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The European Union Clinical Trials Register allows you to search for protocol and results information on:

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Clinical Trial Results:
A Randomized, Double-Blind, Phase 3 Study to Evaluate the Activity of Momelotinib (MMB) versus Danazol (DAN) in Symptomatic, Anemic Subjects with Primary Myelofibrosis (PMF), Post-Polycythemia Vera (PV) Myelofibrosis, or Post Essential Thrombocythemia (ET) Myelofibrosis who were Previously Treated with JAK Inhibitor Therapy

Summary
EudraCT number	2019-000583-18
Trial protocol	GB DE SE DK FR CZ ES PL HU AT IT RO
Global end of trial date	29 Dec 2022

Results information
Results version number	v1
This version publication date	11 Aug 2023
First version publication date	11 Aug 2023
Other versions	v2

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

SRA-MMB-301

ISRCTN number

-

US NCT number

NCT04173494

WHO universal trial number (UTN)

-

Sponsor organisation name

Sierra Oncology LLC – a GSK company

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS

Public contact

GSK Response Center, Sierra Oncology, a GlaxoSmithKline company, 1 877-379-3718, GSKClinicalSupportHD@gsk.com

Scientific contact

GSK Response Center, Sierra Oncology LLC – a GSK company, 1 877-379-3718, GSKClinicalSupportHD@gsk.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

14 Apr 2023

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

29 Dec 2022

Was the trial ended prematurely?

No

Main objective of the trial

To determine the efficacy of MMB versus DAN assessed by improvement in Myelofibrosis Symptom Assessment Form version (v) 4.0 (MFSAF) total symptom score (TSS) in participants with PMF, post-PV myelofibrosis (MF), or post-ET MF who were previously treated with approved Janus kinase (JAK) inhibitor therapy

Protection of trial subjects

Not applicable

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

07 Feb 2020

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

Bulgaria: 5

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Czechia: 1

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

France: 13

Country: Number of subjects enrolled

Germany: 14

Country: Number of subjects enrolled

Hungary: 13

Country: Number of subjects enrolled

Israel: 18

Country: Number of subjects enrolled

Italy: 32

Country: Number of subjects enrolled

New Zealand: 2

Country: Number of subjects enrolled

Poland: 14

Country: Number of subjects enrolled

Romania: 8

Country: Number of subjects enrolled

Singapore: 4

Country: Number of subjects enrolled

Korea, Republic of: 11

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

Taiwan: 2

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

United States: 24

Worldwide total number of subjects

195

EEA total number of subjects

119

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

40

From 65 to 84 years

151

85 years and over

4

Subject disposition

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Recruitment details

This study evaluated the activity of Momelotinib (MMB) versus Danazol (DAN) in Symptomatic, Anemic participants. This study consists of Randomized Double-blind (DB) Treatment Period (TP) and Open-label extended Treatment Period (OLP).

Screening details

A total of 195 participants were enrolled in the study.

Period 1 title

Randomized DB TP (Up to Week 24)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

MMB 200 mg Once Daily (QD) + Placebo

Arm description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Arm type

Experimental

Investigational medicinal product name

Placebo matching DAN

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo matching DAN was was administered orally BID

Investigational medicinal product name

MMB 200 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

MMB was administered with a dose of 200 mg orally QD.

DAN 300 mg BID + Placebo

Arm description

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 enrolled in an open-label extended treatment period. Participants switched to receive 200 mg of MMB orally QD during open-label extended treatment period. All participants elected to receive MMB as open-label treatment during the open-label extended treatment period.

Arm type

Active comparator

Investigational medicinal product name

Placebo matching MMB

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matching MMB was was administered orally QD

Investigational medicinal product name

DAN 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

DAN was administered with a dose of 300 mg orally BID.

Number of subjects in period 1	MMB 200 mg Once Daily (QD) + Placebo	DAN 300 mg BID + Placebo
Started	130	65
Completed	94	38
Not completed	36	27
Adverse event, serious fatal	9	7
Consent withdrawn by subject	6	5
Physician decision	-	1
Leukemic Transformation	2	2
Adverse event, non-fatal	7	4
Death	4	3
Lost to follow-up	1	-
Disease Progression	1	2
Lack of efficacy	6	3

Period 2 title

Open-Label extended TP(Weeks 24 to 77.6)

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MMB 200 mg Once Daily (QD) + Placebo

Arm description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Arm type

Experimental

Investigational medicinal product name

Placebo matching DAN

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo matching DAN was was administered orally BID

Investigational medicinal product name

MMB 200 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

MMB was administered with a dose of 200 mg orally QD.

DAN 300 mg BID + Placebo

Arm description

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 enrolled in an open-label extended treatment period. Participants switched to receive 200 mg of MMB orally QD during open-label extended treatment period. All participants elected to receive MMB as open-label treatment during the open-label extended treatment period.

Arm type

Active comparator

Investigational medicinal product name

DAN 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

DAN was administered with a dose of 300 mg orally BID.

Investigational medicinal product name

Placebo matching MMB

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matching MMB was was administered orally QD

Investigational medicinal product name

MMB 200 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

MMB was administered with a dose of 200 mg orally QD.

Number of subjects in period 2 ^[1]	MMB 200 mg Once Daily (QD) + Placebo	DAN 300 mg BID + Placebo
Started	93	36
Completed	0	0
Not completed	93	41
Adverse event, serious fatal	8	-
Physician decision	4	3
Consent withdrawn by subject	4	3
Leukemic Transformation	-	1
Adverse event, non-fatal	3	1
Death	6	3
Continuing in MMB extension study	61	27
Disease Progression	1	1
Lack of efficacy	6	2
Joined	0	5
Protocol defined criteria	-	5

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 93 participants from Randomized Treatment Phase entered in Open-label Phase.

Baseline characteristics

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Reporting group title

MMB 200 mg Once Daily (QD) + Placebo

Reporting group description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Reporting group title

DAN 300 mg BID + Placebo

Reporting group description

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 enrolled in an open-label extended treatment period. Participants switched to receive 200 mg of MMB orally QD during open-label extended treatment period. All participants elected to receive MMB as open-label treatment during the open-label extended treatment period.

