Comparison of the Treatments of Obinutuzumab + Venetoclax Versus Obinutuzumab + Chlorambucil in Patients With Chronic Lymphocytic Leukemia

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02242942
• Collaborator: AbbVie (Industry), German CLL Study Group (Other)
• Enrollment: 445
• Locations: 137
• Arms: 3
• Anticipated Duration (Months): 128
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This open-label, multicenter, randomized Phase III study is designed to compare the efficacy and safety of a combined regimen of obinutuzumab and venetoclax versus obinutuzumab + chlorambucil in participants with chronic lymphocytic leukemia (CLL) and coexisting medical conditions. The time on study treatment was approximately one year and the follow-up period will be up to 9 years.

Condition or Disease	Intervention/Treatment	Phase
Lymphocytic Leukemia, Chronic	Drug: Chlorambucil; Drug: Venetoclax; Drug: Obinutuzumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 445 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions
• Actual Study Start Date: Dec 31, 2014
• Actual Primary Completion Date: Aug 17, 2018
• Anticipated Study Completion Date: Aug 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Safety Run-in Obinutuzumab + Venetoclax Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.	Drug: Venetoclax; Venetoclax, oral tablet: 20 mg daily during Cycle 1, Day 22-28; 50 mg daily during Cycle 2, Day 1-7; 100 mg daily during Cycle 2, Day 8-14; 200 mg daily during Cycle 2, Day 15-21; 400 mg daily during Cycle 2, Day 22-28 and on Day 1-28 for all subsequent cycles until the end of Cycle 12.; Other Names: ABT-0199, GDC-0199 ; Drug: Obinutuzumab; Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6; Other Names: GA-101; Gazyva
Experimental: Obinutuzumab + Chlorambucil Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Drug: Chlorambucil; Chlorambucil 0.5 milligrams per kilogram (mg/kg) orally at Day 1 and Day 15 at of each 28 day cycle for 12 cycles.; Drug: Obinutuzumab; Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6; Other Names: GA-101; Gazyva
Experimental: Obinutuzumab + Venetoclax Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.	Drug: Venetoclax; Venetoclax, oral tablet: 20 mg daily during Cycle 1, Day 22-28; 50 mg daily during Cycle 2, Day 1-7; 100 mg daily during Cycle 2, Day 8-14; 200 mg daily during Cycle 2, Day 15-21; 400 mg daily during Cycle 2, Day 22-28 and on Day 1-28 for all subsequent cycles until the end of Cycle 12.; Other Names: ABT-0199, GDC-0199 ; Drug: Obinutuzumab; Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6; Other Names: GA-101; Gazyva

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria [Baseline until disease progression or death up to approximately 3.75 years]

   PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.

Secondary Outcome Measures

1. Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria [Baseline until disease progression or death up to approximately 3.75 years]

   PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.

2. Percentage of Participants With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria [At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)]

   OR was defined as complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.

3. Percentage of Participants With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria [At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)]

   CRR was defined as the rate of a clinical response of CR or CRi according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri).

4. Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment [At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)]

   MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood.

5. Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Treatment [At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)]

   MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow.

6. Overall Survival (OS) [Baseline until death, up to approximately 10.75 years]

   OS was defined as the time between the date of randomization and the date of death due to any cause.

7. Percentage of Participants With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment [Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months]

   MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood.

8. Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment [Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months]

   MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow.

9. Percentage of Participants With OR at Completion of Combination Treatment Response Assessment [Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months]

   OR was defined as CR, CRi or PR according to IWCLL 2008 criteria. CR required all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.

10. Duration of Objective Response (DOR) [Time from the first occurrence of a documented objective response to the time of PD as determined by the investigator or death from any cause, up to approximately 10.75 years]

    PD was defined as lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia.

11. Percentage of Participants By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD) [Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months)]

    CR: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: any two for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PD: lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. SD: a non-response and used to characterize participants who did not achieve a CR or a PR, and who have not exhibited PD.

12. Event-Free Survival [Time between date of randomization and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 10.75 years]

13. Time to Next Anti-Leukemic Treatment [Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 10.75 years]

14. Number of Participants With Adverse Events (AEs) [Up to approximately 10.75 years]

    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs.

15. Percentage of Participants With CD19 + /CD5+ B Cells or CD14+ Monocytes [Baseline up to approximately 10.75 years]

16. Percentage of Participants With Human-Anti-Human Antibodies [Baseline up to approximately 10.75 years]

17. Percentage of Participants Recorded as Premature Study Withdrawals [Up to approximately 10.75 years]

18. Plasma Concentrations of Venetoclax [Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4]

19. Serum Concentrations of Obinutuzumab [Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4]

20. Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score [Baseline up to approximately 10.75 years]

    The MDASI-CLL is a questionnaire of 25 items related to CLL specific symptoms that a participant may have experienced in the past 24 hours. Participants were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, and numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, and constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, and enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is "not present" or "did not interfere" with the participant's activities and 10 indicating "as bad as you can imagine" or "interfered completely". Scores were averaged (range 0 to 10) for each of three parts.

21. Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30) [Baseline up to approximately 10.75 years]

    The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality-of-life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from "not at all" to "very much," and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from "very poor" to "excellent." Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).

22. Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L) [Baseline up to approximately 10.75 years]

    The EQ-5D-3L questionnaire is a generic, preference based health utility measure that assesses 5 health states (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and is used to build a composite of the patient's health status. The EQ-5D-3L was employed in this study to calculate health utilities for economic modeling, which ranged 0-1. The EQ-5D-3L also contained a visual analog scale (VAS) to assess the participant's overall health, which ranged from 0-100 with a higher score indicating a worse health status.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Documented previously untreated CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria

• CLL requiring treatment according to IWCLL criteria

• Total Cumulative Illness Rating Scale (CIRS score) greater than (>) 6

• Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as per protocol, unless cytopenia is due to marrow involvement of CLL

• Adequate liver function

• Life expectancy > 6 months

• Agreement to use highly effective contraceptive methods per protocol

Exclusion Criteria:

• Transformation of CLL to aggressive Non-Hodgkin's lymphoma (Richter's transformation or pro-lymphocytic leukemia)

• Known central nervous system involvement

• Participants with a history of confirmed progressive multifocal leukoencephalopathy (PML)

• An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system

• Participants with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia

• Inadequate renal function

• History of prior malignancy, except for conditions as listed in the protocol if participants have recovered from the acute side effects incurred as a result of previous therapy

• Use of investigational agents or concurrent anti-cancer treatment within the last 4 weeks of registration

