Clinical trial NCT04003974
Conditions: Facioscapulohumeral Muscular Dystrophy (FSHD)
Keywords: FSHD, FSHD1 Muscular Dystrophies Muscular Dystrophy Facioscapulohumeral Muscular Disorders Musculoskeletal Diseases Neuromuscular Diseases
Sponsor: Fulcrum Therapeutics
Start date: 2019-08-09; Completion date: 2021-01-28
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to evaluate the safety and efficacy of Losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks.

Detailed description:
This study is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter study designed to evaluate the efficacy and safety of losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks. Patients will participate in this study for approximately 53 weeks. This will include a 4-week screening period, a 48-week, placebo-controlled treatment period and a 7 day safety follow-up period. Patients must have a confirmed diagnosis of FSHD1 and genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy. Patients will be randomized to receive 15 mg of losmapimod or placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks. All patients will be asked to attend the study clinic for each scheduled visit.

The primary endpoint of the study is to evaluate the efficacy of losmapimod in inhibiting or reducing expression of DUX4, as measured by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies of FSHD patients. Secondary endpoints include evaluation of the safety and tolerability of losmapimod, the plasma concentrations of losmapimod, levels of losmapimod in skeletal muscle and losmapimod target engagement in blood and skeletal muscle in FSHD patients.

This study was conducted during the Coronavirus Disease-2019 (COVID-19) Pandemic. The pandemic restrictions limited some assessments in the FSHD1 population in the clinic, including collection of some data for Week 24.

Arms: arm 1: FSHD1 patients with genetic confirmation will receive Losmapimod 15 mg twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks. arm 2: FSHD1 patients with genetic confirmation will receive a Placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks.
Interventions: intervention 1: Losmapimod oral tablet intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Losmapimod will be administered with food when possible. intervention 2: Placebo will be administered with food when possible

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
IND: 138739 
EUDRACT: 2019-001181-15 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week, 
Parallel-Group Study of the Efficacy and Safety of Losmapimod in 
Treating Subjects with Facioscapulohumeral Muscular Dystrophy (FSHD) 
with Open-Label Extension (OLE) 
 
PROTOCOL FIS-002-2019 
Sponsor: 
Fulcrum Therapeutics 
26 Landsdowne Street 
Cambridge, MA 02139 USA 
Sponsor Contact: 
 
Senior Medical Director 
Fulcrum Therapeutics 
26 Landsdowne Street 
Cambridge, MA 02139 USA 
Telephone: 
Medical Monitor: 
Version of Protocol:  
Version 4.0 (COVID-19 Pandemic Emergency Amendment) 
Date of Protocol:  
10 April 2020 
 
CONFIDENTIAL  
All financial and nonfinancial support for this study will be provided by Fulcrum 
Therapeutics. The concepts and information contained in this document or generated during 
the study are considered proprietary and may not be disclosed in whole or in part without the 
expressed, written consent of Fulcrum Therapeutics. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R2): Good Clinical Practice.  
 
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SUMMARY OF CHANGES TO THE PROTOCOL 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 27 March 2019 
Original version 
Version 2.0, 30 July 2019 
x 
Clarified benefit/risk ratio 
x 
Clarified exclusion criterion #18 
x 
Clarified unblinding procedure in the event 
of an emergency 
x 
Added instructions for missed doses and 
study drug compliance details 
x 
Added adverse events of special interest and 
stopping criteria for abnormal liver tests 
x 
Updated the process for calculating the 
number of D4Z4 repeats 
x 
Updated language for the analysis of the 
primary endpoint and secondary endpoints 
to match the statistical analysis plan 
x 
Clarified collection time points in the 
schedule of events 
x 
Updated language referencing regulatory 
authorities 
x 
Clarified that the sponsor has no plans to 
provide study drug to subjects after study 
closure or termination 
Version 3.0, 27 November 2019 
x 
Added an open-label extension (OLE) to the 
protocol. Added language to differentiate 
the placebo-controlled treatment period part 
of the study versus the OLE part of the 
study. Clarified that baseline is prior to the 
first dose in the placebo-controlled 
treatment period. 
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10 April 2020 
x 
Change from baseline in lean muscle tissue 
volume and fat fraction in FSHD1 subjects, 
as measured by musculoskeletal (MSK) 
magnetic resonance imaging (MRI), 
changed from exploratory 
objective/endpoint to a secondary 
objective/endpoint and revised to include 
muscle fat infiltration (MFI). 
x 
Increased the number of randomized 
subjects from approximately 66 to 
approximately 76. 
x 
Clarified that for scheduled study visits that 
are split over 2 days, the visits may not be 
more than 5 business days apart. 
x 
Clarified that subjects can travel for MRI or 
muscle biopsy if needed, but the use of a 
study-approved MRI scanner should be 
consistent during the trial. 
x 
Clarified in inclusion criterion #3 that 
“appropriate documentation” is 
documentation from an accredited 
laboratory. 
x 
Clarified in inclusion criterion #4 that a 
RICCI score between 2 and 4 does not 
include subjects that use wheelchairs or 
walkers for any reason.  
x 
Clarified in exclusion criterion #12 that that 
subjects should not be vaccinated with a live 
attenuated vaccine throughout the study. 
x 
Added clarifications on the identity of 
investigational product, study drug 
packaging, study drug accountability, and 
compliance. 
x 
Clarified pregnancy reporting. 
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Fulcrum Therapeutics 
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10 April 2020 
x 
Removed collection of blood sample for 
coagulation at the early termination visit and 
7-day safety follow up visit. 
x 
Clarified that a full physical examination 
will be performed at the screening visit and 
the 7-day safety follow up visit and a 
symptom directed physical examination will 
be performed at all other visits. 
x 
Added additional details for the safety and 
tolerability endpoint. Revised the secondary 
and exploratory endpoints to include 
specific time points. 
x 
Clarified that functional workspace is a part 
of the reachable workspace (RWS) 
assessment 
Version 4.0, 10 April 2020 
(COVID-19 Pandemic Emergency 
Amendment) 
x 
This amendment includes permanent 
changes to the ReDUX4 protocol. 
x 
Refer to the ReDUX4 Emergency 
Guidance document implemented 
31 March 2020 for details related to 
temporary procedures enacted during 
the COVID-19 pandemic.  
x 
Extended randomized placebo-controlled 
portion of the study from 24 to 48 weeks 
due to the COVID-19 pandemic and 
disruptions to the protocol-defined clinical 
trial conduct 
x 
Noted that enrollment has been completed 
x 
All Week 24 efficacy assessments moved to 
Week 48 
x 
Muscle biopsies will be performed at 
Week 16 or at Week 36 for those subjects 
unable to have the biopsy at Week 16 due to 
the COVID-19 pandemic 
x 
Removed the one-time biopsy from the 
open-label extension (OLE) portion of the 
study 
x 
Added an interim analysis to be performed 
after a minimum of 22 paired muscle 
biopsies have been collected. 
x 
Removed OLE secondary endpoints 
evaluating long-term efficacy in subjects 
originally randomized to losmapimod and in 
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Protocol FIS-002-2019, Version 4.0 (COVID-19 Pandemic Emergency Amendment) 
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subjects originally randomized to placebo 
during the placebo-controlled treatment 
period, to evaluate the efficacy of 
losmapimod in inhibiting or reducing 
expression of DUX4, the root cause of 
FSHD, as measured by a subset of DUX4-
regulated gene transcripts in skeletal muscle 
biopsies 
x 
Elevated placebo-controlled treatment 
period secondary objective and endpoint for 
evaluation of safety and tolerability of 
losmapimod in FSHD1 subjects  
 
x 
Removed measurement of the metabolite, 
GSK198602 
 
Key changes to the current version of the protocol are summarized below:  
 
