cmax cycle 1, week 1
61.355
Cmax cycle 1, week 2
241.192
Cmax cycle 4
312.745
Ctrough cycle 1, week 1
3.551
Ctrough cycle 1, week 2
9.496
Ctrough cycle 2
24.281
Ctrough cycle 3
25.632
Ctrough cycle 4
58.640
Ctrough cycle 5
70.398
29. Secondary Outcome
Title Time of Occurrence of Cmax (Tmax) of Ofatumumab
Description Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4.
Time Frame Cycle 1 Week 1, Cycle 1 Week 2, Cycle 4

Outcome Measure Data

Analysis Population Description
PK Population: Participants for whom a pharmacokinetic sample was obtained were analyzed, only participants available at the specified time points were analyzed(represented by n=X in the category titles)
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
Measure Participants 183
cycle 1, week 1
6.106
cycle 1, week 2
5.004
cycle 4
4.878

Adverse Events

Time Frame Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 5 years.
Adverse Event Reporting Description Analysis was done in the safety Population included subjects who received at least one dose of a study drug. This population was used for all safety measurements. In the analyses, subjects were grouped based on the treatment they receive regardless of how they are randomized.
Arm/Group Title Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Arm/Group Description Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status. Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
All Cause Mortality
Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 40/181 (22.1%) 42/178 (23.6%)
Serious Adverse Events
Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 108/181 (59.7%) 86/178 (48.3%)
Blood and lymphatic system disorders
Agranulocytosis 0/181 (0%) 2/178 (1.1%)
Anaemia 11/181 (6.1%) 12/178 (6.7%)
Aplasia pure red cell 1/181 (0.6%) 0/178 (0%)
Autoimmune haemolytic anaemia 2/181 (1.1%) 2/178 (1.1%)
Febrile neutropenia 18/181 (9.9%) 15/178 (8.4%)
Granulocytopenia 1/181 (0.6%) 0/178 (0%)
Haemolysis 0/181 (0%) 1/178 (0.6%)
Haemolytic anaemia 0/181 (0%) 2/178 (1.1%)
Immune thrombocytopenic purpura 0/181 (0%) 2/178 (1.1%)
Leukopenia 2/181 (1.1%) 1/178 (0.6%)
Lymphadenopathy 1/181 (0.6%) 0/178 (0%)
Neutropenia 17/181 (9.4%) 14/178 (7.9%)
Pancytopenia 5/181 (2.8%) 5/178 (2.8%)
Thrombocytopenia 7/181 (3.9%) 10/178 (5.6%)
Cardiac disorders
Acute myocardial infarction 2/181 (1.1%) 2/178 (1.1%)
Angina pectoris 0/181 (0%) 2/178 (1.1%)
Atrial fibrillation 2/181 (1.1%) 3/178 (1.7%)
Bradycardia 0/181 (0%) 1/178 (0.6%)
Cardiac arrest 1/181 (0.6%) 1/178 (0.6%)
Cardiac failure 1/181 (0.6%) 1/178 (0.6%)
Cardiac failure acute 0/181 (0%) 4/178 (2.2%)
Cardiac failure congestive 0/181 (0%) 1/178 (0.6%)
Cardiopulmonary failure 0/181 (0%) 1/178 (0.6%)