• Participants with active bacterial, viral, or fungal infection requiring systemic treatment within the last two months prior to registration

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products

• Hypersensitivity to chlorambucil, obinutuzumab, or venetoclax or to any of the excipients

• Pregnant women and nursing mothers

• Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] serology) or positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing)

• Participants with known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus-1 (HTLV-1)

• Requires the use of warfarin, marcumar, or phenprocoumon

• Received agents known to be strong and moderate Cytochrome P450 3A inhibitors or inducers within 7 days prior to the first dose of study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	San Diego Pacific Hematology Assocates	Encinitas	California	United States	92024-1375
3	UC San Diego Health System	La Jolla	California	United States	92093
4	Banner MD Anderson Cancer Center	Greeley	Colorado	United States	85234
5	Moffitt Cancer Center	Tampa	Florida	United States	33612
6	Winship Cancer Institute	Atlanta	Georgia	United States	30322
7	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
8	Henry Ford Hospital	Detroit	Michigan	United States	48202
9	Joe Arrington Cancer Center	Lubbock	Texas	United States	79410
10	Hospital Italiano	Buenos Aires		Argentina	C1181ACH
11	Liverpool Hospital	Liverpool	New South Wales	Australia	2170
12	Tweed Hospital	Tweed Heads	New South Wales	Australia	2485
13	The Townsville Hospital	Douglas	Queensland	Australia	4814
14	Princess Alexandra Hospital Woolloongabba; Clinical Hematology and Medical Oncology	Woolloongabba	Queensland	Australia	4102
15	Royal Adelaide Hospital; Haematology Clinical Trials	Adelaide	South Australia	Australia	5000
16	Ashford Cancer Centre Research; Internal Medicine/Medical Oncology	Ashford	South Australia	Australia	5035
17	Box Hill Hospital	Box Hill	Victoria	Australia	3128
18	The Northern Hospital	Epping	Victoria	Australia	VIC 3076
19	Monash Medical Centre; Haematology	Melbourne	Victoria	Australia	3168
20	Tiroler Landeskrankenanstalten Ges.M.B.H.; Innere Medizin Abt. Für Hämatologie & Onkologie	Innsbruck		Austria	6020
21	Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Hämatologie & Hämostaseologie	Wien		Austria	1090
22	Hanusch-Krankenhaus; Iii. Medizinische Abt.	Wien		Austria	1140
23	Wilhelminenspital; I. Medizinische Abt.	Wien		Austria	1160
24	Hospital das Clinicas - UFRGS	Porto Alegre	RS	Brazil	90035-903
25	Instituto de Ensino e Pesquisa Sao Lucas - IEP	Sao Paulo	SP	Brazil	01236-030
26	Hospital Sírio-Libanês	Sao Paulo	SP	Brazil	01308-050
27	Hospital das Clinicas - FMUSP	Sao Paulo	SP	Brazil	05403-900
28	Hospital Santa Marcelina	Sao Paulo	SP	Brazil	08270-070
29	UMHAT Dr Georgi Stranski; Hematology	Pleven		Bulgaria	5800
30	UMHAT " Sveti Georgi" Plovdiv - Clinic of Oncology and Hematology	Plovdiv		Bulgaria	4002
31	University Hospital Sv.Georgi Clnic of Hematology; Hematology	Plovdiv		Bulgaria	4002
32	University Multiprofile Hospital For Active Treatment "Sveti Ivan Rilski" EAD; clinical hematology	Sofia		Bulgaria	1431
33	MHAT Hristo Botev; First Internal Department	Vratsa		Bulgaria	3000
34	Tom Baker Cancer Centre; Dept of Medicine	Calgary	Alberta	Canada	T2N 4N2
35	Queen Elizabeth II Health Sciences Centre; Oncology	Halifax	Nova Scotia	Canada	B3H 2Y9
36	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
37	University Hospital Center Zagreb; Haematology Department	Zagreb		Croatia	10000
38	University Hospital Merkur Clinic for Internal Medicine/ Hematology	Zagreb		Croatia	10000
39	Herlev Hospital	Herlev		Denmark	2730
40	Rigshospitalet	København Ø		Denmark	2100
41	Sjællands Universitetshospital, Roskilde	Roskilde		Denmark	4000
42	Sygehus Lillebælt, Vejle	Vejle		Denmark	7100
43	North Estonia medical Centre; Hematology	Tallinn		Estonia	13419
44	Tartu Uni Hospital; Hematology - Oncology Clinic	Tartu		Estonia	51014
45	CHU Besançon - Hôpital Jean Minjoz	Besançon Cedex		France	25030
46	Institut d'Hématologie de Basse Normandie	Caen		France	14000
47	Chu Estaing; Hematologie Clinique Adultes	Clermont Ferrand		France	63003
48	Hopital Henri Mondor	Creteil		France	94000
49	CHU de Dijon - Hopital le Bocage	Dijon		France	21000
50	CHU de Grenoble	Grenoble		France	38043
51	Centre Jean Bernard	Le Mans		France	72015
52	Centre Leon Berard; Departement Oncologie Medicale	Lyon		France	69373
53	Hôpital Saint Eloi; Service d'Hématologie et Oncologie Clinique - Recherche Clinique	Montpellier		France	34295
54	Hopital Hotel Dieu Et Hme;Hopital De Jour	Nantes		France	44093
55	Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)	Paris		France	75475
56	Hopital Pontchaillou; Hematologie Clinique	Rennes		France	35033
57	Centre Henri Becquerel; Hematologie	Rouen		France	76038
58	CH de Toulon Hôpital Sainte Musse	Toulon		France	83056
59	Institut Gustave Roussy - Hematologie	Villejuif		France	94805
60	Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.	Aachen		Germany	52074
61	Gesundheitszentrum St. Marien GmbH; Med. II, Hämatologie/Onkologie	Amberg		Germany	92224
62	Charite - Universitätsmedizin Berlin	Berlin		Germany	12203
63	Charite - Campus Virchow-Klinikum	Berlin		Germany	13353
64	BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie	Dresden		Germany	01307
65	Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik und Poliklinik I	Dresden		Germany	01307
66	Universitätsklinikum Essen; Klinik für Hämatologie	Essen		Germany	45122
67	Klinik Esslingen; Klinik für Allgemeine Innere Medizin, Onkologie/Haematologie	Esslingen		Germany	73730
68	Klinikum Frankfurt/Oder	Frankfurt/Oder		Germany	15236