Change and Rationale 
Affected Sections 
x 
Extended randomized placebo-controlled 
portion of the study from 24 to 48 weeks as 
the COVID-19 pandemic is preventing many 
of the Week 24 visits to the sites to take place. 
The extension in the length of the randomized 
placebo-controlled portion of the study will 
enable longer-term assessment of safety and 
efficacy of losmapimod versus placebo for the 
treatment of FSHD.  
Section 3.1.1, Section 3.2.2, Section 4.2, 
Section 5.2, Section 6, Section 7.1, Table 13-1 
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Change and Rationale 
Affected Sections 
x 
All Week 24 efficacy assessments moved to 
Week 48. The extension in the length of the 
randomized placebo-controlled portion of the 
study will enable longer-term assessment of 
safety and efficacy of losmapimod versus 
placebo, including clinical outcome measures 
considered relevant in FSHD, especially 
considering the slowly progressing nature of 
the disease. 
Section 3.1.1, Section 7.1.2, Section 7.1.3, 
Section 7.6.1, Table 13-1 
x 
As the COVID-19 pandemic is preventing 
many of the 16-week biopsies from being 
performed due to restrictions on travel and 
study visits, flexibility was added to allow 
muscle biopsies to be performed at Week 16 
or at Week 36 for those subjects unable to 
have the biopsy at Week 16. The primary 
endpoint of this clinical trial is dependent on 
muscle biopsies. Muscle biopsies performed 
at Week 36 will enable adequate assessment 
of efficacy.  
Section 3.1.1, Section 6.1.1, Section 6.3.1, 
Section 6.3.2, Section 7.1.1, Section 7.3, 
Section 7.6.1, Section 7.6.2, Table 13-1 
x 
Removed the one-time biopsy from the OLE 
portion of the study. This biopsy will now be 
performed at Week 36 during the 
placebo-controlled portion of the study. The 
Week 36 biopsy will enable an assessment of 
the long-term durability of the effect of 
losmapimod treatment.   
Section 2.2.2, Section 3.1.2, Section 7.2.2, 
Table 13-2 
x 
Noted that enrollment has completed. 
Section 3.1.1, Section 4.1 
x 
Study drug dispensation, compliance , and 
accountability procedures were clarified. 
Section 5.2, Section 5.7 
x 
Description of analysis sets were updated.  
Section 7.4 
x 
Elevated placebo-controlled treatment period 
secondary objective and endpoint for 
evaluation of safety and tolerability of 
losmapimod in FSHD1 subjects. 
Section 2.1.2; Section 7.1.2 
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Change and Rationale 
Affected Sections 
x 
Details on the number of individuals who 
have been dosed with losmapimod were 
added. 
Section 1.4 
x 
Added an interim analysis to be performed 
after a minimum of 22 paired muscle biopsies 
have been collected. This interim analysis will 
provide timely data to inform the further 
development of losmapimod for the treatment 
of FSHD.  
Section 5.6, Section 7, Section 7.6.8 
x 
Added hypothesis testing on key study 
endpoints using the full analysis set. 
Section 7.6.1 
x 
Removed the secondary endpoint in the OLE 
portion of the study that evaluates the efficacy 
of losmapimod in inhibiting or reducing 
expression of DUX4, the root cause of FSHD, 
as measured by a subset of DUX4-regulated 
gene transcripts in skeletal muscle biopsies. 
The muscle biopsy assessment was removed 
from the OLE portion of the study  
Section 2.2.2, Section 3.1.2, Table 13-2 
x 
Removed measurement of the metabolite, 
GSK198602, as it is inactive and not 
clinically relevant.  
Section 2.1.2, Section 3.1.1, Section 6.3.1, 
Section 7.1.2, Section 7.4, Section 7.6.5 
x 
Removed collection of target engagement 
sampling from OLE portion of the study 
Section 2.2.2, Section 3.1.2, Section 6.3.2, 
Section 7.2.2, Table 13-2 
x 
Clarified that coagulation testing prior to 
muscle biopsies is optional and institutional 
guidelines should be followed. Coagulation 
testing during the OLE portion of the study 
was removed to reflect the removal of the 
one-time muscle biopsy. 
Table 13-1, Table 13-2 
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Change and Rationale 
Affected Sections 
x 
Language was added to address subjects who 
have already rolled over to the OLE portion of 
the study prior to the implementation of the 
COVID-19 Pandemic Emergency protocol 
version 4. 
Section 3.1, Section 3.1.1, Section 5.2, 
Section 6, Section 7.4,  Table 13-1 
Typographical and administrative changes were 
also made to improve the clarity of the document. 
Throughout 
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Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-002-2019, Version 4.0 (COVID-19 Pandemic Emergency Amendment) 
10 April 2020 
 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and 
Safety of Losmapimod in Treating Subjects with Facioscapulohumeral Muscular Dystrophy 
(FSHD) with Open-Label Extension (OLE)” and the accompanying investigator’s brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 4.0 (COVID-19 Pandemic Emergency 
Amendment), dated 10 April 2020, the International Council for Harmonisation harmonised 
tripartite guideline E6(R2): Good Clinical Practice and all applicable government 
regulations. I will not make changes to the protocol before consulting with Fulcrum 
Therapeutics or implement protocol changes without independent ethics committee approval 
except to eliminate an immediate risk to subjects. I agree to administer study treatment only 
to subjects under my personal supervision or the supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Fulcrum Therapeutics. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
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Page 13 
Table of Contents 
Table of Contents .....................................................................................................................13 
List of Tables ............................................................................................................................17 
List of Figures ..........................................................................................................................17 
Protocol Synopsis.....................................................................................................................18 
List of Abbreviations................................................................................................................26 
1 
Introduction ......................................................................................................................29 
1.1 
Background .............................................................................................................29 
1.2 
Nonclinical Information ..........................................................................................31 
1.3 
Clinical Pharmacology ............................................................................................32 
1.4 
Clinical Safety .........................................................................................................33 
1.5 
Benefit/Risk Assessment .........................................................................................34 
2 
Study Objectives...............................................................................................................37 
2.1 
Placebo-Controlled Treatment Period .....................................................................37 
2.1.1 
Primary Objective ....................................................................................37 
2.1.2 
Secondary Objectives ..............................................................................37 
2.1.3 
Exploratory Objectives ............................................................................37 
2.2 
Open-Label Extension ............................................................................................38 
2.2.1 
Primary Objective ....................................................................................38 
2.2.2 
Secondary Objectives ..............................................................................38 
2.2.3 
Exploratory Objectives ............................................................................38 
3 
Investigational Plan ..........................................................................................................40 
3.1 
Study Design ...........................................................................................................40 
3.1.1 
Placebo-Controlled Treatment Period ......................................................40 
3.1.2 
Open-Label Extension .............................................................................43 
3.2 
Rationale of Study Design ......................................................................................44 
3.2.1 
Rationale of Dose Selection .....................................................................44 
3.2.2 
Rationale of Study Design .......................................................................46 
4 
Subject Selection and Withdrawal Criteria ......................................................................49 
4.1 
Selection of Study Population .................................................................................49 
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Page 14 
4.1.1 
Inclusion Criteria .....................................................................................49 
4.1.2 
Exclusion Criteria ....................................................................................50 
4.2 
Withdrawal of Subjects from Study Treatment and/or the Study ...........................53 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................53 
4.2.2 
Handling of Withdrawals .........................................................................54 
4.2.3 
Replacements ...........................................................................................55 
5 
Study Treatments ..............................................................................................................56 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................56 
5.2 
Treatments Administered ........................................................................................56 
5.3 
Identity of Investigational Product..........................................................................57 
5.4 
Management of Clinical Supplies ...........................................................................57 
5.4.1 
Study Drug Packaging and Storage .........................................................57 
5.4.2 
Study Drug Accountability ......................................................................58 
5.4.3 
Medication Errors and Overdose .............................................................58 
5.5 
Lifestyle Restrictions ..............................................................................................58 
5.5.1 
Contraception Requirements....................................................................59 
5.6 
Blinding...................................................................................................................60 
5.7 
Treatment Compliance ............................................................................................61 
5.8 
Prior and Concomitant Therapy ..............................................................................61 
6 
Study Assessments and Procedures ..................................................................................63 
6.1 
Efficacy Assessments ..............................................................................................63 
6.1.1 
Skeletal Muscle Needle Biopsy ...............................................................63 
6.1.2 
Skeletal Muscle Magnetic Resonance Imaging .......................................64 
6.2 
Safety and Tolerability Assessments .......................................................................64 
6.2.1 
Adverse Events ........................................................................................64 
6.2.1.1 
Definitions of Adverse Events .................................................................64 
6.2.1.2 
Serious Adverse Events ...........................................................................65 
6.2.1.3 
Adverse Events of Special Interest ..........................................................65 
6.2.1.4 
Eliciting and Documenting Adverse Events ............................................66 
6.2.1.5 
Reporting Adverse Events .......................................................................67 
6.2.1.6 
Reporting Serious Adverse Events ..........................................................68 
6.2.1.7 
Suspected Unexpected Serious Adverse Reactions .................................68 
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6.2.1.8 
Assessment of Severity ............................................................................69 
6.2.1.9 
Assessment of Causality ..........................................................................69 
6.2.1.10 Follow-Up of Subjects Reporting Adverse Events ..................................70 
6.2.2 
Laboratory Analyses ................................................................................70 
6.2.3 
Medical History .......................................................................................73 
6.2.4 
Vital Signs ................................................................................................73 
6.2.5 
Physical Examinations .............................................................................73 
6.2.6 
Twelve-Lead Electrocardiograms ............................................................74 
6.3 
Pharmacokinetic and Pharmacodynamic Assessments ...........................................74 
6.3.1 
Pharmacokinetic Assessments .................................................................74 
6.3.2 
Pharmacodynamic Assessments ..............................................................75 
6.4 
Other Assessments ..................................................................................................75 
6.4.1 
Reachable Work Space ............................................................................75 
6.4.2 
Timed Up and Go .....................................................................................76 
6.4.3 
Dynamometry ..........................................................................................77 
6.4.4 
Motor Function Measure Domain 1.........................................................77 
6.4.5 
FSHD Health Index .................................................................................77 
6.4.6 
Patients’ Global Impression of Change ...................................................78 
6.4.7 
Genetic Confirmation of FSHD1 .............................................................78 
6.5 
Safety Review Committee ......................................................................................79 
6.6 
Pregnancy ................................................................................................................79 
6.7 
Sample Collections .................................................................................................80 
7 
Statistical and Analytical Plan ..........................................................................................81 
7.1 
Placebo-Controlled Treatment Period .....................................................................81 
7.1.1 
Primary Endpoint .....................................................................................81 
7.1.2 
Secondary Endpoints ...............................................................................81 
7.1.3 
Exploratory Endpoints .............................................................................82 
7.2 
Open-Label Extension ............................................................................................82 
7.2.1 
Primary Endpoint .....................................................................................82 
7.2.2 
Secondary Endpoints ...............................................................................83 
7.2.3 
Exploratory Endpoints .............................................................................83 
7.3 
Sample Size Calculations ........................................................................................83 
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7.4 
Analysis Sets ...........................................................................................................84 
7.5 
Description of Subgroups to Be Analyzed ..............................................................85 
7.6 
Statistical Analysis Methodology ...........................................................................85 
7.6.1 
Hypothesis Testing on Key Study Endpoints ...........................................85 
7.6.2 
Analysis of Primary Endpoints ................................................................86 
7.6.3 
Analysis of Secondary Endpoints ............................................................86 
7.6.4 
Analyses of Exploratory Endpoints .........................................................87 
7.6.5 
Pharmacokinetic and Pharmacodynamic Analyses ..................................87 
7.6.6 
Safety Analyses ........................................................................................88 
7.6.7 
Other Analyses .........................................................................................88 
7.6.8 
Interim Analyses ......................................................................................88 
8 
Data Quality Assurance ....................................................................................................90 
8.1 
Data Management ...................................................................................................90 
9 
Ethics ................................................................................................................................91 
9.1 
Independent Ethics Committee or Institutional Review Board ..............................91 
9.2 
Ethical Conduct of the Study ..................................................................................91 
9.3 
Subject Information and Consent............................................................................91 
10 Investigator’s Obligations ................................................................................................93 
10.1 Confidentiality ........................................................................................................93 
10.2 Financial Disclosure and Obligations .....................................................................93 
10.3 Investigator Documentation ....................................................................................94 
10.4 Study Conduct .........................................................................................................94 
10.5 Adherence to Protocol.............................................................................................95 
10.6 Adverse Events and Study Report Requirements ...................................................95 
10.7 Investigator’s Final Report .....................................................................................95 
10.8 Records Retention ...................................................................................................95 
10.9 Publications .............................................................................................................95 
11 Study Management ...........................................................................................................97 
11.1 Monitoring ..............................................................................................................97 
11.1.1 
Safety Review Committee .......................................................................97 
11.1.2 
Monitoring of the Study ...........................................................................97 
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11.1.3 
Inspection of Records ..............................................................................97 
11.2 Management of Protocol Amendments and Deviations..........................................98 
11.2.1 
Modification of the Protocol ....................................................................98 
11.2.2 
Protocol Deviations..................................................................................98 
11.3 Study Termination ...................................................................................................99 
11.4 Final Report ............................................................................................................99 
12 Reference List.................................................................................................................101 
13 Appendices .....................................................................................................................106 
13.1 Appendix: Schedules of Events ............................................................................106 
13.2 Appendix: Drugs Potentially Affecting Muscle Function .................................... 115 
 
List of Tables 
Table 7-1 
Alpha at Interim Analysis and Final Analysis for Different Sample Sizes at 
Interim Analysis (O’Brien-Fleming Method) ................................................. 89 
Table 13-1 
Schedule of Events: Placebo-Controlled Treatment Period .......................... 107 
Table 13-2 
Schedule of Events: Open-Label Extension (Visits will Occur Quarterly Until 
Study Drug Approval or Study Is Discontinued) ...........................................112 
 
List of Figures 
Figure 3-1 
Schematic of Study Design for the Placebo-Controlled Treatment Period..... 42 
 
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Page 18 
Protocol Synopsis 
Protocol Number: 
FIS-002-2019 
Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
48-Week, Parallel-Group Study of the Efficacy and Safety of 
Losmapimod in Treating Subjects with Facioscapulohumeral 
Muscular Dystrophy (FSHD) with Open-Label Extension (OLE) 
Sponsor: 
Fulcrum Therapeutics 
26 Landsdowne Street 
Cambridge, MA 02139 USA 
Study Phase: 
2 
Study Sites: 
Up to 25 sites  
Indication: 
FSHD 
Rationale: 
Treatment of FSHD with losmapimod is predicted to reduce 
double homeobox 4 (DUX4) in affected skeletal muscle. It is 
anticipated that the proposed human dose of losmapimod for 
FSHD at 15 mg orally (PO) twice daily (BID) will provide drug 
concentrations in skeletal muscles sufficient to significantly 
inhibit p38α/β, resulting in the reduction of aberrant expression 
of DUX4.  
This study will be conducted in 2 parts: a randomized, 
double-blind placebo-controlled treatment period for 48 weeks, 
followed by an open-label treatment period with losmapimod. 
The placebo-controlled treatment period will evaluate the 
efficacy and safety of losmapimod in treating subjects with 
FSHD1 over 48 weeks. The open-label extension (OLE) will 
evaluate the safety, tolerability, and efficacy of long-term dosing 
with losmapimod in treating subjects with FSHD1.  
Prior to the COVID-19 pandemic, subjects who reached the 
Week 24 visit had the option to roll over into the OLE. Subjects 
that have already rolled over to the OLE prior to the COVID-19 
pandemic will remain on open label treatment. Their next clinic 
visit will follow the assessments for the Week 36 and Week 48 
visit in the placebo-controlled portion of the study in the 
COVID-19 Pandemic Emergency protocol version 4.0.These 
subjects will not undergo the Week 36 biopsy. Subjects who did 
not roll over prior to the COVID-19 pandemic will roll over into 
the OLE at the Week 48 visit as described in the COVID-19 
Pandemic Emergency protocol version 4.0.  
 
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Objectives: 
Placebo-Controlled Treatment Period  
Primary Objective: 
x To evaluate the efficacy of losmapimod in inhibiting or 
reducing expression of DUX4, the root cause of FSHD, 
as measured by a subset of DUX4-regulated gene 
transcripts in skeletal muscle biopsies from FSHD1 
subjects 
Secondary Objectives:  
x To evaluate the safety and tolerability of losmapimod in 
FSHD1 subjects 
x To evaluate the change from baseline in muscle fat 
fraction (MFF), lean muscle volume (LMV), and muscle 
fat infiltration (MFI) in FSHD1 subjects, as measured by 
musculoskeletal (MSK) magnetic resonance imaging 
(MRI) 
x To evaluate the plasma concentrations of losmapimod in 
FSHD1 subjects 
x To evaluate the levels of losmapimod in skeletal muscle 
in FSHD1 subjects 
x To evaluate losmapimod target engagement in blood and 
in skeletal muscle in FSHD1 subjects 
Exploratory Objectives: 
x To evaluate the change from baseline in the following 
clinical outcome assessments (COAs): 
o Reachable Work Space (RWS) with and without 
weights 
o Classic and FSHD Timed Up and Go (TUG) 
o Muscle strength by hand-held quantitative 
dynamometry 
o Motor Function Measure (MFM) Domain 1 
o FSHD Health Index (FSHD-HI) 
o Patients’ Global Impression of Change (PGIC) 
x To evaluate the change from baseline in inflammatory, 
immune, apoptotic, and other muscle disease transcripts 
in muscle biopsy and circulating proteins in plasma and 
serum 
 
 
 