Reporting group values	MMB 200 mg Once Daily (QD) + Placebo	DAN 300 mg BID + Placebo	Total
Number of subjects	130	65	195
Age categorical
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: Participants
All participants	130	65	195
Age Continuous
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: years
arithmetic mean (standard deviation)	69.85 ( 8.24 )	71.46 ( 6.99 )	-
Sex: Female, Male
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: Participants
Female	51	21	72
Male	79	44	123
Ethnicity (NIH/OMB)
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: Subjects
Hispanic or Latino	5	6	11
Not Hispanic or Latino	115	54	169
Unknown or Not Reported	10	5	15
Race (NIH/OMB)
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	12	6	18
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	2	2	4
White	107	50	157
More than one race	0	0	0
Unknown or Not Reported	9	7	16

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo- Randomized DB TP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 mg of MMB orally QD and a DAN-placebo orally BID during the randomized 24-week double-blind treatment period.

Subject analysis set title

DAN 300 mg BID + Placebo- Randomized DB TP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period.

Subject analysis set title

MMB 200 mg QD- Open-Label Extended TP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period.

Subject analysis set title

DAN 300 mg BID to MMB 200 mg QD- Open-Label Extended TP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants who received DAN 300 mg BID during randomized period switched to receive 200 mg of MMB orally QD during open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis sets values	MMB 200 mg QD + Placebo	MMB 200 mg QD + Placebo	MMB 200 mg QD + Placebo	MMB 200 mg QD + Placebo	MMB 200 mg QD + Placebo	MMB 200 mg QD + Placebo- Randomized DB TP	DAN 300 mg BID + Placebo- Randomized DB TP	MMB 200 mg QD- Open-Label Extended TP	DAN 300 mg BID to MMB 200 mg QD- Open-Label Extended TP	MMB 200 mg QD + Placebo
Number of subjects	130	92	32	40	63	130	65	93	41	89
Age categorical
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: Participants
All participants
Age Continuous
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: years
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )
Sex: Female, Male
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: Participants
Female
Male
Ethnicity (NIH/OMB)
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: Subjects
Hispanic or Latino
Not Hispanic or Latino
Unknown or Not Reported
Race (NIH/OMB)
Baseline characteristics were measured in the Intention-To-Treat (ITT) Analysis Set, which included all randomized participants.
Units: Subjects
American Indian or Alaska Native	0
Asian	12
Native Hawaiian or Other Pacific Islander	0
Black or African American	2
White	107
More than one race	0
Unknown or Not Reported	9

End points

Top of page

Reporting group title

MMB 200 mg Once Daily (QD) + Placebo

Reporting group description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Reporting group title

DAN 300 mg BID + Placebo

Reporting group description

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 enrolled in an open-label extended treatment period. Participants switched to receive 200 mg of MMB orally QD during open-label extended treatment period. All participants elected to receive MMB as open-label treatment during the open-label extended treatment period.

Reporting group title

MMB 200 mg Once Daily (QD) + Placebo

Reporting group description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Reporting group title

DAN 300 mg BID + Placebo

Reporting group description

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 enrolled in an open-label extended treatment period. Participants switched to receive 200 mg of MMB orally QD during open-label extended treatment period. All participants elected to receive MMB as open-label treatment during the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo- Randomized DB TP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 mg of MMB orally QD and a DAN-placebo orally BID during the randomized 24-week double-blind treatment period.

Subject analysis set title

DAN 300 mg BID + Placebo- Randomized DB TP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period.

Subject analysis set title

MMB 200 mg QD- Open-Label Extended TP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period.

Subject analysis set title

DAN 300 mg BID to MMB 200 mg QD- Open-Label Extended TP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants who received DAN 300 mg BID during randomized period switched to receive 200 mg of MMB orally QD during open-label extended treatment period.

Subject analysis set title

MMB 200 mg QD + Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants were randomized to receive 200 milligrams (mg) of MMB orally QD and a DAN-placebo orally twice daily (BID) during the randomized 24-week double-blind treatment period. Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period. Participants who discontinued treatment prior to Week 24 due to splenic progression or other reasons, but completed assessments, were unblinded. Participants who discontinued MMB during the randomized treatment period were not eligible to receive MMB in the open-label extended treatment period. Participants who were randomized to MMB during the randomized treatment period with confirmed splenic progression could not proceed to the open-label extended treatment period.

Primary: Total Symptom Score (TSS) Response Rate at Week 24

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End point title

Total Symptom Score (TSS) Response Rate at Week 24 ^[1]

End point description

Myelofibrosis Symptom Assessment Form (MFSAF) TSS version (v) 4.0 response rate was defined as percentage of participants with a >= 50 percent (%) reduction from Baseline in mean MFSAF TSS over consecutive 28-day period immediately before end of Week 24. TSS response rate was measured using MFSAF v4.0. MFSAF v4.0 comprises 7 domains representing 7 most relevant symptoms of myelofibrosis (MF) identified through existing participant and clinician-based evidence: fatigue,night sweats,pruritus,abdominal discomfort,pain under left ribs,early satietyand bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0(absent) to 10(worst imaginable). The MFSAF TSS was calculated as sum of scores of 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from Baseline corresponded to a lessening of MF symptoms. Baseline was the last assessment done before or on the day of first dose date

End point type

Primary

End point timeframe

Baseline and Week 24

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[2]	130 ^[3]
Units: Percentage of participants
number (confidence interval 95%)	9.23 (3.46 to 19.02)	24.62 (17.49 to 32.94)

Notes
[2] - Intent-To-Treat (ITT) Analysis Set, which included all randomized participants
[3] - Intent-To-Treat (ITT) Analysis Set, which included all randomized participants

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0095

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Cochran-Mantel-Haenszel

Point estimate

15.67

Confidence interval

level

95%

sides

2-sided

lower limit

5.54

upper limit

25.81

Primary: Percentage of Participants with Transfusion Independence (TI) at Week 24

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End point title

Percentage of Participants with Transfusion Independence (TI) at Week 24 ^[4]

End point description

TI status was defined as not receiving red blood cell (RBC) or whole blood transfusion for >=12 weeks, with no hemoglobin (Hgb) level < 8 grams per deciliter (g/dL) during the same interval. Percentage of participants with TI have been presented.