69	Uniklinikum Freiburg	Freiburg		Germany	79106
70	Uni Göttingen, Georg-August-Universität; Klinik für Hämatologie und Medizinische Onkologie	Göttingen		Germany	37075
71	Universitaetsklinikum Heidelberg	Heidelberg		Germany	69120
72	Stiftung Kathol. Krankenhaus Marienhospital Herne Klinik Mitte	Herne		Germany	44625
73	Praxisklinik für Hämatologie und Onkologie Koblenz	Koblenz		Germany	56068
74	Universitätsklinikum Köln; Innere Medizin I; Onkologie, Hämatologie	Köln		Germany	50931
75	Tagesklinik Landshut; Hämatologie/Onkologie	Landshut		Germany	84028
76	Klinikum rechts der Isar der Technischen Universität München	Munchen		Germany	81675
77	Klinikum Schwäbisch Gmünd	Mutlangen		Germany	73557
78	Kliniken Maria Hilf GmbH; Innere Medizin I; Hämatologie und internistische Onkologie	Mönchengladbach		Germany	41063
79	München Klinik Schwabing; Klinik für Hämatologie, Onkologie, Immunologie	München		Germany	80804
80	Klinikum der Universität München, Campus Großhadern; Medizinische Klinik und Poliklinik III	München		Germany	81377
81	Gemeinschaftspraxis Dr. med. Holger Klaproth	Neunkirchen/Saar		Germany	66538
82	Brüderkrankenhaus St. Josef Paderborn	Paderborn		Germany	33098
83	Krankenhaus Barmherzige Bruder Regensburg	Regensburg		Germany	93049
84	Marienhospital	Stuttgart		Germany	70199
85	Robert-Bosch-Krankenhaus	Stuttgart		Germany	70376
86	Universitätsklinikum Tübingen	Tübingen		Germany	72076
87	Universtitätsklinikum Ulm; Klinik für Innere Medizin III	Ulm		Germany	89081
88	Medizinisches Versorgungszentrum Nuklearmedizin-Strahlentherapie-Onkologie	Weiden		Germany	92367
89	Arcispedale S. Anna; Sezione Di Ematologia	Ferrara	Emilia-Romagna	Italy	44100
90	Ospedali Riuniti Papardo-Piemonte; Struttura Complessa Di Ematologia	Messina	Lazio	Italy	98158
91	Uni Cattolica; Divisione Di Ematologia	Roma	Lazio	Italy	00168
92	AOU Città della Salute e della Scienza di Torino - Presidio Le Molinette	Torino	Lazio	Italy	10126
93	Ospedale San Raffaele	Milano	Lombardia	Italy	20132
94	Az. Osp. S. Maria; Dept. Di Oncologia Medica	Terni	Umbria	Italy	05100
95	Ospedale dell' Angelo; U.O. Ematologia	Venezia Mestre	Veneto	Italy	30174
96	Hospital General de Culiacan	Culiacan		Mexico	80230
97	Canterbury Health Laboratories; Haematology	Christchurch		New Zealand	8011
98	Dunedin Hospital	Dunedin		New Zealand
99	Midcentral District Health Board	Palmerston North		New Zealand	4442
100	Wellington Hospital	Wellington		New Zealand	6012
101	Uniwersytecki Szpital Kliniczny w Białymstoku, Klinika Hematologii z Pododdziałem Chorob Naczyn	Bialystok		Poland	15-2
102	Samodzielny Public Zaklad	Chorzów		Poland	41-500
103	Wojewódzki Szpital Specjalistyczny im.MikołajaKopernika;KlinikaHematologiiUniwersytetuMedycznego	Lodz		Poland	9351
104	Wojewodzki Szpital Specjalistyczny im. J. Korczaka; Oddział Chorób Wewnetrznych/Hematologiczny	Slupsk		Poland	76-200
105	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wrocławiu; Klinika Hematologii	Wroclaw		Poland	5036
106	Fundeni Clinical Inst. ; Hematology Dept	Bucharest		Romania	022328
107	Institutul Regional de Oncologie Iasi; Clinica de Hematologie	Iasi		Romania	700483
108	Spitalul Clinic Judetean de Urgenta Targu-Mures; compartiment Hematologie	Targu-mures		Romania	540136
109	Republican Clinical Oncologic Dispensary of Republic Of Tatarstan	Kazan		Russian Federation	420029
110	Moscow State Budgetary Healthcare Institution	Moscow		Russian Federation	123182
111	Regional Clinical Hospital N.A. Semashko; Hematology	Nizhny Novgorod		Russian Federation	603126
112	Penza Regional Oncology Dispensary	Penza		Russian Federation	440071
113	Clinical MSCh No1	Perm		Russian Federation	614077
114	Rostov State Medical Uni ; Hematology	Rostov-na-donu		Russian Federation	344022
115	SBEI of HPE "Bashkir State Medical University" of MoH RF	Ufa		Russian Federation	450000
116	Complejo Hospitalario de Navarra	Pamplona	Navarra	Spain	31008
117	Hospital Universitario de Canarias;servicio de Hematologia	La Laguna	Tenerife	Spain	38320
118	Hospital del Mar; Servicio de Hematologia	Barcelona		Spain	08003
119	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona		Spain	08035
120	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona		Spain	08036
121	Hospital Universitario de la Princesa; Servicio de Hematologia	Madrid		Spain	28006
122	Hospital Universitario La Paz	Madrid		Spain	28034
123	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
124	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid		Spain	28041
125	Hospital Clinico Universitario de Salamanca;Servicio de Hematologia	Salamanca		Spain	37007
126	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
127	Complejo Hospitalario de Toledo- H. Virgen de la Salud; Servicio de Hematología	Toledo		Spain	45004
128	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia		Spain	46010
129	Hospital Arnau de Vilanova (Valencia) Servicio de Hematologia	Valencia		Spain	46015
130	Inselspital Bern; Hämatologie und Hämatologisches Zentrallabor	Bern		Switzerland	3010
131	Luzerner Kantonsspital, Hämatologie	Luzern		Switzerland	6000
132	Universitätsspital Zürich Medizin Hämatologie; Klinik für Hämatologie	Zürich		Switzerland	8091
133	Birmingham Heartlands Hospital	Birmingham		United Kingdom	B9 5SS
134	Boston Pilgrim Hospital	Boston,Lincolnshire		United Kingdom	PE21 9QS
135	Western General Hospital; Department of Haematology	Edinburgh		United Kingdom	EH4 2XU
136	Lincoln County Hospital	Lincoln		United Kingdom	LN2 5QY
137	University Hospital Southampton NHS Foundation Trust	Southhampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Hoffmann-La Roche
• AbbVie
• German CLL Study Group

