Clincosm LogoSign in Get a demo

A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT02055820
Collaborator
AbbVie (Industry)
267
Enrollment
52
Locations
2
Arms
67.3
Actual Duration (Months)
5.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter, open-label, dose-finding study of venetoclax administered orally in combination with rituximab (R) or obinutuzumab (G) and standard doses of cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP) in participants with Non-Hodgkin's Lymphoma (NHL). The study consisted of 2 stages: a dose-finding Phase Ib stage and a Phase II expansion stage. In the Phase I portion of the study, participants were randomized to one of 2 treatment arms venetoclax in combination with R-CHOP (Arm A) and venetoclax in combination with G-CHOP (Arm B) and explored the doses of venetoclax in combination with R-CHOP and G-CHOP. The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and G-CHOP was determined during the dose-finding stage. For the Phase II portion of the study, the venetoclax dose for venetoclax + R-CHOP was on a non-continuous dosing schedule as determined by the Phase Ib portion of the study based on safety and tolerability observed in participants treated in the dose escalation portion of the study. On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed through a press release that the primary endpoint of investigator-assessed PFS was not met. Given these results, Arm B (venetoclax + G-CHOP) was not expanded in Phase II in patients who are first-line with DLBCL.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
267 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase Ib/II, Open-Label Study Evaluating the Safety, Efficacy and Pharmacokinetics of GDC-0199 (ABT-199) in Combination With Rituximab (R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Patients With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL
Actual Study Start Date :
Nov 17, 2013
Actual Primary Completion Date :
Jun 28, 2017
Actual Study Completion Date :
Jun 28, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Venetoclax + G-CHOP Arm

Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Drug: Venetoclax
Venetoclax 200 to 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4-10 of Cycle 1 and Days 1-10 of Cycles 2-8 during Phase I and MTD will be administered according to the same schedule during Phase II.
Other Names:
  • GDC-0199, ABT-199

    • Drug: Cyclophosphamide
    Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

    Drug: Obinutuzumab
    Obinutuzumab will be administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).

    Drug: Doxorubicin
    Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

    Drug: Vincristine
    Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

    Drug: Prednisone
    Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.
    Experimental: Venetoclax + R-CHOP Arm

    Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

    Drug: Venetoclax
    Venetoclax 200 to 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4-10 of Cycle 1 and Days 1-10 of Cycles 2-8 during Phase I and MTD will be administered according to the same schedule during Phase II.
    Other Names:
  • GDC-0199, ABT-199

    • Drug: Cyclophosphamide
    Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

    Drug: Rituximab
    Rituximab 375 mg/m^2 dose will be administered IV on Day 1 of every 21-day cycle.
    Other Names:
  • MabThera/Rituxan

    • Drug: Doxorubicin
    Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

    Drug: Vincristine
    Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

    Drug: Prednisone
    Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

    Outcome Measures

    Primary Outcome Measures

    1. Safety: Number of Participants With Dose-Limiting Toxicities (DLTs) [Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days)]

      DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade >/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not be attributed by the investigator to an alternative, clearly identifiable cause such as tumor progression, concurrent illness or medical condition, or concomitant medication and that occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was considered a DLT for dose-escalation purposes. Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose delay were considered DLTs.

    2. Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Scan Using the Modified Lugano Classification Assessed by Independent Review Committee (IRC) [Baseline up to end of treatment (up to approximately 6 months)]

      CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy

    3. Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co-Expressing Both Bcl-2 and c-Myc Proteins (DE-DLBCL) Participants Assessed by IRC [Baseline up to end of treatment (up to approximately 6 months)]

      CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.

    Secondary Outcome Measures

    1. Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC) [Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days)]

      AUC was calculated based on measurement of venetoclax concentration in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts. Data are reported as hour*micrograms per milliliter (hr*mcg/mL)

    2. Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax) [Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)]

      Tmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.

    3. Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax) [Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)]

      Cmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts. Data are reported as micrograms per milliliter

    4. Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval [Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)]

      Cmin was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.

    5. Prednisone Plasma PK: AUC [Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)]

      AUC was determined based on measurement of Predisone concentrations in plasma over time.

    6. Prednisone Plasma PK: Tmax [Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)]

      Tmax was determined based on measurement of Predisone concentrations in plasma over time.

    7. Prednisone Plasma PK: Cmax [Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)]

      Cmax was determined based on measurement of Predisone concentrations in plasma over time.

    8. Rituximab PK: Cmax [End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)]

      Cmax was determined using the post-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.

    9. Rituximab PK: Cmin Within the Dosing Interval [Pre-dose on Cycle 2 Day 1 (cycle length = 21 days)]

      Cmin was determined using the pre-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose on Day 1 of Cycle 2.

    10. Obinutuzumab PK: Cmax [End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)]

      Cmax was determined using the post-dose obinutuzumab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.

    11. Cyclophosphamide PK: Cmax [End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)]

      Cmax was determined using the post-dose Cyclophosphamide plasma concentrations on Cycle 1 Day 1.

    12. Doxorubicin PK: Cmax [End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)]

      Cmax was determined using the post-dose Doxorubicin plasma concentrations.

    13. Vincristine PK: Cmax [End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)]

      Cmax was determined using the post-dose Vincristine plasma concentrations.

    14. Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification Assessed by IRC [Baseline to end of treatment (up to approximately 6 months)]

      Objective Response defined as PR (partial response) or CR (complete response) at end of treatment. CR: Lymph nodes and extra-lymphatic sites with score 1, 2 or 3 on a 5-point scale (with a higher score being a worse outcome). No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PR: Lymph nodes and extralymphatic sites with score of 4 or 5 on the 5-point scale with reduced uptake compared with baseline and residual mass(es) of any size. CT-based response criteria for PR must also be met. No new lesions. In bone marrow residual uptake could be higher than in normal marrow but must be reduced compared with baseline; persistent focal changes in the marrow to be considered for further evaluation with magnetic resonance imaging (MRI) or biopsy or an interval scan. OR=PR+CR

    15. Percentage of Participants Who Are Alive and Without Disease Progression at Month 12 [Month 12]

      Progressive disease (PD) was determined using the modified Lugano classification criteria. For PET-CT-based PD: Score 4 (uptake moderately > liver) or 5 (uptake markedly higher than liver and/or new lesions) with an increase in intensity of uptake from baseline in target nodes and nodal lesions, new FDG-uptake foci of extranodal lesions consistent with lymphoma at interim or end-of-treatment assessment, no non-measured lesions, new FDG-uptake foci consistent with lymphoma, new or recurrent FDG-uptake foci in bone marrow. For CT-based PD: >/= 50% decrease in SPD of up to 6 target measureable nodes and extranodal sites; non-measured lesion should be absent/normal, have regressed, but not increased; no new lesions.

    16. Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification [Baseline up to end of treatment (approx. 6 months)]

      CR was defined as follows according to modified Lugano classification for CT-based response: Target nodes/nodal masses must have regressed to </= 1.5 cm in longest transverse diameter of a lesion (LDi), no extra-lymphatic sites of disease, absence of non-measured lesions, organ enlargement must have regressed to normal, no new lesions, and if the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.

    17. Safety: Percentage of Participants With Adverse Events [Baseline up to approximately 36 months]

      An adverse event 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 adverse event 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 adverse events.

    18. Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy [Baseline up to Cycle 6 (cycle length = 21 days)]

      Maintenance of relative dose intensity was defined as a dose intensity of >/= 90%.

    19. Relative Dose Intensity of Venetoclax [Baseline up to Cycle 6 (cycle length = 21 days)]

      Dose intensity was categorized as < 80%, 80% to < 85%, 85% to < 90%, or >/= 90%.

    Eligibility Criteria

    Criteria

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

    • At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as > 1.5 cm in its longest dimension, which is also FDG avid by screening PET scan.

    • Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment

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

    • Adequate hematologic function

    • For female participants of childbearing potential, agreement to use highly effective forms of contraception

    Dose-Escalation Portion of the Study:

    • Participants must have histologically confirmed B-cell NHL, except MCL or SLL

    • Participants must have never received previous R-CHOP treatment

    • Any relapsed/refractory participants that are enrolled during the dose escalation should have received only a single previous treatment regimen

    Expansion Portion of the Study:
    • Participants must have previously untreated CD20-positive DLBCL and IPI score must be 2-5
    Exclusion Criteria:
    General Exclusion Criteria:

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

    • Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab

    • Prior anthracycline therapy

    • Participants with ongoing corticosteroid use >30 mg per day of prednisone or equivalent

    • CNS lymphoma or primary mediastinal DLBCL

    • Vaccination with live vaccines within 28 days prior to randomization

    • Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1

    • History of other malignancy that could affect compliance with the protocol or interpretation of results

    • Evidence of significant, uncontrolled concomitant disease

    • Significant cardiovascular disease or significant pulmonary disease

    • Left ventricular ejection fraction less than (<) 50% as defined by multiple-gated acquisition (MUGA)

    • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1

    • Received the following agents within 7 days prior to the first dose of venetoclax: steroid therapy for anti-neoplastic intent; strong and moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers; grapefruit/grapefruit products, seville oranges or star fruit within 3 days prior to the first dose of venetoclax

    • Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis

    • Recent major surgery

    • Women who are pregnant or lactating

    Dose-Escalation Portion of the Study:
    • Participants with confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL)
    Expansion Portion of the Study:

    • Participants with transformed lymphoma (participants with discordant bone marrow involvement (i.e., low grade histology in bone marrow) may be considered after discussion with the Medical Monitor)

    • Prior therapy for NHL

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 St. Jude Heritage Healthcare Fullerton California United States 92835
    2 UCLA Jonsson Comprehensive Cancer Center Los Angeles California United States 90095
    3 Central Coast Medical Oncology Santa Maria California United States 93454
    4 The West Clinici Saint Louis Missouri United States 63129
    5 Hackensack University Medical Center; WFAN - Imus Pediatric Center Hackensack New Jersey United States 07601
    6 San Juan Oncology Associates Farmington New Mexico United States 87401
    7 Memorial Sloan-Kettering Cancer Center New York New York United States 10065
    8 Uni of Rochester Medical Center; Wilmot Cancer Center, Pharmacy Department Rochester New York United States 14642
    9 Tennessee Oncology Nashville Tennessee United States 37203
    10 Concord Repatriation General Hospital Concord New South Wales Australia 2139
    11 Princess Alexandra Hospital Woolloongabba Queensland Australia 4102
    12 Peter MacCallum Cancer Centre-East Melbourne Melbourne Victoria Australia 3000
    13 Royal Melbourne Hospital Parkville Victoria Australia 3050
    14 LKH - Universitätsklinikum der PMU Salzburg Salzburg Austria 5020
    15 Medizinische Universität Wien Wien Austria 1090
    16 Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
    17 BC Cancer Agency, CSI Kelowna British Columbia Canada V1Y 5L3
    18 BC Cancer Agency Vancouver Centre - PARENT; BC Cancer Agency Vancouver British Columbia Canada V5Z 4E6
    19 Jewish General Hospital; Research Unit Montréal Quebec Canada H3T 1E2
    20 CHU de Quebec - Hôpital de l' Enfant Jésus Quebec Canada G1J 1Z4
    21 Fakultni nemocnice Brno Brno Czechia 613 00
    22 Fakultni nemocnice Hradec Kralove Hradec Kralove Czechia 500 05
    23 Fakultni nemocnice Ostrava Ostrava - Poruba Czechia 708 52
    24 Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK Praha 2 Czechia 128 08
    25 Hopital Henri Mondor, Unite Hemopathies lymphoides Creteil France 94010
    26 Centre Hospitalier Départemental Les Oudairies La Roche sur Yon France 85025
    27 Clinique Victor Hugo; Pharmacie Le Mans France 72015
    28 Hopital Claude Huriez - CHU Lille Lille France 59037
    29 Hopital Saint Eloi Montpellier France 34295
    30 CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la Procreation Nantes France 44093
    31 Hôpital Saint-Louis Paris France 75475
    32 Centre Hospitalier Lyon Sud Pierre-Benite France 69495
    33 CHU Rennes - Hopital Pontchaillou Rennes cedex 09 France 35033
    34 Centre Henri Becquerel; Hematologie Rouen France 76038
    35 Hôpital de Brabois Adultes Vandoeuvre-les-nancy France 54511
    36 Semmelweis Egyetem Budapest Hungary 1083
    37 Orszagos Onkologiai Intezet Budapest Hungary 1122
    38 Debreceni Egyetem; Belgyogyaszati Klinika Hematologiai Tanszek Debrecen Hungary 4032
    39 Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione G. Pascale Napoli Campania Italy 80131
    40 Azienda Ospedaliero Universitaria San Martino Genova Liguria Italy 16132
    41 Azienda Ospedaliera Città della Salute e della Scienza di Torino Torino Piemonte Italy 10126
    42 Azienda Ospedaliera Vincenzo Cervello Palermo Sicilia Italy 90127
    43 Azienda Ospedaliero Universitaria Pisana; U.O. Farmaceutica Pisa Toscana Italy 56100
    44 Amsterdam UMC Location VUMC Amsterdam Netherlands 1081 HV
    45 Erasmus Medisch Centrum Rotterdam Netherlands 3015 GD
    46 UMC Utrecht Utrecht Netherlands 3508 GA
    47 Hospital del Mar Barcelona Spain 08003
    48 Hospital Universitari Vall d'Hebron Barcelona Spain 08035
    49 ICO l´Hospitalet - Hospital Duran i Reynals; Hematology Barcelona Spain 08907
    50 Hospital Universitario La Paz Madrid Spain 280146
    51 Hospital Universitario Ramon y Cajal Madrid Spain 28034
    52 Hospital Universitario de Salamanca Salamanca Spain 37007

    Sponsors and Collaborators

    • Hoffmann-La Roche
    • AbbVie

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT02055820
    Other Study ID Numbers:
    • GO27878
    • 2013-003749-40
    First Posted:
    Feb 5, 2014
    Last Update Posted:
    Jun 11, 2020
    Last Verified:
    May 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Lymphoma
    Lymphoma, Non-Hodgkin
    Lymphoma, B-Cell
    Prednisone
    Cyclophosphamide
    Rituximab
    Doxorubicin
    Vincristine
    Venetoclax
    Obinutuzumab

