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Clinical Trial Results:
A Phase 3, Randomized, Open-Label, Multicenter Study Comparing the Efficacy and Safety of the Bruton’s Tyrosine Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects with Waldenström’s Macroglobulinemia (WM)

Summary
EudraCT number	2016-002980-33
Trial protocol	DE BE SE ES NL PL GR GB CZ FR IT
Global end of trial date	21 Jun 2022

Results information
Results version number	v2(current)
This version publication date	10 Nov 2023
First version publication date	14 Apr 2023
Other versions	v1
Version creation reason	Changes to summary attachments Removal of incorrect secondary identifier number

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BGB-3111-302

ISRCTN number

US NCT number

NCT03053440

WHO universal trial number (UTN)

Sponsor organisation name

BeiGene

Sponsor organisation address

1840 Gateway Drive, San Mateo, CA , United States, 94404

Public contact

BeiGene Clinical Support, BeiGene USA, Inc., +1 877-828-5568, clinicaltrials@beigene.com

Scientific contact

BeiGene Clinical Support, BeiGene USA, Inc., +1 877-828-5568, clinicaltrials@beigene.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Jul 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Jun 2022

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of zanubrutinib (BGB-3111) vs ibrutinib in subjects with MYD88MUT WM

Protection of trial subjects

This study was conducted in accordance with sponsor procedures, which comply with the principles of GCP, International Council on Harmonisation Guidelines, the Declaration of Helsinki, and applicable local regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Dec 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 62

Country: Number of subjects enrolled

United States: 19

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Poland: 16

Country: Number of subjects enrolled

Spain: 18

Country: Number of subjects enrolled

Sweden: 7

Country: Number of subjects enrolled

United Kingdom: 30

Country: Number of subjects enrolled

Czechia: 7

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

Greece: 11

Country: Number of subjects enrolled

Italy: 23

Worldwide total number of subjects

201

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

134

85 years and over

Subject disposition

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Recruitment details

A total of 229 participants were randomized to Arms A and B in 12 countries in Europeen Union, United Kingdom and United States.

Screening details

The screening period consisted of Days -35 to -1.

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A: Ibrutinib

Arm description

Participants diagnosed with WM with mutated MYD88 gene received 420 mg ibrutinib once daily orally until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor

Arm type

Experimental

Investigational medicinal product name

Ibrutininb

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ibrutinib 420 milligrams (mg) once a day

Arm B: Zanubrutinib

Arm description

Participants diagnosed with WM with mutated MYD88 gene received 160 mg zanubrutinib twice daily orally until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor

Arm type

Experimental

Investigational medicinal product name

Zanubrutinib

Investigational medicinal product code

Other name

Brukinsa, BGB-3111

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Zanubrutinib 160 mg twice a day

Number of subjects in period 1	Arm A: Ibrutinib	Arm B: Zanubrutinib
Started	99	102
Completed	0	0
Not completed	99	102
Adverse event, serious fatal	19	14
Consent withdrawn by subject	9	8
Physician decision	2	1
Sponsor's decision to end study	20	13
Lost to follow-up	1	-
Enrolled in Long-term extension study	48	66

Baseline characteristics

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Reporting group title

Arm A: Ibrutinib

Reporting group description

Reporting group title

Arm B: Zanubrutinib

Reporting group description

Reporting group values	Arm A: Ibrutinib	Arm B: Zanubrutinib	Total
Number of subjects	99	102	201
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	69.9 ± 8.58	69.2 ± 10.26	-
Gender categorical
Units: Subjects
Female	34	33	67
Male	65	69	134
Ethnicity
Units: Subjects
Hispanic or Latino	4	4	8
Not Hispanic or Latino	91	82	173
Unknown or Not Reported	4	16	20
Race
Units: Subjects
Asian	0	4	4
White	94	88	182
Unknown or Not Reported	5	10	15

End points

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Reporting group title

Arm A: Ibrutinib

Reporting group description

Reporting group title

Arm B: Zanubrutinib

Reporting group description

Primary: Percentage of participants achieving either a complete response (CR) or very good partial response (VGPR) using an adaptation of the response criteria updated at the Sixth IWWM as assessed by an independent review committee (IRC)

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End point title

Percentage of participants achieving either a complete response (CR) or very good partial response (VGPR) using an adaptation of the response criteria updated at the Sixth IWWM as assessed by an independent review committee (IRC)

End point description

Percentage of participants with CR, defined as normal serum immunoglobulin M (IgM) levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values. Intent to Treat (ITT) Analysis Set: Includes all randomized participants assigned to an arm.