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Open-Label Extension 
Primary Objective:  
x To evaluate the safety and tolerability of long-term 
dosing of losmapimod in FSHD1 subjects 
Secondary Objectives:  
x To evaluate the change from baseline in MFF, LMV, and 
MFI in FSHD1 subjects, as measured by MSK MRI 
x To evaluate the plasma concentrations of losmapimod in 
FSHD1 subjects 
Exploratory Objectives: 
x To evaluate the change from baseline in the following 
COAs: 
o RWS with and without weights 
o Classic and FSHD TUG 
o Muscle strength by hand-held quantitative 
dynamometry 
o MFM Domain 1 
o FSHD-HI 
o PGIC 
x To evaluate the change from baseline in inflammatory, 
immune, apoptotic, and other muscle disease transcripts 
in circulating proteins in plasma and serum 
Study Population: 
Males and females between 18 and 65 years of age, inclusive, 
who have a confirmed diagnosis of FSHD1 with 1 to 9 repeats 
via assessment of the size of the D4Z4 array on chromosome 4; 
a clinical severity score of 2 to 4 (RICCI score; range 0-5), 
inclusive, at screening; and an MRI-eligible muscle for biopsy, 
as determined by a central reader. Enrollment has completed for 
this study. A total of 80 subjects have been enrolled. 
Study Design: 
This study will be conducted in 2 parts: a randomized, 
double-blind placebo-controlled treatment period for 48 weeks, 
followed by an open-label treatment period with losmapimod. 
The placebo-controlled treatment period will evaluate the 
efficacy and safety of losmapimod in treating subjects with 
FSHD1 over 48 weeks. The OLE will evaluate the safety, 
tolerability, and efficacy of long-term dosing with losmapimod 
in treating subjects with FSHD1. 
During the placebo-controlled treatment period, a total of 
approximately 76 subjects with FSHD1 will be randomized 1:1 
to receive 15 mg PO of losmapimod (n=38) or placebo (n=38) 
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tablets BID for 48 weeks. Blood samples for pharmacokinetic 
(losmapimod concentrations) endpoints will be collected at 
Day 1, Week 4, Week 16, and Week 36 at the following time 
points: immediately predose and 4 hours (±30 minutes) after 
administration of the study dose. Pharmacokinetic samples will 
also be taken, when feasible, after dosing during the Week 12, 
Week 24, and Week 48 visits, preferably ≥1 hour after dosing. 
Blood samples for target engagement will be collected at Day 1 
and Week 16 or Week 36, at the following time points: 
immediately predose and 4 hours (±30 minutes) after 
administration of the study dose. Serum and plasma samples 
taken at baseline (Day 1; predose) and at Weeks 4, 12, 16, 24, 
36, and 48 (predose or postdose) will be used to aid in the 
discovery of potential biomarkers of FSHD disease activity and 
treatment effects. 
Musculoskeletal MRIs will be performed at screening, Week 12, 
and Week 48. Muscle biopsies will be taken at Day 1 and 
Week 16 or Week 36, if the muscle biopsy could not be 
performed at Week 16 due to the COVID-19 pandemic. In 
skeletal muscle, change from baseline in aberrant DUX4 
activity, losmapimod concentrations, and target engagement will 
be evaluated at Day 1 and Week 16 or Week 36. A portion of the 
muscle biopsies may be used to aid in the discovery of potential 
biomarkers of FSHD disease activity and treatment effects. 
Once subjects reach Week 48, they will have the option to roll 
over into the OLE, with all subjects receiving 15 mg PO of 
losmapimod tablets BID. Subjects who wish to roll over into the 
OLE must complete all procedures from the Week 48 end of 
placebo-controlled treatment period/start of OLE visit. Prior to 
the COVID-19 pandemic, subjects who reached the Week 24 
visit had the option to roll over into the OLE. Subjects that have 
already rolled over to the OLE prior to the COVID-19 pandemic 
will remain on open label treatment. Their next clinic visits will 
follow the assessments for the Week 36 and Week 48 visit in the 
placebo-controlled portion of the study in the COVID-19 
Pandemic Emergency protocol version 4.0. These subjects will 
not undergo the Week 36 biopsy. Subjects who did not roll over 
prior to the COVID-19 pandemic will roll over into the OLE at 
the Week 48 visit as described in the COVID-19 Pandemic 
Emergency protocol version 4.0.  
During the OLE, subjects will attend clinic visits approximately 
every 12 weeks until study drug approval or until the study is 
discontinued by the sponsor. 
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Blood samples for pharmacokinetics (losmapimod 
concentration) will be collected after dosing at each clinic visit, 
preferably ≥1 hour after dosing. Serum and plasma samples will 
be collected twice a year (ie, every 24 weeks [Week 72, 
Week 96, Week 120, Week 144, Week 168, etc.]) and will be 
used to aid in the discovery of potential biomarkers of FSHD 
disease activity and treatment effects. 
Musculoskeletal MRIs will be performed twice a year (ie, every 
24 weeks [Week 72, Week 96, Week 120, Week 144, Week 168, 
etc.]) 
Safety and tolerability will be evaluated throughout the study 
based on the assessment of adverse events (AEs), AEs of special 
interest (AESIs), serious adverse events (SAEs), laboratory tests, 
electrocardiograms (ECGs), vital signs, and physical 
examinations.  
Estimated Study 
Duration: 
Subjects will complete a 4-week screening period followed by a 
48-week placebo-controlled treatment period. Subjects who 
rolled over to the OLE portion of the study prior to the 
COVID-19 pandemic (under protocol version 3.0) will remain 
on open-label treatment. These subjects completed a 4-week 
screening period followed by a 24-week placebo-controlled 
treatment period. At their next clinic visits, these subjects will 
follow the assessments for the Week 36 visit followed by the 
Week 48 visit in the placebo-controlled portion of the study 
under the COVID-19 Pandemic Emergency protocol version 4.0. 
During the OLE, subjects will attend clinic visits approximately 
every 12 weeks until study drug approval or until the study is 
discontinued by the sponsor. All subjects will complete a safety 
follow-up visit 7 (±3) days after their last dose of study drug. 
Efficacy Assessments: 
x Change from baseline in DUX4 activity in affected skeletal 
muscle, as measured by quantitative reverse transcription 
polymerase chain reaction in a panel of DUX4-regulated 
gene transcripts 
x Change from baseline in MFF, LMV, and MFI, as measured 
by MSK MRI 
Pharmacokinetic and 
Pharmacodynamic 
Assessments: 
x Plasma concentrations of losmapimod  
x Concentrations of losmapimod in skeletal muscle biopsy at 
steady state  
x Target engagement parameters in blood and skeletal muscle 
biopsy 
 