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Feb 12, 2018
• Statistical Analysis Plan - Nov 8, 2018

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02242942
• Other Study ID Numbers: BO25323; 2014-001810-24; CLL14
• First Posted: Sep 17, 2014
• Last Update Posted: Jun 30, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Venetoclax; Obinutuzumab; Chlorambucil

Study Results

Participant Flow

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.	Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.
Period Title: Overall Study
STARTED	216	216	13
Treated	214	212	13
COMPLETED	0	0	0
NOT COMPLETED	216	216	13

Baseline Characteristics

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax	Safety Run-in Obinutuzumab + Venetoclax	Total
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.	Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.	Total of all reporting groups
Overall Participants	216	216	13	445
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	71.1 (8.0)	71.1 (8.2)	75.4 (7.8)	71.1 (8.1)
Sex: Female, Male (Count of Participants)
Female	73 33.8%	70 32.4%	5 38.5%	148 33.3%
Male	143 66.2%	146 67.6%	8 61.5%	297 66.7%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	20 9.3%	22 10.2%	1 7.7%	43 9.7%
Not Hispanic or Latino	172 79.6%	165 76.4%	12 92.3%	349 78.4%
Not Stated	19 8.8%	22 10.2%	0 0%	41 9.2%
Unknown	5 2.3%	7 3.2%	0 0%	12 2.7%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	1 0.5%	0 0%	0 0%	1 0.2%
Black or African American	3 1.4%	1 0.5%	0 0%	4 0.9%
Native Hawaiian or other Pacific Islande	0 0%	3 1.4%	0 0%	3 0.7%
Unknown	18 8.3%	20 9.3%	0 0%	38 8.5%
White	194 89.8%	192 88.9%	13 100%	399 89.7%

Outcome Measures

1. Secondary Outcome

Title	Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria
Description	PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.
Time Frame	Baseline until disease progression or death up to approximately 3.75 years

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised 28 days.	Participants received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised 28 days.
Measure Participants	216	216
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratios were estimated by Cox regression model. Stratification factors: Binet and Geographic region.

2. Primary Outcome

Title	Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria
Description	PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.
Time Frame	Baseline until disease progression or death up to approximately 3.75 years

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised 28 days.	Participants received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised 28 days.
Measure Participants	216	216
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.23 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratios were estimated by Cox regression model. Stratification factors: Binet and Geographic region.

3. Secondary Outcome

Title	Percentage of Participants With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria
Description	OR was defined as complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.
Time Frame	At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised 28 days.	Participants received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised 28 days.
Measure Participants	216	216
Number (95% Confidence Interval) [percentage of participants]	71.3 33%	84.7 39.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	P-value was assessed using Cochran-Mantel-Haenszel (CMH) test stratified by the IvRS randomization stratification factors.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in Response Rates
	Estimated Value	13.43
	Confidence Interval	(2-Sided) 95%; 5.47 to 21.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% Confidence Interval (CI) for difference in rates were constructed using Anderson-Hauck method.

4. Secondary Outcome

Title	Percentage of Participants With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria
Description	CRR was defined as the rate of a clinical response of CR or CRi according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri).
Time Frame	At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised 28 days.	Participants received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised 28 days.
Measure Participants	216	216
Number (95% Confidence Interval) [percentage of participants]	23.1 10.7%	49.5 22.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was assessed using CMH test stratified by the IvRS randomization stratification factors.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in Response Rates
	Estimated Value	26.39
	Confidence Interval	(2-Sided) 95%; 17.41 to 35.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for difference in rates were constructed using Anderson-Hauck method.

5. Secondary Outcome

Title	Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment
Description	MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood.
Time Frame	At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Measure Participants	216	216
Number (95% Confidence Interval) [percentage of participants]	35.2 16.3%	75.5 35%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in MRD Negative Rates
	Estimated Value	40.28
	Confidence Interval	(2-Sided) 95%; 31.45 to 49.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for difference in rates were constructed using Anderson-Hauck method.

6. Secondary Outcome

Title	Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Treatment
Description	MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow.
Time Frame	At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Measure Participants	216	216
Number (95% Confidence Interval) [percentage of participants]	17.1 7.9%	56.9 26.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in MRD Negative Rates
	Estimated Value	39.81
	Confidence Interval	(2-Sided) 95%; 31.27 to 48.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for difference in rates were constructed using Anderson-Hauck method.

7. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time between the date of randomization and the date of death due to any cause.
Time Frame	Baseline until death, up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Percentage of Participants With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment
Description	MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood.
Time Frame	Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Measure Participants	216	216
Number (95% Confidence Interval) [percentage of participants]	38.4 17.8%	71.3 33%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in MRD Negative Rates
	Estimated Value	32.87
	Confidence Interval	(2-Sided) 95%; 23.76 to 41.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for difference in rates were constructed using Anderson-Hauck method.

9. Secondary Outcome

Title	Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment
Description	MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow.
Time Frame	Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Measure Participants	216	216
Number (95% Confidence Interval) [percentage of participants]	13.0 6%	51.4 23.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in MRD Negative Rates
	Estimated Value	38.43
	Confidence Interval	(2-Sided) 95%; 30.15 to 46.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for difference in rates were constructed using Anderson-Hauck method.

10. Secondary Outcome

Title	Percentage of Participants With OR at Completion of Combination Treatment Response Assessment
Description	OR was defined as CR, CRi or PR according to IWCLL 2008 criteria. CR required all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.
Time Frame	Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Measure Participants	216	216
Number (95% Confidence Interval) [percentage of participants]	86.6 40.1%	88.4 40.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5612
	Comments	P-value was assessed using Cochran-Mantel-Haenszel (CMH) test stratified by the IvRS randomization stratification factors.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in Response Rates
	Estimated Value	1.85
	Confidence Interval	(2-Sided) 95%; -4.63 to 8.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% Confidence Interval (CI) for difference in rates were constructed using Anderson-Hauck method.

11. Secondary Outcome

Title	Duration of Objective Response (DOR)
Description	PD was defined as lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia.
Time Frame	Time from the first occurrence of a documented objective response to the time of PD as determined by the investigator or death from any cause, up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Percentage of Participants By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD)
Description	CR: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: any two for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PD: lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. SD: a non-response and used to characterize participants who did not achieve a CR or a PR, and who have not exhibited PD.
Time Frame	Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months)

Outcome Measure Data

Analysis Population Description

ITT population was defined as all randomized participants.