End point type

Primary

End point timeframe

Week 24

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[5]	130 ^[6]
Units: Percentage of Participants
number (confidence interval 95%)	20.00 (11.10 to 31.77)	30.0 (22.28 to 38.66)

Notes
[5] - ITT Analysis Set
[6] - ITT Analysis Set

Statistical Analysis 1

Statistical analysis description

If the lower bound of the confidence interval (CI) is greater than 0, MMB was to be declared non-inferior to DAN.

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

P-value

= 0.0116

Method

Cochran-Mantel-Haenszel

Parameter type

Non-inferiority difference

Point estimate

13.58

Confidence interval

level

95%

sides

2-sided

lower limit

1.86

upper limit

25.3

Notes
[7] - Non-inferiority difference, defined as p(MMB) - (0.8) *p(DAN) where p(MMB) is percentage of participants with TI status in MMB arm and p(DAN) is percentage of participants with TI status in DAN arm.

Secondary: Splenic Response Rate (SRR) of >=25% at Week 24

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End point title

Splenic Response Rate (SRR) of >=25% at Week 24 ^[8]

End point description

Splenic response rate (SRR) is defined as the percentage of participants who have reduction in spleen volume of >=25% from Baseline at the end of Week 24. Baseline was the last assessment done before or on the day of first dose date.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[9]	130 ^[10]
Units: Percentage of Participants
number (confidence interval 95%)	6.15 (1.70 to 15.01)	39.23 (30.79 to 48.18)

Notes
[9] - ITT Analysis Set
[10] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Cochran-Mantel-Haenszel

Point estimate

33.05

Confidence interval

level

95%

sides

2-sided

lower limit

22.59

upper limit

43.51

Secondary: Change from Baseline in MFSAF TSS at Week 24

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End point title

Change from Baseline in MFSAF TSS at Week 24 ^[11]

End point description

TSS was measured using the MFSAF v4.0. The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing participant and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). The MFSAF TSS was calculated as the sum of scores of the 7 domains for a possible range of scores of 0 to 70, with a higher TSS corresponding to more severe symptoms. A reduction from Baseline corresponded to a lessening of MF symptoms. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value. Only those participants with data available at specified time points were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	37 ^[12]	92 ^[13]
Units: Scores on a scale
least squares mean (standard error)	-3.13 ( 1.62 )	-9.36 ( 1.08 )

Notes
[12] - ITT Analysis Set
[13] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0014

Method

mixed model for repeated measures (MMRM)

Parameter type

Least Squares Mean Difference

Point estimate

-6.22

Confidence interval

level

95%

sides

2-sided

lower limit

-10

upper limit

-2.43

Secondary: Splenic Response Rate (SRR) of >= 35% at Week 24

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End point title

Splenic Response Rate (SRR) of >= 35% at Week 24 ^[14]

End point description

Splenic response rate (SRR) is defined as the percentage of participants who have reduction in spleen volume of >=35 % from Baseline at the end of Week 24. Baseline was the last assessment done before or on the day of first dose date.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[15]	130 ^[16]
Units: Percentage of Participants
number (confidence interval 95%)	3.08 (0.37 to 10.68)	22.31 (15.48 to 30.44)

Notes
[15] - ITT Analysis Set
[16] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0011

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Cochran-Mantel-Haenszel

Point estimate

18.18

Confidence interval

level

95%

sides

2-sided

lower limit

9.77

upper limit

26.59

Secondary: Percentage of participants with zero RBC units transfused over 24-Weeks

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End point title

Percentage of participants with zero RBC units transfused over 24-Weeks ^[17]

End point description

Percentage of participants with zero RBC units transfused over 24-weeks were reported.

End point type

Secondary

End point timeframe

Up to 24 weeks

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[18]	130 ^[19]
Units: Percentage of participants
number (confidence interval 95%)	16.92 (8.76 to 28.27)	35.38 (27.20 to 44.25)

Notes
[18] - ITT Analysis Set
[19] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0012

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Cochran-Mantel-Haenszel

Point estimate

17.2

Confidence interval

level

95%

sides

2-sided

lower limit

7.99

upper limit

26.4

Secondary: Percentage of participants with <=4 RBC units transfused over 24-weeks

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End point title

Percentage of participants with <=4 RBC units transfused over 24-weeks ^[20]

End point description

Percentage of participants with <=4 RBC units transfused over 24-weeks were reported.

End point type

Secondary

End point timeframe

Up to 24 weeks

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[21]	130 ^[22]
Units: Percentage of participants
number (confidence interval 95%)	44.62 (32.27 to 57.47)	55.38 (46.42 to 64.10)

Notes
[21] - ITT Analysis Set
[22] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1133

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Cochran-Mantel-Haenszel

Point estimate

10.62

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

23.64

Secondary: Duration of MFSAF TSS Response

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End point title

Duration of MFSAF TSS Response ^[23]

End point description

Duration of MFSAF TSS response is defined as the number of days from the start of the initial 28-day period in which a participant had a >= 50% reduction from Baseline TSS to the first day of the 7-day assessment that determines the mean TSS for the 28-day period during which the participants TSS equals or exceeds their Baseline value. Only those participants with data available at specified time point were analyzed. 99999 indicates <25% of participants experienced the event within the treatment arm. Hence, median and inter-quartile range could not be derived.

End point type

Secondary

End point timeframe

Up to a maximum of 77.6 weeks

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	6 ^[24]	32 ^[25]
Units: Days
median (inter-quartile range (Q1-Q3))	99999 (-99999 to 99999)	286.00 (286.00 to 286.00)

Notes
[24] - ITT Analysis Set
[25] - ITT Analysis Set

No statistical analyses for this end point

Secondary: Mean cumulative number of whole blood units transfused over 24 weeks

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End point title

Mean cumulative number of whole blood units transfused over 24 weeks ^[26]

End point description

Cumulative transfusion risk was calculated as the estimated mean cumulative number of whole blood units transfused during the study.