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Safety Assessments: 
Adverse events, AESIs, SAEs, laboratory tests, ECGs, vital 
signs, and physical examinations 
Other Assessments: 
x Change from baseline in COAs  
o RWS with and without weights 
o Classic and FSHD TUG 
o Muscle strength by hand-held quantitative 
dynamometry 
o MFM Domain 1 
o FSHD-HI 
o PGIC 
x Change from baseline in inflammatory, immune, apoptotic, 
and other muscle disease transcripts in muscle biopsy and 
circulating proteins in plasma and serum 
Study Drug, Dosage, 
and Route of 
Administration: 
Placebo-Controlled Treatment Period: 
Losmapimod tablets 15 mg (provided as two 7.5 mg tablets) PO 
BID or matching placebo tablets PO BID for 48 weeks (or 24 
weeks if rolled over to the OLE under protocol version 3.0, prior 
to the COVID-19 pandemic)  
Open-Label Extension: 
Losmapimod tablets 15 mg (provided as two 7.5 mg tablets) PO 
BID until study drug approval or until the study is discontinued 
by the sponsor 
Study drug should be administered with food. 
Sample Size: 
Assuming an effect size of 0.70, a sample size of 68 subjects 
(34 subjects per group) will be needed to provide 80% power 
with a 2-sided test at a 0.05 significance level to detect a 
difference between losmapimod and placebo in change from 
baseline in DUX4 activity in affected skeletal muscle after 16  or 
36 weeks (depending upon when the muscle biopsy was 
performed) during the placebo-controlled treatment period. 
Assuming that approximately 10% of subjects will be 
non-evaluable, approximately 76 subjects will be randomly 
assigned at a 1:1 ratio to losmapimod and placebo (38 subjects 
per group). 
Statistical Methods: 
Continuous variables will be summarized using the mean, 
standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized using frequency 
counts and percentages. All statistical tests will be 2-sided and 
performed using a 0.05 significance level. 
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The primary endpoint for the placebo-controlled treatment 
period will be evaluated using an analysis of covariance 
(ANCOVA) model to analyze the change from baseline in 
DUX4 activity in affected skeletal muscle after 16 weeks or 36 
weeks of treatment, with repeat number category and treatment 
group as fixed effects and baseline DUX4 activity in affected 
skeletal muscle as a covariate. Least-square (LS) mean, standard 
error, and 95% confidence interval (CI) of the LS mean will be 
provided for each treatment group. The difference in LS means 
between treatment groups and 95% CI of the difference will also 
be calculated. The final p-value will be compared against the 
significance level of approximately 0.05. All available data will 
be used. The full analysis set will be used for the primary 
analysis in the placebo-controlled treatment period. 
Secondary endpoints will be summarized using descriptive 
statistics. Continuous endpoints with multiple post-baseline 
assessments will be analyzed using mixed-effect model for 
repeated measures methods including repeat number category, 
treatment group, visit, and treatment-by-visit interaction as fixed 
effects and baseline value as a covariate; continuous endpoints 
with a single post-baseline assessment will be analyzed using 
ANCOVA methods, with repeat number category and treatment 
group as fixed effects and baseline value as a covariate.  
Secondary endpoints in the OLE will be summarized according 
to the treatment assigned at randomization. For all subjects, 
changes in measurements will be calculated relative to 
measurements obtained at baseline (ie, prior to first dose in the 
placebo-controlled treatment period). 
Hypothesis testing on key study endpoints will be conducted 
using the FAS. A sequential testing procedure will be used to 
control for Type I Error to test the following key study 
endpoints: DUX4 change from baseline at Week 16 or Week 36; 
LMV change from baseline at Week 48, and FSHD TUG change 
from baseline at Week 48. 
Safety data in the placebo-controlled treatment period will be 
analyzed using the safety analysis set and summarized by 
treatment group and visit (if applicable) using descriptive 
statistics. Safety data in the OLE will be analyzed using the 
open-label analysis set. Treatment-emergent AEs will be 
summarized by Medical Dictionary for Regulatory Activities 
system organ class and preferred term; separate summaries will 
be produced for treatment-related AEs, AESIs, SAEs, and 
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discontinuations due to AEs. Laboratory tests, vital signs, 
findings from physical examinations, and ECGs will be 
summarized for changes over time during treatment using 
descriptive statistics.  
Interim Analysis 
One interim analysis (IA) will be performed after a minimum of 
22 paired muscle biopsies have been collected. A group 
sequential method (O’Brien Fleming Spending Function) will be 
used to ensure an overall significance level of 0.05 (double-
sided) due to multiple looks at the DUX4 primary endpoint.  
Version and Date of 
Protocol: 
Version 4.0 (COVID-19 Pandemic Emergency Amendment, 
10 April 2020  
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List of Abbreviations 
Abbreviation 
Definition 
3D 
3-dimensional 
β-hCG 
β-human chorionic gonadotropin 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
AUC 
area under the plasma concentration-time curve 
AUC0-inf 
area under the plasma concentration-time curve extrapolated to 
infinity 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
COA 
clinical outcome assessment 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
DILI 
drug-induced liver injury 
DUX4 
double homeobox 4 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ET 
early termination  
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
FSHD 
facioscapulohumeral muscular dystrophy 
FSHD1 
facioscapulohumeral muscular dystrophy type 1 
FSHD2 
facioscapulohumeral muscular dystrophy type 2 
FSHD-HI 
Facioscapulohumeral Muscular Dystrophy Health Index 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HSP27 
heat shock protein 27 
IB 
investigator's brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
LMV 
lean muscle volume 
LS 
least-square 
MAPK 
mitogen-activated protein kinase 
MATE 
multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFF 
muscle fat fraction 
MFI 
muscle fat infiltration 
MFM 
Motor Function Measure 
MMRM 
mixed-effect model for repeated measures 
MRI 
magnetic resonance imaging 
MSK 
musculoskeletal 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptides 
OCT 
organic cation transporter 
OLE 
open-label extension 
PD 
pharmacodynamic(s) 
PGIC 
Patients’ Global Impression of Change 
pHSP27 
phosphorylated heat shock protein 27 
PK 
pharmacokinetic(s) 
PO 
orally 
PPS 
per-protocol set 
QRT-PCR 
quantitative reverse transcription polymerase chain reaction 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
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Abbreviation 
Definition 
RWS 
Reachable Work Space 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SRC 
safety review committee 
STIR 
short tau inversion recovery 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum plasma concentration 
TUG 
Timed Up and Go 
ULN 
upper limit of normal 
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1 
Introduction 
1.1 
Background 
Facioscapulohumeral muscular dystrophy (FSHD) is a rare disabling disease with an 
estimated worldwide population prevalence of between 1:15,000 and 1:20,000 (Statland and 
Tawil, 2014), or approximately 16,000 to 21,000 affected individuals in the United States. A 
higher prevalence rate of 12/100,000 was reported in a population-based study in the 
Netherlands (Deenen et al, 2014). About two-thirds of cases are familial-inherited in an 
autosomal dominant fashion, and one-third are sporadic. FSHD is characterized by 
descending progressive skeletal muscle weakness affecting the face, shoulders, arms, and 
trunk, followed by weakness of the distal lower extremities and pelvic girdle. Symptoms 
typically first appear later in the second decade of life but can begin at any age (Tawil et al, 
2015). Most cases present with shoulder girdle weakness, which is eventually found in nearly 
all patients (Padberg, 1982). Muscle biopsies show myopathic or dystrophic changes, 
including variability in fiber size, rounded fibers, central nuclei, necrotic or regenerating 
fibers, increased connective tissue, and fatty deposition. Up to one-third of muscle biopsies 
show a lymphocyte-predominant perivascular inflammatory infiltrate (Statland et al, 2015b). 
Muscle strength, as measured by quantitative muscle testing, decreases at an average rate of 
1% to 4% per year (Statland and Tawil, 2014). The most frequent newly developed functional 
motor limitations include difficulty getting up from lying down in bed and difficulty using 
arms for activities of daily living (Statland and Tawil, 2014). The 6-year risk of wheelchair 
use is 24% (Statland et al, 2015a). All quality of life domains on the 36-Item Short Form 
Health Survey are significantly impaired, and over half of patients with FSHD report at least 
mild to moderate pain (Morís et al, 2018; Padua et al, 2009). Asymmetry of muscle 
involvement is common. Cardiac muscle is spared, and respiratory muscles are involved in a 
minority of patients. 
FSHD is caused by aberrant overexpression of the double homeobox 4 (DUX4) gene, a 
homeobox transcription factor. DUX4 is located within D4Z4 macrosatellite repeats on 
chromosome 4q35 and is not normally expressed in adult skeletal muscle when the number 
of repeats is >10. Approximately 95% of patients with FSHD have type 1 (FSHD1), in which 
the D4Z4 repeat array is contracted to 1 to 10 units on one allele (Lemmers et al, 2010; 
Statland and Tawil, 2014). FSHD patients carrying a smaller number of repeats (1 to 3 units) 
are, on average, more severely affected (Tawil et al, 1996). Loss of these repetitive elements 
(referred to as contraction) leads to de-repression of the D4Z4 locus and expression of DUX4 
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(de Greef et al, 2008; Statland and Tawil, 2014). Stable inherited transmission of the repeat is 
reported within affected families and kindreds, with the most comprehensive analysis 
conducted on a larger Utah kindred in which the repeat size is the same in multiple, distantly 
related branches (Flanigan et al, 2001; Lemmers et al, 2004). Patients with FSHD type 2 
(FSHD2) have a pathological mutation in a key regulatory protein encoded by the structural 
maintenance of chromosomes flexible hinge domain 1 (SMCHD1) gene, resulting in reduced 
methylation of the D4Z4 repeat array and aberrant DUX4 expression (Lemmers et al, 2012). 
DUX4 pathological activation in skeletal muscle as a result of the D4Z4 repeat contraction 
(in FSHD1) or SMCHD1 mutations (in FSHD2) leads to a large, well-characterized 
transcriptional deregulation cascade (Bosnakovski et al, 2014; Homma et al, 2015; 
Jagannathan et al, 2016; Shadle et al, 2017; Yao et al, 2014). DUX4 transcriptional 
deregulation results in the activation of innumerable pathological cell processes, including 
inflammatory and immune signaling, oxidative stress, and programmed cell death. The end 
result of aberrant DUX4 activity is myofiber death with the replacement of skeletal muscle 
by fat, resulting in a clinical manifestation of progressive loss of strength and accumulation 
of physical disability.  
Compounds that reduce DUX4 and its DUX4-regulated transcripts should provide a robust 
disease-modifying therapeutic approach for the treatment of FSHD at its root cause. 
There are currently no approved disease-modifying treatments for FSHD. Low-intensity 
aerobic exercise tailored to the patient’s distribution of weakness may provide limited 
beneficial effect (Janssen et al, 2016). Limited range of motion in the shoulder girdle stems 
from periscapular muscle weakness; in such cases, surgical scapular fixation (scapulodesis) 
can result in some functional improvement for select patients (Tawil et al, 2015). Very few 
compounds are currently in clinical development for FSHD, and no therapy has been proven 
to reduce disease severity or delay the progression of the disease; therefore, there is a high 
unmet need for an effective therapy for FSHD. 
Fulcrum is developing losmapimod, a selective p38α and β kinase small molecule inhibitor 
that specifically reduces DUX4 in FSHD myotubes, for treatment of FSHD. Extensive 
exposure and safety data from previous clinical studies with losmapimod provide robust 
evidence supporting its safety and tolerability, including during chronic dosing, and provide a 
rationale for the dosing regimen selected. This study will evaluate the efficacy and safety of 
losmapimod in treating subjects with FSHD1. 
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1.2 
Nonclinical Information 
In vitro studies, including absorption, distribution, metabolism, and excretion assessments, 
specifically indicate that losmapimod is a highly selective p38α/β mitogen-activated protein 
kinase (MAPK) inhibitor with a limited risk of significant interaction with other kinases, 
transporters, or cytochrome P450 enzymes at pharmacologically relevant concentrations. 
Further in vitro characterization of the effects of losmapimod in FSHD patient-derived 
immortalized myotubes showed potent and selective inhibition of the p38α pathway, DUX4 
mRNA and protein production, and DUX4-regulated gene expression program as well as 
profound inhibition of apoptosis and prevention of death of the FSHD myotubes. 
In vivo muscle pharmacokinetic (PK)/pharmacodynamic (PD) studies in non-fasted mice and 
rats demonstrated that a single dose of losmapimod (0.3 mg/kg, orally [PO]) resulted in 
clinically relevant plasma exposure, significant muscle exposure, and significant p38α/β 
MAPK pathway inhibition in skeletal muscles. Muscle PK experiments in mice and rats 
demonstrated that losmapimod rapidly distributes to the target tissue and achieves a 
muscle:plasma ratio of ≥0.6. The muscle exposures achieved are predicted to result in a 
>50% reduction in DUX4-dependent targets in FSHD patient skeletal muscle based on the in 
vitro data obtained using FSHD patient myotubes. The PK/PD analysis additionally indicated 
that significant p38α/β MAPK pathway inhibition would be expected in muscle with the 
proposed clinical dose of 15 mg PO twice daily (BID) (Barbour et al, 2013; Lomas et al, 
2012). Losmapimod displayed reasonable oral bioavailability (>30%) in mouse, rat, and 
cynomolgus monkey and low clearance (<30% hepatic blood flow) in every species tested 
except dog; these results were supported by in vitro microsomal stability experiments. The 
half-life following oral administration ranged from 1 to 3.2 hours, depending on the route, 
dose, and preclinical species.  
Metabolism occurs primarily via hydrolysis of the cyclopropylamide group by 
carboxylesterase-1 to form a pharmacologically inactive primary metabolite, referred to as 
GSK198602 (Barbour et al, 2013; Barbour et al, 2015; Ino et al, 2015). The ratio of 
metabolite to parent is approximately 0.03 to 0.25 in nonclinical species, but it is higher 
(2-fold) in humans. The major metabolite, GSK198602, is unlikely to interact with other 
kinases, transporters, or cytochrome P450 enzymes. 
Losmapimod produced no concerning effects either in vitro in human ether-a-go-go related 
gene assays or in vivo on neurobehavioral function (rats), respiratory function (rats), or 
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cardiovascular function, including electrocardiogram (ECG) and QTc monitoring (monkeys) 
at multiple exposures and concentrations well above the clinical exposure levels. Data from 
genotoxicity assessments indicate that losmapimod does not present a genotoxic hazard to 
humans. The totality of the nonclinical package indicated that there were no findings in 
chronic toxicology (rodent and non-rodent), safety pharmacology, or genetic toxicity studies 
that would preclude the oral administration of losmapimod to humans. There were also no 
concerns in carcinogenicity studies. 
1.3 
Clinical Pharmacology 
Elimination of losmapimod is almost exclusively by metabolism, with only 2% of the 
administered dose recovered as unchanged drug in urine and feces. The principal route of 
metabolism is via hydrolysis of the cyclopropylamide group to form a pharmacologically 
inactive metabolite, GSK198602. The predominant route of elimination of losmapimod, 
mostly as the GSK198602 metabolite, is via urine (approximately 65% of the dose), with 
approximately 29% of the dose eliminated via feces. The absolute oral bioavailability of the 
tablet formulation is 62%. 
Following a single intravenous dose of losmapimod, the steady-state volume of distribution 
indicated extensive tissue distribution. After single-dose oral administration of 1 to 60 mg 
losmapimod, the maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve extrapolated to infinity (AUC0-inf) of losmapimod increased in an 
approximately dose-proportional manner for doses up to 20 mg but increased less than 
proportionally from 20 mg to 60 mg, likely due to saturation of absorption. The terminal 
half-life was approximately 10 hours for losmapimod and approximately 12 hours for 
GSK198602. After single-dose oral administration of losmapimod, exposure (area under the 
plasma concentration-time curve [AUC]) was approximately 2-fold higher for GSK198602 
than it was for its parent losmapimod. The time to maximum plasma concentration (Tmax) of 
losmapimod was reached approximately 1 to 4 hours after dose administration, while the 
Tmax of GSK198602 was approximately 3 to 4 hours after dose administration. 
Steady-state plasma concentrations of losmapimod were achieved 2 to 3 days after the 
initiation of repeat dosing. Slight accumulation (up to approximately 30%, on average) for 
AUC and Cmax after once or BID dosing was observed. Consistent with single-dose 
administration, exposure (AUC) was approximately 2-fold higher for the metabolite 