Arm/Group Title	Obinutuzumab + Chlorambucil	Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Measure Participants	216	216
CR	56.0 25.9%	70.4 32.6%
CRi	5.6 2.6%	7.9 3.7%
PR	29.2 13.5%	13.4 6.2%
SD	1.9 0.9%	0.5 0.2%
PD	0.5 0.2%	0.5 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Obinutuzumab + Chlorambucil, Obinutuzumab + Venetoclax
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7169
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value was assessed using CMH test stratified by the IvRS randomization stratification factors.
Method of Estimation	Estimation Parameter	Difference in Response Rates
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; -4.66 to 6.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for difference in rates were constructed using Anderson-Hauck method.

13. Secondary Outcome

Title	Event-Free Survival
Time Frame	Time between date of randomization and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Time to Next Anti-Leukemic Treatment
Time Frame	Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs.
Time Frame	Up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	Percentage of Participants With CD19 + /CD5+ B Cells or CD14+ Monocytes
Time Frame	Baseline up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Secondary Outcome

Title	Percentage of Participants With Human-Anti-Human Antibodies
Time Frame	Baseline up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

Title	Percentage of Participants Recorded as Premature Study Withdrawals
Time Frame	Up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Secondary Outcome

Title	Plasma Concentrations of Venetoclax
Time Frame	Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4

Outcome Measure Data

Analysis Population Description

Analysis population consisted of subjects from whom one or more plasma samples were collected and who had received at least one 400 mg dose of venetoclax. Pre-dose and post-dose data may not come from the same participants. Total number analyzed is therefore higher than the number analyzed for each time point.

Arm/Group Title	Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Measure Participants	184
Pre-Dose	0.578 (0.533)
4 hours Post-Dose	1.21 (0.765)

20. Secondary Outcome

Title	Serum Concentrations of Obinutuzumab
Time Frame	Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4

Outcome Measure Data

Analysis Population Description

Analysis population consisted of subjects from whom one or more serum samples were collected and who had received at least one dose of obinutuzumab and one dose of 400 mg venetoclax. Pre-dose and post-dose data may not come from the same participants. Total number analyzed is therefore higher than the number analyzed for each time point.

Arm/Group Title	Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Measure Participants	184
Pre-Dose	258 (140)
4 hours Post-Dose	568 (187)

21. Secondary Outcome

Title	Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score
Description	The MDASI-CLL is a questionnaire of 25 items related to CLL specific symptoms that a participant may have experienced in the past 24 hours. Participants were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, and numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, and constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, and enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is "not present" or "did not interfere" with the participant's activities and 10 indicating "as bad as you can imagine" or "interfered completely". Scores were averaged (range 0 to 10) for each of three parts.
Time Frame	Baseline up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

22. Secondary Outcome

Title	Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)
Description	The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality-of-life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from "not at all" to "very much," and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from "very poor" to "excellent." Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).
Time Frame	Baseline up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

