Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Participants with High Risk Chronic Lymphocytic Leukemia (CLL)

Study identifier:ACE-CL-006

ClinicalTrials.gov identifier:NCT02477696

EudraCT identifier:2014-005530-64

CTIS identifier:2023-509347-27-00

Recruitment Complete

Official Title

A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase III Study of Acalabrutinib (ACP-196) versus Ibrutinib in Previously Treated Subjects with High Risk Chronic Lymphocytic Leukemia

Medical condition

Chronic Lymphocytic Leukemia

Phase

Phase 3

Healthy volunteers

Study drug

Acalabrutinib, Ibrutinib

Sex

All

Actual Enrollment

533

Study type

Interventional

Age

18 Years - n/a

Date

Study Start Date: 28 Jul 2015

Primary Completion Date: 15 Sept 2020

Estimated Study Completion Date: 03 Jan 2028

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: Single Blind
Primary Purpose: Treatment

Verification:

Verified 01 Jan 2025 by AcertaPharma

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

- Men and women ≥ 18 years of age.
- ECOG performance status of 0 to 2.
- Diagnosis of CLL.
- Must have ≥ 1 of the following high-risk prognostic factors:
*Presence of 17p del by central laboratory.
*Presence of 11q del by central laboratory.
- Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment
- Must have received ≥ 1 prior therapies for CLL.
- Meet the following laboratory parameters:
*Absolute neutrophil count (ANC) ≥ 750 cells/μL or ≥ 500 cells/μL in participants with documented bone marrow involvement, and independent of growth factor support 7 days before assessment.
*Platelet count ≥ 30,000 cells/μL without transfusion support 7 days before assessment. Participants with transfusion-dependent thrombocytopenia are excluded.
* Serum aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤ 3.0 x upper limit of normal (ULN).
*Total bilirubin ≤ 1.5 x ULN.
*Estimated creatinine clearance ≥ 30 mL/min.

Exclusion Criteria

- Known CNS lymphoma or leukemia.
- Known prolymphocytic leukemia or history of, or currently suspected, Richter’s syndrome.
- Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
- Prior exposure to ibrutinib or to a B-cell receptor (BCR) inhibitor or a B-cell lymphoma-2 (BCL-2) inhibitor.
- Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
- Prior radio- or toxin-conjugated antibody therapy.
- Prior allogeneic stem cell or autologous transplant.
- Major surgery within 4 weeks before first dose of study drug.
- Prior malignancy, except for adequately treated lentigo maligna melanoma, non-melanomatous skin cancer, in situ cervical carcinoma or other malignancy treated with no evidence of active disease > 3 years before Screening and at low risk for recurrence.
- Significant cardiovascular disease within 6 months of screening.
- Known history of infection with human immunodeficiency virus (HIV).
- History of stroke or intracranial hemorrhage within 6 months before randomization.
- History of bleeding diathesis.
- Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists within 7 days of first dose of study drug.
- Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor/inducer.

Location

Research Site

New Hyde Park, NY, United States, 11042

Location

Research Site

Istanbul, Turkey, 34452

Location

Research Site

Creteil, France, 94010

Location

Research Site

Harvey, IL, United States, 60426

Location

Research Site

Lodz, Poland, 93-510

Location

Research Site

Amsterdam, Netherlands, 1105 AZ

Location

Research Site

Murcia, Spain, 30008

Location

Research Site

Tampa, FL, United States, 33612

Arms	Assigned Interventions
Experimental: Acalabrutinib Participants will receive oral acalabrutinib 100 mg twice daily (BID) until disease progression (PD), or unacceptable toxicity, or other reasons for discontinuation, whichever occurs first.	Drug: Acalabrutinib Participants will receive oral acalabrutinib as stated in arm description. Other Name: ACP-196
Active Comparator: Ibrutinib Participants will receive oral ibrutinib 420 mg once daily (QD) until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurrs first.	Drug: Ibrutinib Participants will receive oral ibrutinib as stated in arm description.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 533 participants were randomized in this study of which 529 participants were treated (4 participants were randomized but not treated).

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg twice daily (BID) until disease progression (PD), or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg once daily (QD) until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Participant Flow: Overall Study

	Acalabrutinib	Ibrutinib
STARTED	268	265
Treated	265	264
COMPLETED	0	0
NOT COMPLETED	268	265
Death	89	106
Lost to Follow-up	7	5
Withdrawal by Subject	37	34
Physician Decision	7	9
Study terminated by sponsor	103	99
Other reasons including transition to commercial drug	23	12
Missing/Unknown	2	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Intent-to-treat (ITT) population included all participants randomized and were analyzed according to the arm to which they were randomly assigned.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Baseline Measures

	Acalabrutinib	Ibrutinib	Total
Number of Participants [units: Participants]	268	265	533
Age Continuous [units: Years] Mean ± Standard Deviation Age (years)	65.5 ± 9.3	65.3 ± 9.6	65.4 ± 9.4
Sex: Female, Male [units: Participants] Sex
Female	83	71	154
Male	185	194	379
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0	0	0
Asian	1	2	3
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	5	8	13
White	257	245	502
More than one race	0	0	0
Unknown or Not Reported	5	10	15
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	8	5	13
Not Hispanic or Latino	235	237	472
Unknown or Not Reported	25	23	48

