COMPLEMENT 1: Ofatumumab + Chlorambucil vs Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00748189
• Collaborator: (none)
• Enrollment: 447
• Locations: 154
• Arms: 2
• Actual Duration (Months): 112.8
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and efficacy of ofatumumab added to chlorambucil in patients with untreated Chronic Lymphocytic Leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukaemia, Lymphocytic, Chronic	Drug: chlorambucil, tablets; Drug: ofatumumab (GSK1841157) infusion	Phase 3

Detailed Description

Chlorambucil, is currently approved for treatment of frontline chronic lymphocytic leukemia, especially, but not limited to the ailing and elderly patient population. Several other more aggressive treatment options are available (e.g. fludarabine), however they are not suitable for all CLL patients, especially the ailing and elderly, due to greater toxicity. Ofatumumab is effective with low toxicity. The addition of ofatumumab to chlorambucil offers potentially a more effective therapy, with limited toxicity. The objective of this study was to evaluate progression-free survival (PFS), overall response and overall survival in subjects with previously untreated CLL with ofatumumab added to chlorambucil versus chlorambucil.

Study Design

• Study Type: Interventional
• Actual Enrollment: 447 participants
• Allocation: Randomized
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Open Label, Randomized, Multicenter Trial of Ofatumumab Added to Chlorambucil Versus Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia
• Actual Study Start Date: Dec 22, 2008
• Actual Primary Completion Date: Mar 20, 2013
• Actual Study Completion Date: May 17, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ofatumumab + chlorambucil ofatumumab dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days; chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 treatment cycles	Drug: chlorambucil, tablets; 2mg tablets, chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 cycles; Drug: ofatumumab (GSK1841157) infusion; iv infusion; dose: cycle 1 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1 every 28 days; Other Names: chlorambucil tablets
Active Comparator: chlorambucil chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 cycles	Drug: chlorambucil, tablets; 2mg tablets, chlorambucil dose: 10mg/m2 PO at days 1-7 every 28 days; duration: minimum of 3 cycles until best response or maximum of 12 cycles

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS), as Assessed by the Independent Review Committee (IRC) [From randomization to the date of first documented disease progression or death due to any cause, whichever occured first, reported between day of first patient randomized up to about 49 months]

   PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression (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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event or death occurred after extensive lost-to-follow-up time or if new anti-cancer therapy was started were censored at the date of the last visit with adequate assessment.

Secondary Outcome Measures

1. Number of Participants With the Best Overall Response (OR), as Assessed by the IRC [From randomization until the 259th PFS event occurred, up to about 49 months]

   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.

2. Number of Participants Who Were Negative for Minimal Residual Disease (MRD) [From randomization until the 259th PFS event occurred (Median follow-up approximately 28.9 months)]

   MRD 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.

3. Overall Survival [From randomization up to about 111 months]

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

4. Time to Response, as Assessed by the IRC [From randomization uo to about 27 months]

   Time to response is defined as the time from randomization to the first response (CR, CRi, nPR, or PR). 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. Participants with unknown or missing responses were considered as non-responders. Only responders (CR, CRi, PR, nPR) were included in the analysis.

5. Duration of Response (DOR), as Assessed by the IRC [From randomization up to about 43 months]

   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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time (>= 12 weeks) were censored at the date of the last visit with adequate assessment. Par. with unknown or missing responses were considered as non-responders.

6. Time to Progression, as Assessed by the IRC [From randomization up to about 49 months]

   Time to progression is defined as the time from the date of randomization to disease progression (PD). PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlarged 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. Participants who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time were censored at the date of the last visit with adequate assessment.

7. Time to Next Therapy [From randomization up to about 49 months]

   Time to next therapy is defined as the time from randomization until the start of the next-line of treatment.

8. Number of Participants With Improvement in ECOG Performance Status of 0 or 1 [Baseline, Cycle 3 Day 1, 1 month Follow-up]

   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. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead. Participants with an ECOG performance status of 0 or 1 are shown..

9. Number of Participants With Improvement in Constitutional Symptoms (CS) [Baseline, Cycle 3 Day 1, and 1 month Follow-up]

   Assessment for the presence of the following symptoms were performed at Screening, Day 1 of each treatment cycle and at every Follow-up visit: night sweats (without signs of infection); unexplained, unintentional weight loss >= 10% within the previous 6 months; recurrent, unexplained fever of greater than 38 degrees celsius or 100.5 degrees fahrenheit for 2 weeks; and extreme fatigue. The best response refers to overall best response in terms of CR, CRi, PR or nPR. Data are presented for constitutional response= yes and no.

10. Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result [Baseline, Cycle 4 Day 1, 1 Month Follow-up, and 6 Month Follow-up]

    Serum samples for analysis of HAHA were collected at Baseline (Screening), Cycle 4 Day 1 (after 3 months of treatment), and at 1 month and 6 months post last dose of ofatumumab. 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 and further evaluated in the titration test to obtain a titer of HAHA.

11. Cmax and Ctrough of Ofatumumab [Cycle 1 Day 1,Cycle 1 Day 8, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, and Cycle 9 Day 1]

    Blood samples were collected to assess the plasma concentration of ofatumumab. Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) were determined. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of treatment.

12. Total Plasma Clearance (CL) of Ofatumumab [Cycle 4 Day 1]

    Plasma clearance is defined as the plasma volume which is totally cleared of drug per unit of time. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.

13. AUC(0-tau) of Ofatumumab [Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1]

    Area under the concentration time curve over the dosing interval [AUC(0-tau)] is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the ofatumumab plasma concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of ofatumumab. For estimation of AUC(0-tau), blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hous after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.

14. Volume of Distribution at Steady State (Vss) of Ofatumumab [Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1]

    Volume of distribution at steady state (Vss) is defined as the distribution of a drug between plasma and the rest of the body at steady state. Blood samples were collected from participants who received ofatumumab plus chlorambucil at predose and 0.5 hour after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.

15. Plasma Half Life (t1/2) of Ofatumumab [Cycle 4 Day 1]

    The terminal half-life (t1/2) of ofatumumab is defined as the time required for the plasma concentration of ofatumumab to reach half of its original concentration. Blood samples were collected to assess the plasma half-life of ofatumumab. Blood samples were collected from participants who received ofatumumab plus chlorambucil pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.

16. Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM) [Cycle 3 Day 1]

    Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The maximum observed concentration (Cmax) of chlorambucil and PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].

17. Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM) [Cycle 3 Day 1]

    Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) and over 6 hours (AUC[0-6]) of chlorambucil and AUC(0-6) of PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].

18. Change From Baseline in Health Related Quality of Life (HRQOL) [Baseline, Cycle 4 day 1, cycle 7 day 1, 1 month follow-up, 6 month follow-up, 12 month follow-up]

    HRQOL was assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTCQLQC30), Chronic Lymphocytic Leukemia module (EORTC QLQ-CLL16), EuorQoL-Five Dimension (EQ-5D), and HCQ. Period (P)1 (Day 85, Day 169, Day 253) and P2 (scheduled follow-up (FU) and withdrawal visits) analysis were considered. Baseline (BL) for P1 was defined as score from screening visit and BL for P2 was defined as the last on-treatment score. The 2 principal QoL outcomes were pre-specified as the Global Health scale (GHS/QOL) of the EORTC QLQ-C30 and fatigue scale of the EORTC QLQ-CLL16. For EORTC QLQ-C30,GHS/Qol, the possible scale range was 0-100 (with 100 being 'best') and a positive difference from BL is indicative of better functioning (range -100 to +100). For the EORTC QLQ-CLL16 fatigue scale, the possible scale range was 0-100 (with 0 being 'best') and a negative difference from BL represents an improvement in fatigue (range -100 to +100).

19. Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) [From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.]

    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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

20. Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher [From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.]

    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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs. 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).

21. Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia) [From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.]

    Participants with a Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented by treatment cycle. 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).

22. Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease [From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.]

    AIHA is a disease 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 diagnosed with AIHA are presented.

23. Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study [From start of treatment to the last study visit/withdrawal visit (Median follow-up approximately 28.9 months)]

    Participants who received no transfusion and at least one transfusion during the study are presented. Participants who took any blood products are counted in this table.

24. Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM [From start of treatment up to 30 days after last treatment]

    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. IgA, IgG, and IgM were measured in the blood samples of the participants. Baseline IgA, IgG, and IgM values are the last pre-dose assessment values performed on Cycle 1 Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• confirmed CLL diagnosis and active CLL requiring treatment

• considered inappropriate for fludarabine-based therapy

• not been treated for CLL before

• 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

Exclusion Criteria:

• prior CLL therapy

• abnormal/inadequate blood values, liver, and kidney function

• certain heart problems, active or chronic infections, serious significant diseases, active autoimmune hemolytic anemia (AIHA) requiring treatment, other current cancer or within last 5 years