End point type

Secondary

End point timeframe

Up to Week 24

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[27]	130 ^[28]
Units: Whole blood units
arithmetic mean (standard deviation)	10.86 ( 13.203 )	6.55 ( 8.413 )

Notes
[27] - ITT Analysis Set
[28] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0006

Method

Anderson & Gill proportional means model

Parameter type

Hazard ratio (HR)

Point estimate

0.556

Confidence interval

level

95%

sides

2-sided

lower limit

0.397

upper limit

0.778

Secondary: Duration of TI response

Top of page

End point title

Duration of TI response ^[29]

End point description

Duration of TI is defined as the number of days from (a) the first day of a 12-week period that satisfies the 12-week TI status definition, to (b) the first RBC transfusion or Hgb level < 8 g/dL (except in the case of clinically overt bleeding). Only those participants with data available at specified time point were analyzed. 99999 indicates <25% of participants experienced the event within the treatment arm. Hence, median and inter-quartile range could not be derived.

End point type

Secondary

End point timeframe

Up to a maximum of 77.6 weeks

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	13 ^[30]	39 ^[31]
Units: Days
median (inter-quartile range (Q1-Q3))	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[30] - ITT Analysis Set
[31] - ITT Analysis Set

No statistical analyses for this end point

Secondary: Percentage of participants with Transfusion Dependence (TD) status at Week 24

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End point title

Percentage of participants with Transfusion Dependence (TD) status at Week 24 ^[32]

End point description

TD status at Week 24 is defined as requirement of >=4 RBC units in an 8-week period immediately prior to the end of Week 24.

End point type

Secondary

End point timeframe

Week 24

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[33]	130 ^[34]
Units: Percentage of participants
number (confidence interval 95%)	24.62 (14.77 to 36.87)	15.38 (9.66 to 22.76)

Notes
[33] - ITT Analysis Set
[34] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1602

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified CMH

Point estimate

-8.26

Confidence interval

level

95%

sides

2-sided

lower limit

-20.18

upper limit

3.66

Secondary: Percentage of participants with a hemoglobin response

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End point title

Percentage of participants with a hemoglobin response ^[35]

End point description

Hemoglobin responses are defined as increases of >= 1, >= 1.5, or >= 2 g/dL from Baseline in Hgb, as measured over a (rolling) period of at least 12 consecutive weeks falling entirely before the end of Week 24. Baseline was the last assessment done before or on the day of first dose date. Data has been reported for percentage of participants who had >= 1, >= 1.5, or >= 2 g/dL increase from Baseline in hemoglobin.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[36]	130 ^[37]
Units: Percentage of participants
number (confidence interval 95%)
>=1g/dL Increase	33.85 (22.57 to 46.65)	53.08 (44.13 to 61.88)
>=1.5g/dL Increase	23.08 (13.53 to 35.19)	40.00 (31.51 to 48.95)
>=2g/dL Increase	20.00 (11.10 to 31.77)	29.23 (21.59 to 37.85)

Notes
[36] - ITT Analysis Set
[37] - ITT Analysis Set

Statistical Analysis 1

Statistical analysis description

>=1g/dL Increase in Hemoglobin response

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0124

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified CMH

Point estimate

19

Confidence interval

level

95%

sides

2-sided

lower limit

4.68

upper limit

33.32

Statistical Analysis 2

Statistical analysis description

>=1.5g/dL Increase in Hemoglobin response

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0282

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified CMH

Point estimate

15.68

Confidence interval

level

95%

sides

2-sided

lower limit

2.47

upper limit

28.9

Statistical Analysis 3

Statistical analysis description

>=2g/dL Increase in Hemoglobin response

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2844

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified CMH

Point estimate

6.97

Confidence interval

level

95%

sides

2-sided

lower limit

-5.41

upper limit

19.35

Secondary: Number of Baseline TD Participants With TI Status at Week 24

Top of page

End point title

Number of Baseline TD Participants With TI Status at Week 24 ^[38]

End point description

Participants were defined as having TD if they met both of the following requirements in the 8 weeks immediately before the end of Week 24: >= 4 red blood cell or whole blood units were transfused (except in the case of clinically overt bleeding), each in response to a hemoglobin assessment of <= 9.5 g/dL; and there were >= 2 hemoglobin assessments with >= 28 days between the earliest and latest hemoglobin assessments. TI status was defined as not requiring red blood cell transfusion (except in the case of clinically overt bleeding) for >= 12 weeks immediately prior to the end of Week 24, with hemoglobin levels >= 8 g/dL. Only those participants with data available at specified time points were analyzed.

End point type

Secondary

End point timeframe

Week 24

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	34 ^[39]	63 ^[40]
Units: Participants	3	9

Notes
[39] - ITT Analysis Set
[40] - ITT Analysis Set

No statistical analyses for this end point

Secondary: Duration of TI in Baseline TD Participants

Top of page

End point title

Duration of TI in Baseline TD Participants ^[41]

End point description

Duration of TI is defined as the number of days from (a) the first day of a 12-week period that satisfies the 12-week TI status definition, to (b) the first RBC transfusion or Hgb level < 8 g/dL (except in the case of clinically overt bleeding). Only those participants with data available at specified time points were analyzed. 99999 indicates <50% of participants experienced the event within the treatment arm. Hence, median and third-quartile could not be derived.