Outcome Measures

1. Primary Outcome Measure: Progression-free Survival (PFS) Based on Independent Review Committee (IRC) Assessment [ Time Frame: Baseline (Days -28 to -1) through 55.2 months (maximum observed duration) ]

Measure Type	Primary
Measure Name	Progression-free Survival (PFS) Based on Independent Review Committee (IRC) Assessment
Measure Description	The PFS is defined as the time from date of randomization to the date of first IRC-assessed PD or death due to any cause, whichever occurred first. PD (per International Workshop on Chronic Lymphocytic Leukemia [iwCLL] 2008 criteria): Lymphocytes >= 50% increase over baseline, or >= 50% increase in lymphadenopathy/hepatomegaly/splenomegaly, or >= 50% platelets or > 2 g/dL hemoglobin decreases from baseline secondary to chronic lymphocytic leukemia (CLL). The PFS is assessed using the Kaplan-Meier method.
Time Frame	Baseline (Days -28 to -1) through 55.2 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all participants randomized and were analyzed according to the arm to which they were randomly assigned.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	268	265
Progression-free Survival (PFS) Based on Independent Review Committee (IRC) Assessment [units: Months] Median (95% Confidence Interval)	38.4 (33.0 to 38.6)	38.4 (33.0 to 41.6)

Statistical Analysis 1 for Progression-free Survival (PFS) Based on Independent Review Committee (IRC) Assessment

Groups^[1]	All groups
Hazard Ratio (HR)^[5]	1.00
95% Confidence Interval	( 0.79 to 1.27 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	Cox Proportional Hazards model stratified by 17p deletion status (yes versus no) and number of prior therapies (1-3 versus >=4).

2. Secondary Outcome Measure: Number of Participants With Treatment-emergent Infections Grade >= 3 [ Time Frame: Day 1 through 83.5 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Number of Participants With Treatment-emergent Infections Grade >= 3
Measure Description	Number of participants with treatment-emergent infections Grade >=3 are reported.
Time Frame	Day 1 through 83.5 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	266	263
Number of Participants With Treatment-emergent Infections Grade >= 3 [units: Participants]	98	101

No statistical analysis provided for Number of Participants With Treatment-emergent Infections Grade >= 3

3. Secondary Outcome Measure: Number of Participants With Treatment-emergent Richter's Transformation [ Time Frame: Day 1 through 83.5 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Number of Participants With Treatment-emergent Richter's Transformation
Measure Description	Richter's transformation is defined as the occurrence of an aggressive lymphoma in participants with a previous or concomitant diagnosis of CLL. Richter’s transformation was assessed by central pathology. Number of participants with treatment-emergent Richter’s transformation are reported.
Time Frame	Day 1 through 83.5 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	266	263
Number of Participants With Treatment-emergent Richter's Transformation [units: Participants]	13	14

No statistical analysis provided for Number of Participants With Treatment-emergent Richter's Transformation

4. Secondary Outcome Measure: Number of Participants with Treatment-emergent Atrial Fibrillation [ Time Frame: Day 1 through 83.5 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Number of Participants with Treatment-emergent Atrial Fibrillation
Measure Description	Number of participants with treatment-emergent atrial fibrillation (including atrial flutter) are reported.
Time Frame	Day 1 through 83.5 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	266	263
Number of Participants with Treatment-emergent Atrial Fibrillation [units: Participants]	32	49

No statistical analysis provided for Number of Participants with Treatment-emergent Atrial Fibrillation

5. Secondary Outcome Measure: Overall Survival (OS) [ Time Frame: Baseline (Days -28 to -1) through 83.7 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Overall Survival (OS)
Measure Description	The OS is defined as the time from date of randomization to date of death due to any cause. The OS is assessed using the Kaplan-Meier method.
Time Frame	Baseline (Days -28 to -1) through 83.7 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population included all participants randomized and were analyzed according to the arm to which they were randomly assigned.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	268	265
Overall Survival (OS) [units: Months] Median (95% Confidence Interval)	NA (NA to NA) ^[1]	NA (65.0 to NA) ^[1]

No statistical analysis provided for Overall Survival (OS)

6. Secondary Outcome Measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: Day 1 through 83.5 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Measure Description	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Time Frame	Day 1 through 83.5 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	266	263
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [units: Participants]
Any TEAEs	262	259
Any TESAEs	161	177

No statistical analysis provided for Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

7. Secondary Outcome Measure: Number of Participants With Treatment-emergent Laboratory Abnormalities [ Time Frame: Day 1 through 83.5 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Number of Participants With Treatment-emergent Laboratory Abnormalities
Measure Description	Number of participants with treatment-emergent laboratory abnormalities are reported. Laboratory abnormality is defined as any abnormal finding during analysis of hematology and serum chemistry.
Time Frame	Day 1 through 83.5 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	266	263
Number of Participants With Treatment-emergent Laboratory Abnormalities [units: Participants]
Absolute neutrophil count (decreased)	124	135
Haemoglobin (decreased)	139	131
Platelets (decreased)	119	116
Leukocytes (decreased)	60	64
Leukocytes (increased)	68	84
Absolute lymphocyte count (ALC) (decreased)	66	65
ALC (increased)	71	72
Alanine aminotransferase (increased)	73	70
Albumin (decreased)	31	44
Alkaline phosphatase (increased)	66	60
Aspartate aminotransferase (increased)	42	58
Bilirubin (increased)	46	69
Calcium (decreased)	56	71
Calcium (increased)	15	11
Creatinine (increased)	164	168
Glucose (decreased)	5	13
Glucose (increased)	21	23
Phosphate (decreased)	93	74
Potassium (decreased)	27	40
Potassium (increased)	62	52
Sodium (decreased)	26	37
Sodium (increased)	70	46
Urate (increased)	70	96