    Study Results

    Participant Flow

    Recruitment Details At start the trial had a randomised-controlled component, until July 2016 once the arm B (Gazyva) got closed following the publication of results of another trial. Since July 2016, the trial was single-arm, not randomised anymore, and kept including patients in only 1 arm (Arm A, rituximab).
    Pre-assignment Detail The data reported for participant flow is based on safety population, which includes all participants who received at least one dose of study medication.
    Arm/Group Title Venetoclax 200 mg +R-CHOP Venetoclax 400 mg +R-CHOP Venetoclax 600 mg +R-CHOP Venetoclax 800 mg +R-CHOP Venetoclax 800 mg +R-CHOP Phase II Venetoclax 200 mg +G-CHOP Venetoclax 400 mg +G-CHOP Venetoclax 600 mg +G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg +G-CHOP B
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-10; Cycles 2-8 Days 1-10, Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Period Title: Phase I: Dose-Finding
    STARTED 7 3 8 6 0 7 7 6 6 6
    COMPLETED 6 3 7 3 0 5 5 6 6 6
    NOT COMPLETED 1 0 1 3 0 2 2 0 0 0
    Period Title: Phase I: Dose-Finding
    STARTED 0 0 0 0 208 0 0 0 0 0
    COMPLETED 0 0 0 0 159 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 49 0 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Venetoclax 200 mg +R-CHOP Venetoclax 400 mg +R-CHOP Venetoclax 600 mg +R-CHOP Venetoclax 800 mg +R-CHOP Venetoclax 800 mg +R-CHOP Phase II Venetoclax 200 mg +G-CHOP Venetoclax 400 mg +G-CHOP Venetoclax 600 mg +G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg +G-CHOP B Total
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-10; Cycles 2-8 Days 1-10, Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Total of all reporting groups
    Overall Participants 7 3 8 6 208 7 7 6 6 6 264
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    67.0
    (9.2)
    61.0
    (13.1)
    57.0
    (9.5)
    56.3
    (11.9)
    61.4
    (12.8)
    52.1
    (16.2)
    60.9
    (6.3)
    66.7
    (4.2)
    60.5
    (13.7)
    66.8
    (6.7)
    61.2
    (12.5)
    Sex: Female, Male (Count of Participants)
    Female
    3
    42.9%
    2
    66.7%
    2
    25%
    2
    33.3%
    94
    45.2%
    2
    28.6%
    5
    71.4%
    4
    66.7%
    4
    66.7%
    2
    33.3%
    120
    45.5%
    Male
    4
    57.1%
    1
    33.3%
    6
    75%
    4
    66.7%
    114
    54.8%
    5
    71.4%
    2
    28.6%
    2
    33.3%
    2
    33.3%
    4
    66.7%
    144
    54.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    1.9%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    1.5%
    Not Hispanic or Latino
    6
    85.7%
    1
    33.3%
    2
    25%
    3
    50%
    151
    72.6%
    6
    85.7%
    3
    42.9%
    4
    66.7%
    5
    83.3%
    6
    100%
    187
    70.8%
    Unknown or Not Reported
    1
    14.3%
    2
    66.7%
    6
    75%
    3
    50%
    53
    25.5%
    1
    14.3%
    4
    57.1%
    2
    33.3%
    1
    16.7%
    0
    0%
    73
    27.7%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    5
    2.4%
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    6
    2.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    1.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    1.1%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    1.9%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    1.5%
    White
    6
    85.7%
    1
    33.3%
    2
    25%
    2
    33.3%
    154
    74%
    7
    100%
    2
    28.6%
    4
    66.7%
    5
    83.3%
    4
    66.7%
    187
    70.8%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    1
    14.3%
    2
    66.7%
    6
    75%
    4
    66.7%
    42
    20.2%
    0
    0%
    4
    57.1%
    2
    33.3%
    1
    16.7%
    2
    33.3%
    64
    24.2%