End point type

Primary

End point timeframe

Up to approximately 2 years and 7 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	102
Units: Percentage of Participants
number (confidence interval 95%)	19.2 (12.0 to 28.3)	28.4 (19.9 to 38.2)

Statistical analysis 1

Comparison groups

Arm A: Ibrutinib v Arm B: Zanubrutinib

Number of subjects included in analysis

201

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0921 ^[1]

Method

Cochran-Mantel-Haenszel

Parameter type

Risk difference (RD)

Point estimate

10.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

Notes
[1] - Based on Cochran-Mantel-Haenszel test stratified by the stratification factors per IRT. p Value is 2-sided

Secondary: Percentage of Participants Achieving Major Response Rate (MRR) as assessed by IRC

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End point title

Percentage of Participants Achieving Major Response Rate (MRR) as assessed by IRC

End point description

MRR defined as the proportion of participants achieving a best response of response of CR, VGPR, or partial response (PR). MRR defined as the proportion of participants achieving a best response of response of CR, VGPR, or partial response (PR). ITT Analysis Set

End point type

Secondary

End point timeframe

Up to approximately 2 years and 7 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	100
Units: Percentage of Participants
number (confidence interval 95%)	77.8 (68.3 to 85.5)	77.5 (68.1 to 85.1)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as assessed by IRC

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End point title

Duration of Response (DOR) as assessed by IRC

End point description

DOR defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first. ITT Analysis set

End point type

Secondary

End point timeframe

Up to approximately 2 years and 7 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99 ^[2]	102 ^[3]
Units: Months
median (confidence interval 95%)	9999 (9999 to 9999)	9999 (9999 to 9999)

Notes
[2] - 9999 = Not Estimable due to insufficient number of events
[3] - 9999 = Not Estimable due to insufficient number of events

No statistical analyses for this end point

Secondary: Percentage of participants achieving either CR or VGPR in as assessed by the investigator

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End point title

Percentage of participants achieving either CR or VGPR in as assessed by the investigator

End point description

Percentage of participants with CR, defined as normal serum immunoglobulin M (IgM) levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at Baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values. ITT Analysis set

End point type

Secondary

End point timeframe

Up to approximately 5 years and 5 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	101
Units: Percentage of Participants
number (confidence interval 95%)	25.3 (17.1 to 35.0)	38.2 (28.8 to 48.4)

No statistical analyses for this end point

Secondary: DOR in as assessed by the Investigator

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End point title

DOR in as assessed by the Investigator

End point description

DOR is defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first. ITT Analysis Set

End point type

Secondary

End point timeframe

Up to approximately 5 years and 5 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99 ^[4]	102 ^[5]
Units: Months
median (confidence interval 95%)	9999 (53.5 to 9999)	9999 (9999 to 9999)

Notes
[4] - 9999 = Not Estimable due to insufficient number of events
[5] - 9999 = Not Estimable due to insufficient number of events

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) as assessed by the Investigator

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End point title

Progression Free Survival (PFS) as assessed by the Investigator

End point description

PFS as assessed by the Investigator, defined as time from randomization to the first documentation of progression (per modified IWWM criteria) or death, whichever occurs first. ITT Analysis Set

End point type

Secondary

End point timeframe

Up to approximately 5 years and 5 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99 ^[6]	102 ^[7]
Units: Months
median (confidence interval 95%)	9999 (54.4 to 9999)	9999 (9999 to 9999)

Notes
[6] - 9999 = Not Estimable due to insufficient number of events
[7] - 9999 = Not Estimable due to insufficient number of events

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) as assessed by the IRC

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End point title

Progression Free Survival (PFS) as assessed by the IRC

End point description

PFS as assessed by the IRC, defined as time from randomization to the first documentation of progression (per modified IWWM criteria) or death, whichever occurs first. ITT Analysis Set

End point type

Secondary

End point timeframe

Up to approximately 2 years and 7 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99 ^[8]	102 ^[9]
Units: Months
median (confidence interval 95%)	9999 (9999 to 9999)	9999 (9999 to 9999)

Notes
[8] - 9999 = Not Estimable due to insufficient number of events
[9] - 9999 = Not Estimable due to insufficient number of events

No statistical analyses for this end point

Secondary: Percentage of participants with Resolution of all Treatment-precipitating Symptoms

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End point title

Percentage of participants with Resolution of all Treatment-precipitating Symptoms

End point description

End point type

Secondary

End point timeframe

Up to approximately 5 years and 5 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	102
Units: Percentage of Participants
number (not applicable)	78.6	79.2

No statistical analyses for this end point

Secondary: Percentage of participants with an anti-Lymphoma effect

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End point title

Percentage of participants with an anti-Lymphoma effect

End point description

ITT Analysis Set

End point type

Secondary

End point timeframe

Up to approximately 5 years and 5 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	102
Units: Percentage of Participants
number (not applicable)	84.2	78.8

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-Emergent adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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End point title

Number of Participants with Treatment-Emergent adverse Events (TEAEs) and Serious Adverse Events (SAEs)

End point description

Safety Analysis Set includes all participants who received any dose of zanubrutinib or ibrutinib

End point type

Secondary

End point timeframe

Up to approximately 5 years and 5 months

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	98	101
Units: Percentage of Participants
number (not applicable)
Participants with At Least 1 TEAE	98	101
Participants with SAEs	50	59

No statistical analyses for this end point

Secondary: DOR as Assessed by IRC: Event -Free Rate

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End point title

DOR as Assessed by IRC: Event -Free Rate

End point description

Estimated percentage of participants who were event-free based on Kaplan-Meier method.

End point type

Secondary

End point timeframe

12 and 18 months from the date of randomization (up to approximately 2 years and 7 months)

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	102
Units: Percentage of Participants
number (confidence interval 95%)
12 Months	87.9 (77.0 to 93.8)	94.4 (85.8 to 97.9)
18 Months	87.9 (77.0 to 93.8)	85.2 (71.7 to 92.6)

No statistical analyses for this end point

Secondary: DOR as Assessed by the Investigator: Event-Free Rate

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End point title

DOR as Assessed by the Investigator: Event-Free Rate

End point description

Estimated percentage of participants who were event-free based on Kaplan-Meier method.