• 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	Sedona	Arizona	United States	86336
2	Novartis Investigative Site	Tucson	Arizona	United States	85704
3	Novartis Investigative Site	Murrieta	California	United States	92562
4	Novartis Investigative Site	Aurora	Colorado	United States	80012
5	Novartis Investigative Site	Denver	Colorado	United States	80204
6	Novartis Investigative Site	Boca Raton	Florida	United States	33486
7	Novartis Investigative Site	New Port Richey	Florida	United States	34655
8	Novartis Investigative Site	Ocala	Florida	United States	34471
9	Novartis Investigative Site	Ocoee	Florida	United States	34761
10	Novartis Investigative Site	Marietta	Georgia	United States	30060
11	Novartis Investigative Site	Chicago	Illinois	United States	60612
12	Novartis Investigative Site	Indianapolis	Indiana	United States	46227
13	Novartis Investigative Site	Lee's Summit	Missouri	United States	64064
14	Novartis Investigative Site	Raleigh	North Carolina	United States	27607
15	Novartis Investigative Site	Abilene	Texas	United States	79606-5208
16	Novartis Investigative Site	Arlington	Texas	United States	76014
17	Novartis Investigative Site	Austin	Texas	United States	78731
18	Novartis Investigative Site	Dallas	Texas	United States	75230
19	Novartis Investigative Site	Dallas	Texas	United States	75231
20	Novartis Investigative Site	Fort Worth	Texas	United States	76104
21	Novartis Investigative Site	Midland	Texas	United States	79701
22	Novartis Investigative Site	Odessa	Texas	United States	79761
23	Novartis Investigative Site	San Antonio	Texas	United States	78217
24	Novartis Investigative Site	San Antonio	Texas	United States	78229
25	Novartis Investigative Site	Tyler	Texas	United States	75702
26	Novartis Investigative Site	Waco	Texas	United States	76712
27	Novartis Investigative Site	Webster	Texas	United States	77598-4420
28	Novartis Investigative Site	Seattle	Washington	United States	98133
29	Novartis Investigative Site	Vancouver	Washington	United States	98684
30	Novartis Investigative Site	Yakima	Washington	United States	98902
31	Novartis Investigative Site	Brugge		Belgium	8000
32	Novartis Investigative Site	Bruxelles		Belgium	1200
33	Novartis Investigative Site	Gent		Belgium	9000
34	Novartis Investigative Site	Haine-Saint-Paul		Belgium	7100
35	Novartis Investigative Site	Leuven		Belgium	3000
36	Novartis Investigative Site	Porto Alegre	Rio De Janeiro	Brazil	91350-200
37	Novartis Investigative Site	Sao Paulo	São Paulo	Brazil	05403-000
38	Novartis Investigative Site	Sao Paulo	São Paulo	Brazil	05651-901
39	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
40	Novartis Investigative Site	Montreal	Quebec	Canada	H3A1A1
41	Novartis Investigative Site	Sherbrooke	Quebec	Canada	J1H 5N4
42	Novartis Investigative Site	Brno		Czechia	625 00
43	Novartis Investigative Site	Hradec Kralove		Czechia
44	Novartis Investigative Site	Praha 10		Czechia	100 34
45	Novartis Investigative Site	Creteil		France	94010
46	Novartis Investigative Site	Pierre Benite		France	69495
47	Novartis Investigative Site	Karlsruhe	Baden-Wuerttemberg	Germany	76137
48	Novartis Investigative Site	Mannheim	Baden-Wuerttemberg	Germany	68161
49	Novartis Investigative Site	Stuttgart	Baden-Wuerttemberg	Germany	70190
50	Novartis Investigative Site	Ulm	Baden-Wuerttemberg	Germany	89081
51	Novartis Investigative Site	Erlangen	Bayern	Germany	91052
52	Novartis Investigative Site	Muenchen	Bayern	Germany	81241
53	Novartis Investigative Site	Regensburg	Bayern	Germany	93049
54	Novartis Investigative Site	Wuerzburg	Bayern	Germany	97070
55	Novartis Investigative Site	Frankfurt	Hessen	Germany	65929
56	Novartis Investigative Site	Kassel	Hessen	Germany	34119
57	Novartis Investigative Site	Hannover	Niedersachsen	Germany	30625
58	Novartis Investigative Site	Lehrte	Niedersachsen	Germany	31275
59	Novartis Investigative Site	Essen	Nordrhein-Westfalen	Germany	45122
60	Novartis Investigative Site	Koeln	Nordrhein-Westfalen	Germany	50937
61	Novartis Investigative Site	Moenchengladbach-Rheydt	Nordrhein-Westfalen	Germany	41239
62	Novartis Investigative Site	Muenster	Nordrhein-Westfalen	Germany	48149
63	Novartis Investigative Site	Saarbruecken	Saarland	Germany	66113
64	Novartis Investigative Site	Athens,		Greece	11 527
65	Novartis Investigative Site	Thessaloniki		Greece	564 29
66	Novartis Investigative Site	Thessaloniki		Greece	57010
67	Novartis Investigative Site	Ahmedabad		India	380009
68	Novartis Investigative Site	Bangalore		India	560029
69	Novartis Investigative Site	Mumbai		India	400012
70	Novartis Investigative Site	Mumbai		India	400014
71	Novartis Investigative Site	New Delhi		India	110029
72	Novartis Investigative Site	Pune		India	411001
73	Novartis Investigative Site	Cork		Ireland
74	Novartis Investigative Site	Dublin		Ireland	7
75	Novartis Investigative Site	Galway		Ireland
76	Novartis Investigative Site	James Street		Ireland	8
77	Novartis Investigative Site	Limerick		Ireland
78	Novartis Investigative Site	Tullamore		Ireland
79	Novartis Investigative Site	Waterford		Ireland
80	Novartis Investigative Site	Potenza	Basilicata	Italy	85100
81	Novartis Investigative Site	Napoli	Campania	Italy	80131
82	Novartis Investigative Site	Albano Laziale (Roma)	Lazio	Italy	00041
83	Novartis Investigative Site	Genova	Liguria	Italy	16132
84	Novartis Investigative Site	Brescia	Lombardia	Italy	25123
85	Novartis Investigative Site	Milano	Lombardia	Italy	20132
86	Novartis Investigative Site	Milano	Lombardia	Italy	20133
87	Novartis Investigative Site	Milano	Lombardia	Italy	20162
88	Novartis Investigative Site	Ascoli Piceno	Marche	Italy	63100
89	Novartis Investigative Site	Novara	Piemonte	Italy	28100
90	Novartis Investigative Site	Bari	Puglia	Italy	70124
91	Novartis Investigative Site	Palermo	Sicilia	Italy	90146
92	Novartis Investigative Site	Venezia - Mestre	Veneto	Italy	30174
93	Novartis Investigative Site	Vicenza	Veneto	Italy	36100
94	Novartis Investigative Site	Udine		Italy	33100
95	Novartis Investigative Site	Amersfoort		Netherlands	3818 ES
96	Novartis Investigative Site	Amsterdam		Netherlands	1105 AZ
97	Novartis Investigative Site	Den Haag		Netherlands	2545 CH
98	Novartis Investigative Site	Groningen		Netherlands	9713 GZ
99	Novartis Investigative Site	Nijmegen		Netherlands	6525 GA
100	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
101	Novartis Investigative Site	Rotterdam		Netherlands	3075 EA
102	Novartis Investigative Site	Bialystok		Poland	15-276
103	Novartis Investigative Site	Chorzow		Poland	41-500
104	Novartis Investigative Site	Lodz		Poland	93-510
105	Novartis Investigative Site	Slupsk		Poland	76-200
106	Novartis Investigative Site	Warszawa		Poland	02-776
107	Novartis Investigative Site	Wroclaw		Poland	50-367
108	Novartis Investigative Site	Moscow		Russian Federation	115478
109	Novartis Investigative Site	Moscow		Russian Federation	125101
110	Novartis Investigative Site	Moscow		Russian Federation	125167
111	Novartis Investigative Site	Novosibirsk		Russian Federation	630051
112	Novartis Investigative Site	St'Petersburg		Russian Federation	191024
113	Novartis Investigative Site	St. Petersburg		Russian Federation	197 089
114	Novartis Investigative Site	Barcelona		Spain	08003
115	Novartis Investigative Site	Barcelona		Spain	08025
116	Novartis Investigative Site	Hospitalet de Llobregat (Barcelona)		Spain	08907
117	Novartis Investigative Site	Madrid		Spain	28006
118	Novartis Investigative Site	Madrid		Spain	28041
119	Novartis Investigative Site	Madrid		Spain	28046
120	Novartis Investigative Site	Salamanca		Spain	37007
121	Novartis Investigative Site	Valencia		Spain	46010
122	Novartis Investigative Site	Lulea		Sweden	SE-971 80
123	Novartis Investigative Site	Stockholm		Sweden	SE-141 86
124	Novartis Investigative Site	Uppsala		Sweden	SE-751 85
125	Novartis Investigative Site	Plymouth	Devon	United Kingdom	PL6 8DH
126	Novartis Investigative Site	Taunton	Somerset	United Kingdom	TA1 5DA
127	Novartis Investigative Site	Sunderland	Tyne	United Kingdom	SR4 7TP
128	Novartis Investigative Site	Bath		United Kingdom	BA1 3NG
129	Novartis Investigative Site	Belfast		United Kingdom	BT9 7AB
130	Novartis Investigative Site	Birmingham		United Kingdom	B9 5SS
131	Novartis Investigative Site	Bournemouth		United Kingdom	BH7 7DW
132	Novartis Investigative Site	Bradford		United Kingdom	BD9 6RJ
133	Novartis Investigative Site	Cambridge		United Kingdom	CB2 0QQ
134	Novartis Investigative Site	Canterbury, Kent		United Kingdom
135	Novartis Investigative Site	Carshalton		United Kingdom	SM5 1AA
136	Novartis Investigative Site	Cornwall		United Kingdom	TR1 3LJ
137	Novartis Investigative Site	Dudley		United Kingdom	DY1 2HQ
138	Novartis Investigative Site	Exeter		United Kingdom	EX2 5DW
139	Novartis Investigative Site	Glasgow		United Kingdom	G12 OYN
140	Novartis Investigative Site	Leeds		United Kingdom	LS9 7TF
141	Novartis Investigative Site	Liverpool		United Kingdom	L7 8XP
142	Novartis Investigative Site	London		United Kingdom	EC1M 6BQ
143	Novartis Investigative Site	London		United Kingdom	SE5 9RS
144	Novartis Investigative Site	Manchester		United Kingdom	M13 9WL
145	Novartis Investigative Site	Milton Keynes		United Kingdom	MK6 5LD
146	Novartis Investigative Site	Newcastle-upon-Tyne		United Kingdom	NE7 7DN
147	Novartis Investigative Site	Norwich		United Kingdom	NR4 7UY
148	Novartis Investigative Site	Oxford		United Kingdom	OX3 7LJ
149	Novartis Investigative Site	Peterborough		United Kingdom	PE3 9GZ
150	Novartis Investigative Site	Rhyl, Denbighshire		United Kingdom	LL18 5UJ
151	Novartis Investigative Site	Salford		United Kingdom	M6 8HD
152	Novartis Investigative Site	Stoke on Trent		United Kingdom	ST4 6QG
153	Novartis Investigative Site	Swindon		United Kingdom	SN3 6BB
154	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: NCT00748189
• Other Study ID Numbers: OMB110911; OMB110911
• First Posted: Sep 8, 2008
• Last Update Posted: Jun 25, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Novartis Pharmaceuticals: Safety; Untreated; Efficacy; Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia (CLL), untreated; Ofatumumab; Oncology
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Ofatumumab; Chlorambucil