End point type

Secondary

End point timeframe

Up to a maximum of 77.6 weeks

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	34 ^[42]	63 ^[43]
Units: Days
median (inter-quartile range (Q1-Q3))	99999 (196.0 to 99999)	99999 (224.0 to 99999)

Notes
[42] - ITT Analysis Set
[43] - ITT Analysis Set

No statistical analyses for this end point

Secondary: Number of participants with serious adverse events (SAEs) and non-serious adverse events (non-SAEs)- up to Week 24

Top of page

End point title

Number of participants with serious adverse events (SAEs) and non-serious adverse events (non-SAEs)- up to Week 24

End point description

An Adverse event (AE) is any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. An SAE is an AE that Results in death, life threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly/birth defect or any important medical events as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events. Safety analysis set included all participants in the ITT Analysis set who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	MMB 200 mg QD + Placebo- Randomized DB TP	DAN 300 mg BID + Placebo- Randomized DB TP
Number of subjects analysed	130 ^[44]	65 ^[45]
Units: Participants
Any non-SAEs	108	55
Any SAEs	45	26

Notes
[44] - Safety analysis set
[45] - Safety analysis set

No statistical analyses for this end point

Secondary: Number of participants with serious adverse events (SAEs) and non-serious adverse events (non-SAEs)- From Week 24 to Week 204

Top of page

End point title

Number of participants with serious adverse events (SAEs) and non-serious adverse events (non-SAEs)- From Week 24 to Week 204

End point description

An AE is any untoward medical occurrence in a trial participant administered an investigational product(s), a comparator product, or an approved drug regardless of the causal relationship with treatment. An SAE is an AE that Results in death, life threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly/birth defect or any important medical events as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.

End point type

Secondary

End point timeframe

From Week 24 to Week 204

End point values	MMB 200 mg QD- Open-Label Extended TP	DAN 300 mg BID to MMB 200 mg QD- Open-Label Extended TP
Number of subjects analysed	93 ^[46]	41 ^[47]
Units: Participants
Any non-SAEs	57	28
Any SAEs	30	12

Notes
[46] - Safety analysis set
[47] - Safety analysis set

No statistical analyses for this end point

Secondary: Leukemia-free Survival (LFS)

Top of page

End point title

Leukemia-free Survival (LFS) ^[48]

End point description

LFS is defined as the interval from first study drug dosing date (or randomization date for participants who did not receive treatment) to any evidence of leukemic transformation and/or death (from any cause). Values are presented based on the Kaplan-Meier analysis. All participants (overall population) were included in analysis. 99999 indicates <50% of participants experienced the event within the treatment arm. Hence, median and third-quartile could not be derived and 88888 indicates <75% of participants experienced the event within the treatment arm. Hence, third-quartile could not be derived.

End point type

Secondary

End point timeframe

Up to a maximum of 77.6 weeks

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[49]	130 ^[50]
Units: Days
median (inter-quartile range (Q1-Q3))	99999 (284.0 to 99999)	624.0 (325.0 to 88888)

Notes
[49] - ITT Analysis Set
[50] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.432

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.804

Confidence interval

level

95%

sides

2-sided

lower limit

0.466

upper limit

1.386

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS) ^[51]

End point description

Overall survival is defined as the interval from the first study drug dosing date (or randomization date for participants who did not receive treatment) to death from any cause. Values are presented based on the Kaplan-Meier analysis. All participants (overall population) were included in analysis. 99999 indicates <50% of participants experienced the event within the treatment arm. Hence, median and third-quartile could not be derived and 88888 indicates <75% of participants experienced the event within the treatment arm. Hence, third-quartile could not be derived.

End point type

Secondary

End point timeframe

Up to a maximum of 77.6 weeks

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	65 ^[52]	130 ^[53]
Units: Days
median (inter-quartile range (Q1-Q3))	99999 (309.00 to 99999)	624.0 (333.0 to 88888)

Notes
[52] - ITT Analysis Set
[53] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6879

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.504

upper limit

1.572

Secondary: Change From Baseline in Disease-related Fatigue as Assessed by MFSAF TSS v4.0 at Week 24

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End point title

Change From Baseline in Disease-related Fatigue as Assessed by MFSAF TSS v4.0 at Week 24 ^[54]

End point description

The MFSAF v4.0 comprises 7 domains representing the 7 most relevant symptoms of MF identified through existing participant- and clinician-based evidence: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Participants scored each symptom domain using an 11-point numeric rating scale ranging from 0 (absent) to 10 (worst imaginable). The total possible range of scores was 0 to 70, with higher scores corresponding to more severe MF symptoms. An increase in score from Baseline indicated a worsening of MF symptoms, and a decrease in score from Baseline indicated an improvement in MF symptoms. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value. Only those participants with data available at specified time points were analyzed.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	37 ^[55]	92 ^[56]
Units: Scores on a scale
least squares mean (standard error)	-0.82 ( 0.31 )	-1.53 ( 0.20 )

Notes
[55] - ITT Analysis Set
[56] - ITT Analysis Set

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0513

Method

MMRM

Parameter type

Least Squares Mean Difference

Point estimate

-0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-1.42

upper limit

0

Secondary: Change From Baseline in Cancer-related Fatigue as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at Week 24

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End point title

Change From Baseline in Cancer-related Fatigue as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at Week 24 ^[57]

End point description

The EORTC QLQ-C30 is comprised of 5 functional scales (physical, role, emotional, social, cognitive), eight single item symptom scales (fatigue, pain, nausea/vomiting, appetite loss, constipation, diarrhea, insomnia, dyspnea), as well as sub-scales assessing global health/quality of life and financial impact. Most items use a 4-point Likert scale from "not at all" to "very much" and a one-week recall period with the exception of the final two items which use a 7 point scale response from "very poor" to "excellent". Scores were averaged and transformed to a 0-100 scale, with higher scores representing better functioning/quality of life. An increase in scores from Baseline indicated an improved functioning/quality of life, and a decrease in scores from Baseline indicated a worsened functioning/quality of life. Baseline was the last assessment done before or on the day of first dose date. Change from Baseline was defined as the post-Baseline value minus Baseline value.