GSK198602 than it was for its parent losmapimod. 
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Sex, body weight, and age factors did not result in the need for dose adjustments (Yang et al, 
2013). The PK in healthy Japanese subjects are generally similar to those observed in 
previous studies in healthy non-Japanese subjects with regard to various PK characteristics 
such as exposure, dose proportionality, and half-life for both losmapimod and the metabolite 
GSK198602 (Ino et al, 2015). 
A high-fat meal with a dose of 15 mg losmapimod increased the AUC (by approximately 
10%) and Cmax (by approximately 40%) of losmapimod compared to the values observed in 
the fasted state. Tmax was delayed, on average, by 1 hour when losmapimod was administered 
with a high-fat meal. The increase in the exposure measures, ie, AUC and Cmax, and the delay 
in Tmax following a high-fat meal compared to the fasted state are not considered clinically 
significant. 
1.4 
Clinical Safety 
Losmapimod, which is currently in Phase 2 clinical studies for the treatment of FSHD, is a 
potent p38α/β inhibitor that has been administered to more than 3,600 subjects in GSK and 
Fulcrum clinical studies, including in a Phase 3 study. 
The original developer of losmapimod (GSK) performed extensive testing across at least 
10 indications but never in FSHD or other muscle disorders in the clinic. Although 
development was discontinued due to lack of efficacy in previously tested indications, 
losmapimod demonstrated a favorable PK, PD, safety, and tolerability profile in more than 
3,500 subjects in over 20 studies. Subject data are available from 9 GSK-sponsored 
completed studies in healthy subjects (4 single dose studies, 3 repeat dose studies and 
2 single and repeat dose studies), 1 single dose study in a patient population (rheumatoid 
arthritis), and 11 completed repeat dose studies in patient populations (including 
cardiovascular disease, chronic obstructive pulmonary disease [COPD], renal disease, 
rheumatoid arthritis, major depressive disorder, and neuropathic pain).  
From the 9 completed Phase 1 clinical trials in healthy subjects, losmapimod was well 
tolerated at single doses up to 60 mg and repeat doses up to 10 mg BID for 2 weeks followed 
by 20 mg daily for 2 weeks. There were no deaths or non-fatal serious adverse events (SAEs) 
reported during any of these studies. 
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In the 11 completed repeat dose studies in patients, adverse events (AEs) during treatment 
were typically reported by a similar proportion of patients on losmapimod and placebo (61% 
[815/1327] and 55% [406/735], respectively). Losmapimod did not consistently result in 
more AEs leading to permanent discontinuation of study drug or withdrawal from study than 
placebo.  
A thorough QT study (PM1116628) was conducted with losmapimod at 7.5 mg BID or 
20 mg daily or with placebo administered for 5 days. At the 20 mg dose of losmapimod, the 
upper bound of the 90% confidence interval (CI) of the ΔΔQT interval corrected for heart 
rate by Fridericia’s formula (QTcF) (change from baseline in QTcF compared to that for 
placebo) exceeded the 10 msec threshold at the 24-hour postdose time point. For the 7.5 mg 
BID dose, the upper bound of the 90% CI of ΔΔQTcF exceeded the 10 msec threshold at 
multiple time points. No subjects experienced QTcF values >480 msec or QTcF changes 
from baseline ≥60 msec at any time in the study. Although the upper bound of the 90% CI 
exceeded the 10 msec regulatory threshold of concern in the primary PD analysis, GSK 
stated that there was no clinically relevant effect on the QT interval, as there was no 
clinically relevant concentration QTc effect using standard placebo/baseline subtracted 
measured QTc data. Additional information on the QTc interval and its behavior, as 
demonstrated in the large cohort of patients treated with losmapimod obtained from 
Study PM1116197, supported the lack of a QT effect. PK/PD modeling using the raw QTcF 
and plasma concentration data showed that at plasma losmapimod concentrations 4 times the 
exposure at the therapeutic dose (7.5 mg BID), ie, at exposures approximately 2-fold higher 
than 15 mg BID, the predicted upper bound of the 90% CI of ''QTcF did not exceed 
10 msec and the predicted median ''QTcF was less than 5 msec. Further details are 
presented in the investigator’s brochure (IB). 
In summary, review of studies in healthy volunteers and patient populations did not identify 
differences in the type, frequency, or severity of AEs or SAEs between losmapimod and 
placebo. No definitive safety signals have been identified.  
Further details regarding the nonclinical and clinical data are presented in the IB. 
1.5 
Benefit/Risk Assessment 
Losmapimod has been widely tested in various subject populations across at least 10 adult 
indications, including coronary artery disease, rheumatoid arthritis, and COPD. The majority 
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of these studies lasted 24 weeks, with dosing in one study of up to 52 weeks. The safety data 
from these studies demonstrate satisfactory safety and tolerability; the severe and/or serious 
events that have been reported were generally specific to the population under study. Thus, 
COPD and respiratory events occurred in the studies evaluating subjects with COPD. 
Similarly, serious cardiac events were observed in those studies that evaluated subjects with 
coronary artery disease. As these events were generally indication specific, the risk of their 
occurrence in the FSHD population is considered minimal. 
Hepatotoxicity 
In clinical trials to date, elevations in transaminases have occurred in few subjects among 
over 3,500 exposures of losmapimod. These have generally been mild, asymptomatic, and 
reversible, and the majority were confounded by other medications or clinical conditions. In 
11 integrated repeat-dose studies in various patient populations, the frequency of liver events 
was 0.9% in the losmapimod group (further details are presented in the IB). Preclinical data 
demonstrate reversible increases in rat liver weight with no clinical chemistry or microscopic 
correlate. However, hepatotoxicity has been observed after repeat dose administration of 
some p38 MAPK inhibitors. The mechanism of hepatoxicity for those compounds has not 
been elucidated and thus applicability to losmapimod is unknown. Exclusion criteria 
(Section 4.1.2), data collection, and study drug stopping criteria (Section 6.2.1.3) relating to 
liver tests are well defined. 
Renal Function 
In clinical studies with losmapimod, a small asymptomatic increase in serum creatinine of 
1% to 7% was noted; this increase appeared to attenuate with continued therapy as well as 
with discontinuation and may be related to inhibition of renal transporters (further details are 
presented in Section 5.3.2.6.2 of the IB). Individuals with severe renal impairment are 
excluded from the study (Section 4.1.2). Renal function (Section 6.2.2) and AEs 
(Section 6.2.1) will be monitored during the trial.  
Embryo-Fetal Malformations 
Embryo-fetal malformations in rats and rabbits have been observed with losmapimod. Study 
drug will not be administered to women of childbearing potential unless they are employing 
adequate contraceptive measures (Section 5.5.1). Pregnancy testing is required before 
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randomization and before dispensation of study drug at all other visits, as specified in the 
schedule of events (Table 13-1 and Table 13-2). Study drug will be discontinued if a female 
participant becomes pregnant during the treatment period. Unexpected pregnancies will be 
reported with instructions for appropriate follow-up (Section 6.6).  
Drug-Drug Interactions 
Losmapimod is considered unlikely to have a clinically relevant drug-drug interaction with 
substrates or inhibitors of cytochrome P450, P-gp, human organic anion transporting 
polypeptides (OATP) 1B1 and OATP1B3, human organic anion transporter (OAT) 1, or 
human renal organic cation transporter (OCT) 2. Losmapimod inhibits multidrug and toxin 
extrusion (MATE) 1 and MATE2-K renal transporters in vitro with a low risk of clinically 
relevant interaction. Both losmapimod and its major metabolite, GSK198602, are in vitro 
inhibitors of human breast cancer resistance protein (BCRP), and GSK198602 is a relatively 
potent in vitro inhibitor of OAT3 (further details are presented in the IB). If possible, avoid 
co-administration of study drug with MATE 1, BCRP, or OAT3 substrates with a narrow 
therapeutic index. Careful monitoring for adverse effects of these agents is advised if, in the 
opinion of the investigator, co-administration is warranted (Section 6.2.1). The inhibition of 
MATE2-K is not considered a clinical drug-drug interaction risk when comparing potency of 
in vitro transporter inhibition to projected losmapimod Cmax values at the 15 mg BID dose. 
Infection/Immunity 
Based on its pharmacology, losmapimod has a modest but broad inhibitory influence on 
various inflammatory cytokines. Thus, losmapimod may theoretically have an impact on 
immunity, and be associated with an increased risk of infection. Incidence of infections to 
date has been similar in losmapimod versus placebo in controlled studies (further details are 
presented in the IB). Information for all infections identified as SAEs will be collected 
(Section 6.2.1.2). Subjects who have received attenuated live vaccines within 6 weeks prior 
to randomization will be excluded (Section 4.1.2).  
Given the lack of approved therapy for FSHD and the progressive debilitating nature of the 
disease, in conjunction with the well characterized current safety profile of losmapimod, the 
potential benefit of therapy with losmapimod outweighs the potential risks of drug 
administration.  
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2 
Study Objectives 
2.1 
Placebo-Controlled Treatment Period 
2.1.1 Primary Objective 
The primary objective of the placebo-controlled treatment period is to evaluate the efficacy 
of losmapimod in inhibiting or reducing expression of DUX4, the root cause of FSHD, as 
measured by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies from 
FSHD1 subjects. 
2.1.2 Secondary Objectives 
The secondary objectives of the placebo-controlled treatment period are as follows: 
x To evaluate the safety and tolerability of losmapimod in FSHD1 subjects 
x To evaluate the change from baseline in muscle fat fraction (MFF), lean muscle 
volume (LMV), and muscle fat infiltration (MFI) in FSHD1 subjects, as measured by 
musculoskeletal (MSK) magnetic resonance imaging (MRI) 
x To evaluate the plasma concentrations of losmapimod in FSHD1 subjects 
x To evaluate the levels of losmapimod in skeletal muscle in FSHD1 subjects 
x To evaluate losmapimod target engagement in blood and in skeletal muscle in FSHD1 
subjects 
2.1.3 Exploratory Objectives 
The exploratory objectives of the placebo-controlled treatment period are as follows: 
x To evaluate the change from baseline in the following clinical outcome assessments 
(COAs): 
o Reachable Work Space (RWS) with and without weights 
o Classic and FSHD Timed Up and Go (TUG) 
o Muscle strength by hand-held quantitative dynamometry 
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o Motor Function Measure (MFM) Domain 1 
o FSHD Health Index (FSHD-HI) 
o Patients’ Global Impression of Change (PGIC)  
x To evaluate the change from baseline in inflammatory, immune, apoptotic, and other 
muscle disease transcripts in muscle biopsy and circulating proteins in plasma and 
serum  
2.2 
Open-Label Extension 
2.2.1 Primary Objective 
The primary objective of the open-label extension (OLE) is to evaluate the safety and 
tolerability of long-term dosing of losmapimod in FSHD1 subjects. 
2.2.2 Secondary Objectives 
The secondary objectives of the OLE are as follows: 
x To evaluate the change from baseline in MFF, LMV, and MFI in FSHD1 subjects, as 
measured by MSK MRI 
x To evaluate the plasma concentrations of losmapimod in FSHD1 subjects  
2.2.3 Exploratory Objectives 
The exploratory objectives of the OLE are as follows: 
x To evaluate the change from baseline in the following COAs: 
o RWS with and without weights 
o Classic and FSHD TUG 
o Muscle strength by hand-held quantitative dynamometry 
o MFM Domain 1 
o FSHD-HI 
o PGIC 
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x To evaluate the change from baseline in inflammatory, immune, apoptotic, and other 
muscle disease transcripts in circulating proteins in plasma and serum  
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3 
Investigational Plan 
3.1 
Study Design 
This study will be conducted in 2 parts: a randomized, double blind placebo-controlled 
treatment period for 48 weeks, followed by an open-label treatment period with losmapimod. 
The placebo-controlled treatment period will evaluate the efficacy and safety of losmapimod 
in treating subjects with FSHD1 over 48 weeks. The OLE will evaluate the safety, 
tolerability, and efficacy of long-term dosing with losmapimod in treating subjects with 
FSHD1.  
Prior to the COVID-19 pandemic, subjects who reached the Week 24 visit had the option to 
roll over into the OLE. Subjects that have already rolled over to the OLE prior to the 
COVID-19 pandemic will remain on open label treatment. Their next clinic visits will follow 
the assessments for the Week 36 and Week 48 visit in the placebo-controlled portion of the 
study in the COVID-19 Pandemic Emergency protocol version 4.0. These subjects will not 
undergo the Week 36 biopsy. Subjects who did not roll over prior to the COVID-19 pandemic 
will roll over into the OLE at the Week 48 visit as described in the COVID-19 Pandemic 
Emergency protocol version 4.0. 
3.1.1 Placebo-Controlled Treatment Period 
During the placebo-controlled treatment period, a total of approximately 76 subjects with 
FSHD1 will be randomized 1:1 to receive 15 mg PO of losmapimod (n=38) or placebo 
(n=38) tablets BID for 48 weeks.  
At the time of this protocol amendment (10 April 2020), enrollment was completed. A total 
of 80 subjects have been enrolled. Twelve subjects had rolled over to the OLE portion of the 
study at Week 24, prior to the COVID-19 pandemic (under protocol version 3.0). At their 
next clinic visits, these 12 subjects will follow the assessments for the Week 36 visit followed 
by the Week 48 visit in the placebo-controlled portion of the study under the COVID-19 
Pandemic Emergency protocol version 4.0. These subjects will continue to receive open label 
losmapimod during this time. 
Subjects will participate in the placebo-controlled treatment period for approximately 
53 weeks, including the following: 
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x a 4-week screening period: Day -28 until Day -1 before the first study drug 
administration 
x a 48-week placebo-controlled treatment period 
x for subjects who choose not to roll over into the OLE, a safety follow-up visit 7 days 
(±3 days) after the last dose of study drug (OLE visits and procedures are described in 
Section 3.1.2) 
The 12 subjects who rolled over to the OLE portion of the study at Week 24, prior to the 
COVID-19 pandemic (under protocol version 3.0), participated in the placebo-controlled 
portion of the study for approximately 29 weeks including the following:  
x a 4-week screening period: Day -28 until Day -1 before the first study drug 
administration 
x a 24-week placebo-controlled treatment period 
x for subjects who chose not to roll over into the OLE, a safety follow-up visit 7 days 
(±3 days) after the last dose of study drug (OLE visits and procedures are described in 
Section 3.1.2) 
During the placebo-controlled treatment period, subjects will be asked to attend the study 
clinic at each scheduled visit (Table 13-1). Study drug (losmapimod or placebo) will be 
administered BID and should be taken with food. 
Blood samples for PK (losmapimod concentrations) endpoints will be collected at Day 1, 
Week 4, Week 16, and Week 36 at the following time points: immediately predose and 
4 hours (±30 minutes) after administration of the study dose. Pharmacokinetic samples will 
also be taken, when feasible, after dosing during the Week 12, Week 24, and Week 48 visits, 
preferably ≥1 hour after dosing. Blood samples for target engagement will be collected at 
Day 1, and Week 16 or Week 36, at the following time points: immediately predose and 
4 hours (±30 minutes) after administration of the study dose. Serum and plasma samples 
taken at baseline (Day 1; predose) and at Weeks 4, 12, 16, 24, 36, and 48 (predose or 
postdose) will be used to aid in the discovery of potential biomarkers of FSHD disease 
activity and treatment effects. 
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Musculoskeletal MRIs will be performed at screening, Week 12, and Week 48. Muscle 
biopsies will be taken at Day 1 and Week 16 or Week 36, if the muscle biopsy could not be 
performed at Week 16 due to the COVID-19 pandemic. In skeletal muscle, change from 
baseline in aberrant DUX4 activity, losmapimod concentrations, and target engagement will 
be evaluated at Day 1 and Week 16 or Week 36. A portion of the muscle biopsies may be 
used to aid in the discovery of potential biomarkers of FSHD disease activity and treatment 
effects. 
Safety and tolerability will be evaluated based on the assessment of AEs, AEs of special 
interest (AESIs), SAEs, laboratory tests, ECGs, vital signs, and physical examinations.  
The full schedule of assessments for the placebo-controlled treatment period is provided in 
Table 13-1. Scheduled visits may be split over 2 days if required, with a maximum of 
5 business days in between visits. Unscheduled visits may be performed if clinically 
indicated. Subjects can travel for MRI or muscle biopsy if needed, but the use of a study-
approved MRI scanner should be consistent during the trial. 
A schematic of the study design is presented in Figure 3-1. 
Figure 3-1 
Schematic of Study Design for the Placebo-Controlled Treatment 
Period 
 