Study Results

Participant Flow

Pre-assignment Detail	Eligible participants (par.) were stratified by age (<65 years vs. >=65years), stage (Binet A vs. B vs. C) and Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2). Participants in each stratum were then centrally randomized in a 1:1 ratio to receive ofatumumab plus chlorambucil (O+CHL) or chlorambucil alone (CHL).

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Period Title: Overall Study
STARTED	226	221
COMPLETED	10	9
NOT COMPLETED	216	212

Baseline Characteristics

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil	Total
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Total of all reporting groups
Overall Participants	226	221	447
Age, Customized (Years) [Median (Full Range) ]
Years	70	69	69
Sex: Female, Male (Count of Participants)
Female	86 38.1%	79 35.7%	165 36.9%
Male	140 61.9%	142 64.3%	282 63.1%
Race/Ethnicity, Customized (Count of Participants)
African American/African Heritage	2 0.9%	4 1.8%	6 1.3%
American Indian or Alaskan Native	1 0.4%	0 0%	1 0.2%
Asian - Central/South Asian Heritage	22 9.7%	19 8.6%	41 9.2%
Asian - Mixed Race	0 0%	2 0.9%	2 0.4%
White	201 88.9%	196 88.7%	397 88.8%

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 (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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event or death occurred after extensive lost-to-follow-up time or if new anti-cancer therapy was started were censored at the date of the last visit with adequate assessment.
Time Frame	From randomization to the date of first documented disease progression or death due to any cause, whichever occured first, reported between day of first patient randomized up to about 49 months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all par. randomized to study treatment regardless of whether or not they received treatment. PFS was assessed by a blinded independent review committee according to the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	226	221
Median (95% Confidence Interval) [Months]	13.1	22.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil, Ofatumumab + Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratios are obtained using the Pike estimator.

2. Secondary Outcome

Title	Number 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 until the 259th PFS event occurred, up to about 49 months

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed. OR was according to the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines. The 95% exact binomial confidence interval is for CR+CRi+nPR+PR.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	226	221
CR	3 1.3%	27 12.2%
CRi	0 0%	5 2.3%
nPR	0 0%	1 0.5%
PR	152 67.3%	149 67.4%

3. Secondary Outcome

Title	Number of Participants Who Were Negative for Minimal Residual Disease (MRD)
Description	MRD 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 until the 259th PFS event occurred (Median follow-up approximately 28.9 months)

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	226	221
MRD negative, irrespective of response	8 3.5%	26 11.8%
MRD negative, with an IRC-assessed CR	0 0%	10 4.5%

4. Secondary Outcome

Title	Overall Survival
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 total IRC-assessed PFS events occurred. Participants who had not died were censored at the date of last contact.
Time Frame	From randomization up to about 111 months

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	226	221
Median (95% Confidence Interval) [Months]	84.67	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil, Ofatumumab + Chlorambucil
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.363
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	hazard ratios are obtained using the Pike estimator. A hazard ratio <1 indicates a lower risk with O+CHL treatment compared with chlorambucil

5. 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 (CR, CRi, nPR, or PR). 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. Participants with unknown or missing responses were considered as non-responders. Only responders (CR, CRi, PR, nPR) were included in the analysis.
Time Frame	From randomization uo to about 27 months

Outcome Measure Data

Analysis Population Description

ITT population. Time to response was measured using the International Workshop for CLL (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines 2008.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	154	182
Median (95% Confidence Interval) [Months]	1.9	1.2

6. 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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time (>= 12 weeks) were censored at the date of the last visit with adequate assessment. Par. with unknown or missing responses were considered as non-responders.
Time Frame	From randomization up to about 43 months

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed. Only responders (CR, CRi, PR, nPR) were included in the analysis.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	154	182
Median (95% Confidence Interval) [Months]	13.2	22.1

7. 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 disease progression (PD). PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlarged 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. Participants who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time were censored at the date of the last visit with adequate assessment.
Time Frame	From randomization up to about 49 months

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	226	221
Median (95% Confidence Interval) [Months]	13.6	23.1