No statistical analysis provided for Number of Participants With Treatment-emergent Laboratory Abnormalities

8. Secondary Outcome Measure: Number of Participants With Abnormal Vital Signs Reported as TEAEs [ Time Frame: Day 1 through 83.5 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Number of Participants With Abnormal Vital Signs Reported as TEAEs
Measure Description	Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (body temperature, blood pressure, heart rate, and respiratory rate).
Time Frame	Day 1 through 83.5 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	266	263
Number of Participants With Abnormal Vital Signs Reported as TEAEs [units: Participants]
Abnormal loss of weight	0	1
Blood pressure fluctuation	0	1
Blood pressure increased	2	3
Blood pressure decreased	1	0
Blood pressure systolic increased	0	1
Body temperature decreased	1	0
Body temperature increased	0	1
Bradycardia	3	1
Breath sounds abnormal	0	1
Cardiac murmur	1	2
Dyspnoea	40	27
Dyspnoea exertional	2	5
Heart rate increased	0	1
Heart rate irregular	1	0
Hypertension	26	70
Hypotension	15	7
Hyperpyrexia	1	0
Orthostatic hypotension	2	1
Palpitations	12	15
Pyrexia	66	55
Tachycardia	7	7
Weight decreased	29	23
Weight increased	13	10
White coat hypertension	0	1

No statistical analysis provided for Number of Participants With Abnormal Vital Signs Reported as TEAEs

9. Secondary Outcome Measure: Percentage of Participants With Lymphocytosis [ Time Frame: Day 1 through 83.5 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Percentage of Participants With Lymphocytosis
Measure Description	Percentage of participants with at least one occurrence of treatment-related lymphocytosis defined as an elevation in ALC of >= 50% compared with baseline and a postbaseline assessment of > 5000/μL in the peripheral blood are reported.
Time Frame	Day 1 through 83.5 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	266	263
Percentage of Participants With Lymphocytosis [units: Percentage of participants] Number (95% Confidence Interval)	72.5 (66.7 to 77.7)	74.3 (68.6 to 79.5)

No statistical analysis provided for Percentage of Participants With Lymphocytosis

10. Secondary Outcome Measure: Number of Participants With Electrocardiogram (ECG) Abnormality at Baseline [ Time Frame: Baseline (Days -28 to -1) ]

Measure Type	Secondary
Measure Name	Number of Participants With Electrocardiogram (ECG) Abnormality at Baseline
Measure Description	Number of participants with ECG abnormality at baseline are reported.
Time Frame	Baseline (Days -28 to -1)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	266	263
Number of Participants With Electrocardiogram (ECG) Abnormality at Baseline [units: Participants]
Abnormal, not clinically significant	86	98
Abnormal, clinically significant	4	1

No statistical analysis provided for Number of Participants With Electrocardiogram (ECG) Abnormality at Baseline

11. Secondary Outcome Measure: Number of Participants With Shift from Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Baseline (Days -28 to -1) through 83.5 months (maximum observed duration) ]

Measure Type	Secondary
Measure Name	Number of Participants With Shift from Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
Measure Description	The ECOG performance status assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=death. Number of participants with shift from baseline (Days -28 to -1) to worst Grade 3 and 4 in ECOG performance status are reported.
Time Frame	Baseline (Days -28 to -1) through 83.5 months (maximum observed duration)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population included all participants who received at least one dose of study drug and were analyzed as treated. Here, "number of participants analyzed" (N) signified those participants who had a baseline value and at least 1 postbaseline value of ECOG performance status score during the study.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Measured Values

	Acalabrutinib	Ibrutinib
Number of Participants Analyzed [units:participants]	259	253
Number of Participants With Shift from Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status [units: Participants]
Baseline=0; Postbaseline=3	0	1
Baseline=1; Postbaseline=3	3	5
Baseline=2; Postbaseline=3	4	1
Baseline=0; Postbaseline=4	0	0
Baseline=1; Postbaseline=4	0	0
Baseline=2; Postbaseline=4	0	0

No statistical analysis provided for Number of Participants With Shift from Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

Serious Adverse Events

Time Frame	Day 1 through 83.5 months (maximum observed duration).
Additional Description	The AE/SAE data are reported for safety population. Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Serious Adverse Events

Acalabrutinib

Ibrutinib

Total, serious adverse events

# participants affected / at risk

161/266 (60.53%)

177/263 (67.30%)

Blood and lymphatic system disorders

Pancytopenia¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Infections and infestations

Abdominal infection¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Abscess limb¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Anal abscess¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Appendicitis¹,^†

# participants affected / at risk

1/266 (0.38%)

2/263 (0.76%)

# events

Infections and infestations

Arthritis bacterial¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Aspergillus infection¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Bacteraemia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Bacterial infection¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Bacterial sepsis¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Blood and lymphatic system disorders

Thrombocytopenia¹,^†

# participants affected / at risk

6/266 (2.26%)