    Outcome Measures

    1. Primary Outcome
    Title Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)
    Description DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade >/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not be attributed by the investigator to an alternative, clearly identifiable cause such as tumor progression, concurrent illness or medical condition, or concomitant medication and that occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was considered a DLT for dose-escalation purposes. Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose delay were considered DLTs.
    Time Frame Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    Safety population: All participants who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses. Here, participants in the Dose Finding phase were analyzed.
    Arm/Group Title Venetoclax 200 mg + R-CHOP Venetoclax 400 mg + R-CHOP Venetoclax 600 mg + R-CHOP Venetoclax 800mg + R-CHOP Venetoclax 200mg + G-CHOP Venetoclax 400mg + G-CHOP Venetoclax 600mg + G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg + G-CHOP B
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + G-CHOP 800 mg A Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm venetoclax was delivered in Cycle 1 on Days 4-10 and Cycles 2-8 on Days 1-10. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm ventoclax was delivered in Cycle 1 on Days 4-8 and Cycles 2-8 on Days 1-5. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 7 3 8 6 7 7 6 6 6
    Number [Participants]
    1
    14.3%
    0
    0%
    1
    12.5%
    0
    0%
    2
    1%
    1
    14.3%
    1
    14.3%
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Scan Using the Modified Lugano Classification Assessed by Independent Review Committee (IRC)
    Description CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy
    Time Frame Baseline up to end of treatment (up to approximately 6 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
    Arm/Group Title Venetoclax + R-CHOP 800 mg Phase II
    Arm/Group Description Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 211
    Number (95% Confidence Interval) [Percentage of participants]
    68.2
    974.3%
    3. Primary Outcome
    Title Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co-Expressing Both Bcl-2 and c-Myc Proteins (DE-DLBCL) Participants Assessed by IRC
    Description CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
    Time Frame Baseline up to end of treatment (up to approximately 6 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for subgroup of the ITT, DE Participants.
    Arm/Group Title Venetoclax + R-CHOP 800 mg Phase II
    Arm/Group Description Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 81
    Number (95% Confidence Interval) [Percentage of participants]
    66.7
    952.9%
    4. Secondary Outcome
    Title Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)
    Description AUC was calculated based on measurement of venetoclax concentration in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts. Data are reported as hour*micrograms per milliliter (hr*mcg/mL)
    Time Frame Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Reporting according to study drug received. One participant mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.
    Arm/Group Title Venetoclax 800mg + R-CHOP Venetoclax 200 mg + R-CHOP Venetoclax 400 mg + R-CHOP Venetoclax 600 mg + R-CHOP Venetoclax + R-CHOP 800 mg Venetoclax 200mg + G-CHOP Venetoclax 400mg + G-CHOP Venetoclax 600mg + G-CHOP Venetoclax + G-CHOP 800mg
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I and II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 1 6 4 8 124 7 7 6 10
    Mean (Standard Deviation) [hr*mcg/mL]
    .66
    (NA)
    2.51
    (.97)
    3.87
    (2.41)
    3.70
    (1.59)
    4.51
    (2.32)
    2.55
    (1.13)
    4.33
    (1.31)
    5.13
    (2.41)
    6.20
    (1.71)
    5. Secondary Outcome
    Title Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)
    Description Tmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.
    Time Frame Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Reporting according to study drug received. One participant mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.
    Arm/Group Title Venetoclax + R-CHOP 100 mg Venetoclax 200 mg + R-CHOP Venetoclax 400 mg + R-CHOP Venetoclax 600 mg + R-CHOP Venetoclax 800mg + R-CHOP Venetoclax 200mg + G-CHOP Venetoclax 400mg + G-CHOP Venetoclax 600mg + G-CHOP Venetoclax + G-CHOP 800 mg
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 1 6 4 8 124 7 7 6 10
    Mean (Standard Deviation) [Hour]
    4.0
    (NA)
    4.59
    (1.08)
    6.50
    (1.91)
    5.52
    (2.07)
    5.53
    (1.55)
    5.72
    (1.42)
    6.56
    (1.51)
    5.30
    (2.38)
    5.79
    (1.47)
    6. Secondary Outcome
    Title Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)
    Description Cmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts. Data are reported as micrograms per milliliter
    Time Frame Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Reporting according to study drug received. One participant mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.
    Arm/Group Title Venetoclax + R-CHOP 100 mg Venetoclax 200 mg + R-CHOP Venetoclax 400 mg + R-CHOP Venetoclax 600 mg + R-CHOP Venetoclax 800mg + R-CHOP Venetoclax 200mg + G-CHOP Venetoclax 400mg + G-CHOP Venetoclax 600mg + G-CHOP Venetoclax + G-CHOP 800 mg
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 1 6 4 8 124 7 7 6 10
    Mean (Standard Deviation) [Ug/ML]
    .09
    (NA)
    .58
    (.32)
    .92
    (.64)
    .85
    (.33)
    1.15
    (.48)
    .52
    (.21)
    1.26
    (.30)
    1.00
    (.58)
    1.54
    (.37)
    7. Secondary Outcome
    Title Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval
    Description Cmin was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.
    Time Frame Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Reporting according to study drug received. One participant mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.
    Arm/Group Title Venetoclax + R-CHOP 100 mg Venetoclax 200 mg + R-CHOP Venetoclax 400 mg + R-CHOP Venetoclax 600 mg + R-CHOP Venetoclax 800mg + R-CHOP Venetoclax 200mg + G-CHOP Venetoclax 400mg + G-CHOP Venetoclax 600mg + G-CHOP Venetoclax + G-CHOP 800 mg
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 1 3 2 4 126 7 5 5 6
    Mean (Standard Deviation) [mcg/mL]
    0.0714
    (0.00)
    0.522
    (0.441)
    0.253
    (0.247)
    0.387
    (0.141)
    0.640
    (0.451)
    0.134
    (0.107)
    0.395
    (0.381)
    0.612
    (0.535)
    0.628
    (0.395)
    8. Secondary Outcome
    Title Prednisone Plasma PK: AUC
    Description AUC was determined based on measurement of Predisone concentrations in plasma over time.
    Time Frame Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All participants who received study drug and provided at least one post-treatment PK sample. A similar dose strength of prednisone (100 mg) was administered across the treatment arms/venetoclax dose groups. Hence, the data are presented as an overall summary in Cycles 1 and 2.
    Arm/Group Title Venetoclax PK Popluation
    Arm/Group Description All participants in the study. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 54
    Cycle 1, Day 1
    195
    (72.8)
    Cycle 2, Day 1
    184
    (81.2)
    9. Secondary Outcome
    Title Prednisone Plasma PK: Tmax
    Description Tmax was determined based on measurement of Predisone concentrations in plasma over time.
    Time Frame Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. A similar dose strength of prednisone (100 mg) was administered across the treatment arms/venetoclax dose groups. Hence, the data are presented as an overall summary in Cycles 1 and 2.
    Arm/Group Title Venetoclax PK Popluation
    Arm/Group Description All participants in the study. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 54
    Cycle 1, Day 1
    2.19
    (1.61)
    Cycle 2, Day 1
    3.80
    (2.52)
    10. Secondary Outcome
    Title Prednisone Plasma PK: Cmax
    Description Cmax was determined based on measurement of Predisone concentrations in plasma over time.
    Time Frame Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. A similar dose strength of prednisone (100 mg) was administered across the treatment arms/venetoclax dose groups. Hence, the data are presented as an overall summary in Cycles 1 and 2.
    Arm/Group Title Venetoclax PK Popluation
    Arm/Group Description All participants in the study. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 54
    Cycle 1, Day 1
    49.9
    (28.7)
    Cycle 2, Day 1
    43.2
    (17.6)
    11. Secondary Outcome
    Title Rituximab PK: Cmax
    Description Cmax was determined using the post-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.
    Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. The Cmax of rituximab is presented at the 800 mg Venetoclax dose group. Hence, the data is not presented by the treatment arms/Venetoclax dose groups.
    Arm/Group Title Venetoclax 800 mg
    Arm/Group Description All participants in the study, who received 800 mg venetoclax. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 7
    Mean (Standard Deviation) [mcg/mL]
    173
    (39.4)
    12. Secondary Outcome
    Title Rituximab PK: Cmin Within the Dosing Interval
    Description Cmin was determined using the pre-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose on Day 1 of Cycle 2.
    Time Frame Pre-dose on Cycle 2 Day 1 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. The Cmin of rituximab is presented at the 800 mg Venetoclax dose group. Hence, the data is not presented by the treatment arms/Venetoclax dose groups.
    Arm/Group Title Venetoclax 800 mg
    Arm/Group Description All participants in the study, who received 800 mg venetoclax. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 8
    Mean (Standard Deviation) [mcg/mL]
    26.1
    (13)
    13. Secondary Outcome
    Title Obinutuzumab PK: Cmax
    Description Cmax was determined using the post-dose obinutuzumab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.
    Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. The Cmax of obinutuzumab is presented at the 800 mg Venetoclax dose group. Hence, the data is not presented by the treatment arms/Venetoclax dose groups.
    Arm/Group Title Venetoclax 800 mg
    Arm/Group Description All participants in the study, who received 800 mg venetoclax. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 10
    Mean (Standard Deviation) [mcg/mL]
    326
    (76)
    14. Secondary Outcome
    Title Cyclophosphamide PK: Cmax
    Description Cmax was determined using the post-dose Cyclophosphamide plasma concentrations on Cycle 1 Day 1.
    Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Given a single dose strength of Cyclophosphamide was administered across the different Venetoclax dose groups and treatment arms, hence the data are presented as an overall summary.
    Arm/Group Title Venetoclax PK Popluation
    Arm/Group Description All participants in the study. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 36
    Mean (Standard Deviation) [mcg/mL]
    32.1
    (7.51)
    15. Secondary Outcome
    Title Doxorubicin PK: Cmax
    Description Cmax was determined using the post-dose Doxorubicin plasma concentrations.
    Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Given a single dose strength of Doxorubicin was administered across the different Venetoclax dose groups and treatment arms, hence the data are presented as an overall summary.
    Arm/Group Title Venetoclax PK Popluation
    Arm/Group Description All participants in the study. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 24
    Mean (Standard Deviation) [mcg/mL]
    1260
    (911)
    16. Secondary Outcome
    Title Vincristine PK: Cmax
    Description Cmax was determined using the post-dose Vincristine plasma concentrations.
    Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Given a single dose strength of Vincristine was administered across the different Venetoclax dose groups and treatment arms, hence the data are presented as an overall summary.
    Arm/Group Title Venetoclax PK Popluation
    Arm/Group Description All participants in the study. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 28
    Mean (Standard Deviation) [mcg/mL]
    54.0
    (44.6)
    17. Secondary Outcome
    Title Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification Assessed by IRC
    Description Objective Response defined as PR (partial response) or CR (complete response) at end of treatment. CR: Lymph nodes and extra-lymphatic sites with score 1, 2 or 3 on a 5-point scale (with a higher score being a worse outcome). No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PR: Lymph nodes and extralymphatic sites with score of 4 or 5 on the 5-point scale with reduced uptake compared with baseline and residual mass(es) of any size. CT-based response criteria for PR must also be met. No new lesions. In bone marrow residual uptake could be higher than in normal marrow but must be reduced compared with baseline; persistent focal changes in the marrow to be considered for further evaluation with magnetic resonance imaging (MRI) or biopsy or an interval scan. OR=PR+CR
    Time Frame Baseline to end of treatment (up to approximately 6 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
    Arm/Group Title Venetoclax + R-CHOP 800 mg Phase II
    Arm/Group Description Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 211
    Number (95% Confidence Interval) [Percentage of Participants]
    81.5
    1164.3%
    18. Secondary Outcome
    Title Percentage of Participants Who Are Alive and Without Disease Progression at Month 12
    Description Progressive disease (PD) was determined using the modified Lugano classification criteria. For PET-CT-based PD: Score 4 (uptake moderately > liver) or 5 (uptake markedly higher than liver and/or new lesions) with an increase in intensity of uptake from baseline in target nodes and nodal lesions, new FDG-uptake foci of extranodal lesions consistent with lymphoma at interim or end-of-treatment assessment, no non-measured lesions, new FDG-uptake foci consistent with lymphoma, new or recurrent FDG-uptake foci in bone marrow. For CT-based PD: >/= 50% decrease in SPD of up to 6 target measureable nodes and extranodal sites; non-measured lesion should be absent/normal, have regressed, but not increased; no new lesions.
    Time Frame Month 12

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
    Arm/Group Title Venetoclax 200 mg + R-CHOP Venetoclax 400 mg + R-CHOP Venetoclax 600 mg + R-CHOP Venetoclax 800mg + R-CHOP Venetoclax + R-CHOP 800 mg Phase II Venetoclax 200mg + G-CHOP Venetoclax 400mg + G-CHOP Venetoclax 600mg + G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg + G-CHOP B
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + G-CHOP 800 mg A Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm venetoclax was delivered in Cycle 1 on Days 4-10 and Cycles 2-8 on Days 1-10. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm ventoclax was delivered in Cycle 1 on Days 4-8 and Cycles 2-8 on Days 1-5. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 7 3 8 6 211 7 7 6 6 6
    Number (95% Confidence Interval) [Percentage of Participants]
    85.71
    1224.4%
    100.00
    3333.3%
    87.50
    1093.8%
    66.67
    1111.2%
    88.99
    42.8%
    100.00
    1428.6%
    75.00
    1071.4%
    100.00
    1666.7%
    100.00
    1666.7%
    100.00
    1666.7%
    19. Secondary Outcome
    Title Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification
    Description CR was defined as follows according to modified Lugano classification for CT-based response: Target nodes/nodal masses must have regressed to </= 1.5 cm in longest transverse diameter of a lesion (LDi), no extra-lymphatic sites of disease, absence of non-measured lesions, organ enlargement must have regressed to normal, no new lesions, and if the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
    Time Frame Baseline up to end of treatment (approx. 6 months)