End point type

Secondary

End point timeframe

24, 36 and 48 months from the date of randomization (up to approximately 5 years and 5 months)

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	102
Units: Percentage of Participants
number (confidence interval 95%)
24 Months	87.7 (77.8 to 93.4)	89.7 (80.4 to 94.7)
36 Months	77.5 (65.9 to 85.6)	81.1 (70.1 to 88.4)
48 Months	73.9 (61.6 to 82.8)	81.1 (70.1 to 88.4)

No statistical analyses for this end point

Secondary: PFS as Assessed by IRC: Event-Free Rate

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End point title

PFS as Assessed by IRC: Event-Free Rate

End point description

Estimated percentage of participants who were event-free based on Kaplan-Meier method

End point type

Secondary

End point timeframe

12 and 18 months from the date of randomization (up to approximately 2 years and 7 months)

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	102
Units: Percentage of Participants
number (confidence interval 95%)
12 Months	87.2 (78.6 to 92.5)	89.7 (81.7 to 94.3)
18 Months	83.8 (74.5 to 89.9)	85.0 (75.2 to 91.2)

No statistical analyses for this end point

Secondary: PFS as Assessed by the Investigator: Event-Free Rate

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End point title

PFS as Assessed by the Investigator: Event-Free Rate

End point description

Percentage of participants who were event-free based on Kaplan-Meier method.

End point type

Secondary

End point timeframe

24, 36 and 48 months from the date of randomization (up to approximately 5 years and 5 months)

End point values	Arm A: Ibrutinib	Arm B: Zanubrutinib
Number of subjects analysed	99	102
Units: Percentage of Participants
number (confidence interval 95%)
24 Months	80.6 (70.9 to 87.3)	88.5 (80.2 to 93.5)
36 Months	74.8 (64.5 to 82.5)	78.3 (68.4 to 85.5)
48 Months	67.3 (56.3 to 76.1)	78.3 (68.4 to 85.5)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to Approximately 5 years 5 months