3/263 (1.14%)

# events

Infections and infestations

Biliary sepsis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Blister infected¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Bone abscess¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Brain abscess¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

4/266 (1.50%)

2/263 (0.76%)

# events

Infections and infestations

Bronchopulmonary aspergillosis¹,^†

# participants affected / at risk

2/266 (0.75%)

1/263 (0.38%)

# events

Infections and infestations

COVID-19¹,^†

# participants affected / at risk

15/266 (5.64%)

14/263 (5.32%)

# events

Infections and infestations

COVID-19 pneumonia¹,^†

# participants affected / at risk

2/266 (0.75%)

5/263 (1.90%)

# events

Infections and infestations

Campylobacter infection¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Cellulitis¹,^†

# participants affected / at risk

3/266 (1.13%)

4/263 (1.52%)

# events

Blood and lymphatic system disorders

Thrombocytopenic purpura¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Cellulitis staphylococcal¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Cerebral aspergillosis¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Infections and infestations

Chronic sinusitis¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Infections and infestations

Clostridium difficile colitis¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Infections and infestations

Clostridium difficile infection¹,^†

# participants affected / at risk

2/266 (0.75%)

1/263 (0.38%)

# events

Infections and infestations

Coccidioidomycosis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Cryptococcosis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Cystitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Dermatitis infected¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

3/266 (1.13%)

1/263 (0.38%)

# events

Infections and infestations

Diarrhoea infectious¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Encephalitis viral¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Epstein-barr virus infection reactivation¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Escherichia pyelonephritis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Escherichia sepsis¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Infections and infestations

Escherichia urinary tract infection¹,^†

# participants affected / at risk

3/266 (1.13%)

2/263 (0.76%)

# events

Infections and infestations

Fungal abscess central nervous system¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

1/266 (0.38%)

2/263 (0.76%)

# events

Infections and infestations

Gastrointestinal infection¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Groin abscess¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Cardiac disorders

Aortic valve stenosis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Haematoma infection¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Haemophilus infection¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Infections and infestations

Hepatitis e¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Herpes zoster¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Infections and infestations

Herpes zoster meningoencephalitis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Hydrocele male infected¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Infected bite¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Infected skin ulcer¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Infection¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Infections and infestations

Infectious pleural effusion¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

8/266 (3.01%)

16/263 (6.08%)

# events

Infections and infestations

Infective exacerbation of bronchiectasis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

3/266 (1.13%)

3/263 (1.14%)

# events

Infections and infestations

Klebsiella sepsis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

1/266 (0.38%)

4/263 (1.52%)

# events

Infections and infestations

Lymphadenitis bacterial¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Meningitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Metapneumovirus infection¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Necrotising ulcerative gingivostomatitis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Neutropenic sepsis¹,^†

# participants affected / at risk

2/266 (0.75%)

1/263 (0.38%)

# events

Cardiac disorders

Atrial flutter¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Nocardiosis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Norovirus infection¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Oral candidiasis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Oral fungal infection¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Orchitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Otitis media¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Parainfluenzae virus infection¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Infections and infestations

Peritonsillar abscess¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Picornavirus infection¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Cardiac disorders

Atrioventricular block¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Pneumococcal infection¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Pneumococcal sepsis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Pneumocystis jirovecii pneumonia¹,^†

# participants affected / at risk

5/266 (1.88%)

0/263 (0.00%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

33/266 (12.41%)

30/263 (11.41%)

# events

Infections and infestations

Pneumonia acinetobacter¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Pneumonia bacterial¹,^†

# participants affected / at risk

2/266 (0.75%)

1/263 (0.38%)

# events

Infections and infestations

Pneumonia haemophilus¹,^†

# participants affected / at risk

1/266 (0.38%)

2/263 (0.76%)

# events

Infections and infestations

Pneumonia influenzal¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Pneumonia klebsiella¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Pneumonia mycoplasmal¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Cardiac disorders

Atrioventricular block second degree¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Infections and infestations

Pneumonia pneumococcal¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Pneumonia pseudomonal¹,^†

# participants affected / at risk

5/266 (1.88%)

0/263 (0.00%)

# events

Infections and infestations

Pneumonia staphylococcal¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Pneumonia streptococcal¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Pneumonia viral¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Post procedural cellulitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Postoperative wound infection¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Infections and infestations

Pseudomonal sepsis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Pulmonary nocardiosis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Respiratory tract infection¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Cardiac disorders

Bradyarrhythmia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Rhinovirus infection¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Salmonella sepsis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Sepsis¹,^†

# participants affected / at risk

5/266 (1.88%)

7/263 (2.66%)

# events

Infections and infestations

Septic shock¹,^†

# participants affected / at risk

2/266 (0.75%)

2/263 (0.76%)

# events

Infections and infestations

Soft tissue infection¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Staphylococcal infection¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Infections and infestations

Staphylococcal sepsis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Stenotrophomonas infection¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Systemic infection¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

15/266 (5.64%)

13/263 (4.94%)

# events

Cardiac disorders

Bradycardia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Tonsillitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

4/266 (1.50%)

2/263 (0.76%)

# events

Infections and infestations

Urinary tract candidiasis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

3/266 (1.13%)

7/263 (2.66%)