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
    Arm/Group Title Venetoclax + R-CHOP 800 mg Phase II
    Arm/Group Description Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 211
    Number (95% Confidence Interval) [Percentage of Participants]
    37.4
    534.3%
    20. Secondary Outcome
    Title Safety: Percentage of Participants With Adverse Events
    Description An adverse event 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 adverse event 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 adverse events.
    Time Frame Baseline up to approximately 36 months

    Outcome Measure Data

    Analysis Population Description
    Safety population: All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses
    Arm/Group Title Venetoclax 200 mg + R-CHOP Venetoclax 400 mg + R-CHOP Venetoclax 600 mg + R-CHOP Venetoclax 800mg + R-CHOP Venetoclax + R-CHOP 800 mg Phase II Venetoclax 200mg + G-CHOP Venetoclax 400mg + G-CHOP Venetoclax 600mg + G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg + G-CHOP B
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + G-CHOP 800 mg A Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm venetoclax was delivered in Cycle 1 on Days 4-10 and Cycles 2-8 on Days 1-10. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm ventoclax was delivered in Cycle 1 on Days 4-8 and Cycles 2-8 on Days 1-5. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 7 3 8 6 208 7 7 6 6 6
    Number [Percentage of Participants]
    100.00
    1428.6%
    100.00
    3333.3%
    100.00
    1250%
    100.00
    1666.7%
    99.0
    47.6%
    100.00
    1428.6%
    100.00
    1428.6%
    100.00
    1666.7%
    100.00
    1666.7%
    100.00
    1666.7%
    21. Secondary Outcome
    Title Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy
    Description Maintenance of relative dose intensity was defined as a dose intensity of >/= 90%.
    Time Frame Baseline up to Cycle 6 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    Safety population: All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses. Overall R-CHOP and G-CHOP arms were analyzed for this outcome measure.
    Arm/Group Title Venetoclax + R-CHOP Arm Venetoclax 600mg + G-CHOP
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    Measure Participants 232 32
    Cyclophosphamide
    89.5
    1278.6%
    77.4
    2580%
    Doxorubicin
    88.6
    1265.7%
    77.4
    2580%
    Vincristine
    86.6
    1237.1%
    78.1
    2603.3%
    Prednisone
    87.4
    1248.6%
    81.3
    2710%
    22. Secondary Outcome
    Title Relative Dose Intensity of Venetoclax
    Description Dose intensity was categorized as < 80%, 80% to < 85%, 85% to < 90%, or >/= 90%.
    Time Frame Baseline up to Cycle 6 (cycle length = 21 days)

    Outcome Measure Data

    Analysis Population Description
    Safety population: All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses
    Arm/Group Title Venetoclax 200 mg + R-CHOP Venetoclax 400 mg + R-CHOP Venetoclax 600 mg + R-CHOP Venetoclax 800mg + R-CHOP Venetoclax + R-CHOP 800 mg Phase II Venetoclax 200mg + G-CHOP Venetoclax 400mg + G-CHOP Venetoclax 600mg + G-CHOP Venetoclax + G-CHOP 800 mg Venetoclax + G-CHOP 800mg B
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days.
    Measure Participants 7 3 8 6 208 7 7 6 6 6
    <80%
    71.4
    0.00
    12.5
    0.00
    26.0
    100.00
    14.3
    50.0
    83.3
    100.0
    80-<85%
    0.00
    0.00
    12.5
    0.00
    3.4
    0.00
    14.3
    16.7
    0.00
    0.00
    85-<90%
    0.00
    0.00
    12.5
    0.00
    2.9
    0.00
    0.00
    0.00
    16.7
    0.00
    >=90%
    28.6
    100.00
    62.5
    100.00
    67.6
    0.00
    71.4
    33.3
    0.00
    0.00