Coronary artery disease 1/181 (0.6%) 1/178 (0.6%)
Extrasystoles 0/181 (0%) 1/178 (0.6%)
Myocardial infarction 0/181 (0%) 1/178 (0.6%)
Myocardial ischaemia 1/181 (0.6%) 1/178 (0.6%)
Pericardial effusion 0/181 (0%) 1/178 (0.6%)
Tachycardia paroxysmal 0/181 (0%) 1/178 (0.6%)
Congenital, familial and genetic disorders
Epidermolysis 1/181 (0.6%) 0/178 (0%)
Gastrointestinal disorders
Abdominal pain 1/181 (0.6%) 0/178 (0%)
Abdominal pain upper 1/181 (0.6%) 0/178 (0%)
Anal fistula 0/181 (0%) 1/178 (0.6%)
Ascites 0/181 (0%) 1/178 (0.6%)
Colitis 1/181 (0.6%) 1/178 (0.6%)
Constipation 2/181 (1.1%) 0/178 (0%)
Diarrhoea 3/181 (1.7%) 3/178 (1.7%)
Gastrointestinal haemorrhage 3/181 (1.7%) 1/178 (0.6%)
Gastrooesophageal reflux disease 1/181 (0.6%) 1/178 (0.6%)
Ileus 1/181 (0.6%) 0/178 (0%)
Ileus paralytic 1/181 (0.6%) 0/178 (0%)
Inguinal hernia 2/181 (1.1%) 0/178 (0%)
Mouth ulceration 1/181 (0.6%) 0/178 (0%)
Nausea 2/181 (1.1%) 0/178 (0%)
Oesophagitis 0/181 (0%) 2/178 (1.1%)
Proctalgia 1/181 (0.6%) 0/178 (0%)
Salivary hypersecretion 1/181 (0.6%) 0/178 (0%)
Stomatitis 1/181 (0.6%) 0/178 (0%)
Vomiting 1/181 (0.6%) 1/178 (0.6%)
General disorders
Asthenia 0/181 (0%) 1/178 (0.6%)
Chills 1/181 (0.6%) 0/178 (0%)
Death 3/181 (1.7%) 1/178 (0.6%)
Fatigue 1/181 (0.6%) 0/178 (0%)
General physical health deterioration 0/181 (0%) 2/178 (1.1%)
Hyperthermia 1/181 (0.6%) 0/178 (0%)
Malaise 0/181 (0%) 1/178 (0.6%)
Oedema peripheral 1/181 (0.6%) 2/178 (1.1%)
Pyrexia 9/181 (5%) 5/178 (2.8%)
Sudden death 0/181 (0%) 1/178 (0.6%)
Hepatobiliary disorders
Cholecystitis 1/181 (0.6%) 0/178 (0%)
Hepatic failure 2/181 (1.1%) 0/178 (0%)
Hepatic function abnormal 0/181 (0%) 1/178 (0.6%)
Hepatitis 2/181 (1.1%) 0/178 (0%)
Hyperbilirubinaemia 1/181 (0.6%) 0/178 (0%)
Immune system disorders
Anaphylactic reaction 1/181 (0.6%) 0/178 (0%)
Graft versus host disease 0/181 (0%) 1/178 (0.6%)
Infections and infestations
Acinetobacter bacteraemia 0/181 (0%) 1/178 (0.6%)
Acinetobacter infection 0/181 (0%) 1/178 (0.6%)
Anal abscess 0/181 (0%) 1/178 (0.6%)
Appendicitis 1/181 (0.6%) 0/178 (0%)
Atypical mycobacterial infection 0/181 (0%) 1/178 (0.6%)
Atypical pneumonia 0/181 (0%) 1/178 (0.6%)
Bacteraemia 0/181 (0%) 1/178 (0.6%)
Bacterial infection 0/181 (0%) 1/178 (0.6%)
Bacterial sepsis 0/181 (0%) 1/178 (0.6%)
Bronchitis 3/181 (1.7%) 2/178 (1.1%)
Campylobacter gastroenteritis 0/181 (0%) 1/178 (0.6%)
Campylobacter infection 0/181 (0%) 1/178 (0.6%)
Cellulitis 2/181 (1.1%) 2/178 (1.1%)
Clostridium difficile colitis 0/181 (0%) 1/178 (0.6%)
Cytomegalovirus infection 1/181 (0.6%) 1/178 (0.6%)
Device related infection 1/181 (0.6%) 1/178 (0.6%)
Diarrhoea infectious 1/181 (0.6%) 0/178 (0%)
Diverticulitis 1/181 (0.6%) 0/178 (0%)
Endocarditis 0/181 (0%) 1/178 (0.6%)