# events

Infections and infestations

Urinary tract infection bacterial¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Urinary tract infection enterococcal¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Urinary tract infection pseudomonal¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Urosepsis¹,^†

# participants affected / at risk

2/266 (0.75%)

1/263 (0.38%)

# events

Infections and infestations

Varicella zoster virus infection¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Infections and infestations

Viral pharyngitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Cardiac disorders

Bundle branch block¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Infections and infestations

Wound infection bacterial¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Infections and infestations

Wound infection staphylococcal¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Ankle fracture¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Injury, poisoning and procedural complications

Clavicle fracture¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Injury, poisoning and procedural complications

Fall¹,^†

# participants affected / at risk

4/266 (1.50%)

1/263 (0.38%)

# events

Injury, poisoning and procedural complications

Femur fracture¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Injury, poisoning and procedural complications

Fibula fracture¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Hand fracture¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Hip fracture¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Cardiac disorders

Cardiac arrest¹,^†

# participants affected / at risk

2/266 (0.75%)

3/263 (1.14%)

# events

Injury, poisoning and procedural complications

Humerus fracture¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Limb injury¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Injury, poisoning and procedural complications

Lower limb fracture¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Meniscus injury¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Injury, poisoning and procedural complications

Pelvic fracture¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Post procedural complication¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Splenic rupture¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Injury, poisoning and procedural complications

Subdural haematoma¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Injury, poisoning and procedural complications

Subdural haemorrhage¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Injury, poisoning and procedural complications

Tibia fracture¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Cardiac disorders

Cardiac asthma¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Injury, poisoning and procedural complications

Upper limb fracture¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Investigations

Blood lactate dehydrogenase increased¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Investigations

Blood magnesium decreased¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Investigations

Clostridium test positive¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Investigations

Glomerular filtration rate decreased¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Investigations

Hepatic enzyme increased¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Investigations

Weight decreased¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Metabolism and nutrition disorders

Cachexia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Dehydration¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

4/266 (1.50%)

6/263 (2.28%)

# events

Metabolism and nutrition disorders

Hypercalcaemia¹,^†

# participants affected / at risk

2/266 (0.75%)

3/263 (1.14%)

# events

Metabolism and nutrition disorders

Hyperglycaemia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Metabolism and nutrition disorders

Hypernatraemia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Metabolism and nutrition disorders

Hyperuricaemia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Hypocalcaemia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Hypoglycaemia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Hypokalaemia¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Hypomagnesaemia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Hyponatraemia¹,^†

# participants affected / at risk

2/266 (0.75%)

2/263 (0.76%)

# events

Metabolism and nutrition disorders

Hypophagia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Cardiac disorders

Cardiac failure chronic¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Hypophosphataemia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Hypovolaemia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Metabolism and nutrition disorders

Malnutrition¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Metabolism and nutrition disorders

Tumour lysis syndrome¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Musculoskeletal and connective tissue disorders

Flank pain¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Musculoskeletal and connective tissue disorders

Groin pain¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Musculoskeletal and connective tissue disorders

Joint instability¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Muscle spasms¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Cardiac disorders

Cardiac tamponade¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Musculoskeletal and connective tissue disorders

Myalgia¹,^†

# participants affected / at risk

2/266 (0.75%)

1/263 (0.38%)

# events

Musculoskeletal and connective tissue disorders

Osteoarthritis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Osteonecrosis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Musculoskeletal and connective tissue disorders

Osteopenia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Rhabdomyolysis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Acute myeloid leukaemia¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Adenocarcinoma of colon¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Cardiac disorders

Cardio-respiratory arrest¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Basal cell carcinoma¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Benign mesenteric neoplasm¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Bladder cancer¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Bladder transitional cell carcinoma¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Burkitt's lymphoma¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Endometrial adenoma¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Leukaemic infiltration pulmonary¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Lipoma¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Lung adenocarcinoma¹,^†

# participants affected / at risk

3/266 (1.13%)

2/263 (0.76%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Lung neoplasm¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Cardiac disorders

Mitral valve incompetence¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Lung neoplasm malignant¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Malignant melanoma¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Malignant melanoma in situ¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Meningioma¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Metastases to lung¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Non-small cell lung cancer¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Ovarian cancer metastatic¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Pancreatic carcinoma metastatic¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Polycythaemia vera¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Prostate cancer¹,^†

# participants affected / at risk

1/266 (0.38%)

6/263 (2.28%)

# events

Cardiac disorders

Myocardial infarction¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Rectosigmoid cancer¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Renal cancer¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Renal cell carcinoma¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Renal neoplasm¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Squamous cell carcinoma of lung¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Squamous cell carcinoma of skin¹,^†

# participants affected / at risk

1/266 (0.38%)

2/263 (0.76%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Squamous cell carcinoma of the parotid gland¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Squamous cell carcinoma of the vulva¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Thymoma¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Tumour associated fever¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Blood and lymphatic system disorders

Autoimmune haemolytic anaemia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Cardiac disorders

Myocardial ischaemia¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Tumour pain¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Cerebral infarction¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Nervous system disorders

Cerebral ischaemia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Cerebrovascular accident¹,^†

# participants affected / at risk

3/266 (1.13%)

2/263 (0.76%)

# events

Nervous system disorders

Cerebrovascular disorder¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Demyelinating polyneuropathy¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Facial paralysis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Guillain-barre syndrome¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Nervous system disorders