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	35 ^[58]	89 ^[59]
Units: Scores on a scale
least squares mean (standard error)	-3.52 ( 3.65 )	-14.34 ( 2.35 )

Notes
[58] - ITT Analysis Set. Only those participants with data available at specified time points were analyzed
[59] - ITT Analysis Set. Only those participants with data available at specified time points were analyzed

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0113

Method

MMRM

Parameter type

Least Squares Mean Difference

Point estimate

-10.82

Confidence interval

level

95%

sides

2-sided

lower limit

-19.15

upper limit

-2.48

Secondary: Change From Baseline in Physical Function Score as Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b at Week 24

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End point title

Change From Baseline in Physical Function Score as Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b at Week 24 ^[60]

End point description

PROMIS Physical Function Short Form 10b consists of 14 questions; each with a 5-point response. PROMIS short form assesses self-reported capability of a participant rather than actual performance of physical activities. This includes functioning of one's upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back) as well as instrumental activities of daily living, such as running errands. Participants scored each response on a scale from 1 (unable to do) to 5 (without any difficulty, or not at all). Total possible range of scores was 14 to 70, with higher scores corresponding to a greater physical function ability. An increase in score from Baseline indicated an improvement in physical function ability and a decrease in score from Baseline indicated a reduction in physical function ability. Baseline was last assessment done before or on the day of first dose date. Change from Baseline was defined as post-Baseline value minus Baseline value

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.

End point values	DAN 300 mg BID + Placebo	MMB 200 mg QD + Placebo
Number of subjects analysed	32 ^[61]	89 ^[62]
Units: Scores on a scale
least squares mean (standard error)	-0.11 ( 1.21 )	1.19 ( 0.77 )

Notes
[61] - ITT Analysis Set. Only those participants with data available at specified time points were analyzed
[62] - ITT Analysis Set. Only those participants with data available at specified time points were analyzed

Statistical Analysis 1

Comparison groups

DAN 300 mg BID + Placebo v MMB 200 mg QD + Placebo

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.357

Method

MMRM

Parameter type

Least Squares Mean Difference

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

-1.49

upper limit

4.11

Adverse events

Top of page

Timeframe for reporting adverse events

All-cause mortality, Serious adverse events (SAEs) and non-SAEs were collected up to Week 24 for Randomized Double-Blind Treatment Period and From Week 24 to a maximum of 77.6 weeks for the Open-Label Extended Treatment Period

Adverse event reporting additional description

Serious adverse events (SAEs) and non-SAEs were measured in the Safety analysis set, which included all participants in the ITT analysis set who received at least one dose of study drug. All-cause mortality was measured in the ITT analysis set, which included all randomized participants. Data are presented per treatment received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

MMB 200 mg QD + Placebo- Randomized DB TP

Reporting group description

Participants were randomized to receive 200 mg of MMB orally QD and a DAN-placebo orally BID during the randomized 24-week double-blind treatment period.

Reporting group title

DAN 300 mg BID to MMB 200 mg QD- Open-Label Extended TP

Reporting group description

Participants who completed the randomized treatment period, discontinued treatment early due to splenic progression, or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants who received DAN 300 mg BID during randomized period switched to receive 200 mg of MMB orally QD during open-label extended treatment period.

Reporting group title

MMB 200 mg QD- Open-Label Extended TP

Reporting group description

Participants who completed the randomized treatment period or discontinued treatment early for other reasons but completed scheduled assessments through Week 24 were enrolled in an open-label extended treatment period. Participants continued to receive 200 mg of MMB orally QD during the open-label extended treatment period.

Reporting group title

DAN 300 mg BID + Placebo- Randomized DB TP

Reporting group description

Participants were randomized to receive 300 mg of DAN orally BID and MMB-placebo orally QD during the randomized 24-week double-blind treatment period.