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Ibrutinib

Reporting group description

Ibrutinib

Reporting group title

Zanubrutinib

Reporting group description

Zanubrutinib

Serious adverse events	Ibrutinib	Zanubrutinib
Total subjects affected by serious adverse events
subjects affected / exposed	50 / 98 (51.02%)	59 / 101 (58.42%)
number of deaths (all causes)	18	14
number of deaths resulting from adverse events	7	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 98 (0.00%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphoma transformation
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endometrial adenocarcinoma
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nodular melanoma
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Vascular disorders
Peripheral vascular disorder
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	2 / 98 (2.04%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Adverse drug reaction
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 98 (3.06%)	4 / 101 (3.96%)
occurrences causally related to treatment / all	1 / 3	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug withdrawal syndrome
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Amyloidosis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal prolapse
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 98 (2.04%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	1 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal oedema
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 98 (0.00%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory disorder
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Interferon gamma release assay positive
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 98 (1.02%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Contusion
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital haematoma
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stress fracture
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Subdural haemorrhage
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute left ventricular failure
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	1 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	5 / 98 (5.10%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	4 / 5	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	2 / 98 (2.04%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiomegaly
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Coronary artery disease
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial haemorrhage
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lethargy
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	2 / 98 (2.04%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 98 (3.06%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	1 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 98 (1.02%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 98 (0.00%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic disorder
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 98 (0.00%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 98 (0.00%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperviscosity syndrome
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye haemorrhage
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Anal inflammation
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oral blood blister
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic disorder
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	2 / 98 (2.04%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Chronic kidney disease
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	2 / 98 (2.04%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bacterial sepsis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Brain abscess
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	2 / 98 (2.04%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cryptococcal fungaemia
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	2 / 98 (2.04%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 98 (2.04%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis bacterial
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neurocryptococcosis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 98 (1.02%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 98 (0.00%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paronychia
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	14 / 98 (14.29%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	6 / 15	0 / 4
deaths causally related to treatment / all	1 / 2	0 / 0
Pneumonia viral
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural sepsis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post-acute COVID-19 syndrome
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative abscess
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	4 / 98 (4.08%)	3 / 101 (2.97%)
occurrences causally related to treatment / all	1 / 4	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal endocarditis
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	1 / 98 (1.02%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 98 (2.04%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 98 (2.04%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection staphylococcal
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 98 (1.02%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 98 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Ibrutinib	Zanubrutinib
Total subjects affected by non serious adverse events
subjects affected / exposed	96 / 98 (97.96%)	99 / 101 (98.02%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	5 / 98 (5.10%)	4 / 101 (3.96%)
occurrences all number	5	4
Seborrhoeic keratosis
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences all number	3	0
Squamous cell carcinoma of skin
subjects affected / exposed	5 / 98 (5.10%)	3 / 101 (2.97%)
occurrences all number	6	3
Bladder transitional cell carcinoma
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences all number	4	0
Vascular disorders
Haematoma
subjects affected / exposed	9 / 98 (9.18%)	5 / 101 (4.95%)
occurrences all number	11	7
Hypertension
subjects affected / exposed	24 / 98 (24.49%)	16 / 101 (15.84%)
occurrences all number	46	20
Hypotension
subjects affected / exposed	2 / 98 (2.04%)	4 / 101 (3.96%)
occurrences all number	3	4
General disorders and administration site conditions
Fatigue
subjects affected / exposed	19 / 98 (19.39%)	26 / 101 (25.74%)
occurrences all number	25	49
Drug withdrawal syndrome
subjects affected / exposed	2 / 98 (2.04%)	4 / 101 (3.96%)
occurrences all number	3	4
Chills
subjects affected / exposed	4 / 98 (4.08%)	3 / 101 (2.97%)
occurrences all number	5	3
Chest pain
subjects affected / exposed	5 / 98 (5.10%)	4 / 101 (3.96%)
occurrences all number	5	4
Asthenia
subjects affected / exposed	6 / 98 (6.12%)	9 / 101 (8.91%)
occurrences all number	9	14
Pyrexia
subjects affected / exposed	12 / 98 (12.24%)	16 / 101 (15.84%)
occurrences all number	21	30
Peripheral swelling