Enterococcal sepsis 1/181 (0.6%) 0/178 (0%)
Epididymitis 1/181 (0.6%) 0/178 (0%)
Erysipelas 1/181 (0.6%) 0/178 (0%)
Escherichia infection 0/181 (0%) 1/178 (0.6%)
Escherichia urinary tract infection 1/181 (0.6%) 0/178 (0%)
Febrile infection 1/181 (0.6%) 1/178 (0.6%)
Gastroenteritis 0/181 (0%) 2/178 (1.1%)
Gastroenteritis salmonella 2/181 (1.1%) 0/178 (0%)
Gastrointestinal candidiasis 0/181 (0%) 1/178 (0.6%)
H1N1 influenza 0/181 (0%) 1/178 (0.6%)
Hepatitis B 1/181 (0.6%) 1/178 (0.6%)
Hepatitis B reactivation 1/181 (0.6%) 0/178 (0%)
Herpes zoster 1/181 (0.6%) 2/178 (1.1%)
Infected skin ulcer 0/181 (0%) 1/178 (0.6%)
Infection 1/181 (0.6%) 1/178 (0.6%)
Infective exacerbation of bronchiectasis 1/181 (0.6%) 0/178 (0%)
Intervertebral discitis 1/181 (0.6%) 0/178 (0%)
Lower respiratory tract infection 6/181 (3.3%) 2/178 (1.1%)
Neutropenic infection 0/181 (0%) 2/178 (1.1%)
Neutropenic sepsis 4/181 (2.2%) 5/178 (2.8%)
Oral candidiasis 0/181 (0%) 2/178 (1.1%)
Oropharyngeal candidiasis 0/181 (0%) 1/178 (0.6%)
Pharyngitis 0/181 (0%) 1/178 (0.6%)
Pneumococcal sepsis 0/181 (0%) 1/178 (0.6%)
Pneumocystis jirovecii infection 1/181 (0.6%) 0/178 (0%)
Pneumocystis jirovecii pneumonia 0/181 (0%) 2/178 (1.1%)
Pneumonia 28/181 (15.5%) 29/178 (16.3%)
Pneumonia fungal 0/181 (0%) 1/178 (0.6%)
Pneumonia haemophilus 0/181 (0%) 1/178 (0.6%)
Pneumonia respiratory syncytial viral 1/181 (0.6%) 0/178 (0%)
Pneumonia viral 1/181 (0.6%) 0/178 (0%)
Postoperative wound infection 0/181 (0%) 1/178 (0.6%)
Pseudomembranous colitis 1/181 (0.6%) 0/178 (0%)
Pulmonary tuberculosis 1/181 (0.6%) 0/178 (0%)
Respiratory tract infection 1/181 (0.6%) 2/178 (1.1%)
Salmonella sepsis 1/181 (0.6%) 0/178 (0%)
Sepsis 4/181 (2.2%) 8/178 (4.5%)
Septic shock 1/181 (0.6%) 3/178 (1.7%)
Skin infection 1/181 (0.6%) 0/178 (0%)
Soft tissue infection 1/181 (0.6%) 0/178 (0%)
Systemic mycosis 1/181 (0.6%) 0/178 (0%)
Tonsillitis 2/181 (1.1%) 0/178 (0%)
Upper respiratory tract infection 4/181 (2.2%) 5/178 (2.8%)
Urinary tract infection 6/181 (3.3%) 6/178 (3.4%)
Urinary tract infection bacterial 0/181 (0%) 1/178 (0.6%)
Injury, poisoning and procedural complications
Hip fracture 0/181 (0%) 1/178 (0.6%)
Procedural pneumothorax 0/181 (0%) 1/178 (0.6%)
Radius fracture 0/181 (0%) 1/178 (0.6%)
Spinal compression fracture 0/181 (0%) 1/178 (0.6%)
Thoracic vertebral fracture 1/181 (0.6%) 0/178 (0%)
Investigations
Haemoglobin decreased 1/181 (0.6%) 0/178 (0%)
Neutrophil count decreased 1/181 (0.6%) 0/178 (0%)
Platelet count decreased 1/181 (0.6%) 0/178 (0%)
Weight decreased 1/181 (0.6%) 0/178 (0%)
Metabolism and nutrition disorders
Decreased appetite 1/181 (0.6%) 0/178 (0%)
Dehydration 0/181 (0%) 1/178 (0.6%)
Diabetes mellitus 1/181 (0.6%) 0/178 (0%)