8. 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.
Time Frame	From randomization up to about 49 months

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	99	64
Median (95% Confidence Interval) [Months]	24.67	39.82

9. Secondary Outcome

Title	Number of Participants With Improvement in ECOG Performance Status of 0 or 1
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. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead. Participants with an ECOG performance status of 0 or 1 are shown..
Time Frame	Baseline, Cycle 3 Day 1, 1 month Follow-up

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). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	227	217
ECOG (0, 1) at Baseline	209 92.5%	200 90.5%
ECOG (0, 1) at Cycle 3 Day 1	184 81.4%	189 85.5%
ECOG (0, 1) 1 Month Follow-up	183 81%	191 86.4%

10. Secondary Outcome

Title	Number of Participants With Improvement in Constitutional Symptoms (CS)
Description	Assessment for the presence of the following symptoms were performed at Screening, Day 1 of each treatment cycle and at every Follow-up visit: night sweats (without signs of infection); unexplained, unintentional weight loss >= 10% within the previous 6 months; recurrent, unexplained fever of greater than 38 degrees celsius or 100.5 degrees fahrenheit for 2 weeks; and extreme fatigue. The best response refers to overall best response in terms of CR, CRi, PR or nPR. Data are presented for constitutional response= yes and no.
Time Frame	Baseline, Cycle 3 Day 1, and 1 month Follow-up

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). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	226	221
CS present, Baseline, n=226, 221	120 53.1%	118 53.4%
CS present, Cycle 3 Day 1, n=198, 199	44 19.5%	33 14.9%
CS present, 1 Month Follow-up, n=198, 200	23 10.2%	22 10%

11. Secondary Outcome

Title	Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result
Description	Serum samples for analysis of HAHA were collected at Baseline (Screening), Cycle 4 Day 1 (after 3 months of treatment), and at 1 month and 6 months post last dose of ofatumumab. 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 and further evaluated in the titration test to obtain a titer of HAHA.
Time Frame	Baseline, Cycle 4 Day 1, 1 Month Follow-up, and 6 Month Follow-up

Outcome Measure Data

Analysis Population Description

Safety population: all participants who received at least 1 dose of a study drug. Only participants with post-ofatumumab HAHA Results are included.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	0	217
Number [Participants]	0 0%

12. Secondary Outcome

Title	Cmax and Ctrough of Ofatumumab
Description	Blood samples were collected to assess the plasma concentration of ofatumumab. Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) were determined. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of treatment.
Time Frame	Cycle 1 Day 1,Cycle 1 Day 8, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, and Cycle 9 Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: all participants for whom a pharmacokinetic sample was obtained and analyzed.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for up to 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle up to 12 cycles in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for up to 12 cycles.
Measure Participants	0	193
Cmax, Cycle 1 Day 1, n=0, 176	51.8 (1.03)
Cmax, Cycle 1 Day 8, n=0, 193	241 (0.46)
Cmax, Cycle 4 Day 1, n=0, 169	285 (0.44)
Ctrough, Cycle 1 Day 8, n=0, 99	2.5 (5.85)
Ctrough, Cycle 2 Day 1, n=0, 138	5.2 (15.37)
Ctrough, Cycle 3 Day 1, n=0, 142	6.2 (17.06)
Ctrough, Cycle 4 Day 1, n=0, 147	15.5 (7.99)
Ctrough, Cycle 5 Day 1, n=0, 149	33.5 (3.61)
Ctrough, Cycle 6 Day 1, n=0, 155	45.9 (2.77)
Ctrough, Cycle 9 Day 1, n=0, 56	55.6 (3.50)

13. Secondary Outcome

Title	Total Plasma Clearance (CL) of Ofatumumab
Description	Plasma clearance is defined as the plasma volume which is totally cleared of drug per unit of time. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.
Time Frame	Cycle 4 Day 1

Outcome Measure Data

Analysis Population Description

PK Population.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for up to 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle up to 12 cycles in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for up to 12 cycles.
Measure Participants	0	183
Geometric Mean (Geometric Coefficient of Variation) [Milliliter/hour (mL/h)]	15.4 (0.73)

14. Secondary Outcome

Title	AUC(0-tau) of Ofatumumab
Description	Area under the concentration time curve over the dosing interval [AUC(0-tau)] is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the ofatumumab plasma concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of ofatumumab. For estimation of AUC(0-tau), blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hous after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.
Time Frame	Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1

Outcome Measure Data

Analysis Population Description

PK Population. Only those participants available at the indicated time points were assessed. The number of participants assessed at each time point is indicated by "n=X,X.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for up to 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle up to 12 cycles in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for up to 12 cycles.
Measure Participants	0	208
Cycle 1 Day 1, n=0, 193	2621 (0.76)
Cycle 1 Day 8, n=0, 208	25369 (0.87)
Cycle 4 Day 1, n=0, 183	65100 (0.73)

15. Secondary Outcome

Title	Volume of Distribution at Steady State (Vss) of Ofatumumab
Description	Volume of distribution at steady state (Vss) is defined as the distribution of a drug between plasma and the rest of the body at steady state. Blood samples were collected from participants who received ofatumumab plus chlorambucil at predose and 0.5 hour after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.
Time Frame	Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1

Outcome Measure Data

Analysis Population Description

PK Population. Only those participants available at the indicated time points were assessed. The number of participants assessed at each time point is indicated by "n=X,X.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for up to 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle up to 12 cycles in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for up to 12 cycles.
Measure Participants	0	208
Vss, Cycle 1 Day 1, n=0, 193	7.78 (0.55)
Vss, Cycle 1 Day 8, n=0, 208	7.77 (0.54)
Vss, Cycle 4 Day 1, n=0, 183	8.06 (0.53)

16. Secondary Outcome

Title	Plasma Half Life (t1/2) of Ofatumumab
Description	The terminal half-life (t1/2) of ofatumumab is defined as the time required for the plasma concentration of ofatumumab to reach half of its original concentration. Blood samples were collected to assess the plasma half-life of ofatumumab. Blood samples were collected from participants who received ofatumumab plus chlorambucil pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.
Time Frame	Cycle 4 Day 1

Outcome Measure Data

Analysis Population Description

PK Population

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for up to 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle up to 12 cycles in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for up to 12 cycles.
Measure Participants	0	183
Geometric Mean (Geometric Coefficient of Variation) [hours]	445 (1.05)

17. Secondary Outcome

Title	Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM)
Description	Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The maximum observed concentration (Cmax) of chlorambucil and PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].
Time Frame	Cycle 3 Day 1

Outcome Measure Data

Analysis Population Description

Chlorambucil/PAAM pharmacokinetic (PK) Population (substudy): all participants for whom a chlorambucil/PAAM sample is obtained and analyzed.