Haemorrhage intracranial¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Cardiac disorders

Palpitations¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

2/266 (0.75%)

4/263 (1.52%)

# events

Nervous system disorders

Ischaemic stroke¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Language disorder¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Nervous system disorders

Memory impairment¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Multifocal motor neuropathy¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Muscle spasticity¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Nervous system disorders

Paraesthesia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Nervous system disorders

Partial seizures¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Post herpetic neuralgia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Nervous system disorders

Seizure¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Cardiac disorders

Pericardial effusion¹,^†

# participants affected / at risk

2/266 (0.75%)

2/263 (0.76%)

# events

Nervous system disorders

Somnolence¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

3/266 (1.13%)

4/263 (1.52%)

# events

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Psychiatric disorders

Confusional state¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Psychiatric disorders

Delirium¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Psychiatric disorders

Psychotic disorder¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Renal and urinary disorders

Acute kidney injury¹,^†

# participants affected / at risk

2/266 (0.75%)

6/263 (2.28%)

# events

Renal and urinary disorders

Chronic kidney disease¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Renal and urinary disorders

Haematuria¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Cardiac disorders

Pericarditis¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Renal and urinary disorders

Nephrolithiasis¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Renal and urinary disorders

Renal colic¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Renal and urinary disorders

Renal failure¹,^†

# participants affected / at risk

1/266 (0.38%)

2/263 (0.76%)

# events

Renal and urinary disorders

Renal impairment¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Reproductive system and breast disorders

Oedema genital¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Reproductive system and breast disorders

Prostatitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Reproductive system and breast disorders

Vulvar dysplasia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Bronchiectasis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Bronchospasm¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Cardiac disorders

Supraventricular tachycardia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

3/266 (1.13%)

3/263 (1.14%)

# events

Respiratory, thoracic and mediastinal disorders

Epistaxis¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Hypoxia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Lung disorder¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Lung infiltration¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Respiratory, thoracic and mediastinal disorders

Mediastinal haematoma¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Cardiac disorders

Ventricular fibrillation¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Pleural effusion¹,^†

# participants affected / at risk

1/266 (0.38%)

5/263 (1.90%)

# events

Respiratory, thoracic and mediastinal disorders

Pleurisy¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Pneumonitis¹,^†

# participants affected / at risk

2/266 (0.75%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Pneumothorax¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary granuloma¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary haematoma¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary hypertension¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary mass¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Congenital, familial and genetic disorders

Arteriovenous malformation¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Respiratory failure¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Respiratory, thoracic and mediastinal disorders

Tonsillar disorder¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Tonsillar hypertrophy¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Skin and subcutaneous tissue disorders

Rash maculo-papular¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Skin and subcutaneous tissue disorders

Skin haemorrhage¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Ear and labyrinth disorders

Sudden hearing loss¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Skin and subcutaneous tissue disorders

Skin ulcer¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Vascular disorders

Aortic disorder¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Vascular disorders

Aortic dissection¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Vascular disorders

Circulatory collapse¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Vascular disorders

Deep vein thrombosis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Vascular disorders

Embolism¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Vascular disorders

Embolism venous¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Vascular disorders

Haemorrhagic infarction¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Endocrine disorders

Hypercalcaemia of malignancy¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Vascular disorders

Hypotension¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Vascular disorders

Orthostatic hypotension¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Vascular disorders

Superficial vein thrombosis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Vascular disorders

Thrombophlebitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Vascular disorders

Vasculitis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Eye disorders

Cataract¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Blood and lymphatic system disorders

Coagulopathy¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Eye disorders

Dacryoadenitis acquired¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Eye disorders

Retinal detachment¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Eye disorders

Vitreous haemorrhage¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

2/266 (0.75%)

4/263 (1.52%)

# events

Gastrointestinal disorders

Abdominal pain upper¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Abdominal wall haematoma¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Ascites¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Colitis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Colitis ischaemic¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Colitis ulcerative¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Blood and lymphatic system disorders

Febrile neutropenia¹,^†

# participants affected / at risk

4/266 (1.50%)

6/263 (2.28%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

3/266 (1.13%)

3/263 (1.14%)

# events

Gastrointestinal disorders

Duodenal ulcer¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Duodenal ulcer perforation¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Erosive oesophagitis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Gastric ulcer¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Gastrointestinal haemorrhage¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Gastrointestinal ulcer¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Ileus¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Blood and lymphatic system disorders

Haemolytic anaemia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Incarcerated inguinal hernia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Inguinal hernia¹,^†

# participants affected / at risk

0/266 (0.00%)

3/263 (1.14%)

# events

Gastrointestinal disorders

Intestinal obstruction¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Intestinal perforation¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

Gastrointestinal disorders

Mallory-weiss syndrome¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Pancreatitis acute¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Pharyngo-oesophageal diverticulum¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Pneumatosis intestinalis¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Gastrointestinal disorders

Rectal haemorrhage¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Sigmoid mesocolon hernia¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Splenic artery aneurysm¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Upper gastrointestinal haemorrhage¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Volvulus¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

General disorders and administration site conditions

Chest discomfort¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

General disorders and administration site conditions

Chest pain¹,^†

# participants affected / at risk

1/266 (0.38%)

2/263 (0.76%)