    Adverse Events

    Time Frame Baseline up to approximately 67 months
    Adverse Event Reporting Description Safety population: All participants, who were enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population.
    Arm/Group Title Venetoclax 200 mg +R-CHOP Venetoclax 400 mg +R-CHOP Venetoclax 600 mg +R-CHOP Venetoclax 800 mg +R-CHOP Venetoclax 800 mg +R-CHOP Phase II Venetoclax 200 mg +G-CHOP Venetoclax 400 mg +G-CHOP Venetoclax 600 mg +G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg +G-CHOP B
    Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-10; Cycles 2-8 Days 1-10, Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
    All Cause Mortality
    Venetoclax 200 mg +R-CHOP Venetoclax 400 mg +R-CHOP Venetoclax 600 mg +R-CHOP Venetoclax 800 mg +R-CHOP Venetoclax 800 mg +R-CHOP Phase II Venetoclax 200 mg +G-CHOP Venetoclax 400 mg +G-CHOP Venetoclax 600 mg +G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg +G-CHOP B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/7 (14.3%) 0/3 (0%) 1/8 (12.5%) 4/6 (66.7%) 33/208 (15.9%) 1/7 (14.3%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/6 (0%)
    Serious Adverse Events
    Venetoclax 200 mg +R-CHOP Venetoclax 400 mg +R-CHOP Venetoclax 600 mg +R-CHOP Venetoclax 800 mg +R-CHOP Venetoclax 800 mg +R-CHOP Phase II Venetoclax 200 mg +G-CHOP Venetoclax 400 mg +G-CHOP Venetoclax 600 mg +G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg +G-CHOP B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/7 (71.4%) 2/3 (66.7%) 4/8 (50%) 3/6 (50%) 116/208 (55.8%) 5/7 (71.4%) 4/7 (57.1%) 3/6 (50%) 5/6 (83.3%) 5/6 (83.3%)
    Blood and lymphatic system disorders
    AGRANULOCYTOSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ANAEMIA 0/7 (0%) 0 1/3 (33.3%) 1 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    FEBRILE NEUTROPENIA 3/7 (42.9%) 5 0/3 (0%) 0 1/8 (12.5%) 2 2/6 (33.3%) 3 57/208 (27.4%) 89 1/7 (14.3%) 1 2/7 (28.6%) 2 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 3
    HAEMOLYTIC ANAEMIA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    LEUKOPENIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    NEUTROPENIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 19/208 (9.1%) 24 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    THROMBOCYTOPENIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 2/6 (33.3%) 4 0/6 (0%) 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ATRIAL FIBRILLATION 1/7 (14.3%) 1 1/3 (33.3%) 1 0/8 (0%) 0 0/6 (0%) 0 6/208 (2.9%) 6 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ATRIOVENTRICULAR BLOCK 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CARDIAC ARREST 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    CARDIAC FAILURE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CARDIAC FAILURE CONGESTIVE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CARDIOGENIC SHOCK 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CARDIOMYOPATHY 0/7 (0%) 0 1/3 (33.3%) 1 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    LEFT VENTRICULAR FAILURE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    MYOCARDIAL ISCHAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SINUS TACHYCARDIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SUPRAVENTRICULAR TACHYCARDIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TACHYCARDIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    Eye disorders
    OPTIC NEUROPATHY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Gastrointestinal disorders
    DIARRHOEA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DIVERTICULAR PERFORATION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DUODENAL STENOSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DYSPHAGIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    ENTEROCOLITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTRIC DILATATION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTRIC PERFORATION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTRIC STENOSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTRIC ULCER 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTRIC ULCER PERFORATION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    GASTROINTESTINAL PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HAEMATEMESIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ILEAL PERFORATION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ILEUS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    NAUSEA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    OBSTRUCTION GASTRIC 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    OESOPHAGEAL STENOSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PANCREATITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    RECTAL HAEMORRHAGE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SMALL INTESTINAL OBSTRUCTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    STOMATITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    UPPER GASTROINTESTINAL HAEMORRHAGE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    VOMITING 0/7 (0%) 0 1/3 (33.3%) 1 0/8 (0%) 0 0/6 (0%) 0 5/208 (2.4%) 5 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    General disorders
    ASTHENIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    FATIGUE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INFLAMMATION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PYREXIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 7/208 (3.4%) 7 1/7 (14.3%) 2 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SUDDEN CARDIAC DEATH 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Hepatobiliary disorders
    BILE DUCT STONE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CHOLECYSTITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    CHOLECYSTITIS ACUTE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DRUG-INDUCED LIVER INJURY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Immune system disorders
    HYPOGAMMAGLOBULINAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Infections and infestations
    ACUTE SINUSITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ATYPICAL PNEUMONIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    BACTERIAL SEPSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    BRONCHITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CELLULITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CLOSTRIDIUM COLITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CLOSTRIDIUM DIFFICILE INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DEVICE RELATED INFECTION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DIVERTICULITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    EMPYEMA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ESCHERICHIA PYELONEPHRITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ESCHERICHIA URINARY TRACT INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTROENTERITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTROENTERITIS NOROVIRUS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HERPES SIMPLEX 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 5 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INFLUENZA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    LOWER RESPIRATORY TRACT INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    LUNG INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 4 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0
    MENINGITIS VIRAL 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    NASOPHARYNGITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    OOPHORITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ORAL CANDIDIASIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ORAL HERPES 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PNEUMOCYSTIS JIROVECII INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    PNEUMONIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 9/208 (4.3%) 9 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PNEUMONIA RESPIRATORY SYNCYTIAL VIRAL 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PSEUDOMONAL SEPSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    RECTAL ABSCESS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    RESPIRATORY TRACT INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    RHINOVIRUS INFECTION 1/7 (14.3%) 1 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SEPSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 6/208 (2.9%) 6 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    SIALOADENITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SINUSITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SKIN INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    STAPHYLOCOCCAL SEPSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    UPPER RESPIRATORY TRACT INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    URINARY TRACT INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    URINARY TRACT INFECTION PSEUDOMONAL 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    VASCULAR DEVICE INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Injury, poisoning and procedural complications
    CONTUSION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INFUSION RELATED REACTION 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 1/208 (0.5%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    LIGAMENT RUPTURE 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    POST LUMBAR PUNCTURE SYNDROME 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SPINAL FRACTURE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TOXICITY TO VARIOUS AGENTS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Investigations
    BLOOD POTASSIUM INCREASED 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    C-REACTIVE PROTEIN INCREASED 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Metabolism and nutrition disorders
    DECREASED APPETITE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DEHYDRATION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DIABETES MELLITUS INADEQUATE CONTROL 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HYPERKALAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1
    HYPOKALAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HYPONATRAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TUMOUR LYSIS SYNDROME 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    JOINT SWELLING 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PAIN IN EXTREMITY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SPONDYLOLISTHESIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE MYELOID LEUKAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ADENOLYMPHOMA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GLIOBLASTOMA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HISTIOCYTOSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    LUNG NEOPLASM MALIGNANT 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    MYELODYSPLASTIC SYNDROME 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Nervous system disorders
    CAROTID SINUS SYNDROME 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    EPILEPSY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HYPOGLOSSAL NERVE PARESIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    POLYNEUROPATHY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PRESYNCOPE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SYNCOPE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TRANSIENT ISCHAEMIC ATTACK 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Psychiatric disorders
    CONFUSIONAL STATE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    PSYCHOTIC DISORDER 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    COUGH 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DYSPNOEA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HAEMOPTYSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INTERSTITIAL LUNG DISEASE 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ORGANISING PNEUMONIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PLEURAL EFFUSION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PNEUMOTHORAX 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PRODUCTIVE COUGH 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PULMONARY EMBOLISM 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Skin and subcutaneous tissue disorders