Arm/Group Title	Study OMB110911: Ofatumumab + Chlorambucil	Study LEUA1001: Chlorambucil
Arm/Group Description	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL, Non-Hodgkin's lymphoma or other refractory malignancies received three different formulations of a 0.2 mg/kilogram(kg) chlorambucil tablet orally with a two-day interval between drug administration.
Measure Participants	7	12
Chlorambucil Cmax/Dose	27.1 (0.32)	38.4 (0.36)
PAAM Cmax/Dose	19.3 (0.23)	24.3 (0.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil, Ofatumumab + Chlorambucil
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Comparability of dose-normalized chlorambucil Cmax values with ofatumumab in current study and without ofatumumab in prior study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Cmax/Dose
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 90%; 0.53 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of Cmax/Dose is the ratio of dose-normalized chlorambucil Cmax values when given with ofatumumab in the current study and without ofatumumab in the prior study (LEUA1001).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil, Ofatumumab + Chlorambucil
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Comparability of dose-normalized PAAM Cmax values with ofatumumab in current study and without ofatumumab in prior study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Cmax/Dose
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 90%; 0.63 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of Cmax/Dose is the ratio of dose-normalized PAAM Cmax values when given with ofatumumab in the current study and without ofatumumab in the prior study (LEUA1001).

18. Secondary Outcome

Title	Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM)
Description	Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) and over 6 hours (AUC[0-6]) of chlorambucil and AUC(0-6) of PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].
Time Frame	Cycle 3 Day 1

Outcome Measure Data

Analysis Population Description

Chlorambucil/PAAM pharmacokinetic (PK) Population (substudy): all participants for whom a chlorambucil/PAAM sample is obtained and analyzed.

Arm/Group Title	Study OMB110911: Ofatumumab + Chlorambucil	Study LEUA1001: Chlorambucil
Arm/Group Description	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL, Non-Hodgkin's lymphoma or other refractory malignancies received three different formulations of a 0.2 mg/kilogram(kg) chlorambucil tablet orally with a two-day interval between drug administration.
Measure Participants	7	12
Chlorambucil AUC(0-6)/Dose	67.84 (0.24)	65.43 (0.44)
Chlorambucil AUC(0-inf)/Dose	74.42 (0.23)	67.10 (0.45)
PAAM AUC(0-6)/Dose	71.52 (0.26)	80.32 (0.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil, Ofatumumab + Chlorambucil
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Comparability of dose-normalized chlorambucil AUC(0-6) values with ofatumumab in current study and without ofatumumab in prior study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of AUC(0-6)/Dose
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 90%; 0.77 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of AUC(0-6)/Dose is the ratio of dose-normalized chlorambucil AUC(0-6) values when given with ofatumumab in the current study and without ofatumumab in the prior study (LEUA1001).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil, Ofatumumab + Chlorambucil
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Comparability of dose-normalized chlorambucil AUC(0-inf) values with ofatumumab in current study and without ofatumumab in prior study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of AUC(0-inf)/Dose
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 90%; 0.82 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of AUC(0-inf)/Dose is the ratio of dose-normalized chlorambucil AUC(0-inf) values when given with ofatumumab in the current study and without ofatumumab in the prior study (LEUA1001).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Chlorambucil, Ofatumumab + Chlorambucil
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Comparability of dose-normalized PAAM AUC(0-6) values with ofatumumab in current study and without ofatumumab in prior study
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of AUC(0-6)/Dose
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 90%; 0.72 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of AUC(0-6)/Dose is the ratio of dose-normalized PAAM AUC(0-6) values when given with ofatumumab in the current study and without ofatumumab in the prior study (LEUA1001).

19. Secondary Outcome

Title	Change From Baseline in Health Related Quality of Life (HRQOL)
Description	HRQOL was assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTCQLQC30), Chronic Lymphocytic Leukemia module (EORTC QLQ-CLL16), EuorQoL-Five Dimension (EQ-5D), and HCQ. Period (P)1 (Day 85, Day 169, Day 253) and P2 (scheduled follow-up (FU) and withdrawal visits) analysis were considered. Baseline (BL) for P1 was defined as score from screening visit and BL for P2 was defined as the last on-treatment score. The 2 principal QoL outcomes were pre-specified as the Global Health scale (GHS/QOL) of the EORTC QLQ-C30 and fatigue scale of the EORTC QLQ-CLL16. For EORTC QLQ-C30,GHS/Qol, the possible scale range was 0-100 (with 100 being 'best') and a positive difference from BL is indicative of better functioning (range -100 to +100). For the EORTC QLQ-CLL16 fatigue scale, the possible scale range was 0-100 (with 0 being 'best') and a negative difference from BL represents an improvement in fatigue (range -100 to +100).
Time Frame	Baseline, Cycle 4 day 1, cycle 7 day 1, 1 month follow-up, 6 month follow-up, 12 month follow-up

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). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the ITT Population.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	226	221
P1, Cycle 4 Day 1, QLQC30 GHS/QoL score, n=139,159	1.92 (21.22)	6.08 (21.08)
P1, Cycle 7 Day 1, QLQC30 GHS/QoL score, n=52, 55	8.01 (22.20)	6.97 (17.55)
P1,Cycle 4 Day 1,QLQCLL16 fatigue score, n=145,163	-4.71 (27.48)	-4.60 (24.23)
P1, Cycle 7 Day 1,QLQCLL16 fatigue score, n=55,57	-1.21 (25.43)	-9.36 (22.93)
P2,1 month FU, QLQC30 GHS/QoL score, n=118, 150	4.79 (23.13)	0.56 (18.31)
P2, 6 month FU, QLQC30 GHS/QoL score, n=83, 129	3.01 (22.07)	3.75 (20.83)
P2, 12 month FU, QLQC30 GHS/QoL score, n=48, 96	3.82 (18.27)	1.22 (17.69)
P2, 1 month FU, QLQCLL16 fatigue score, n=121, 152	-1.24 (21.75)	-0.33 (19.13)
P2, 6 month FU, QLQCLL16 fatigue score, n=85, 131	-7.06 (18.96)	-2.93 (19.34)
P2, 12 month FU, QLQCLL16 fatigue score, n=51, 95	-2.94 (17.86)	0.88 (16.91)