# events

Blood and lymphatic system disorders

Lymphadenopathy¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

General disorders and administration site conditions

Death¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

General disorders and administration site conditions

Fatigue¹,^†

# participants affected / at risk

2/266 (0.75%)

1/263 (0.38%)

# events

General disorders and administration site conditions

Gait disturbance¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

General disorders and administration site conditions

General physical health deterioration¹,^†

# participants affected / at risk

0/266 (0.00%)

2/263 (0.76%)

# events

General disorders and administration site conditions

Malaise¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

General disorders and administration site conditions

Mass¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

General disorders and administration site conditions

Multiple organ dysfunction syndrome¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Blood and lymphatic system disorders

Neutropenia¹,^†

# participants affected / at risk

3/266 (1.13%)

1/263 (0.38%)

# events

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

11/266 (4.14%)

6/263 (2.28%)

# events

General disorders and administration site conditions

Soft tissue inflammation¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

General disorders and administration site conditions

Tissue infiltration¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Hepatobiliary disorders

Bile duct stone¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Hepatobiliary disorders

Cholecystitis acute¹,^†

# participants affected / at risk

2/266 (0.75%)

0/263 (0.00%)

# events

Hepatobiliary disorders

Cholelithiasis¹,^†

# participants affected / at risk

1/266 (0.38%)

1/263 (0.38%)

# events

Hepatobiliary disorders

Hyperbilirubinaemia¹,^†

# participants affected / at risk

1/266 (0.38%)

0/263 (0.00%)

# events

Immune system disorders

Amyloidosis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Immune system disorders

Food allergy¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

Immune system disorders

Haemophagocytic lymphohistiocytosis¹,^†

# participants affected / at risk

0/266 (0.00%)

1/263 (0.38%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 25.0

Other Adverse Events

Time Frame	Day 1 through 83.5 months (maximum observed duration).
Additional Description	The AE/SAE data are reported for safety population. Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Acalabrutinib	Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Ibrutinib	Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.

Other Adverse Events

Acalabrutinib

Ibrutinib

Total, other (not including serious) adverse events

# participants affected / at risk

251/266 (94.36%)

251/263 (95.44%)

Immune system disorders

Hypogammaglobulinaemia¹,^†

# participants affected / at risk

13/266 (4.89%)

15/263 (5.70%)

# events

Blood and lymphatic system disorders

Thrombocytopenia¹,^†

# participants affected / at risk

38/266 (14.29%)

36/263 (13.69%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

35/266 (13.16%)

23/263 (8.75%)

# events

Infections and infestations

COVID-19¹,^†

# participants affected / at risk

29/266 (10.90%)

24/263 (9.13%)

# events

Infections and infestations

Conjunctivitis¹,^†

# participants affected / at risk

12/266 (4.51%)

15/263 (5.70%)

# events

Infections and infestations

Herpes zoster¹,^†

# participants affected / at risk

24/266 (9.02%)

16/263 (6.08%)

# events

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

26/266 (9.77%)

42/263 (15.97%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

11/266 (4.14%)

15/263 (5.70%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

9/266 (3.38%)

19/263 (7.22%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

30/266 (11.28%)

28/263 (10.65%)

# events

Infections and infestations

Oral herpes¹,^†

# participants affected / at risk

18/266 (6.77%)

17/263 (6.46%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

33/266 (12.41%)

32/263 (12.17%)

# events

Infections and infestations

Respiratory tract infection¹,^†

# participants affected / at risk

12/266 (4.51%)

14/263 (5.32%)

# events

Infections and infestations

Sinusitis¹,^†

# participants affected / at risk

26/266 (9.77%)

22/263 (8.37%)

# events

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

53/266 (19.92%)

48/263 (18.25%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

73/266 (27.44%)

65/263 (24.71%)

# events

122

106

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

24/266 (9.02%)

38/263 (14.45%)

# events

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

31/266 (11.65%)

47/263 (17.87%)

# events

Injury, poisoning and procedural complications

Fall¹,^†

# participants affected / at risk

14/266 (5.26%)

10/263 (3.80%)

# events

Investigations

Weight decreased¹,^†

# participants affected / at risk

29/266 (10.90%)

23/263 (8.75%)

# events

Metabolism and nutrition disorders

Decreased appetite¹,^†

# participants affected / at risk

19/266 (7.14%)

26/263 (9.89%)

# events

Metabolism and nutrition disorders

Hyperuricaemia¹,^†

# participants affected / at risk

17/266 (6.39%)

19/263 (7.22%)

# events

Metabolism and nutrition disorders

Hypokalaemia¹,^†

# participants affected / at risk

13/266 (4.89%)

25/263 (9.51%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

55/266 (20.68%)

70/263 (26.62%)

# events

120

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

27/266 (10.15%)

40/263 (15.21%)

# events

Musculoskeletal and connective tissue disorders

Muscle spasms¹,^†

# participants affected / at risk

16/266 (6.02%)

41/263 (15.59%)

# events

Musculoskeletal and connective tissue disorders

Myalgia¹,^†

# participants affected / at risk

25/266 (9.40%)

24/263 (9.13%)

# events

Musculoskeletal and connective tissue disorders

Neck pain¹,^†

# participants affected / at risk

14/266 (5.26%)

6/263 (2.28%)

# events

Musculoskeletal and connective tissue disorders

Pain in extremity¹,^†

# participants affected / at risk

23/266 (8.65%)