Gout 1/181 (0.6%) 0/178 (0%)
Hypercalcaemia 1/181 (0.6%) 0/178 (0%)
Hyperglycaemia 1/181 (0.6%) 0/178 (0%)
Hyperkalaemia 1/181 (0.6%) 0/178 (0%)
Hyperuricaemia 1/181 (0.6%) 0/178 (0%)
Hypocalcaemia 1/181 (0.6%) 0/178 (0%)
Hyponatraemia 0/181 (0%) 1/178 (0.6%)
Starvation 1/181 (0.6%) 0/178 (0%)
Tumour lysis syndrome 1/181 (0.6%) 0/178 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 1/181 (0.6%) 0/178 (0%)
Back pain 2/181 (1.1%) 0/178 (0%)
Muscle spasms 1/181 (0.6%) 0/178 (0%)
Musculoskeletal pain 1/181 (0.6%) 0/178 (0%)
Myositis 1/181 (0.6%) 0/178 (0%)
Pain in extremity 1/181 (0.6%) 0/178 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia 1/181 (0.6%) 0/178 (0%)
Adenocarcinoma of colon 1/181 (0.6%) 0/178 (0%)
Bladder papilloma 1/181 (0.6%) 0/178 (0%)
Chronic lymphocytic leukaemia 1/181 (0.6%) 0/178 (0%)
Chronic myeloid leukaemia 1/181 (0.6%) 0/178 (0%)
Colon cancer metastatic 1/181 (0.6%) 0/178 (0%)
Diffuse large B-cell lymphoma 0/181 (0%) 1/178 (0.6%)
Hypopharyngeal cancer 0/181 (0%) 1/178 (0.6%)
Invasive ductal breast carcinoma 1/181 (0.6%) 0/178 (0%)
Lung neoplasm malignant 1/181 (0.6%) 0/178 (0%)
Melanoma recurrent 0/181 (0%) 1/178 (0.6%)
Metastatic squamous cell carcinoma 1/181 (0.6%) 0/178 (0%)
Myelodysplastic syndrome 3/181 (1.7%) 2/178 (1.1%)
Non-small cell lung cancer 1/181 (0.6%) 0/178 (0%)
Plasma cell myeloma 1/181 (0.6%) 0/178 (0%)
Tumour associated fever 1/181 (0.6%) 0/178 (0%)
Nervous system disorders
Carotid arteriosclerosis 1/181 (0.6%) 0/178 (0%)
Carpal tunnel syndrome 1/181 (0.6%) 0/178 (0%)
Cerebral haemorrhage 1/181 (0.6%) 0/178 (0%)
Cerebrovascular accident 1/181 (0.6%) 0/178 (0%)
Dementia 0/181 (0%) 1/178 (0.6%)
Demyelinating polyneuropathy 0/181 (0%) 1/178 (0.6%)
Epilepsy 1/181 (0.6%) 0/178 (0%)
Headache 1/181 (0.6%) 0/178 (0%)
Hepatic encephalopathy 1/181 (0.6%) 0/178 (0%)
Nervous system disorder 1/181 (0.6%) 0/178 (0%)
Peripheral sensory neuropathy 0/181 (0%) 1/178 (0.6%)
Post herpetic neuralgia 1/181 (0.6%) 0/178 (0%)
Seizure 1/181 (0.6%) 0/178 (0%)
Syncope 2/181 (1.1%) 0/178 (0%)
Transient ischaemic attack 2/181 (1.1%) 0/178 (0%)
Vascular encephalopathy 1/181 (0.6%) 1/178 (0.6%)
Renal and urinary disorders
Acute kidney injury 5/181 (2.8%) 2/178 (1.1%)
Calculus urinary 1/181 (0.6%) 0/178 (0%)
Renal colic 1/181 (0.6%) 0/178 (0%)
Renal failure 1/181 (0.6%) 2/178 (1.1%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema 1/181 (0.6%) 0/178 (0%)
Acute respiratory distress syndrome 0/181 (0%) 1/178 (0.6%)
Acute respiratory failure 0/181 (0%) 1/178 (0.6%)
Bronchial haemorrhage 0/181 (0%) 1/178 (0.6%)
Bronchospasm 1/181 (0.6%) 0/178 (0%)
Chronic obstructive pulmonary disease 1/181 (0.6%) 1/178 (0.6%)
Cough 1/181 (0.6%) 0/178 (0%)