Serious adverse events	MMB 200 mg QD + Placebo- Randomized DB TP	DAN 300 mg BID to MMB 200 mg QD- Open-Label Extended TP	MMB 200 mg QD- Open-Label Extended TP	DAN 300 mg BID + Placebo- Randomized DB TP
Total subjects affected by serious adverse events
subjects affected / exposed	45 / 130 (34.62%)	12 / 41 (29.27%)	30 / 93 (32.26%)	26 / 65 (40.00%)
number of deaths (all causes)	25	8	23	16
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Leukaemia cutis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tongue neoplasm malignant stage unspecified
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transformation to acute myeloid leukaemia
subjects affected / exposed	3 / 130 (2.31%)	1 / 41 (2.44%)	0 / 93 (0.00%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
Adenocarcinoma
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	2 / 93 (2.15%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Sudden death
subjects affected / exposed	1 / 130 (0.77%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 130 (2.31%)	1 / 41 (2.44%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	2 / 130 (1.54%)	0 / 41 (0.00%)	1 / 93 (1.08%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
Death
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Complication associated with device
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Prostatitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	1 / 93 (1.08%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 130 (0.77%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Restrictive pulmonary disease
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary arterial hypertension
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Personality change
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
General physical condition abnormal
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Cervical vertebral fracture
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periprosthetic fracture
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 130 (0.77%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Coronary artery disease
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Atrial fibrillation
subjects affected / exposed	2 / 130 (1.54%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Atrial thrombosis
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Subarachnoid haemorrhage
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 130 (2.31%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 130 (3.85%)	1 / 41 (2.44%)	1 / 93 (1.08%)	3 / 65 (4.62%)
occurrences causally related to treatment / all	1 / 5	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3
Blood loss anaemia
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	2 / 93 (2.15%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	3 / 130 (2.31%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Splenic vein thrombosis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	1 / 93 (1.08%)	2 / 65 (3.08%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Splenic haematoma
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastric ulcer perforation
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoperitoneum
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic erosive gastritis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis acute
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Chronic kidney disease
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	4 / 130 (3.08%)	2 / 41 (4.88%)	2 / 93 (2.15%)	3 / 65 (4.62%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 130 (1.54%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Tenosynovitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sarcopenia
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Clostridium difficile colitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 130 (1.54%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	3 / 130 (2.31%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	3 / 130 (2.31%)	0 / 41 (0.00%)	4 / 93 (4.30%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint abscess
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 130 (2.31%)	1 / 41 (2.44%)	1 / 93 (1.08%)	6 / 65 (9.23%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 1	2 / 6
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Listeria sepsis
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 130 (0.77%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 130 (1.54%)	1 / 41 (2.44%)	2 / 93 (2.15%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Escherichia infection
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Enterobacter sepsis
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Splenic abscess
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Urosepsis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	1 / 93 (1.08%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Fluid overload
subjects affected / exposed	2 / 130 (1.54%)	0 / 41 (0.00%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 130 (0.77%)	1 / 41 (2.44%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 130 (0.00%)	0 / 41 (0.00%)	0 / 93 (0.00%)	1 / 65 (1.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 130 (0.00%)	1 / 41 (2.44%)	0 / 93 (0.00%)	0 / 65 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	MMB 200 mg QD + Placebo- Randomized DB TP	DAN 300 mg BID to MMB 200 mg QD- Open-Label Extended TP	MMB 200 mg QD- Open-Label Extended TP	DAN 300 mg BID + Placebo- Randomized DB TP
Total subjects affected by non serious adverse events
subjects affected / exposed	108 / 130 (83.08%)	28 / 41 (68.29%)	57 / 93 (61.29%)	55 / 65 (84.62%)
Vascular disorders
Hypertension
subjects affected / exposed	6 / 130 (4.62%)	5 / 41 (12.20%)	3 / 93 (3.23%)	6 / 65 (9.23%)
occurrences all number	6	5	3	6
General disorders and administration site conditions
Fatigue
subjects affected / exposed	8 / 130 (6.15%)	3 / 41 (7.32%)	6 / 93 (6.45%)	6 / 65 (9.23%)
occurrences all number	10	3	11	10
Oedema peripheral
subjects affected / exposed	9 / 130 (6.92%)	1 / 41 (2.44%)	3 / 93 (3.23%)	9 / 65 (13.85%)
occurrences all number	9	1	3	10
Pyrexia
subjects affected / exposed	11 / 130 (8.46%)	3 / 41 (7.32%)	12 / 93 (12.90%)	5 / 65 (7.69%)
occurrences all number	13	4	13	6
Asthenia
subjects affected / exposed	17 / 130 (13.08%)	0 / 41 (0.00%)	12 / 93 (12.90%)	6 / 65 (9.23%)
occurrences all number	20	0	15	8
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	9 / 130 (6.92%)	0 / 41 (0.00%)	7 / 93 (7.53%)	10 / 65 (15.38%)
occurrences all number	10	0	8	12
Epistaxis
subjects affected / exposed	7 / 130 (5.38%)	3 / 41 (7.32%)	1 / 93 (1.08%)	4 / 65 (6.15%)
occurrences all number	7	3	2	6
Cough
subjects affected / exposed	9 / 130 (6.92%)	2 / 41 (4.88%)	8 / 93 (8.60%)	2 / 65 (3.08%)
occurrences all number	10	2	9	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	9 / 130 (6.92%)	1 / 41 (2.44%)	2 / 93 (2.15%)	5 / 65 (7.69%)
occurrences all number	13	1	4	11
Aspartate aminotransferase increased
subjects affected / exposed	7 / 130 (5.38%)	1 / 41 (2.44%)	3 / 93 (3.23%)	4 / 65 (6.15%)
occurrences all number	9	1	3	5
Blood alkaline phosphatase increased
subjects affected / exposed	10 / 130 (7.69%)	1 / 41 (2.44%)	3 / 93 (3.23%)	0 / 65 (0.00%)
occurrences all number	18	1	3	0
Weight decreased
subjects affected / exposed	14 / 130 (10.77%)	7 / 41 (17.07%)	9 / 93 (9.68%)	3 / 65 (4.62%)
occurrences all number	16	7	9	4
Platelet count decreased
subjects affected / exposed	9 / 130 (6.92%)	1 / 41 (2.44%)	3 / 93 (3.23%)	3 / 65 (4.62%)
occurrences all number	24	2	7	4
Blood creatinine increased
subjects affected / exposed	10 / 130 (7.69%)	4 / 41 (9.76%)	7 / 93 (7.53%)	10 / 65 (15.38%)
occurrences all number	18	4	13	16
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	7 / 130 (5.38%)	0 / 41 (0.00%)	4 / 93 (4.30%)	3 / 65 (4.62%)
occurrences all number	9	0	6	3
Nervous system disorders
Dizziness
subjects affected / exposed	8 / 130 (6.15%)	4 / 41 (9.76%)	1 / 93 (1.08%)	1 / 65 (1.54%)
occurrences all number	9	4	1	1
Paraesthesia
subjects affected / exposed	8 / 130 (6.15%)	0 / 41 (0.00%)	1 / 93 (1.08%)	1 / 65 (1.54%)
occurrences all number	10	0	1	1
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	7 / 130 (5.38%)	2 / 41 (4.88%)	5 / 93 (5.38%)	2 / 65 (3.08%)
occurrences all number	11	2	9	5
Anaemia
subjects affected / exposed	12 / 130 (9.23%)	3 / 41 (7.32%)	9 / 93 (9.68%)	6 / 65 (9.23%)
occurrences all number	34	6	18	11
Thrombocytopenia
subjects affected / exposed	28 / 130 (21.54%)	7 / 41 (17.07%)	13 / 93 (13.98%)	7 / 65 (10.77%)
occurrences all number	50	10	22	11
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	3 / 130 (2.31%)	1 / 41 (2.44%)	2 / 93 (2.15%)	5 / 65 (7.69%)
occurrences all number	3	1	3	6
Abdominal pain
subjects affected / exposed	10 / 130 (7.69%)	1 / 41 (2.44%)	3 / 93 (3.23%)	6 / 65 (9.23%)
occurrences all number	12	2	3	6
Vomiting
subjects affected / exposed	9 / 130 (6.92%)	1 / 41 (2.44%)	3 / 93 (3.23%)	0 / 65 (0.00%)
occurrences all number	10	1	3	0
Nausea
subjects affected / exposed	21 / 130 (16.15%)	0 / 41 (0.00%)	8 / 93 (8.60%)	6 / 65 (9.23%)
occurrences all number	28	0	10	6
Diarrhoea
subjects affected / exposed	29 / 130 (22.31%)	5 / 41 (12.20%)	16 / 93 (17.20%)	6 / 65 (9.23%)
occurrences all number	40	7	21	7
Constipation
subjects affected / exposed	11 / 130 (8.46%)	2 / 41 (4.88%)	4 / 93 (4.30%)	5 / 65 (7.69%)
occurrences all number	13	2	4	5
Skin and subcutaneous tissue disorders
Night sweats
subjects affected / exposed	4 / 130 (3.08%)	0 / 41 (0.00%)	2 / 93 (2.15%)	4 / 65 (6.15%)
occurrences all number	4	0	2	5
Rash
subjects affected / exposed	3 / 130 (2.31%)	0 / 41 (0.00%)	0 / 93 (0.00%)	4 / 65 (6.15%)
occurrences all number	3	0	0	4
Pruritus
subjects affected / exposed	13 / 130 (10.00%)	1 / 41 (2.44%)	6 / 93 (6.45%)	7 / 65 (10.77%)
occurrences all number	14	1	7	7
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 130 (1.54%)	1 / 41 (2.44%)	1 / 93 (1.08%)	5 / 65 (7.69%)
occurrences all number	2	1	1	5
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 130 (3.08%)	3 / 41 (7.32%)	1 / 93 (1.08%)	2 / 65 (3.08%)
occurrences all number	5	4	1	3
Infections and infestations
COVID-19
subjects affected / exposed	9 / 130 (6.92%)	0 / 41 (0.00%)	8 / 93 (8.60%)	0 / 65 (0.00%)
occurrences all number	9	0	8	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	9 / 130 (6.92%)	1 / 41 (2.44%)	4 / 93 (4.30%)	6 / 65 (9.23%)
occurrences all number	13	1	5	8
Hyperkalaemia
subjects affected / exposed	6 / 130 (4.62%)	2 / 41 (4.88%)	2 / 93 (2.15%)	6 / 65 (9.23%)
occurrences all number	7	2	3	12
Hyperuricaemia
subjects affected / exposed	9 / 130 (6.92%)	3 / 41 (7.32%)	3 / 93 (3.23%)	4 / 65 (6.15%)
occurrences all number	9	3	3	6
Hyponatraemia
subjects affected / exposed	3 / 130 (2.31%)	0 / 41 (0.00%)	3 / 93 (3.23%)	4 / 65 (6.15%)
occurrences all number	5	0	3	4