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Abbreviations: BID, twice daily; MRI, magnetic resonance imaging; OLE, open-label extension. 
3.1.2 Open-Label Extension 
Once subjects reach Week 48, they will have the option to roll over into the OLE, with all 
subjects receiving 15 mg PO losmapimod tablets BID. Subjects who wish to roll over into the 
OLE must complete all procedures from the Week 48 end of placebo-controlled treatment 
period/start of OLE visit (Table 13-1).  
Subjects will remain in the OLE until study drug approval or until the study is discontinued 
by the sponsor. All subjects who complete or discontinue from treatment will complete a 
safety follow-up visit 7 days (±3 days) after the last dose of study drug. 
During the OLE, subjects will attend clinic visits approximately every 12 weeks 
(Table 13-2). Study drug (open-label losmapimod) will be administered BID and should be 
taken with food. 
Blood samples for PK (losmapimod concentration) will be collected after dosing at each 
clinic visit, preferably ≥1 hour after dosing. Serum and plasma samples will be collected 
twice a year (ie, every 24 weeks [ Week 72, Week 96, Week 120, Week 144, Week 168, etc.]) 
and will be used to aid in the discovery of potential biomarkers of FSHD disease activity and 
treatment effects. 
Musculoskeletal MRIs will be performed twice a year (ie, every 24 weeks [Week 72, 
Week 96, Week 120, Week 144, Week 168, etc.]) Safety and tolerability will be evaluated 
based on the assessment of AEs, AESIs, SAEs, laboratory tests, ECGs, vital signs, and 
physical examinations.  
The full schedule of assessments for the OLE is provided in Table 13-2. Scheduled visits may 
be split over 2 days if required, with a maximum of 5 business days in between visits. 
Unscheduled visits may be performed if clinically indicated. Subjects can travel for MRI if 
needed, but the use of a study-approved MRI scanner should be consistent during the trial. 
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3.2 
Rationale of Study Design 
3.2.1 Rationale of Dose Selection 
The placebo-controlled treatment period was designed to evaluate the efficacy of 
losmapimod for treatment of FSHD at its root cause and the safety of losmapimod over 
placebo in subjects with FSHD1 over 48 weeks. The OLE was designed to evaluate the 
safety, tolerability, and efficacy of long-term dosing of losmapimod in subjects with FSHD1. 
Losmapimod is being developed for the treatment of FSHD based on its robust nonclinical 
efficacy in inhibiting DUX4 expression and DUX4-regulated downstream gene transcripts 
and reducing apoptosis across multiple FSHD cell lines at achievable clinical exposures with 
minimal impact on myotube differentiation. Based on clinical PK/PD studies (Barbour et al, 
2013), it is predicted that the proposed human dose of losmapimod for FSHD clinical trials at 
15 mg BID would provide drug concentrations in skeletal muscles sufficient to significantly 
inhibit p38α/β and reduce aberrant expression of DUX4. The planned dose to be tested is 
15 mg BID. Prior results indicate the excellent safety and tolerability of losmapimod for 
chronic administration in the clinic and include the convenience of oral administration. 
Heat shock protein 27 (HSP27) is a phosphorylated substrate of p38α/β that has been 
demonstrated to be a relevant target engagement marker of p38 inhibition. There is a clear 
relationship between losmapimod plasma concentrations and target engagement for p38α/β 
MAPK, as measured by phosphorylated HSP27 (pHSP27). Pharmacokinetic/PD modeling 
indicates that the 15 mg PO BID dose should result in 40% to 70% pHSP27 reduction 
(Barbour et al, 2013; Cheriyan et al, 2011, and summarized in the IB). Losmapimod PK in 
humans has been well characterized, including at the exposure levels expected for the 
planned dose of 15 mg BID in the proposed studies. Pharmacokinetic/PD modeling has 
demonstrated that the inhibition of pHSP27 is directly related to the plasma concentration of 
losmapimod and that as the losmapimod concentration changes with time, the resulting 
change in pHSP27 occurs almost instantaneously (Barbour et al, 2013). Preclinical data show 
that this change in pHSP27 correlates with a significant reduction in DUX4 levels and 
transcriptional activity. 
Preclinical in vivo PK/PD studies in non-fasted mice and rats demonstrated that the dose 
levels of losmapimod that achieved clinically relevant plasma exposures also produced 
significant skeletal muscle exposure and p38α/β MAPK pathway inhibition (further details 
provided in the IB). The muscle exposures achieved in rodents that are equivalent to the 
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human 15 mg BID exposures in blood are predicted to result in robust target engagement and 
a >50% reduction in DUX4-dependent targets in FSHD subjects’ skeletal muscle based on 
the in vitro efficacy data in FSHD myotubes. 
Although dosing with 7.5 mg losmapimod BID results in target engagement, it may not be 
robust, especially at the minimum plasma concentration (Cmin). In COPD subjects dosed for 
12 weeks, the target engagement inhibition in predose samples was 21%, while the postdose 
target engagement inhibition was 39% to 44% (GSK study MKI102428). The trough 
losmapimod plasma concentrations maintained in that study were generally <20 ng/mL. 
Importantly, that study did not show any loss of target engagement over 12 weeks of dosing. 
Pharmacokinetic/PD analyses of rodent (Studies FULTX-00002, FULTX-00004, 
FULTX-00005, and FULTX-00006) and human (Barbour et al, 2013) data performed by 
Fulcrum indicated that robust target engagement in muscle should be achieved when plasma 
losmapimod concentrations are >30 ng/mL; therefore, significant p38α/β MAPK inhibition 
would be expected in skeletal muscle with the 15 mg PO BID clinical dose. Although 
increasing concentrations resulted in increases in target engagement in vitro 
(Study FULTX-00008), there is no evidence that increasing the dose above 15 mg PO BID 
will result in significantly greater target engagement. Therefore, clinical dosing beyond 
15 mg BID with the current formulation is not warranted (further details are provided in the 
IB). 
Food was found to increase the oral absorption of losmapimod for tablet formulations of the 
drug. An analysis of AUC0-inf and Cmax showed statistically higher systemic exposure in the 
fed state than in the fasted state. Administration of losmapimod in this study should be 
performed under fed conditions to reduce the potential for PK variability. 
Fulcrum anticipates that a 15 mg BID dosing regimen, as proposed under fed conditions for 
the planned phase 2 studies in FSHD, will result in mean steady-state Cmin and Cmax values of 
approximately 30 ng/mL and 75 ng/mL, respectively; the corresponding values for a 7.5 mg 
PO BID dosing regimen are 16 ng/mL and 38 ng/mL, respectively. Thus, the 15 mg BID 
regimen is expected to maintain steady-state losmapimod plasma concentrations above the 
optimal level of 30 ng/mL needed for robust target engagement, while the 7.5 mg PO BID 
dose would fall below that at predose levels. Importantly, at the proposed dose level of 15 mg 
PO BID, exposures in FSHD subjects are not expected to exceed those previously 
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demonstrated to be safe in humans in multiple previous studies by GSK in healthy volunteers 
and various patient populations (Barbour et al, 2013; Cheriyan et al, 2011; Pascoe et al, 2017; 
Watz et al, 2014).  
3.2.2 Rationale of Study Design 
The placebo-controlled treatment period is a randomized design that includes an active 
treatment group and a placebo group (Section 3.1). The inclusion of a placebo group is 
necessary because there is no available standard of care. The use of a placebo group will 
ensure that any potential for bias is minimized. Additionally, the use of matching placebo 
tablets to the losmapimod tablets will help maintain blinding of the participants to study 
treatment. The OLE will evaluate the safety, tolerability, and efficacy of long-term dosing of 
losmapimod in subjects with FSHD1.  
Efficacy of the reduction in the expression of DUX4-regulated gene transcripts endpoints 
will be assessed with skeletal muscle needle biopsies from lower extremity muscles that meet 
the criteria for biopsy, are safely accessible, and that have been identified as sites of active 
disease by MRI. Physicians experienced in skeletal muscle needle biopsy will perform the 
procedure. In general, these muscle needle biopsies take a short time and are well tolerated, 
including when done repeatedly. In one large series, no complications were reported in 
400 consecutive skeletal muscle needle biopsies. Superficial infection or hematomas are rare 
(<1%; Edwards et al, 1983).  
Misregulated expression of DUX4 and its downstream transcripts is toxic to muscle and 
leads to muscle atrophy and death and replacement by fat (Bosnakovski et al, 2014; 
Vanderplanck et al, 2011; Jones and Jones, 2018). The correlation between MRI 
characteristics, muscle pathology, and expression of DUX4-regulated transcripts was 
established and showed that the presence of an elevated MRI short tau inversion recovery 
(STIR) signal has substantial predictive value in identifying muscles with active disease and 
DUX4 target gene expression (Wang et al, 2019).  
DUX4 protein and mRNA are present at very low levels in FSHD skeletal muscle (Geng et 
al, 2012; Jones et al, 2012). In contrast, DUX4-regulated transcripts are abundant and stably 
expressed. They represent the relevant functional readout of DUX4 protein levels and 
activity. These transcripts are readily measured in skeletal muscle biopsies (Geng et al, 2012; 
Tasca et al, 2012; Yao et al, 2014; Jagannathan et al, 2016; Whiddon et al, 2017; Chen et al, 
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2016; Wang et al, 2019). As DUX4-regulated transcripts in skeletal muscle are uniquely and 
inextricably tied to the expression and function of DUX4, a subset of transcripts will be 
measured in skeletal muscle biopsies by quantitative reverse transcription polymerase chain 
reaction (QRT-PCR) as the primary efficacy endpoint to assess treatment effects on aberrant 
DUX4 activity. 
Standardized MRI protocols for imaging of muscle health and disease in neuromuscular 
disorders, including the measurement of skeletal muscle tissue replacement by fat using the 
Dixon technique (Dixon 1984), have been recommended as a result of 2 consortia organized 
by the TREAT-NMD network (Hollingsworth et al, 2012). The MRI technique to be used in 
this protocol is a standardized, objective, quantitative technique with automatic skeletal 
muscle segmentation for the 3-dimensional (3D) muscle volumes and fat fraction analyses 
via robust algorithms using Dixon imaging to measure the extent of skeletal muscle tissue 
replacement by fat in FSHD patients. Reliable and feasible whole-body MRI acquisition 
protocols and analysis algorithms are readily available for multicenter clinical studies 
focused on abdominal and liver fat. 
It is anticipated that changes in MRI and clinical assessments will take longer to detect than 
changes in DUX4 expression on skeletal muscle biopsy. Evaluation of changes in MRI and 
clinical assessments throughout the study will inform whether treatment with losmapimod 
could slow disease progression by protecting and/or restoring skeletal muscle function. 
Under FIS-002-2019 protocol version 3.0, the randomized, double-blinded, 
placebo-controlled portion of the study was scheduled to end at Week 24 with all primary 
endpoint visits completed by week 16. The COVID-19 pandemic has had a significant impact 
on the conduct of this clinical trial leading to many missing Week 16 and Week 24 visits and 
preventing the rolling over to the long-term OLE part of the study. Research site closures and 
individual study subjects have already missed visits and Fulcrum anticipates that many others 
will be missed unless rapid corrective actions are implemented. In addition, the necessary 
pandemic restrictions limit the assessment of long-term safety in the FSHD1 population in 
the clinic, as well as collection of  critically important efficacy data on Week 24 on clinical 
outcome assessments and MRIs. Further, the investigational drug delivery that currently 
takes place during the clinic visits is also now compromised, resulting in the potential for 
treatment gaps unless home delivery is rapidly enabled.   
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Protocol version 4.0 (COVID-19 Pandemic Emergency Amendment), which follows the 
implementation of the ReDUX4 Emergency Guidance Document (31 March 2020), will 
ensure an adequate assessment of long-term safety of losmapimod compared to placebo, 
allows subjects to continue on the study with minimal treatment disruption, while preserving 
the opportunity to participate in an OLE. The amendment additionally enables assessment of 
the efficacy of losmapimod to treat the underlying cause of FSHD by extending the 
randomized, double-blinded, placebo-controlled portion of the study from 24 to 48 weeks 
when sites impacted by COVID-19 will likely be up and running again. Collection of critical 
data impacted by COVID-19 has been included in additional visits, including muscle biopsy 
(primary endpoint) and target engagement at Week 36 for subjects who missed the Week 16 
visit, and clinical outcome assessments and MRIs at Week 48 for subjects who missed the 
Week 24 visit. The increase in the duration of the randomized, double-blinded, placebo-
controlled portion of the study poses no additional risk to subjects and maintains the ability 
to safely obtain muscle biopsies in the clinic while monitoring safety parameters at home. It 
also allows for rolling over to the long term OLE at the Week 48 visit for those who could 
not do it at Week 24. The amendment continues to provide subjects with the potential for 
benefit and the relation of the anticipated benefit to the risk is at least as favorable as that 
provided by alternatives as there are no approved treatments that can slow, stop or reverse the 
effects of FHSD. Additionally, the planned interim analysis will provide an early assessment 
of the potential treatment effect of losmapimod to treat the underlying cause of FSHD 
providing timely data to inform future development. 
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4 
Subject Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
During the placebo-controlled treatment period, approximately 76 subjects with FSHD1 will 
be randomized at up to 25 sites. Eligibility will be reviewed and documented by an 
appropriately qualified member of the investigator’s team before subjects are enrolled. 
Subjects will be assigned to study treatment only if they meet all of the inclusion criteria and 
none of the exclusion criteria. (Note: Enrollment has completed for this study. A total of 
80 subjects have been enrolled.) 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Capable of understanding the written informed consent, and providing signed, dated, 
and witnessed written informed consent. 
2. Male or female subjects between the ages of 18 and 65 years, inclusive. 
3. Confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the 
D4Z4 array on chromosome 4. Randomization will be stratified to ensure that 
treatment allocation is balanced across FSHD repeat number categories (ie, 1 to 
3 repeats versus 4 to 9 repeats). Genetic confirmation must be obtained before the 
subject is randomized and before the baseline muscle biopsy is performed; genetic 
confirmation can come from previous testing if verified with appropriate 
documentation from an accredited laboratory. Due to stable transmission of repeat 
sizes within families, subjects with a clinical diagnosis of FSHD who have a 