28/263 (10.65%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Basal cell carcinoma¹,^†

# participants affected / at risk

14/266 (5.26%)

13/263 (4.94%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Squamous cell carcinoma of skin¹,^†

# participants affected / at risk

14/266 (5.26%)

9/263 (3.42%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

30/266 (11.28%)

27/263 (10.27%)

# events

Cardiac disorders

Palpitations¹,^†

# participants affected / at risk

11/266 (4.14%)

15/263 (5.70%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

92/266 (34.59%)

56/263 (21.29%)

# events

164

100

Nervous system disorders

Paraesthesia¹,^†

# participants affected / at risk

14/266 (5.26%)

11/263 (4.18%)

# events

Psychiatric disorders

Insomnia¹,^†

# participants affected / at risk

28/266 (10.53%)

13/263 (4.94%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

79/266 (29.70%)

60/263 (22.81%)

# events

118

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

37/266 (13.91%)

26/263 (9.89%)

# events

Respiratory, thoracic and mediastinal disorders

Epistaxis¹,^†

# participants affected / at risk

22/266 (8.27%)

29/263 (11.03%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal congestion¹,^†

# participants affected / at risk

18/266 (6.77%)

16/263 (6.08%)

# events

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹,^†

# participants affected / at risk

22/266 (8.27%)

20/263 (7.60%)

# events

Respiratory, thoracic and mediastinal disorders

Productive cough¹,^†

# participants affected / at risk

20/266 (7.52%)

14/263 (5.32%)

# events

Skin and subcutaneous tissue disorders

Ecchymosis¹,^†

# participants affected / at risk

14/266 (5.26%)

11/263 (4.18%)

# events

Skin and subcutaneous tissue disorders

Onychoclasis¹,^†

# participants affected / at risk

2/266 (0.75%)

18/263 (6.84%)

# events

Skin and subcutaneous tissue disorders

Petechiae¹,^†

# participants affected / at risk

12/266 (4.51%)

24/263 (9.13%)

# events

Skin and subcutaneous tissue disorders

Pruritus¹,^†

# participants affected / at risk

16/266 (6.02%)

12/263 (4.56%)

# events

Skin and subcutaneous tissue disorders

Rash¹,^†

# participants affected / at risk

27/266 (10.15%)

35/263 (13.31%)

# events

Skin and subcutaneous tissue disorders

Rash maculo-papular¹,^†

# participants affected / at risk

12/266 (4.51%)

15/263 (5.70%)

# events

Vascular disorders

Haematoma¹,^†

# participants affected / at risk

24/266 (9.02%)

20/263 (7.60%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

26/266 (9.77%)

70/263 (26.62%)

# events

118

Vascular disorders

Hypotension¹,^†

# participants affected / at risk

14/266 (5.26%)

7/263 (2.66%)

# events

Eye disorders

Cataract¹,^†

# participants affected / at risk

12/266 (4.51%)

17/263 (6.46%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

21/266 (7.89%)

21/263 (7.98%)

# events

Gastrointestinal disorders

Abdominal pain upper¹,^†

# participants affected / at risk

17/266 (6.39%)

18/263 (6.84%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

33/266 (12.41%)

39/263 (14.83%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

93/266 (34.96%)

122/263 (46.39%)

# events

180

236

Gastrointestinal disorders

Dyspepsia¹,^†

# participants affected / at risk

12/266 (4.51%)

35/263 (13.31%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

49/266 (18.42%)

50/263 (19.01%)

# events

Blood and lymphatic system disorders

Increased tendency to bruise¹,^†

# participants affected / at risk

5/266 (1.88%)

14/263 (5.32%)

# events

Gastrointestinal disorders

Stomatitis¹,^†

# participants affected / at risk

9/266 (3.38%)

23/263 (8.75%)

# events

Gastrointestinal disorders

Toothache¹,^†

# participants affected / at risk

6/266 (2.26%)

14/263 (5.32%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

29/266 (10.90%)

36/263 (13.69%)

# events

General disorders and administration site conditions

Asthenia¹,^†

# participants affected / at risk

24/266 (9.02%)

27/263 (10.27%)

# events

General disorders and administration site conditions

Chills¹,^†

# participants affected / at risk

10/266 (3.76%)

17/263 (6.46%)

# events

General disorders and administration site conditions

Fatigue¹,^†

# participants affected / at risk

62/266 (23.31%)

48/263 (18.25%)

# events

General disorders and administration site conditions

Influenza like illness¹,^†

# participants affected / at risk

16/266 (6.02%)

16/263 (6.08%)

# events

General disorders and administration site conditions

Oedema peripheral¹,^†

# participants affected / at risk

33/266 (12.41%)

42/263 (15.97%)

# events

Blood and lymphatic system disorders

Neutropenia¹,^†

# participants affected / at risk

56/266 (21.05%)

65/263 (24.71%)

# events

151

156

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

61/266 (22.93%)

50/263 (19.01%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 25.0

Certain Agreements

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

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

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: MedImmune has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	Acerta Pharma BV
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

Download
Redacted CSR Synopsis
Download
Redacted CSP
Download
Redacted SAP
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Acerta Clinical Trials

1-888-292-9613

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Redacted CSR Synopsis

Redacted CSP

Redacted SAP

Trial Results Summaries