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Were there any global substantial amendments to the protocol? Yes

16 Aug 2019

Protocol Amendment 1: • Clarified criteria for dose reduction due to thrombocytopenia, neutropenia, and nonhematologic or other toxicities; and subsequent dose re-escalation. • Modified thresholds for platelet count recovery required to resume treatment based on Baseline value. • Updated procedures for managing transition from randomized treatment to open-label treatment so treatment assignment would only be unblinded when required to determine eligibility for open-label treatment with MMB or DAN.

18 Dec 2020

Protocol Amendment 2: • Removed interim analysis for sample size reassessment from the study design. • Modified the planned statistical analysis: Moved the MMRM analysis of the MFSAF TSS secondary endpoint to the fourth position in the overall statistical testing hierarchy. – Revised description of the hierarchal statistical testing of secondary endpoints. Updated descriptions of the secondary endpoints. Updated statistics section. • Changed timing of first dose after randomization, JAK inhibitor nontreatment period, exclusion of active anti-MF medication, and Baseline spleen volume assessment to allow flexibility for scheduling randomization and day 1. • Inclusion criteria were modified: Criterion 3: clarified that an MFSAF TSS of >= 10 units was required during screening prior to Baseline day 1. Criteria 4a and 4c: clarified the definition of anemic. – Criterion 5b: added that participants receiving a low dose of a JAK inhibitor could have a reduced taper period, or no taper, with sponsor approval. Criterion 9: clarified that platelet count must be met without requirement for platelet transfusion. • Exclusion criteria were modified: Criterion 1b: clarified that approved JAK inhibitors were prohibited and reduced the study period and window for use. – Criterion 1c: reduced the study period and window for use of anti-MF therapy. Criterion 1e: clarified that investigational JAK inhibitors were prohibited within 4 weeks prior to randomization. Criterion 7: added thalassemia as a cause of clinically significant anemia. • Updated criteria for adjusting or stopping doses to provide guidance that investigator clinical discretion should be used and that in the event of grade 3 or 4 toxicity, relevant laboratory tests should be closely monitored per investigator clinical discretion.

18 Dec 2020

Protocol Amendment 2 (continued): • Clarified the anticipated risks of DAN to emphasize that the provided safety information references the approved indications for DAN and should be interpreted by the investigator for guidance when assessing participants in this study. • Updated criteria for crossing over to open-label MMB to add sponsor approval for short-term use of restricted anti-MF medication to treat severe splenic progression, revise criteria for splenic progression, and add sponsor approval for spleen volume measurements read locally. • Updated restricted treatment use for consistency with exclusion criterion 1 and to clearly define the beginning and end of the study period. • Added that alternative methods, including paper forms, could be used to record Patient Reported Outcome responses in exceptional circumstances, with sponsor approval. • Updated adverse event and serious adverse event reporting criteria and procedures. • Clarified requirements for hepatitis testing. • Added that local laboratory assessments could be used to determine eligibility, with sponsor approval, if central laboratory assessments were not available prior to day 1. • Clarified the window (+/- 7 days) for MFSAF assessments and PRO responses during the open-label extended treatment period. • Added that participants requiring antihypertensive medication should be closely monitored on the day of the first study drug dose and that medication could be administered if clinically necessary. • Added that investigators were to advise participants on the conservation of gametes prior to receiving study drug due to the possibility of infertility. • Updated DAN packaging configuration and procedures for receipt of study drug. • Added that a male condom must be used in combination with a diaphragm (with spermicide). • Added a protocol addendum for guidance on modified study procedures that could be followed during the Coronavirus 2019 (COVID-19) pandemic.

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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