first-degree relative with a genetically confirmed diagnosis of FSHD1 may be entered 
into the study for screening assessments, including MRI. During screening, a 
confirmatory genetic diagnosis is conducted. If genetic testing during screening is 
necessary, the 4-week screening window will not start until the results are obtained 
and verified by the principal investigator.  
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4. Clinical severity score of 2 to 4 (RICCI score; range 0-5), inclusive, at screening. 
Subjects who use a wheelchair or walker for any activity are not permitted to enroll in 
the study. 
5. Has an MRI-eligible muscle for biopsy, as determined by a central reader. 
6. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
7. Willing to practice an approved method of birth control: 
x A female subject is eligible to participate if she is of non-child-bearing potential, 
defined as premenopausal females with permanent sterilization (includes 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female 
subject of any age); or postmenopausal, defined as 12 months of spontaneous 
amenorrhea; or, if of child-bearing potential, if she is using a highly effective 
method for avoidance of pregnancy (defined in Section 5.5.1) and will continue to 
use these methods for the duration of the study and until 90 days after the last 
dose of study drug. The decision to include or exclude women of child-bearing 
potential may be made at the discretion of the investigator and in accordance with 
local practice in relation to adequate contraception. 
x Male subjects must agree to use one of the contraception methods listed in 
Section 5.5.1. This criterion must be followed for the duration of the study and 
until 90 days after the last dose of study drug. 
4.1.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Has a history of any illness or any clinical condition that, in the opinion of the 
investigator, might confound the results of the study or pose an additional risk in 
administering study drug to the subject. This may include, but is not limited to, a 
history of relevant drug or food allergies; history of cardiovascular or central nervous 
system disease; neuromuscular diseases except FSHD (eg, myopathy, neuropathy, 
neuromuscular junction disorders); or clinically significant history of mental disease. 
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2. Previously diagnosed cancer that has not been in complete remission for at least 
5 years. Localized carcinomas of the skin and carcinoma in situ of the cervix that have 
been resected or ablated for cure are not exclusionary. 
3. For subjects who are on drug(s) or supplements that may affect muscle function, as 
determined by the treating physician, or that are included in the list of drugs presented 
in Appendix 13.2: subjects must be on a stable dose of that drug(s) or supplement for 
at least 3 months prior to the first dose of study drug and remain on that stable dose for 
the duration of the study. Changes to the dose or treatment discontinuation during the 
study can only be done for strict medical reasons by the treating physician with clear 
documentation and notification to the sponsor. 
4. History of febrile illness within 5 days before randomization. Subjects who were 
healthy during screening but develop febrile illness in the 5 days before randomization 
need to have the baseline visit postponed until the febrile illness is fully resolved. 
Once the febrile illness is fully resolved, the subject’s baseline visit can be scheduled. 
The duration of the screening visit in such cases can be extended for up to 35 days. 
5. Known active tuberculosis, active opportunistic, or life-threatening infections. 
6. Acute or chronic history of liver disease or known to have current alanine 
aminotransferase ≥2 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN, or 
known history of hepatitis B or C. 
7. Known severe renal impairment (defined as a glomerular filtration rate of 
<30 mL/min/1.73m2). 
8. Positive screen for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV) 
antibody, or antibodies against human immunodeficiency virus (HIV)-1 and -2. 
9. Standard 12-lead ECG demonstrating QTcF >450 msec for male subjects or 
QTcF >470 msec for female subjects at screening. If QTcF exceeds 450 msec for 
males or 470 msec for females, the ECG will be repeated 2 more times, and the 
average of the 3 QTcF values will be used to determine the subject’s eligibility. 
10. History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s) or history or 
evidence of abnormal ECGs that, in the opinion of the investigator or medical monitor, 
would preclude the subject’s participation in the study. 
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11. Blood donation (of approximately 1 pint [500 mL] or more) or any significant loss of 
blood within 90 days before the first dose of study drug, as determined by the 
investigator. 
12. Vaccination with a live attenuated vaccine within 6 weeks of randomization and 
throughout the study. 
13. Use of any anticoagulants for at least 1 month and anti-platelet agents for at least 
1 week before the baseline biopsy, as they increase the risk of hematomas following 
skeletal muscle biopsy. 
14. Male subjects with a female partner who is planning to become pregnant during the 
study or within 90 days after the last dose of study drug. 
15. Positive pregnancy test or is known to be pregnant or lactating. All female subjects of 
child-bearing potential must have a negative serum β-human chorionic gonadotropin 
(β-hCG) pregnancy test at screening and a negative urine pregnancy test prior to 
randomization. 
16. Alcohol, analgesic/opioid, and/or illicit drug abuse, as defined by the American 
Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (American Psychiatric Association, 2013), in the last 6 months before 
screening or a positive test for drugs of abuse at screening. 
17. Any current mental condition (psychiatric disorder, senility, or dementia) that, in the 
opinion of the investigator, may affect study compliance or prevent understanding of 
the aims, investigational procedures, or possible consequences of the study. 
18. Use of another investigational product within 30 days or 5 half-lives (whichever is 
longer), or according to local regulations, or currently participating in a prospective 
study with an investigational product, whether it concerns an experimental drug or a 
medical device. Note: concurrent participation in natural history studies (non-drug, 
non-device studies) may be acceptable if confirmed in writing by the sponsor. 
19. Anticipated inability to comply with any study procedures, including participation in 
study visits according to the visit schedule. 
20. Abnormal laboratory results indicative of any significant medical disease that, in the 
opinion of the investigator, would preclude the subject’s participation in the study. 
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21. Subject, or close relative of the subject, is the investigator or a subinvestigator, 
research assistant, pharmacist, study coordinator, or other staff directly involved with 
the conduct of the study at that site. 
22. Contraindication to needle biopsy. 
23. Contraindication to MRI as per clinic standard practice. 
4.2 
Withdrawal of Subjects from Study Treatment and/or the Study 
The duration of the placebo-controlled treatment period is defined for each subject as the 
time between the date the written informed consent was signed through 1) the completion of 
the Week 48 visit if the subject is rolling over into the OLE or 2) the completion of the safety 
follow-up visit after the end of treatment if the subject is not rolling over into the OLE. The 
duration of the OLE is defined for each subject as the time after completion of the Week 48 
visit through completion of the safety followup visit after the end of treatment or 
discontinuation of the study. 
4.2.1 Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study site. Every effort should be made 
to keep subjects in the study, including if a subject decides to prematurely discontinue study 
treatment. The reasons for subjects not completing the study will be recorded. A subject may 
be withdrawn from the study for any of the following reasons: 
1. The subject does not meet the protocol inclusion or exclusion criteria. 
2. The subject is noncompliant with the protocol. 
3. The subject has a serious or intolerable AE(s) that, in the investigator’s opinion, 
requires withdrawal from the study.  
4. The subject has laboratory safety results that reveal clinically significant 
hematological or biochemical changes from the baseline values. 
5. The subject has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
6. The subject is lost to follow-up. 
7. Other reasons (eg, pregnancy, development of contraindications of use of study drug). 
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8. The subject withdraws consent, or the investigator or sponsor decides to discontinue 
the subject’s participation in the study. 
The investigator will also withdraw a subject if Fulcrum Therapeutics terminates the study. 
Upon occurrence of a serious or intolerable AE, the investigator will confer with the sponsor. 
If a subject is discontinued because of an AE, the event must continue to be followed to 
satisfactory resolution as described in Section 6.2.1.10. Any subject may withdraw his or her 
consent at any time. 
4.2.2 Handling of Withdrawals 
Subjects are free to withdraw from the study or study treatment at any time upon request. 
Subject participation in the study may be stopped at any time at the discretion of the 
investigator or at the request of the sponsor. 
Subjects who discontinue study treatment or active participation in the study will no longer 
receive study drug. When a subject withdraws from the study treatment or active 
participation in the study, the reason(s) for withdrawal shall be recorded by the investigator 
on the relevant page of the electronic case report form (eCRF).  
If a subject prematurely discontinues study treatment, they will be encouraged to remain in 
the study and continue with all other aspects of the study. If appropriate, subjects can restart 
study drug at the 7.5 mg PO BID dose at the investigator’s discretion (depending on the 
reason for discontinuation of study treatment), after approval from the sponsor.  
If a subject decides to prematurely discontinue study treatment and not continue with all 
other aspects of the study, they will be considered to have withdrawn from the study. If a 
subject withdraws from the study, they will be asked to complete the early termination (ET) 
visit as soon as possible after the decision to terminate study participation and to complete 
the safety follow-up visit 7 (±3) days after their last dose of study drug. If the ET visit will be 
scheduled more than 7 days after the last dose of study drug, the safety follow-up and ET 
visits may be combined, with no duplication of assessments required. 
Subjects who fail to return for final assessments will be contacted by the site in an attempt to 
have them comply with the protocol. In the case of subjects being lost to follow-up, at least 
3 documented attempts to contact the subject must be made.  
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It is vital to obtain follow-up data on any subject withdrawn because of an AE or SAE. In 
every case, efforts must be made to undertake protocol-specified, safety, follow-up 
procedures. 
4.2.3 Replacements 
Subjects who withdraw or discontinue will not be replaced. 
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5 
Study Treatments 
5.1 
Method of Assigning Subjects to Treatment Groups 
During the placebo-controlled treatment period, subjects will be randomly assigned at the 
baseline visit (Day 1) to receive losmapimod (active drug) or placebo using a 1:1 allocation 
ratio. Randomization will be stratified to ensure that treatment allocation is balanced across 
FSHD repeat number categories (ie, 1 to 3 repeats versus 4 to 9 repeats). 
An Interactive Response Technology (IRT) system will be used to administer the 
randomization schedule. A designated unblinded statistician separate from the study team 
will generate the randomization schedule using SAS software Version 9.3 or later (SAS 
Institute, Cary, NC) for IRT, which will link sequential subject randomization numbers to 
treatment codes. The randomization will use an appropriate block size, which will not be 
revealed.  
Subjects can be randomized only once. 
During the OLE, all subjects will receive open-label losmapimod.  
5.2 
Treatments Administered 
Study drug tablets in the placebo-controlled treatment period (losmapimod or placebo) and 
the OLE (losmapimod) will be dispensed to subjects at the visits detailed in Table 13-1 and 
Table 13-2, respectively. Subjects  may be provided additional study drug via a courier 
service, as applicable. 
During the placebo-controlled treatment period, subjects will receive 15 mg losmapimod BID 
or placebo BID. In the OLE, subjects will receive 15 mg losmapimod BID. As 7.5 mg 
losmapimod tablets will be used in this study, subjects will be taking 2 tablets PO BID.  
For subjects who rolled over to the OLE under protocol version 3.0, prior to the COVID-19 
pandemic, during the 24-week placebo-controlled treatment period these subjects received 
15 mg losmapimod BID or placebo BID. These subjects will continue on open label 
treatment with 15 mg losmapimod BID. At their next clinic visits, these specific subjects will 
follow the assessments for the Week 36 visit followed by the Week 48 visit in the 
placebo-controlled portion of the study under the COVID-19 Pandemic Emergency protocol 
version 4.0.  
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Study drug (losmapimod or placebo) should be taken with food.  
If a subject misses a dose and it is more than 6 hours until the next planned dose, the subject 
will be instructed to take the missed dose and resume study drug dosing as normal. If it is 
less than 6 hours until the next planned dose, the subject will be instructed to skip the missed 
dose and then resume study drug dosing as normal. 
5.3 
Identity of Investigational Product 
Losmapimod tablets for oral administration are available as white, round, biconvex, plain, 
film-coated tablets containing 7.5 mg of losmapimod as the micronized freebase. 
Losmapimod tablets also contain the inactive excipients microcrystalline cellulose, lactose 
monohydrate, sodium starch glycolate, magnesium stearate, and povidone K29/32, and the 
Opadry White OY-S-28876 film coat contains hypromellulose, titanium dioxide (E171), and 
polyethylene glycol. 
Placebo tablets are identical in appearance to losmapimod and are manufactured using 
commonly used and recognized tablet excipients that are also employed in the active tablets. 
The sponsor will ensure that the study site is provided with adequate supplies of blinded 
losmapimod and placebo (placebo-controlled treatment period) or open-label losmapimod 
(OLE) and that no expired tablets will be dispensed to study subjects. 
5.4 
Management of Clinical Supplies 
5.4.1 Study Drug Packaging and Storage 
All tablets are packed in white high-density polyethylene bottles with a child-resistant 
closure and include an induction-sealed liner. 
During the placebo-controlled treatment period, each dispensation will contain a blinded 
dosage for 1 subject with a sufficient quantity to cover until the next scheduled visit plus 
additional tablets to cover the visit window. If needed, subjects may be provided additional 
study drug via a courier service, as applicable. Study drug will be packaged and labelled in 
accordance with regulatory requirements and in a manner to retain the study blind.  