23. Secondary Outcome

Title	Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)
Description	The EQ-5D-3L questionnaire is a generic, preference based health utility measure that assesses 5 health states (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and is used to build a composite of the patient's health status. The EQ-5D-3L was employed in this study to calculate health utilities for economic modeling, which ranged 0-1. The EQ-5D-3L also contained a visual analog scale (VAS) to assess the participant's overall health, which ranged from 0-100 with a higher score indicating a worse health status.
Time Frame	Baseline up to approximately 10.75 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	All AEs from first dose until 28 days after the last dose up to 1 year. Grade 3-4 AEs: for 6 months after last dose (up to 1.5 years). Major infections (Grade 3-4): for 2 years after the last dose (up to 3 years) irrespective of causality unless disease progressed and participant received leukemic treatment. Before disease progression, SAEs were reported during follow-up (up to 3.75 years). After disease progression, only related SAEs and second primary malignancies were reported.
Adverse Event Reporting Description	All-cause mortality was based on the ITT population defined as all randomized participants. Reporting of serious and non-serious adverse events was based on the safety population defined as all participants who received at least one dose of any study medication (i.e., obinutuzumab, venetoclax, or chlorambucil).
Arm/Group Title	Obinutuzumab + Chlorambucil		Obinutuzumab + Venetoclax		Safety Run-in Obinutuzumab + Venetoclax
Arm/Group Description	Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.		Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.		Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.
All Cause Mortality
	Obinutuzumab + Chlorambucil		Obinutuzumab + Venetoclax		Safety Run-in Obinutuzumab + Venetoclax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/216 (7.9%)		20/216 (9.3%)		2/13 (15.4%)
Serious Adverse Events
	Obinutuzumab + Chlorambucil		Obinutuzumab + Venetoclax		Safety Run-in Obinutuzumab + Venetoclax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/214 (42.1%)		104/212 (49.1%)		10/13 (76.9%)
Blood and lymphatic system disorders
Anaemia	1/214 (0.5%)	1	2/212 (0.9%)	3	0/13 (0%)	0
Autoimmune haemolytic anaemia	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Coombs negative haemolytic anaemia	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Disseminated intravascular coagulation	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Febrile neutropenia	8/214 (3.7%)	10	11/212 (5.2%)	12	3/13 (23.1%)	3
Immune thrombocytopenic purpura	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Neutropenia	1/214 (0.5%)	1	3/212 (1.4%)	3	0/13 (0%)	0
Pancytopenia	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Splenic infarction	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Splenomegaly	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Thrombocytopenia	5/214 (2.3%)	5	2/212 (0.9%)	2	1/13 (7.7%)	1
Cardiac disorders
Acute myocardial infarction	0/214 (0%)	0	2/212 (0.9%)	2	0/13 (0%)	0
Atrial fibrillation	3/214 (1.4%)	3	1/212 (0.5%)	1	0/13 (0%)	0
Atrial flutter	2/214 (0.9%)	3	0/212 (0%)	0	0/13 (0%)	0
Bradycardia	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Cardiac arrest	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Cardiac failure	1/214 (0.5%)	1	3/212 (1.4%)	3	0/13 (0%)	0
Mitral valve incompetence	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Myocardial infarction	3/214 (1.4%)	4	1/212 (0.5%)	1	1/13 (7.7%)	1
Myocardial ischaemia	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Supraventricular tachycardia	2/214 (0.9%)	2	0/212 (0%)	0	0/13 (0%)	0
Tachycardia	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Ventricular fibrillation	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Congenital, familial and genetic disorders
Gilbert's syndrome	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Ear and labyrinth disorders
Vertigo	0/214 (0%)	0	2/212 (0.9%)	2	0/13 (0%)	0
Eye disorders
Amaurosis fugax	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Eye inflammation	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Keratitis	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Gastrointestinal disorders
Colitis	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Diarrhoea	0/214 (0%)	0	2/212 (0.9%)	2	1/13 (7.7%)	1
Duodenal ulcer haemorrhage	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Enteritis	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Faecaloma	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Gastric ulcer perforation	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Inguinal hernia	1/214 (0.5%)	2	2/212 (0.9%)	2	0/13 (0%)	0
Large intestine polyp	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Upper gastrointestinal haemorrhage	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
General disorders
Adverse drug reaction	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Asthenia	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Chest pain	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Chills	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Device related thrombosis	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Fatigue	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
General physical health deterioration	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
Pyrexia	7/214 (3.3%)	8	8/212 (3.8%)	8	2/13 (15.4%)	2
Hepatobiliary disorders
Cholecystitis acute	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Cholelithiasis	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Immune system disorders
Anaphylactic reaction	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Infections and infestations
Atypical pneumonia	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Bronchiolitis	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Bronchitis	2/214 (0.9%)	2	2/212 (0.9%)	2	0/13 (0%)	0
Bronchopulmonary aspergillosis	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Candida infection	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Cellulitis	0/214 (0%)	0	3/212 (1.4%)	3	0/13 (0%)	0
Cholecystitis infective	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Chronic sinusitis	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Cytomegalovirus infection	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Device related infection	0/214 (0%)	0	2/212 (0.9%)	2	0/13 (0%)	0
Eczema infected	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Endocarditis	0/214 (0%)	0	1/212 (0.5%)	2	0/13 (0%)	0
Erysipelas	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Gastroenteritis	2/214 (0.9%)	2	0/212 (0%)	0	0/13 (0%)	0
Gastroenteritis viral	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Gastrointestinal infection	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Hepatitis E	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Herpes zoster	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Infection	2/214 (0.9%)	2	2/212 (0.9%)	4	0/13 (0%)	0
Infectious pleural effusion	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Infective exacerbation of chronic obstructive airways disease	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Influenza	2/214 (0.9%)	2	1/212 (0.5%)	1	1/13 (7.7%)	1
Listeriosis	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Lower respiratory tract infection	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Lung infection	2/214 (0.9%)	2	0/212 (0%)	0	0/13 (0%)	0
Muscle abscess	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Neutropenic infection	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Ophthalmic herpes zoster	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Pneumocystis jirovecii pneumonia	1/214 (0.5%)	1	1/212 (0.5%)	1	1/13 (7.7%)	1
Pneumonia	9/214 (4.2%)	11	10/212 (4.7%)	10	1/13 (7.7%)	1