subjects affected / exposed	12 / 98 (12.24%)	5 / 101 (4.95%)
occurrences all number	12	6
Oedema peripheral
subjects affected / exposed	22 / 98 (22.45%)	19 / 101 (18.81%)
occurrences all number	38	29
Malaise
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Influenza like illness
subjects affected / exposed	5 / 98 (5.10%)	6 / 101 (5.94%)
occurrences all number	7	9
Gait disturbance
subjects affected / exposed	0 / 98 (0.00%)	4 / 101 (3.96%)
occurrences all number	0	4
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 98 (2.04%)	4 / 101 (3.96%)
occurrences all number	2	4
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	20 / 98 (20.41%)	20 / 101 (19.80%)
occurrences all number	29	36
Epistaxis
subjects affected / exposed	21 / 98 (21.43%)	18 / 101 (17.82%)
occurrences all number	35	21
Dyspnoea
subjects affected / exposed	9 / 98 (9.18%)	17 / 101 (16.83%)
occurrences all number	11	22
Oropharyngeal pain
subjects affected / exposed	10 / 98 (10.20%)	4 / 101 (3.96%)
occurrences all number	11	5
Nasal congestion
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	6	2
Dyspnoea exertional
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	3	2
Wheezing
subjects affected / exposed	1 / 98 (1.02%)	4 / 101 (3.96%)
occurrences all number	1	4
Productive cough
subjects affected / exposed	4 / 98 (4.08%)	6 / 101 (5.94%)
occurrences all number	4	7
Pneumonitis
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Rhinorrhoea
subjects affected / exposed	5 / 98 (5.10%)	2 / 101 (1.98%)
occurrences all number	5	2
Psychiatric disorders
Depression
subjects affected / exposed	4 / 98 (4.08%)	3 / 101 (2.97%)
occurrences all number	4	4
Insomnia
subjects affected / exposed	9 / 98 (9.18%)	3 / 101 (2.97%)
occurrences all number	10	4
Anxiety
subjects affected / exposed	7 / 98 (7.14%)	5 / 101 (4.95%)
occurrences all number	7	5
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	5	2
Blood alkaline phosphatase increased
subjects affected / exposed	4 / 98 (4.08%)	0 / 101 (0.00%)
occurrences all number	4	0
Neutrophil count decreased
subjects affected / exposed	4 / 98 (4.08%)	8 / 101 (7.92%)
occurrences all number	9	33
Gamma-glutamyltransferase increased
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	6	2
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	27 / 98 (27.55%)	19 / 101 (18.81%)
occurrences all number	59	38
Fall
subjects affected / exposed	10 / 98 (10.20%)	9 / 101 (8.91%)
occurrences all number	12	17
Joint injury
subjects affected / exposed	4 / 98 (4.08%)	1 / 101 (0.99%)
occurrences all number	5	1
Limb injury
subjects affected / exposed	5 / 98 (5.10%)	5 / 101 (4.95%)
occurrences all number	7	5
Procedural pain
subjects affected / exposed	0 / 98 (0.00%)	4 / 101 (3.96%)
occurrences all number	0	5
Skin laceration
subjects affected / exposed	8 / 98 (8.16%)	5 / 101 (4.95%)
occurrences all number	13	5
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	18 / 98 (18.37%)	7 / 101 (6.93%)
occurrences all number	24	8
Angina pectoris
subjects affected / exposed	4 / 98 (4.08%)	4 / 101 (3.96%)
occurrences all number	4	4
Sinus bradycardia
subjects affected / exposed	3 / 98 (3.06%)	6 / 101 (5.94%)
occurrences all number	3	6
Bradycardia
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	4	1
Atrial flutter
subjects affected / exposed	4 / 98 (4.08%)	1 / 101 (0.99%)
occurrences all number	4	1
Palpitations
subjects affected / exposed	10 / 98 (10.20%)	6 / 101 (5.94%)
occurrences all number	15	8
Nervous system disorders
Dizziness
subjects affected / exposed	14 / 98 (14.29%)	15 / 101 (14.85%)
occurrences all number	16	29
Headache
subjects affected / exposed	15 / 98 (15.31%)	17 / 101 (16.83%)
occurrences all number	20	20
Neuralgia
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences all number	3	0
Paraesthesia
subjects affected / exposed	8 / 98 (8.16%)	4 / 101 (3.96%)
occurrences all number	10	6
Syncope
subjects affected / exposed	6 / 98 (6.12%)	3 / 101 (2.97%)
occurrences all number	7	5
Sciatica
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	4	1
Peripheral sensory neuropathy
subjects affected / exposed	5 / 98 (5.10%)	8 / 101 (7.92%)
occurrences all number	6	10
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	22 / 98 (22.45%)	18 / 101 (17.82%)
occurrences all number	48	57
Thrombocytopenia
subjects affected / exposed	16 / 98 (16.33%)	15 / 101 (14.85%)
occurrences all number	47	61
Neutropenia
subjects affected / exposed	16 / 98 (16.33%)	29 / 101 (28.71%)
occurrences all number	51	87
Lymphadenopathy
subjects affected / exposed	1 / 98 (1.02%)	4 / 101 (3.96%)
occurrences all number	1	4
Increased tendency to bruise
subjects affected / exposed	5 / 98 (5.10%)	3 / 101 (2.97%)
occurrences all number	6	3
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	4 / 98 (4.08%)	3 / 101 (2.97%)
occurrences all number	4	3
Tinnitus
subjects affected / exposed	3 / 98 (3.06%)	6 / 101 (5.94%)
occurrences all number	4	6
Eye disorders
Vision blurred
subjects affected / exposed	6 / 98 (6.12%)	3 / 101 (2.97%)
occurrences all number	7	3
Retinal haemorrhage
subjects affected / exposed	4 / 98 (4.08%)	0 / 101 (0.00%)
occurrences all number	8	0
Ocular hyperaemia
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Dry eye
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	3	2
Cataract
subjects affected / exposed	6 / 98 (6.12%)	3 / 101 (2.97%)
occurrences all number	7	4
Conjunctival haemorrhage
subjects affected / exposed	6 / 98 (6.12%)	5 / 101 (4.95%)
occurrences all number	10	9
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	5 / 98 (5.10%)	1 / 101 (0.99%)
occurrences all number	5	1
Abdominal distension
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	3	2
Abdominal pain
subjects affected / exposed	6 / 98 (6.12%)	4 / 101 (3.96%)
occurrences all number	9	5
Abdominal pain upper
subjects affected / exposed	6 / 98 (6.12%)	4 / 101 (3.96%)
occurrences all number	7	4
Constipation
subjects affected / exposed	12 / 98 (12.24%)	20 / 101 (19.80%)
occurrences all number	18	25
Diarrhoea
subjects affected / exposed	36 / 98 (36.73%)	23 / 101 (22.77%)
occurrences all number	62	38
Gingival bleeding
subjects affected / exposed	5 / 98 (5.10%)	2 / 101 (1.98%)
occurrences all number	6	2
Gastrooesophageal reflux disease
subjects affected / exposed	5 / 98 (5.10%)	4 / 101 (3.96%)
occurrences all number	5	4
Dysphagia
subjects affected / exposed	3 / 98 (3.06%)	3 / 101 (2.97%)
occurrences all number	4	4
Dyspepsia
subjects affected / exposed	7 / 98 (7.14%)	6 / 101 (5.94%)
occurrences all number	7	7
Dry mouth
subjects affected / exposed	4 / 98 (4.08%)	5 / 101 (4.95%)
occurrences all number	4	5
Haemorrhoids
subjects affected / exposed	4 / 98 (4.08%)	2 / 101 (1.98%)
occurrences all number	5	2
Inguinal hernia
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Mouth ulceration
subjects affected / exposed	5 / 98 (5.10%)	2 / 101 (1.98%)
occurrences all number	9	2
Nausea
subjects affected / exposed	15 / 98 (15.31%)	19 / 101 (18.81%)
occurrences all number	22	25
Rectal haemorrhage
subjects affected / exposed	2 / 98 (2.04%)	5 / 101 (4.95%)
occurrences all number	3	5
Stomatitis
subjects affected / exposed	5 / 98 (5.10%)	4 / 101 (3.96%)
occurrences all number	7	4