20. 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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
Time Frame	From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	227	217
Any AE	205 90.7%	208 94.1%
Any SAE	84 37.2%	97 43.9%

21. Secondary Outcome

Title	Number of Participants With 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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs. 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 the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	227	217
Any AE, Grade 3	54 23.9%	67 30.3%
Any AE, Grade 4	31 13.7%	36 16.3%
Any AE, Grade 5	25 11.1%	36 16.3%
Any SAE, Grade 3	36 15.9%	34 15.4%
Any SAE, Grade 4	13 5.8%	19 8.6%
Any SAE, Grade 5	25 11.1%	36 16.3%

22. Secondary Outcome

Title	Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia)
Description	Participants with a Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented by treatment cycle. 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 the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	227	217
Number [Participants]	92 40.7%	83 37.6%

23. Secondary Outcome

Title	Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease
Description	AIHA is a disease 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 diagnosed with AIHA are presented.
Time Frame	From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	227	217
Number [Participants]	6 2.7%	4 1.8%

24. 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 are counted in this table.
Time Frame	From start of treatment to the last study visit/withdrawal visit (Median follow-up approximately 28.9 months)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	227	217
No transfusions	159 70.4%	168 76%
At least one transfusion	68 30.1%	49 22.2%

25. Secondary Outcome

Title	Mean Change From Baseline in the 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. IgA, IgG, and IgM were measured in the blood samples of the participants. Baseline IgA, IgG, and IgM values are the last pre-dose assessment values performed on Cycle 1 Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame	From start of treatment up to 30 days after last treatment

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). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.

Arm/Group Title	Chlorambucil	Ofatumumab + Chlorambucil
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.	Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Measure Participants	227	221
IgA, n=175, 186	0.047 (0.5706)	0.048 (0.4257)
IgG, n=175, 186	-0.458 (3.6177)	-0.268 (2.5430)
IgM n=175, 186	-0.398 (4.7864)	-0.031 (0.2507)