    RASH MACULO-PAPULAR 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Vascular disorders
    EMBOLISM 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HYPOTENSION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Other (Not Including Serious) Adverse Events
    Venetoclax 200 mg +R-CHOP Venetoclax 400 mg +R-CHOP Venetoclax 600 mg +R-CHOP Venetoclax 800 mg +R-CHOP Venetoclax 800 mg +R-CHOP Phase II Venetoclax 200 mg +G-CHOP Venetoclax 400 mg +G-CHOP Venetoclax 600 mg +G-CHOP Venetoclax 800 mg + G-CHOP A Venetoclax 800 mg +G-CHOP B
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 7/7 (100%) 3/3 (100%) 8/8 (100%) 6/6 (100%) 204/208 (98.1%) 7/7 (100%) 7/7 (100%) 6/6 (100%) 6/6 (100%) 6/6 (100%)
    Blood and lymphatic system disorders
    ANAEMIA 4/7 (57.1%) 9 0/3 (0%) 0 1/8 (12.5%) 1 2/6 (33.3%) 2 73/208 (35.1%) 117 1/7 (14.3%) 1 1/7 (14.3%) 1 1/6 (16.7%) 4 5/6 (83.3%) 8 4/6 (66.7%) 5
    FEBRILE NEUTROPENIA 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 3 9/208 (4.3%) 10 0/7 (0%) 0 4/7 (57.1%) 7 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    HAEMOLYTIC ANAEMIA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    LEUKOPENIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 23/208 (11.1%) 47 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    NEUTROPENIA 4/7 (57.1%) 9 2/3 (66.7%) 8 6/8 (75%) 18 3/6 (50%) 10 134/208 (64.4%) 409 2/7 (28.6%) 2 4/7 (57.1%) 17 5/6 (83.3%) 13 6/6 (100%) 16 2/6 (33.3%) 10
    PANCYTOPENIA 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    THROMBOCYTOPENIA 4/7 (57.1%) 7 1/3 (33.3%) 2 3/8 (37.5%) 5 0/6 (0%) 0 52/208 (25%) 89 2/7 (28.6%) 3 3/7 (42.9%) 7 2/6 (33.3%) 6 4/6 (66.7%) 15 2/6 (33.3%) 5
    Cardiac disorders
    ANGINA PECTORIS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    ATRIAL FIBRILLATION 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 7/208 (3.4%) 8 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    CARDIAC FAILURE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PALPITATIONS 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 8/208 (3.8%) 8 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TACHYCARDIA 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    Congenital, familial and genetic disorders
    ICHTHYOSIS 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Ear and labyrinth disorders
    EAR PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TINNITUS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Eye disorders
    DRY EYE 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    EYE PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    LACRIMATION INCREASED 2/7 (28.6%) 2 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    PHOTOPHOBIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    VISION BLURRED 1/7 (14.3%) 1 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 7/208 (3.4%) 7 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    VITREOUS FLOATERS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    ABDOMINAL DISTENSION 2/7 (28.6%) 2 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 14/208 (6.7%) 15 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    ABDOMINAL PAIN 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1 30/208 (14.4%) 38 0/7 (0%) 0 1/7 (14.3%) 1 1/6 (16.7%) 1 3/6 (50%) 4 1/6 (16.7%) 1
    ABDOMINAL PAIN UPPER 0/7 (0%) 0 1/3 (33.3%) 1 1/8 (12.5%) 1 0/6 (0%) 0 7/208 (3.4%) 12 1/7 (14.3%) 1 1/7 (14.3%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    CONSTIPATION 1/7 (14.3%) 1 2/3 (66.7%) 2 3/8 (37.5%) 3 2/6 (33.3%) 2 67/208 (32.2%) 78 6/7 (85.7%) 7 3/7 (42.9%) 3 2/6 (33.3%) 2 2/6 (33.3%) 2 1/6 (16.7%) 1
    DENTAL CARIES 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    DENTAL CYST 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DIARRHOEA 3/7 (42.9%) 10 2/3 (66.7%) 4 2/8 (25%) 2 3/6 (50%) 5 79/208 (38%) 133 5/7 (71.4%) 5 3/7 (42.9%) 6 2/6 (33.3%) 3 2/6 (33.3%) 4 1/6 (16.7%) 1
    DRY MOUTH 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 5/208 (2.4%) 5 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 2 1/6 (16.7%) 1 0/6 (0%) 0
    DYSPEPSIA 1/7 (14.3%) 1 1/3 (33.3%) 1 0/8 (0%) 0 1/6 (16.7%) 1 22/208 (10.6%) 27 1/7 (14.3%) 1 1/7 (14.3%) 1 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    DYSPHAGIA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 7/208 (3.4%) 9 1/7 (14.3%) 1 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    FLATULENCE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTRIC ULCER 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    GASTROINTESTINAL DISORDER 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GASTROOESOPHAGEAL REFLUX DISEASE 1/7 (14.3%) 1 0/3 (0%) 0 1/8 (12.5%) 1 2/6 (33.3%) 2 6/208 (2.9%) 7 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    GINGIVAL PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    HAEMORRHOIDS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 15/208 (7.2%) 17 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    MOUTH ULCERATION 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 2 0/6 (0%) 0 7/208 (3.4%) 7 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    NAUSEA 3/7 (42.9%) 3 2/3 (66.7%) 4 1/8 (12.5%) 1 5/6 (83.3%) 7 108/208 (51.9%) 172 3/7 (42.9%) 5 4/7 (57.1%) 7 3/6 (50%) 4 5/6 (83.3%) 10 4/6 (66.7%) 6
    ORAL PAIN 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PROCTALGIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    STOMATITIS 2/7 (28.6%) 2 1/3 (33.3%) 1 1/8 (12.5%) 1 2/6 (33.3%) 2 24/208 (11.5%) 29 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    TOOTHACHE 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    VOMITING 0/7 (0%) 0 1/3 (33.3%) 1 1/8 (12.5%) 1 2/6 (33.3%) 6 64/208 (30.8%) 111 5/7 (71.4%) 5 4/7 (57.1%) 8 0/6 (0%) 0 4/6 (66.7%) 6 1/6 (16.7%) 1
    General disorders
    ASTHENIA 2/7 (28.6%) 2 1/3 (33.3%) 2 2/8 (25%) 2 0/6 (0%) 0 33/208 (15.9%) 41 2/7 (28.6%) 2 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    CHEST PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 12/208 (5.8%) 12 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    CHILLS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 12/208 (5.8%) 15 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    FATIGUE 5/7 (71.4%) 5 0/3 (0%) 0 3/8 (37.5%) 3 2/6 (33.3%) 4 81/208 (38.9%) 104 5/7 (71.4%) 7 2/7 (28.6%) 2 2/6 (33.3%) 2 3/6 (50%) 4 1/6 (16.7%) 1
    FEELING ABNORMAL 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    GAIT DISTURBANCE 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INFLUENZA LIKE ILLNESS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 4 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INFUSION SITE EXTRAVASATION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    MALAISE 2/7 (28.6%) 2 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 5/208 (2.4%) 5 1/7 (14.3%) 2 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    MUCOSAL INFLAMMATION 1/7 (14.3%) 1 0/3 (0%) 0 2/8 (25%) 2 1/6 (16.7%) 1 19/208 (9.1%) 28 1/7 (14.3%) 1 3/7 (42.9%) 3 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1
    NON-CARDIAC CHEST PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    OEDEMA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    OEDEMA PERIPHERAL 2/7 (28.6%) 2 0/3 (0%) 0 2/8 (25%) 2 0/6 (0%) 0 23/208 (11.1%) 26 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 3/6 (50%) 3 1/6 (16.7%) 1
    PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 7/208 (3.4%) 8 1/7 (14.3%) 1 1/7 (14.3%) 1 0/6 (0%) 0 1/6 (16.7%) 1 2/6 (33.3%) 2
    PYREXIA 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 2/6 (33.3%) 2 50/208 (24%) 68 0/7 (0%) 0 5/7 (71.4%) 7 2/6 (33.3%) 2 1/6 (16.7%) 1 2/6 (33.3%) 2
    UNEVALUABLE EVENT 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Hepatobiliary disorders
    CHOLELITHIASIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    HYPERBILIRUBINAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 5 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Immune system disorders
    HYPERSENSITIVITY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    HYPOGAMMAGLOBULINAEMIA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Infections and infestations
    ANORECTAL INFECTION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    BRONCHITIS 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 2 0/6 (0%) 0 16/208 (7.7%) 18 0/7 (0%) 0 1/7 (14.3%) 1 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1
    CAMPYLOBACTER GASTROENTERITIS 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CANDIDA INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CELLULITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CELLULITIS ORBITAL 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CLOSTRIDIUM DIFFICILE COLITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    CLOSTRIDIUM DIFFICILE INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CONJUNCTIVITIS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DEVICE RELATED INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    ENTEROVIRUS INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ERYSIPELAS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    FURUNCLE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HERPES SIMPLEX 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HERPES ZOSTER 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 1/7 (14.3%) 1 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    INFLUENZA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    LUNG INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 5 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    NASOPHARYNGITIS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 8/208 (3.8%) 9 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    ORAL CANDIDIASIS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 8/208 (3.8%) 9 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 1/6 (16.7%) 1
    ORAL FUNGAL INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    ORAL HERPES 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 5/208 (2.4%) 6 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PNEUMONIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 5/208 (2.4%) 5 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    PSEUDOMONAL BACTERAEMIA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    RHINITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 7/208 (3.4%) 7 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0
    SEPSIS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SINUSITIS BACTERIAL 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SKIN INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    STAPHYLOCOCCAL INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TOOTH ABSCESS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    UPPER RESPIRATORY TRACT INFECTION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 12/208 (5.8%) 15 2/7 (28.6%) 2 0/7 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 2 1/6 (16.7%) 1
    URINARY TRACT INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 16/208 (7.7%) 22 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    VASCULAR DEVICE INFECTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    VIRAL UPPER RESPIRATORY TRACT INFECTION 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    VULVOVAGINAL CANDIDIASIS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Injury, poisoning and procedural complications