Vomiting
subjects affected / exposed	15 / 98 (15.31%)	14 / 101 (13.86%)
occurrences all number	20	27
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	7 / 98 (7.14%)	2 / 101 (1.98%)
occurrences all number	12	5
Dermatitis
subjects affected / exposed	5 / 98 (5.10%)	1 / 101 (0.99%)
occurrences all number	6	1
Actinic keratosis
subjects affected / exposed	5 / 98 (5.10%)	3 / 101 (2.97%)
occurrences all number	6	3
Onychoclasis
subjects affected / exposed	10 / 98 (10.20%)	1 / 101 (0.99%)
occurrences all number	10	1
Petechiae
subjects affected / exposed	5 / 98 (5.10%)	7 / 101 (6.93%)
occurrences all number	6	8
Nail disorder
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Erythema
subjects affected / exposed	3 / 98 (3.06%)	5 / 101 (4.95%)
occurrences all number	3	5
Ecchymosis
subjects affected / exposed	4 / 98 (4.08%)	1 / 101 (0.99%)
occurrences all number	6	1
Rash
subjects affected / exposed	19 / 98 (19.39%)	19 / 101 (18.81%)
occurrences all number	25	25
Rash maculo-papular
subjects affected / exposed	2 / 98 (2.04%)	4 / 101 (3.96%)
occurrences all number	2	6
Pruritus
subjects affected / exposed	6 / 98 (6.12%)	15 / 101 (14.85%)
occurrences all number	10	20
Rash erythematous
subjects affected / exposed	1 / 98 (1.02%)	5 / 101 (4.95%)
occurrences all number	1	6
Purpura
subjects affected / exposed	6 / 98 (6.12%)	4 / 101 (3.96%)
occurrences all number	9	4
Psoriasis
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences all number	3	0
Skin toxicity
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Skin lesion
subjects affected / exposed	3 / 98 (3.06%)	6 / 101 (5.94%)
occurrences all number	3	9
Skin fissures
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	4	2
Rosacea
subjects affected / exposed	5 / 98 (5.10%)	2 / 101 (1.98%)
occurrences all number	5	2
Skin ulcer
subjects affected / exposed	4 / 98 (4.08%)	3 / 101 (2.97%)
occurrences all number	4	3
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	4	1
Urinary retention
subjects affected / exposed	0 / 98 (0.00%)	4 / 101 (3.96%)
occurrences all number	0	6
Haematuria
subjects affected / exposed	13 / 98 (13.27%)	11 / 101 (10.89%)
occurrences all number	17	13
Dysuria
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences all number	3	0
Pollakiuria
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	1 / 98 (1.02%)	4 / 101 (3.96%)
occurrences all number	1	4
Musculoskeletal chest pain
subjects affected / exposed	3 / 98 (3.06%)	3 / 101 (2.97%)
occurrences all number	4	4
Arthralgia
subjects affected / exposed	24 / 98 (24.49%)	24 / 101 (23.76%)
occurrences all number	50	42
Back pain
subjects affected / exposed	18 / 98 (18.37%)	18 / 101 (17.82%)
occurrences all number	23	31
Joint swelling
subjects affected / exposed	4 / 98 (4.08%)	4 / 101 (3.96%)
occurrences all number	5	5
Muscle spasms
subjects affected / exposed	28 / 98 (28.57%)	12 / 101 (11.88%)
occurrences all number	43	15
Myalgia
subjects affected / exposed	3 / 98 (3.06%)	7 / 101 (6.93%)
occurrences all number	4	9
Neck pain
subjects affected / exposed	6 / 98 (6.12%)	3 / 101 (2.97%)
occurrences all number	6	3
Osteoarthritis
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	3	2
Rotator cuff syndrome
subjects affected / exposed	3 / 98 (3.06%)	3 / 101 (2.97%)
occurrences all number	3	3
Pain in extremity
subjects affected / exposed	10 / 98 (10.20%)	15 / 101 (14.85%)
occurrences all number	12	21
Osteoporosis
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	3	1
Infections and infestations
Cellulitis
subjects affected / exposed	7 / 98 (7.14%)	6 / 101 (5.94%)
occurrences all number	18	10
COVID-19
subjects affected / exposed	5 / 98 (5.10%)	9 / 101 (8.91%)
occurrences all number	5	10
Bronchitis
subjects affected / exposed	4 / 98 (4.08%)	4 / 101 (3.96%)
occurrences all number	4	4
Ear infection
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	3	2
Cystitis
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences all number	3	0
Folliculitis
subjects affected / exposed	5 / 98 (5.10%)	2 / 101 (1.98%)
occurrences all number	6	2
Conjunctivitis
subjects affected / exposed	7 / 98 (7.14%)	2 / 101 (1.98%)
occurrences all number	7	3
Furuncle
subjects affected / exposed	4 / 98 (4.08%)	0 / 101 (0.00%)
occurrences all number	7	0
Localised infection
subjects affected / exposed	11 / 98 (11.22%)	2 / 101 (1.98%)
occurrences all number	15	2
Laryngitis
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences all number	3	0
Gastroenteritis
subjects affected / exposed	5 / 98 (5.10%)	6 / 101 (5.94%)
occurrences all number	6	7
Herpes zoster
subjects affected / exposed	4 / 98 (4.08%)	5 / 101 (4.95%)
occurrences all number	4	5
Lower respiratory tract infection
subjects affected / exposed	10 / 98 (10.20%)	8 / 101 (7.92%)
occurrences all number	15	13
Nail infection
subjects affected / exposed	6 / 98 (6.12%)	0 / 101 (0.00%)
occurrences all number	11	0
Nasopharyngitis
subjects affected / exposed	9 / 98 (9.18%)	14 / 101 (13.86%)
occurrences all number	10	21
Onychomycosis
subjects affected / exposed	5 / 98 (5.10%)	1 / 101 (0.99%)
occurrences all number	5	1
Oral herpes
subjects affected / exposed	5 / 98 (5.10%)	1 / 101 (0.99%)
occurrences all number	7	1
Paronychia
subjects affected / exposed	3 / 98 (3.06%)	2 / 101 (1.98%)
occurrences all number	4	2
Pneumonia
subjects affected / exposed	9 / 98 (9.18%)	3 / 101 (2.97%)
occurrences all number	9	3
Respiratory tract infection
subjects affected / exposed	3 / 98 (3.06%)	8 / 101 (7.92%)
occurrences all number	4	10
Rhinitis
subjects affected / exposed	7 / 98 (7.14%)	7 / 101 (6.93%)
occurrences all number	8	12
Sinusitis
subjects affected / exposed	10 / 98 (10.20%)	6 / 101 (5.94%)
occurrences all number	11	9
Skin infection
subjects affected / exposed	7 / 98 (7.14%)	3 / 101 (2.97%)
occurrences all number	16	4
Tooth infection
subjects affected / exposed	5 / 98 (5.10%)	3 / 101 (2.97%)
occurrences all number	9	3
Upper respiratory tract infection
subjects affected / exposed	31 / 98 (31.63%)	33 / 101 (32.67%)
occurrences all number	55	49
Urinary tract infection
subjects affected / exposed	17 / 98 (17.35%)	16 / 101 (15.84%)
occurrences all number	38	25
Wound infection
subjects affected / exposed	3 / 98 (3.06%)	0 / 101 (0.00%)
occurrences all number	3	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 98 (4.08%)	4 / 101 (3.96%)
occurrences all number	6	4
Gout
subjects affected / exposed	5 / 98 (5.10%)	3 / 101 (2.97%)
occurrences all number	6	3
Hyperglycaemia
subjects affected / exposed	4 / 98 (4.08%)	3 / 101 (2.97%)
occurrences all number	10	4
Vitamin D deficiency
subjects affected / exposed	2 / 98 (2.04%)	5 / 101 (4.95%)
occurrences all number	2	5
Iron deficiency
subjects affected / exposed	7 / 98 (7.14%)	7 / 101 (6.93%)
occurrences all number	7	8
Hyponatraemia
subjects affected / exposed	1 / 98 (1.02%)	4 / 101 (3.96%)
occurrences all number	1	4
Hypokalaemia
subjects affected / exposed	6 / 98 (6.12%)	3 / 101 (2.97%)
occurrences all number	6	14
Hypoalbuminaemia
subjects affected / exposed	3 / 98 (3.06%)	1 / 101 (0.99%)
occurrences all number	5	1
Hyperuricaemia
subjects affected / exposed	9 / 98 (9.18%)	4 / 101 (3.96%)
occurrences all number	14	7