Pneumonia fungal	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Pneumonia haemophilus	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Pneumonia respiratory syncytial viral	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Pseudomembranous colitis	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Pyelonephritis	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Respiratory tract infection	1/214 (0.5%)	1	2/212 (0.9%)	2	0/13 (0%)	0
Sepsis	2/214 (0.9%)	2	6/212 (2.8%)	7	1/13 (7.7%)	2
Septic shock	2/214 (0.9%)	2	1/212 (0.5%)	1	1/13 (7.7%)	1
Sinusitis aspergillus	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Soft tissue infection	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Staphylococcal infection	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Urinary tract infection	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Urosepsis	1/214 (0.5%)	2	2/212 (0.9%)	2	0/13 (0%)	0
Varicella zoster virus infection	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Wound infection fungal	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Injury, poisoning and procedural complications
Chillblains	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Clavicle fracture	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Femoral neck fracture	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Femur fracture	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Head injury	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Infusion related reaction	13/214 (6.1%)	13	9/212 (4.2%)	9	1/13 (7.7%)	1
Limb injury	2/214 (0.9%)	2	0/212 (0%)	0	0/13 (0%)	0
Lumbar vertebral fracture	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Overdose	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Pelvic fracture	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Rib fracture	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Subcutaneous haematoma	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Subdural haematoma	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Thoracic vertebral fracture	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Toxicity to various agents	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Transfusion reaction	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Traumatic haemothorax	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Vasoplegia syndrome	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Wound evisceration	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Investigations
Alanine aminotransferase increased	3/214 (1.4%)	3	0/212 (0%)	0	0/13 (0%)	0
Aspartate aminotransferase increased	4/214 (1.9%)	4	0/212 (0%)	0	0/13 (0%)	0
Blood urea increased	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Hepatic enzyme increased	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Prothrombin time prolonged	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Transaminases increased	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
White blood cell count decreased	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Dehydration	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Hypercalcaemia	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Hyperglycaemia	2/214 (0.9%)	2	1/212 (0.5%)	1	0/13 (0%)	0
Hyperkalaemia	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Hypoglycaemia	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Hyponatraemia	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Tumour lysis syndrome	4/214 (1.9%)	4	1/212 (0.5%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	2/214 (0.9%)	2	0/212 (0%)	0	0/13 (0%)	0
Lumbar spinal stenosis	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Musculoskeletal pain	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Spondylitis	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Anal squamous cell carcinoma	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Basal cell carcinoma	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Bladder cancer	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Bladder cancer recurrent	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Bladder neoplasm	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Invasive breast carcinoma	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Invasive ductal breast carcinoma	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Lung adenocarcinoma	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Lung adenocarcinoma stage IV	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Malignant melanoma	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Metastatic malignant melanoma	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Myelodysplastic syndrome	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Pancreatic carcinoma metastatic	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Penile cancer	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Prostate cancer	0/214 (0%)	0	2/212 (0.9%)	2	0/13 (0%)	0
Prostate cancer metastatic	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Salivary gland adenoma	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Sarcoma of skin	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Skin squamous cell carcinoma metastatic	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Squamous cell carcinoma of skin	3/214 (1.4%)	3	2/212 (0.9%)	2	0/13 (0%)	0
T-cell lymphoma	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Nervous system disorders
Cerebral haemorrhage	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Cerebral infarction	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Cerebral ischaemia	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Cerebrovascular accident	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Generalised tonic-clonic seizure	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Headache	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Ischaemic stroke	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Presyncope	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
Radiculopathy	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Seizure	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Syncope	2/214 (0.9%)	2	1/212 (0.5%)	1	0/13 (0%)	0
Transient ischaemic attack	1/214 (0.5%)	1	1/212 (0.5%)	2	1/13 (7.7%)	1
Vertebrobasilar insufficiency	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Psychiatric disorders
Confusional state	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Delirium	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Depression	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Reproductive system and breast disorders
Cystocele	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Bronchitis chronic	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Bronchopneumopathy	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Bronchospasm	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Chronic obstructive pulmonary disease	2/214 (0.9%)	2	3/212 (1.4%)	10	0/13 (0%)	0
Cough	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Dyspnoea	0/214 (0%)	0	2/212 (0.9%)	2	0/13 (0%)	0
Hypoxia	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Lung disorder	1/214 (0.5%)	1	1/212 (0.5%)	1	0/13 (0%)	0
Pleural effusion	2/214 (0.9%)	3	1/212 (0.5%)	1	0/13 (0%)	0
Pneumonia aspiration	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Pneumonitis	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Pulmonary embolism	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Pulmonary oedema	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Blister	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Diabetic foot	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Rash	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Urticaria	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Surgical and medical procedures
Aortic valve replacement	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Medical device removal	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Vascular disorders
Aortic stenosis	0/214 (0%)	0	2/212 (0.9%)	2	0/13 (0%)	0