    FALL 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    HAND FRACTURE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INFUSION RELATED REACTION 1/7 (14.3%) 1 2/3 (66.7%) 2 1/8 (12.5%) 1 2/6 (33.3%) 3 44/208 (21.2%) 48 4/7 (57.1%) 4 1/7 (14.3%) 1 2/6 (33.3%) 2 2/6 (33.3%) 3 3/6 (50%) 4
    MUSCLE STRAIN 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PROCEDURAL PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    THERMAL BURN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TRACHEAL OBSTRUCTION 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ASPARTATE AMINOTRANSFERASE INCREASED 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    BLOOD MAGNESIUM DECREASED 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    BLOOD POTASSIUM INCREASED 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    COMPUTERISED TOMOGRAM THORAX ABNORMAL 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    EJECTION FRACTION DECREASED 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    URINE OUTPUT DECREASED 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    WEIGHT DECREASED 2/7 (28.6%) 3 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 32/208 (15.4%) 33 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 2/6 (33.3%) 2 1/6 (16.7%) 1
    WEIGHT INCREASED 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    WHITE BLOOD CELL COUNT DECREASED 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Metabolism and nutrition disorders
    DECREASED APPETITE 1/7 (14.3%) 1 1/3 (33.3%) 1 1/8 (12.5%) 1 1/6 (16.7%) 1 42/208 (20.2%) 45 2/7 (28.6%) 2 2/7 (28.6%) 2 1/6 (16.7%) 1 2/6 (33.3%) 2 1/6 (16.7%) 1
    DEHYDRATION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 7/208 (3.4%) 11 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    FLUID RETENTION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    GOUT 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    HYPERKALAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 1/7 (14.3%) 1 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    HYPERPHOSPHATAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 1/7 (14.3%) 1 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    HYPERURICAEMIA 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HYPOCALCAEMIA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HYPOCHLORAEMIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    HYPOKALAEMIA 3/7 (42.9%) 4 1/3 (33.3%) 1 2/8 (25%) 2 0/6 (0%) 0 35/208 (16.8%) 44 1/7 (14.3%) 1 2/7 (28.6%) 2 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1
    HYPOMAGNESAEMIA 1/7 (14.3%) 6 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 10/208 (4.8%) 12 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HYPONATRAEMIA 1/7 (14.3%) 2 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    HYPOPHOSPHATAEMIA 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 7/208 (3.4%) 9 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TUMOUR LYSIS SYNDROME 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA 2/7 (28.6%) 4 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 22/208 (10.6%) 23 1/7 (14.3%) 1 2/7 (28.6%) 3 1/6 (16.7%) 2 0/6 (0%) 0 0/6 (0%) 0
    BACK PAIN 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 2/6 (33.3%) 2 29/208 (13.9%) 34 0/7 (0%) 0 2/7 (28.6%) 2 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1
    BONE PAIN 0/7 (0%) 0 1/3 (33.3%) 1 0/8 (0%) 0 1/6 (16.7%) 1 9/208 (4.3%) 10 2/7 (28.6%) 2 1/7 (14.3%) 2 2/6 (33.3%) 2 0/6 (0%) 0 1/6 (16.7%) 1
    MUSCLE SPASMS 1/7 (14.3%) 1 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 5/208 (2.4%) 5 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    MUSCULAR WEAKNESS 2/7 (28.6%) 2 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 10/208 (4.8%) 10 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1
    MUSCULOSKELETAL CHEST PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    MYALGIA 1/7 (14.3%) 1 0/3 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1 12/208 (5.8%) 18 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1
    PAIN IN EXTREMITY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 5/208 (2.4%) 5 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    PAIN IN JAW 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SQUAMOUS CELL CARCINOMA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SQUAMOUS CELL CARCINOMA OF SKIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    Nervous system disorders
    AGEUSIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    CAROTID SINUS SYNDROME 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    COGNITIVE DISORDER 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 2 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DISTURBANCE IN ATTENTION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DIZZINESS 1/7 (14.3%) 1 0/3 (0%) 0 2/8 (25%) 2 1/6 (16.7%) 1 24/208 (11.5%) 33 1/7 (14.3%) 1 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 2/6 (33.3%) 2
    DYSGEUSIA 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1 19/208 (9.1%) 19 1/7 (14.3%) 1 3/7 (42.9%) 3 1/6 (16.7%) 1 2/6 (33.3%) 2 4/6 (66.7%) 4
    HEADACHE 1/7 (14.3%) 1 0/3 (0%) 0 3/8 (37.5%) 3 1/6 (16.7%) 1 28/208 (13.5%) 31 3/7 (42.9%) 5 3/7 (42.9%) 3 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    HYPOAESTHESIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    LETHARGY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    MEMORY IMPAIRMENT 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    NEUROPATHY PERIPHERAL 2/7 (28.6%) 2 1/3 (33.3%) 2 3/8 (37.5%) 3 3/6 (50%) 3 28/208 (13.5%) 33 0/7 (0%) 0 2/7 (28.6%) 2 1/6 (16.7%) 1 1/6 (16.7%) 1 2/6 (33.3%) 3
    PARAESTHESIA 2/7 (28.6%) 2 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 18/208 (8.7%) 26 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PERIPHERAL MOTOR NEUROPATHY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1
    PERIPHERAL SENSORY NEUROPATHY 3/7 (42.9%) 3 1/3 (33.3%) 1 2/8 (25%) 2 2/6 (33.3%) 2 14/208 (6.7%) 14 0/7 (0%) 0 1/7 (14.3%) 1 1/6 (16.7%) 1 1/6 (16.7%) 1 1/6 (16.7%) 1
    POST HERPETIC NEURALGIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    PRESYNCOPE 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    SYNCOPE 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 8 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Psychiatric disorders
    ANXIETY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 9/208 (4.3%) 9 1/7 (14.3%) 3 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    DEPRESSION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 5 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    INSOMNIA 0/7 (0%) 0 0/3 (0%) 0 2/8 (25%) 3 1/6 (16.7%) 1 14/208 (6.7%) 17 2/7 (28.6%) 2 2/7 (28.6%) 3 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    MOOD SWINGS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Renal and urinary disorders
    BLADDER HYPERTROPHY 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    DYSURIA 0/7 (0%) 0 1/3 (33.3%) 1 0/8 (0%) 0 1/6 (16.7%) 1 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    HAEMATURIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    NOCTURIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    POLLAKIURIA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    RENAL FAILURE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    URINARY INCONTINENCE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    URINARY TRACT PAIN 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Reproductive system and breast disorders
    BREAST PAIN 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    TESTICULAR PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    VAGINAL DISCHARGE 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    VULVOVAGINAL DRYNESS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    COUGH 2/7 (28.6%) 2 0/3 (0%) 0 3/8 (37.5%) 4 1/6 (16.7%) 1 51/208 (24.5%) 67 3/7 (42.9%) 3 2/7 (28.6%) 2 0/6 (0%) 0 3/6 (50%) 5 2/6 (33.3%) 2
    DYSPNOEA 2/7 (28.6%) 3 1/3 (33.3%) 2 0/8 (0%) 0 1/6 (16.7%) 1 22/208 (10.6%) 24 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 1
    DYSPNOEA EXERTIONAL 0/7 (0%) 0 1/3 (33.3%) 1 1/8 (12.5%) 1 1/6 (16.7%) 1 4/208 (1.9%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    EPISTAXIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 3/208 (1.4%) 3 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    HICCUPS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 5 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    NASAL CONGESTION 1/7 (14.3%) 1 0/3 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1 11/208 (5.3%) 11 2/7 (28.6%) 2 1/7 (14.3%) 1 0/6 (0%) 0 2/6 (33.3%) 4 1/6 (16.7%) 1
    OROPHARYNGEAL PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 10/208 (4.8%) 13 1/7 (14.3%) 1 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PLEURAL EFFUSION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    PLEURITIC PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    PRODUCTIVE COUGH 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 8/208 (3.8%) 8 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    RHINORRHOEA 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 11/208 (5.3%) 11 1/7 (14.3%) 1 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 1/6 (16.7%) 1
    SINUS PAIN 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    VOCAL CORD DYSFUNCTION 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    WHEEZING 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    Skin and subcutaneous tissue disorders
    ALOPECIA 1/7 (14.3%) 2 0/3 (0%) 0 0/8 (0%) 0 3/6 (50%) 3 28/208 (13.5%) 29 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0 0/6 (0%) 0
    DRY SKIN 0/7 (0%) 0 1/3 (33.3%) 1 0/8 (0%) 0 0/6 (0%) 0 8/208 (3.8%) 9 0/7 (0%) 0 2/7 (28.6%) 2 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    ECCHYMOSIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    HYPERHIDROSIS 1/7 (14.3%) 2 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 3/208 (1.4%) 3 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    NAIL DISCOLOURATION 0/7 (0%) 0 0/3 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1 3/208 (1.4%) 3 0/7 (0%) 0 1/7 (14.3%) 1 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    NIGHT SWEATS 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 4/208 (1.9%) 4 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PIGMENTATION DISORDER 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 0/208 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    PRURITUS 1/7 (14.3%) 1 1/3 (33.3%) 1 0/8 (0%) 0 0/6 (0%) 0 6/208 (2.9%) 8 0/7 (0%) 0 0/7 (0%) 0 1/6 (16.7%) 1 1/6 (16.7%) 2 0/6 (0%) 0
    PURPURA 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    RASH 1/7 (14.3%) 1 0/3 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0 9/208 (4.3%) 9 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0
    RASH MACULO-PAPULAR 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 5/208 (2.4%) 5 1/7 (14.3%) 1 0/7 (0%) 0 2/6 (33.3%) 2 0/6 (0%) 0 0/6 (0%) 0
    SKIN HYPERPIGMENTATION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 1/208 (0.5%) 1 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1
    Vascular disorders
    HOT FLUSH 1/7 (14.3%) 1 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 2/208 (1%) 2 0/7 (0%) 0 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 1 0/6 (0%) 0
    HYPOTENSION 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/6 (0%) 0 13/208 (6.3%) 15 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 1/6 (16.7%) 2 0/6 (0%) 0
    THROMBOPHLEBITIS 0/7 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1 3/208 (1.4%) 3 1/7 (14.3%) 1 0/7 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/6 (0%) 0

    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.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffmann-La Roche
    Phone 800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT02055820
    Other Study ID Numbers:
    • GO27878
    • 2013-003749-40
    First Posted:
    Feb 5, 2014
    Last Update Posted:
    Jun 11, 2020
    Last Verified:
    May 1, 2020