More information

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Were there any global substantial amendments to the protocol? Yes

01 Nov 2016

• Updated background with new zanubrutinib trial results and data on role of MYD88 mutation in responsiveness of WM to BTK inhibitors • Changed the primary objective to the proportion of patients who achieved CR/VGPR, based on the clarification of the primary study hypothesis that stemmed from the updated zanubrutinib data • Added major response rate and VGPR/CR (by investigator assessment) as secondary endpoints • Added antitumor activity and safety of zanubrutinib in MYD88WT WM patients as an exploratory endpoint • Added quality of life and medical resource utilization as exploratory endpoints • Identified patients with MYD88MUT WM as the primary population for randomization and study analyses (Cohort 1) • Revised sample size consideration • Added language describing sequential analysis approach to the primary and secondary endpoints • Identified treatment cohorts based on MYD88 mutational status: Cohort 1 (MYD88MUT) and newly added Cohort 2 (MYD88WT) • Added the inclusion criterion to clarify that treatment-naive patients were considered inappropriate candidates for intensive therapy • Added the inclusion criterion to require measurable disease, in accordance with the response rate primary objective • Added clarification for efficacy assessments in the occasion of study drug holding and plasmapheresis

08 May 2017

• study rationale, benefit/risk assessment, and dose justification • Updated the timing of response assessments to every 4 weeks (each cycle) Increased the screening phase to up to 35 days before randomization • Added EQ-5D to quality-of-life assessments • Updated the timing of bone marrow assessment for the presence of WM • Clarified the study population by providing definitions for relapsed/refractory • Clarified that up to 20% of patients may have been treatment naive • Updated the eligibility criteria to clarify that patients may have had relapsed/refractory or treatment-naive WM considered by their treating physician to be inappropriate for standard chemoimmunotherapy regimens • Clarified blinding of the Independent Review Committee and DMC • Clarified dose modification to allow for study drug to be held for up to 2 consecutive cycles and that more than 1 drug hold was allowed over the course of the study • Removed the ECHO/MUGA from screening and exclusion criteria • Added the requirement for confirmation of disease transformation by biopsy • Added adverse events of special interest • Updated pregnancy and contraception language

02 Feb 2018

• Updated the total number of patients to approximately 210. Cohort 1 included approximately 150 patients with relapsed/refractory disease and 38 treatment-naive MYD88MUT patients. Cohort 2 included approximately 22 MYD88WT patients. • Revised the statistical analysis methods for analyzing relapsed/refractory MYD88MUT patients • Changed the timing of the interim analysis to 6 months after the first 50 patients with relapsed/refractory disease were randomized to Cohort 1 • Updated the sample size considerations to have the power to test the primary endpoint in the Cohort 1 Relapsed/Refractory Analysis Set • Changed the timing of the primary analysis from 9 months to 12 months • Added an assessment of impact of plasmapheresis on zanubrutinib PK as a new exploratory objective and endpoint • Revised the zanubrutinib and ibrutinib guidelines for dose modification, reduction, and discontinuation • Added ventricular arrhythmia as an adverse event of special interest Revised the definition of treatment-emergent adverse event to be consistent with other protocols • Clarified that evaluation of extramedullary disease included evaluation of splenomegaly rather than organomegaly • Clarified that infection prophylaxis was per institutional standards • Clarified when corticosteroid usage was prohibited • Added that all treatment-related serious adverse events were to be followed until resolution or stabilization • Revised the efficacy follow-up to continue even though a patient may have started a new anticancer therapy after the last dose of study drug • Added that patients who continued to benefit from zanubrutinib after disease progression may have remained on study upon discussion with the medical monitor or designee • Added back ECHO/MUGA assessments at screening and when clinically indicated