Adverse Events

Time Frame	Adverse Events and Serious Adverse Events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 111 months
Adverse Event Reporting Description	All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 111 months.
Arm/Group Title	Chlorambucil		Ofatumumab 1000 mg + Chlorambucil		Total
Arm/Group Description	Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.		Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.		All patients.
All Cause Mortality
	Chlorambucil		Ofatumumab 1000 mg + Chlorambucil		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	99/227 (43.6%)		84/217 (38.7%)		183/444 (41.2%)
Serious Adverse Events
	Chlorambucil		Ofatumumab 1000 mg + Chlorambucil		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/227 (25.1%)		53/217 (24.4%)		110/444 (24.8%)
Blood and lymphatic system disorders
Anaemia	5/227 (2.2%)		3/217 (1.4%)		8/444 (1.8%)
Autoimmune haemolytic anaemia	3/227 (1.3%)		0/217 (0%)		3/444 (0.7%)
Eosinophilia	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Febrile neutropenia	5/227 (2.2%)		3/217 (1.4%)		8/444 (1.8%)
Haemolysis	1/227 (0.4%)		1/217 (0.5%)		2/444 (0.5%)
Haemolytic anaemia	2/227 (0.9%)		0/217 (0%)		2/444 (0.5%)
Leukopenia	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Neutropenia	4/227 (1.8%)		6/217 (2.8%)		10/444 (2.3%)
Thrombocytopenia	3/227 (1.3%)		1/217 (0.5%)		4/444 (0.9%)
Cardiac disorders
Atrial fibrillation	0/227 (0%)		2/217 (0.9%)		2/444 (0.5%)
Atrioventricular block complete	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Cardiac arrest	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Cardiac failure	0/227 (0%)		2/217 (0.9%)		2/444 (0.5%)
Cardio-respiratory arrest	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Coronary artery disease	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Myocardial infarction	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Supraventricular tachycardia	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Gastrointestinal disorders
Aphthous ulcer	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Diarrhoea	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Gastritis	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Gastrointestinal haemorrhage	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Gastrooesophageal reflux disease	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Nausea	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Vomiting	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
General disorders
Inflammation	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Non-cardiac chest pain	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Pyrexia	1/227 (0.4%)		5/217 (2.3%)		6/444 (1.4%)
Vascular stent restenosis	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Hepatobiliary disorders
Cholestasis	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Hepatitis cholestatic	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Immune system disorders
Anaphylactic reaction	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Drug hypersensitivity	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Hypersensitivity	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Infections and infestations
Anal abscess	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Arthritis bacterial	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Cellulitis	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Empyema	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Gastroenteritis	1/227 (0.4%)		1/217 (0.5%)		2/444 (0.5%)
Haemophilus infection	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Herpes zoster	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Influenza	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Lower respiratory tract infection	1/227 (0.4%)		3/217 (1.4%)		4/444 (0.9%)
Lung infection	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Neutropenic sepsis	3/227 (1.3%)		2/217 (0.9%)		5/444 (1.1%)
Oral herpes	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Otitis media	1/227 (0.4%)		1/217 (0.5%)		2/444 (0.5%)
Pharyngitis bacterial	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Pneumococcal sepsis	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Pneumonia	11/227 (4.8%)		8/217 (3.7%)		19/444 (4.3%)
Pneumonia legionella	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Pneumonia staphylococcal	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Sepsis	0/227 (0%)		2/217 (0.9%)		2/444 (0.5%)
Septic shock	1/227 (0.4%)		1/217 (0.5%)		2/444 (0.5%)
Tuberculosis	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Urosepsis	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Injury, poisoning and procedural complications
Fall	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Infusion related reaction	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Injury	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Subarachnoid haemorrhage	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Subdural haematoma	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Traumatic ulcer	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Investigations
Haemoglobin decreased	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Hepatic enzyme increased	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
International normalised ratio increased	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Mycobacterium test	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Metabolism and nutrition disorders
Hyperglycaemia	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Tumour lysis syndrome	0/227 (0%)		2/217 (0.9%)		2/444 (0.5%)
Musculoskeletal and connective tissue disorders
Flank pain	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma pancreas	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Prostate cancer	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Nervous system disorders
Central nervous system haemorrhage	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Cerebellar ischaemia	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Cerebral ischaemia	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Cerebrovascular accident	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Cognitive disorder	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Dizziness	1/227 (0.4%)		1/217 (0.5%)		2/444 (0.5%)
Extrapyramidal disorder	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Headache	0/227 (0%)		2/217 (0.9%)		2/444 (0.5%)
Intracranial haematoma	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Peripheral sensory neuropathy	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Seizure	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Syncope	0/227 (0%)		2/217 (0.9%)		2/444 (0.5%)
Tremor	1/227 (0.4%)		1/217 (0.5%)		2/444 (0.5%)
Psychiatric disorders
Confusional state	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Renal and urinary disorders
Haematuria	0/227 (0%)		2/217 (0.9%)		2/444 (0.5%)
Hydronephrosis	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Nephrolithiasis	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Renal colic	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Renal failure	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Bronchiectasis	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Chronic obstructive pulmonary disease	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Dyspnoea	2/227 (0.9%)		2/217 (0.9%)		4/444 (0.9%)
Haemoptysis	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Hypoxia	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Pleural effusion	4/227 (1.8%)		2/217 (0.9%)		6/444 (1.4%)
Pneumonitis	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Pulmonary oedema	0/227 (0%)		2/217 (0.9%)		2/444 (0.5%)
Respiratory distress	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Respiratory failure	0/227 (0%)		4/217 (1.8%)		4/444 (0.9%)
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Dermatitis allergic	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Rash	2/227 (0.9%)		1/217 (0.5%)		3/444 (0.7%)
Rash maculo-papular	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Vascular disorders
Deep vein thrombosis	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Hypotension	0/227 (0%)		1/217 (0.5%)		1/444 (0.2%)
Peripheral artery stenosis	1/227 (0.4%)		0/217 (0%)		1/444 (0.2%)
Other (Not Including Serious) Adverse Events
	Chlorambucil		Ofatumumab 1000 mg + Chlorambucil		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	175/227 (77.1%)		183/217 (84.3%)		358/444 (80.6%)
Blood and lymphatic system disorders
Anaemia	27/227 (11.9%)		16/217 (7.4%)		43/444 (9.7%)
Leukopenia	4/227 (1.8%)		14/217 (6.5%)		18/444 (4.1%)
Neutropenia	36/227 (15.9%)		57/217 (26.3%)		93/444 (20.9%)
Thrombocytopenia	56/227 (24.7%)		30/217 (13.8%)		86/444 (19.4%)
Gastrointestinal disorders
Abdominal pain upper	5/227 (2.2%)		11/217 (5.1%)		16/444 (3.6%)
Constipation	13/227 (5.7%)		10/217 (4.6%)		23/444 (5.2%)
Diarrhoea	31/227 (13.7%)		38/217 (17.5%)		69/444 (15.5%)
Nausea	57/227 (25.1%)		43/217 (19.8%)		100/444 (22.5%)
Vomiting	24/227 (10.6%)		23/217 (10.6%)		47/444 (10.6%)
General disorders
Asthenia	11/227 (4.8%)		18/217 (8.3%)		29/444 (6.5%)
Chills	1/227 (0.4%)		18/217 (8.3%)		19/444 (4.3%)
Fatigue	40/227 (17.6%)		35/217 (16.1%)		75/444 (16.9%)
Oedema peripheral	12/227 (5.3%)		15/217 (6.9%)		27/444 (6.1%)
Pyrexia	18/227 (7.9%)		36/217 (16.6%)		54/444 (12.2%)
Infections and infestations
Bronchitis	10/227 (4.4%)		11/217 (5.1%)		21/444 (4.7%)
Nasopharyngitis	19/227 (8.4%)		9/217 (4.1%)		28/444 (6.3%)
Upper respiratory tract infection	16/227 (7%)		12/217 (5.5%)		28/444 (6.3%)
Injury, poisoning and procedural complications
Infusion related reaction	0/227 (0%)		17/217 (7.8%)		17/444 (3.8%)
Metabolism and nutrition disorders
Decreased appetite	20/227 (8.8%)		13/217 (6%)		33/444 (7.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/227 (3.5%)		11/217 (5.1%)		19/444 (4.3%)
Back pain	12/227 (5.3%)		11/217 (5.1%)		23/444 (5.2%)
Nervous system disorders
Dizziness	15/227 (6.6%)		10/217 (4.6%)		25/444 (5.6%)
Headache	7/227 (3.1%)		18/217 (8.3%)		25/444 (5.6%)
Psychiatric disorders
Insomnia	17/227 (7.5%)		12/217 (5.5%)		29/444 (6.5%)
Respiratory, thoracic and mediastinal disorders
Cough	25/227 (11%)		33/217 (15.2%)		58/444 (13.1%)
Dyspnoea	10/227 (4.4%)		25/217 (11.5%)		35/444 (7.9%)
Skin and subcutaneous tissue disorders
Erythema	2/227 (0.9%)		11/217 (5.1%)		13/444 (2.9%)
Hyperhidrosis	5/227 (2.2%)		12/217 (5.5%)		17/444 (3.8%)
Pruritus	11/227 (4.8%)		26/217 (12%)		37/444 (8.3%)
Rash	21/227 (9.3%)		53/217 (24.4%)		74/444 (16.7%)
Urticaria	2/227 (0.9%)		22/217 (10.1%)		24/444 (5.4%)
Vascular disorders
Flushing	1/227 (0.4%)		11/217 (5.1%)		12/444 (2.7%)
Hypertension	1/227 (0.4%)		11/217 (5.1%)		12/444 (2.7%)
Hypotension	2/227 (0.9%)		12/217 (5.5%)		14/444 (3.2%)

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.