Dyspnoea 3/181 (1.7%) 1/178 (0.6%)
Interstitial lung disease 1/181 (0.6%) 0/178 (0%)
Pleural effusion 1/181 (0.6%) 1/178 (0.6%)
Pneumonitis 0/181 (0%) 1/178 (0.6%)
Pulmonary embolism 0/181 (0%) 1/178 (0.6%)
Pulmonary fibrosis 1/181 (0.6%) 0/178 (0%)
Pulmonary oedema 1/181 (0.6%) 1/178 (0.6%)
Respiratory failure 3/181 (1.7%) 2/178 (1.1%)
Respiratory tract haemorrhage 0/181 (0%) 1/178 (0.6%)
Skin and subcutaneous tissue disorders
Pruritus 1/181 (0.6%) 0/178 (0%)
Skin ulcer 1/181 (0.6%) 1/178 (0.6%)
Vascular disorders
Arteriosclerosis 1/181 (0.6%) 0/178 (0%)
Circulatory collapse 0/181 (0%) 1/178 (0.6%)
Essential hypertension 0/181 (0%) 1/178 (0.6%)
Haemorrhagic vasculitis 0/181 (0%) 1/178 (0.6%)
Hypertension 0/181 (0%) 1/178 (0.6%)
Hypotension 2/181 (1.1%) 0/178 (0%)
Hypovolaemic shock 1/181 (0.6%) 0/178 (0%)
Peripheral ischaemia 0/181 (0%) 1/178 (0.6%)
Shock 0/181 (0%) 1/178 (0.6%)
Thrombophlebitis 0/181 (0%) 1/178 (0.6%)
Venous thrombosis limb 0/181 (0%) 1/178 (0.6%)
Other (Not Including Serious) Adverse Events
Ofatumumab + Fludarabine + Cyclophosphamide_ ITT Subjects Fludarabine + Cyclophosphamide_ ITT Subjects
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 149/181 (82.3%) 123/178 (69.1%)
Blood and lymphatic system disorders
Anaemia 24/181 (13.3%) 38/178 (21.3%)
Leukopenia 27/181 (14.9%) 10/178 (5.6%)
Neutropenia 93/181 (51.4%) 62/178 (34.8%)
Thrombocytopenia 38/181 (21%) 55/178 (30.9%)
Gastrointestinal disorders
Constipation 8/181 (4.4%) 11/178 (6.2%)
Diarrhoea 14/181 (7.7%) 19/178 (10.7%)
Nausea 45/181 (24.9%) 36/178 (20.2%)
Vomiting 19/181 (10.5%) 22/178 (12.4%)
General disorders
Asthenia 13/181 (7.2%) 16/178 (9%)
Chills 14/181 (7.7%) 3/178 (1.7%)
Fatigue 15/181 (8.3%) 11/178 (6.2%)
Pyrexia 26/181 (14.4%) 15/178 (8.4%)
Infections and infestations
Upper respiratory tract infection 13/181 (7.2%) 8/178 (4.5%)
Investigations
Platelet count decreased 12/181 (6.6%) 5/178 (2.8%)
Metabolism and nutrition disorders
Decreased appetite 13/181 (7.2%) 8/178 (4.5%)
Nervous system disorders
Headache 15/181 (8.3%) 6/178 (3.4%)
Respiratory, thoracic and mediastinal disorders
Cough 15/181 (8.3%) 10/178 (5.6%)
Dyspnoea 15/181 (8.3%) 3/178 (1.7%)
Skin and subcutaneous tissue disorders
Pruritus 19/181 (10.5%) 2/178 (1.1%)
Rash 23/181 (12.7%) 8/178 (4.5%)
Vascular disorders
Hypotension 11/181 (6.1%) 4/178 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.

Results Point of Contact

Name/Title Clinical Disclosure Office
Organization Novartis Pharmaceuticals
Phone 862-778-8300
Email Novartis.email@novartis.com
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00824265
Other Study ID Numbers:
  • 110913
First Posted:
Jan 16, 2009
Last Update Posted:
Jun 18, 2020
Last Verified:
Jun 1, 2020