21 Sep 2018

• Clarified for patients with mild hepatic impairment (Child-Pugh Class A) and moderate hepatic impairment (Child-Pugh Class B) to refer to the local prescribing guidelines for specific instructions on ibrutinib dose modifications • Removed the QT/QTc prolonging drug guidance • Removed the adverse events of special interest list, including protocol definitions and associated expedited reporting requirements • Updated Phase 1 first-in-human study data • Clarified the maximum number of repetitions of a failed screening test to be 1 time • Updated the overdose reporting guidance • Added guidance about the potential for opportunistic infections in patients with hematologic malignancies, particularly for those having received prior lymphodepleting chemotherapy or prolonged corticosteroid exposure • Added that patients who remained on the study after disease progression continued to follow the required assessments during the treatment phase • Clarified that the serum IgM value at Cycle 1 Day 1 served as the baseline for all assessments except for patients who had undergone plasmapheresis • Clarified that assessments were performed in the same laboratory using the same methodology throughout the study Clarified that patients with new disease symptoms documented objective evidence of disease progression according to the disease-specific response criteria • Clarified that as part of the tumor assessment, the physical examination was also to be included the evaluation of the presence and degree of enlarged lymph nodes and splenomegaly • Clarified that ECGs were to be performed in triplicate at each timepoint assessment • Clarified the sample collection practices for cryoglobulin, serum immunoglobulins, and immunofixation for patients with cryoglobulinemia at screening • Clarified that the clinical significance of a laboratory test abnormality was at the judgment of the investigator

26 Aug 2019

• Clarified that capsules or other dose forms and strengths were allowed for ibrutinib • Clarified that a barrier method of contraception must have also been used if hormonal contraceptives were used • Added section on dose modifications for zanubrutinib when coadministered with strong/moderate CYP3A inhibitors/inducers • Clarified medications to be used with caution • Clarified use of efficacy criteria with and without consideration of extramedullary disease • Clarified instructions for post-baseline CT scans • Updated lists of moderate and strong CYP3A inhibitors and inducers

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 3, Randomized, Open-Label, Multicenter Study Comparing the Efficacy and Safety of the Bruton’s Tyrosine Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects with Waldenström’s Macroglobulinemia (WM)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of participants achieving either a complete response (CR) or very good partial response (VGPR) using an adaptation of the response criteria updated at the Sixth IWWM as assessed by an independent review committee (IRC)

Primary: Percentage of participants achieving either a complete response (CR) or very good partial response (VGPR) using an adaptation of the response criteria updated at the Sixth IWWM as assessed by an independent review committee (IRC)

Secondary: Percentage of Participants Achieving Major Response Rate (MRR) as assessed by IRC

Secondary: Percentage of Participants Achieving Major Response Rate (MRR) as assessed by IRC

Secondary: Duration of Response (DOR) as assessed by IRC

Secondary: Duration of Response (DOR) as assessed by IRC

Secondary: Percentage of participants achieving either CR or VGPR in as assessed by the investigator

Secondary: Percentage of participants achieving either CR or VGPR in as assessed by the investigator

Secondary: DOR in as assessed by the Investigator

Secondary: DOR in as assessed by the Investigator

Secondary: Progression Free Survival (PFS) as assessed by the Investigator

Secondary: Progression Free Survival (PFS) as assessed by the Investigator

Secondary: Progression Free Survival (PFS) as assessed by the IRC

Secondary: Progression Free Survival (PFS) as assessed by the IRC

Secondary: Percentage of participants with Resolution of all Treatment-precipitating Symptoms

Secondary: Percentage of participants with Resolution of all Treatment-precipitating Symptoms

Secondary: Percentage of participants with an anti-Lymphoma effect

Secondary: Percentage of participants with an anti-Lymphoma effect

Secondary: Number of Participants with Treatment-Emergent adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Secondary: Number of Participants with Treatment-Emergent adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Secondary: DOR as Assessed by IRC: Event -Free Rate

Secondary: DOR as Assessed by IRC: Event -Free Rate

Secondary: DOR as Assessed by the Investigator: Event-Free Rate

Secondary: DOR as Assessed by the Investigator: Event-Free Rate

Secondary: PFS as Assessed by IRC: Event-Free Rate

Secondary: PFS as Assessed by IRC: Event-Free Rate

Secondary: PFS as Assessed by the Investigator: Event-Free Rate

Secondary: PFS as Assessed by the Investigator: Event-Free Rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3, Randomized, Open-Label, Multicenter Study Comparing the Efficacy and Safety of the Bruton’s Tyrosine Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects with Waldenström’s Macroglobulinemia (WM)