Deep vein thrombosis	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Hypertension	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Hypotension	2/214 (0.9%)	2	0/212 (0%)	0	0/13 (0%)	0
Peripheral arterial occlusive disease	1/214 (0.5%)	1	0/212 (0%)	0	0/13 (0%)	0
Thrombophlebitis superficial	0/214 (0%)	0	1/212 (0.5%)	1	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	Obinutuzumab + Chlorambucil		Obinutuzumab + Venetoclax		Safety Run-in Obinutuzumab + Venetoclax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	205/214 (95.8%)		193/212 (91%)		12/13 (92.3%)
Blood and lymphatic system disorders
Anaemia	39/214 (18.2%)	55	33/212 (15.6%)	53	2/13 (15.4%)	2
Leukopenia	13/214 (6.1%)	19	12/212 (5.7%)	23	1/13 (7.7%)	1
Neutropenia	122/214 (57%)	294	121/212 (57.1%)	370	8/13 (61.5%)	12
Thrombocytopenia	49/214 (22.9%)	76	49/212 (23.1%)	86	2/13 (15.4%)	5
Cardiac disorders
Coronary artery disease	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Tachycardia	1/214 (0.5%)	1	5/212 (2.4%)	5	1/13 (7.7%)	1
Ventricular extrasystoles	1/214 (0.5%)	1	1/212 (0.5%)	1	1/13 (7.7%)	1
Ear and labyrinth disorders
Excessive cerumen production	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal pain	10/214 (4.7%)	11	11/212 (5.2%)	15	2/13 (15.4%)	2
Abdominal pain upper	4/214 (1.9%)	4	7/212 (3.3%)	7	1/13 (7.7%)	1
Constipation	19/214 (8.9%)	23	28/212 (13.2%)	32	5/13 (38.5%)	6
Diarrhoea	32/214 (15%)	42	59/212 (27.8%)	99	5/13 (38.5%)	8
Dry mouth	4/214 (1.9%)	4	0/212 (0%)	0	1/13 (7.7%)	1
Dyspepsia	3/214 (1.4%)	3	7/212 (3.3%)	7	1/13 (7.7%)	1
Epigastric discomfort	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Haemorrhoids	0/214 (0%)	0	2/212 (0.9%)	2	1/13 (7.7%)	1
Nausea	46/214 (21.5%)	62	40/212 (18.9%)	61	4/13 (30.8%)	7
Stomatitis	2/214 (0.9%)	2	1/212 (0.5%)	1	1/13 (7.7%)	2
Vomiting	18/214 (8.4%)	22	21/212 (9.9%)	27	3/13 (23.1%)	3
General disorders
Adverse drug reaction	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Asthenia	17/214 (7.9%)	20	14/212 (6.6%)	20	0/13 (0%)	0
Chills	10/214 (4.7%)	13	12/212 (5.7%)	14	1/13 (7.7%)	1
Extravasation	2/214 (0.9%)	2	0/212 (0%)	0	1/13 (7.7%)	1
Fatigue	29/214 (13.6%)	36	32/212 (15.1%)	40	3/13 (23.1%)	6
Influenza like illness	3/214 (1.4%)	3	4/212 (1.9%)	4	1/13 (7.7%)	1
Oedema	7/214 (3.3%)	7	3/212 (1.4%)	3	1/13 (7.7%)	1
Oedema peripheral	16/214 (7.5%)	18	17/212 (8%)	20	1/13 (7.7%)	2
Pyrexia	26/214 (12.1%)	28	40/212 (18.9%)	53	3/13 (23.1%)	4
Sensation of foreign body	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Infections and infestations
Bronchitis	5/214 (2.3%)	6	11/212 (5.2%)	14	1/13 (7.7%)	2
Cystitis	2/214 (0.9%)	2	1/212 (0.5%)	1	1/13 (7.7%)	1
Ear infection	0/214 (0%)	0	2/212 (0.9%)	2	1/13 (7.7%)	1
Eye infection	1/214 (0.5%)	1	0/212 (0%)	0	1/13 (7.7%)	3
Herpes zoster	6/214 (2.8%)	7	9/212 (4.2%)	9	1/13 (7.7%)	1
Influenza	4/214 (1.9%)	4	3/212 (1.4%)	3	1/13 (7.7%)	1
Localised infection	3/214 (1.4%)	3	1/212 (0.5%)	1	1/13 (7.7%)	1
Nasopharyngitis	14/214 (6.5%)	16	16/212 (7.5%)	16	0/13 (0%)	0
Oral herpes	4/214 (1.9%)	5	5/212 (2.4%)	7	1/13 (7.7%)	4
Paronychia	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Pneumonia	3/214 (1.4%)	3	6/212 (2.8%)	9	1/13 (7.7%)	1
Respiratory tract infection	6/214 (2.8%)	7	10/212 (4.7%)	14	1/13 (7.7%)	3
Rhinitis	5/214 (2.3%)	6	2/212 (0.9%)	3	1/13 (7.7%)	1
Sinusitis	6/214 (2.8%)	6	8/212 (3.8%)	8	1/13 (7.7%)	1
Upper respiratory tract infection	15/214 (7%)	17	16/212 (7.5%)	19	2/13 (15.4%)	4
Urinary tract infection	9/214 (4.2%)	10	10/212 (4.7%)	13	1/13 (7.7%)	1
Viral skin infection	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Arthropod bite	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
Eye contusion	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
Fall	8/214 (3.7%)	11	5/212 (2.4%)	7	1/13 (7.7%)	1
Head injury	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Infusion related reaction	103/214 (48.1%)	131	89/212 (42%)	122	9/13 (69.2%)	10
Limb injury	4/214 (1.9%)	4	0/212 (0%)	0	1/13 (7.7%)	1
Skin abrasion	0/214 (0%)	0	2/212 (0.9%)	2	1/13 (7.7%)	1
Investigations
Alanine aminotransferase increased	13/214 (6.1%)	15	11/212 (5.2%)	15	0/13 (0%)	0
Aspartate aminotransferase increased	17/214 (7.9%)	20	12/212 (5.7%)	14	0/13 (0%)	0
Blood albumin decreased	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Blood creatinine increased	6/214 (2.8%)	6	7/212 (3.3%)	9	1/13 (7.7%)	2
Blood glucose increased	1/214 (0.5%)	1	1/212 (0.5%)	1	1/13 (7.7%)	1
Blood lactate dehydrogenase increased	2/214 (0.9%)	2	2/212 (0.9%)	2	2/13 (15.4%)	2
Blood magnesium decreased	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
Blood phosphorus increased	1/214 (0.5%)	1	2/212 (0.9%)	4	1/13 (7.7%)	1
C-reactive protein increased	2/214 (0.9%)	2	4/212 (1.9%)	4	1/13 (7.7%)	1
Neutrophil count decreased	11/214 (5.1%)	32	10/212 (4.7%)	27	0/13 (0%)	0
Procalcitonin increased	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Protein total decreased	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Transaminases increased	2/214 (0.9%)	2	0/212 (0%)	0	1/13 (7.7%)	1
Weight decreased	5/214 (2.3%)	5	5/212 (2.4%)	5	1/13 (7.7%)	1
Metabolism and nutrition disorders
Decreased appetite	6/214 (2.8%)	8	10/212 (4.7%)	10	1/13 (7.7%)	1
Gout	1/214 (0.5%)	2	3/212 (1.4%)	4	1/13 (7.7%)	1
Hyperglycaemia	7/214 (3.3%)	7	14/212 (6.6%)	16	2/13 (15.4%)	4
Hyperkalaemia	5/214 (2.3%)	6	4/212 (1.9%)	13	5/13 (38.5%)	7
Hyperphosphataemia	3/214 (1.4%)	3	4/212 (1.9%)	5	1/13 (7.7%)	1
Tumour lysis syndrome	1/214 (0.5%)	1	2/212 (0.9%)	2	2/13 (15.4%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	18/214 (8.4%)	23	16/212 (7.5%)	19	1/13 (7.7%)	1
Back pain	20/214 (9.3%)	21	21/212 (9.9%)	24	2/13 (15.4%)	2
Groin pain	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Intervertebral disc protrusion	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Muscle spasms	11/214 (5.1%)	11	10/212 (4.7%)	11	1/13 (7.7%)	1
Musculoskeletal chest pain	0/214 (0%)	0	2/212 (0.9%)	4	2/13 (15.4%)	2
Musculoskeletal pain	4/214 (1.9%)	4	7/212 (3.3%)	8	1/13 (7.7%)	2
Pain in extremity	13/214 (6.1%)	14	10/212 (4.7%)	11	1/13 (7.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	5/214 (2.3%)	6	6/212 (2.8%)	6	1/13 (7.7%)	1
Benign breast neoplasm	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Seborrhoeic keratosis	0/214 (0%)	0	2/212 (0.9%)	2	1/13 (7.7%)	1
Skin papilloma	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
Nervous system disorders
Dizziness	17/214 (7.9%)	20	16/212 (7.5%)	18	4/13 (30.8%)	5
Headache	21/214 (9.8%)	24	23/212 (10.8%)	29	3/13 (23.1%)	3
Paraesthesia	1/214 (0.5%)	1	4/212 (1.9%)	4	1/13 (7.7%)	1
Presyncope	1/214 (0.5%)	1	1/212 (0.5%)	1	2/13 (15.4%)	3
Somnolence	0/214 (0%)	0	1/212 (0.5%)	1	1/13 (7.7%)	1
Syncope	4/214 (1.9%)	4	5/212 (2.4%)	5	2/13 (15.4%)	2
Tremor	3/214 (1.4%)	4	6/212 (2.8%)	6	1/13 (7.7%)	1
Psychiatric disorders
Depression	1/214 (0.5%)	1	8/212 (3.8%)	8	1/13 (7.7%)	1
Renal and urinary disorders
Dysuria	2/214 (0.9%)	2	1/212 (0.5%)	1	1/13 (7.7%)	1
Renal failure	1/214 (0.5%)	1	1/212 (0.5%)	1	1/13 (7.7%)	3
Renal impairment	0/214 (0%)	0	2/212 (0.9%)	2	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	24/214 (11.2%)	27	33/212 (15.6%)	37	6/13 (46.2%)	6
Dyspnoea	11/214 (5.1%)	12	11/212 (5.2%)	12	1/13 (7.7%)	2
Epistaxis	4/214 (1.9%)	5	3/212 (1.4%)	3	1/13 (7.7%)	1
Pharyngeal paraesthesia	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Productive cough	3/214 (1.4%)	3	6/212 (2.8%)	6	1/13 (7.7%)	2
Rhinorrhoea	3/214 (1.4%)	3	3/212 (1.4%)	3	1/13 (7.7%)	1
Throat irritation	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Dry skin	6/214 (2.8%)	7	4/212 (1.9%)	4	2/13 (15.4%)	2
Erythema	4/214 (1.9%)	4	2/212 (0.9%)	2	2/13 (15.4%)	2
Pruritus	9/214 (4.2%)	9	18/212 (8.5%)	20	6/13 (46.2%)	6
Rash	12/214 (5.6%)	13	12/212 (5.7%)	12	2/13 (15.4%)	3
Urticaria	5/214 (2.3%)	5	0/212 (0%)	0	1/13 (7.7%)	1
Vascular disorders
Flushing	3/214 (1.4%)	3	2/212 (0.9%)	2	2/13 (15.4%)	2
Hypertension	11/214 (5.1%)	12	12/212 (5.7%)	17	0/13 (0%)	0
Hypotension	8/214 (3.7%)	10	11/212 (5.2%)	15	2/13 (15.4%)	2
Thrombophlebitis	0/214 (0%)	0	0/212 (0%)	0	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.