During the OLE, subjects will be supplied with a sufficient quantity of losmapimod to last 
until the next scheduled visit plus additional tablets to cover the visit window or will be 
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provided additional study drug via a courier, as applicable. Open-label losmapimod will be 
packaged and labelled in accordance with regulatory requirements. 
Further details of study drug packaging, labeling, and distribution of the study medication 
will be provided in the study reference manual. 
Study drug must be stored in a secure area (eg, a locked cabinet), protected from moisture, 
and kept at a controlled room temperature not to exceed 30°C. 
5.4.2 Study Drug Accountability 
During the study, each subject will be provided a sufficient quantity of study drug to allow 
for dosing until their next scheduled visit plus additional tablets to cover the visit window. If 
needed, subjects may be provided additional study drug via a courier service, as applicable. 
At the next scheduled clinic visit, subjects must return their bottles for accountability. 
The investigator will maintain accurate records of receipt of all study drug, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much study drug 
is dispensed and used by each subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drug will be reconciled and 
retained or destroyed according to applicable regulations. 
5.4.3 Medication Errors and Overdose 
No specific antidote for losmapimod is known. In case of overdose or medication errors, 
subjects should be observed and be provided with a supportive standard of care. 
5.5 
Lifestyle Restrictions 
Any nutrients known to modulate cytochrome P450 enzyme activity (eg, grapefruit- or 
Seville orange-containing products or quinine containing drinks [tonic water or bitter lemon]) 
should be avoided 3 days before the first dose of study drug until after the last dose of study 
drug. 
Strenuous physical activity (eg, heavy lifting, weight or fitness training) should be avoided 
for 48 hours prior to each study visit. Routine ambulatory and other activities (eg, walking at 
normal pace) will be permitted, with the level of activities kept as similar as possible on all 
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days of the study. This is especially important on the day of the muscle biopsies and the days 
before it. 
For the screening visit, subjects will be required to fast for at least 4 hours prior to laboratory 
blood samples being taken. For some study visits, if possible, subjects will be asked to take 
the morning medication in the clinic to enable blood sampling before and at specific times 
after taking the study drug. 
5.5.1 Contraception Requirements 
Subjects of child-bearing potential must be willing to practice an approved method of birth 
control for the duration of the study and until 90 days after the last dose of study drug. 
A female subject is eligible to participate if she is of non-child-bearing potential, defined as 
premenopausal females with permanent sterilization (includes hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy in a female subject of any age); or postmenopausal, 
defined as 12 months of spontaneous amenorrhea; or, if of child-bearing potential, if she is 
using a highly effective method for avoidance of pregnancy and will continue to use these 
methods for the duration of the study and until 90 days after the last dose of study drug.  
Male subjects must agree to use one of the contraception methods listed below for the 
duration of the study and until 90 days after the last dose of study drug. 
The following is the all-inclusive list of the highly effective methods for avoiding pregnancy 
in females of child-bearing potential (ie, the methods have a failure rate of less than 1% per 
year when used consistently and correctly and, when applicable, in accordance with the 
product label) (Hatcher et al, 2007): 
x Complete abstinence from penile-vaginal intercourse, when this is the preferred and 
usual lifestyle 
x Oral contraceptive, either combined or progestogen alone 
x Injectable progestogen 
x Implants of etonogestrel or levonorgestrel 
x Estrogenic vaginal ring 
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x Percutaneous contraceptive patches 
x Intrauterine device or intrauterine system 
x Tubal sterilization 
x Essure micro-insert system (provided confirmation of success 3 months after 
procedure) 
x Male partner sterilization (vasectomy with documentation of azoospermia) prior to the 
female subject’s entry into the study, and this male is the sole partner for that subject. 
The information on the male sterility can come from the site personnel’s review of the 
subject’s medical records; medical examination of the subject, and/or semen analysis; 
or interview with the subject on his medical history. Sterilized males (vasectomy with 
documentation of azoospermia) must use condoms until 90 days after last dose of 
study drug. 
x Male condom combined with a female diaphragm, either with or without a vaginal 
spermicidal (foam, gel, film, cream, or suppository). Nonoxynol-9 is the critical 
component in most spermicides. 
5.6 
Blinding 
The placebo-controlled treatment period will be performed in a double-blind fashion. The 
investigator, study staff, subjects, and monitor will remain blinded to subject-level treatment 
assignment until study closure. The sponsor and/or its designee will remain blinded to the 
subject-level treatment assignment until after all subjects have completed the Week 48 visit 
(or have discontinued) and the database from the placebo-controlled treatment period has 
been locked for statistical analyses, after which time they will be unblinded. For the interim 
analysis (IA), DUX4 and demographics data will be presented to the Sponsor as group-level 
summaries, along with associated p-values. 
The study drug and its matching placebo are indistinguishable and will be packaged in the 
same way. There are no tolerability issues that could unblind drug versus placebo. 
A subject’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the subject depends on knowing the study treatment the subject received. In the 
event that the blind needs to be broken because of a medical emergency, the investigator may 
unblind an individual subject’s treatment allocation without the sponsor's prior agreement. As 
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soon as possible, the investigator should contact the medical monitor to discuss the medical 
emergency and the reason for revealing the actual treatment received by that subject. 
For medical emergencies, the treatment assignment will be unblinded through the IRT. 
Reasons for treatment unblinding must be clearly explained and justified in the eCRF. The 
date on which the code was broken together with the identity of the person responsible must 
also be documented. 
During the OLE no blinding will be performed (subjects will receive open-label 
losmapimod); however, the investigator, study staff, subjects, and monitor will remain 
blinded to the original subject-level treatment assignment from the placebo-controlled 
treatment period for the duration of the study. The sponsor and/or its designee will be 
unblinded after all subjects have completed the Week 48 visit (or have discontinued) and the 
database from the placebo-controlled treatment period has been locked for statistical 
analyses.  
5.7 
Treatment Compliance 
Subject compliance will be monitored by tablet counts in the clinic. In addition, subject 
diaries may only be used for a portion of the placebo-controlled portion of the trial to record 
the date and time of each dose taken. This information may also be used to calculate 
compliance. Site staff should encourage the proper use of study drug for those subjects who 
are not compliant. 
5.8 
Prior and Concomitant Therapy 
Use of all concomitant medications taken within 28 days before screening through the safety 
follow-up visit (either at the end of the placebo-controlled treatment period or at the end of 
the OLE, as applicable) will be recorded in the subject’s eCRF. The minimum requirement is 
that drug name and the dates of administration are to be recorded. This will include all 
prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications. 
Any changes in concomitant medications also will be recorded in the subject’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. 
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The use of the following medications is prohibited in this study: 
x Vaccination with a live attenuated vaccine from 6 weeks prior to randomization until 
the safety follow-up visit (either at the end of the placebo-controlled treatment period 
or at the end of the OLE, as applicable) 
x Use of any anticoagulants for at least 1 month and anti-platelet agents for at least 
1 week before each biopsy because these treatments increase the risk of hematomas 
following skeletal muscle needle biopsy 
Subjects who are on drug(s) or supplements that may affect muscle function, as determined 
by the treating physician, or that are included in the list of drugs presented in 
(Appendix 13.2) must be on a stable dose of that drug(s) or supplement for at least 3 months 
prior to the first dose of study drug and remain on that stable dose for the duration of the 
study. Changes to the dose or treatment discontinuation during the study can only be done for 
strict medical reasons by the treating physician with clear documentation and notification to 
the sponsor. 
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6 
Study Assessments and Procedures 
Before performing any study procedures, all potential subjects will sign an informed consent 
form (ICF). Subjects will have the opportunity to have any questions answered before 
signing the ICF. The investigator must address all questions raised by the subject. The 
investigator or designee will also sign the ICF. 
Study visits and the timing of assessments for the placebo-controlled treatment period or the 
OLE are detailed in the schedule of events (Table 13-1 and Table 13-2, respectively). 
Prior to the COVID-19 pandemic, subjects who reached the Week 24 visit had the option to 
roll over into the OLE. Subjects that have already rolled over to the OLE prior to the 
COVID-19 pandemic will remain on open label treatment. Their next clinic visits will follow 
the assessments for the Week 36 and Week 48 visit in the placebo-controlled portion of the 
study in the COVID-19 Pandemic Emergency protocol version 4.0. These subjects will not 
undergo the Week 36 biopsy. Subjects who did not roll over prior to the COVID-19 pandemic 
will roll over into the OLE at the Week 48 visit as described in the COVID-19 Pandemic 
Emergency protocol version 4.0. 
6.1 
Efficacy Assessments 
6.1.1 Skeletal Muscle Needle Biopsy 
The choice of the muscle(s) to be biopsied in this study will be determined by the 
investigator, informed by skeletal muscle MRI during screening. The bilateral vastus 
lateralis, vastus medialis, lateral gastrocnemius, medial gastrocnemius, and tibialis anterior 
will be evaluated for eligibility by MRI using a central reader. Only those muscles that are 
STIR positive with the predetermined range of MFF will be eligible for biopsy. This 
information will be communicated to the sites that will select the muscle or muscles for 
biopsy. Sites will select the best muscle(s) that meet the MRI criteria based on their own 
experience with muscle needle biopsy. The Week 16 or Week 36 muscle needle biopsies (for 
those subjects unable to have the Week 16 muscle biopsy due to the COVID-19 pandemic), 
will be performed in the same approximate muscle region as the pretreatment (Day 1) muscle 
biopsy. 
The muscle tissue collected at each biopsy will be analyzed for DUX4 activity using a 
molecular panel of DUX4-regulated gene transcripts and for drug concentration and target 
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engagement by central laboratories. The tissue will be used to measure other gene transcripts 
and may be used to measure proteins related to the pathology of FSHD as part of exploratory 
biomarker endpoints. 
The specific details of the biopsy procedures, materials to be provided, materials to be 
resourced locally, personnel qualification, and methods for tissue collection, processing, and 
analysis will be specified in the study reference manual.  
6.1.2 Skeletal Muscle Magnetic Resonance Imaging 
Whole-body Dixon MRI for MFF, LMV, and MFI will be performed at the visits noted in 
Table 13-1 and Table 13-2. Subjects will be screened for any contraindications to MRI as per 
clinic standard practice. 
Details will be described in the study MRI manual. The study MRI manual will also describe, 
in detail, all of the steps involved in the acquisition, transmission, quality evaluation, and 
analysis of MRI images between the study site and the central reader. 
6.2 
Safety and Tolerability Assessments 
6.2.1 Adverse Events 
6.2.1.1 Definitions of Adverse Events 
The investigator is responsible for reporting all treatment-emergent AEs (TEAEs) that are 
observed or reported during the study, regardless of their relationship to study drug or their 
clinical significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study, 
regardless of its causal relationship to study drug. Subjects will be instructed to contact the 
investigator at any time after randomization if any symptoms develop. 
A TEAE is defined as any event that was not present before exposure to study drug or any 
event that was already present but worsens in either intensity or frequency after exposure to 
study drug. 
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6.2.1.2 Serious Adverse Events 
An SAE is defined as any event that 
x results in death 
x is immediately life-threatening 
x requires inpatient hospitalization or prolongation of existing hospitalization 
x results in persistent or significant disability/incapacity 
x is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
6.2.1.3 Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern for which ongoing 
monitoring and rapid communication by the investigator to the sponsor can be appropriate. 
Adverse events of special interest for this study include liver tests that meet the criteria for 
potential drug-induced liver injury (DILI), in accordance with the US Food and Drug 
Administration (FDA) “Guidance for Industry-Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation”. 
Liver Tests and Stopping Criteria 
The following 3 laboratory value criteria must be met for potential DILI, or “Hy’s Law”: 
x An elevated alanine transaminase or aspartate transaminase laboratory value that is 
≥3 × ULN 
x An elevated total bilirubin laboratory value that is ≥2 × ULN 
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x An alkaline phosphatase laboratory value that is <2 × ULN 
Study drug should be discontinued for subjects who meet the laboratory criteria for potential 
DILI as a result of within-protocol specific testing or unscheduled testing. This AESI must be 
reported to the sponsor within 24 hours of awareness. Further safety steps should be taken to 
closely observe and follow-up the event until resolution. These steps include, but are not 
limited to: 
x Making every reasonable attempt to have the subject return to the clinic within 
24 hours for repeat liver tests 
x Obtaining a more detailed history of symptoms and prior or concurrent disease, 
concomitant medication use, alcohol use, recreational drug use, and special diets 
x Repeating liver enzyme and serum bilirubin tests twice weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize and the subject 
is asymptomatic 
x Obtaining viral hepatitis serology 
x Considering liver imaging and/or hepatology consultation 
6.2.1.4 Eliciting and Documenting Adverse Events 
Adverse events and SAEs will be assessed from the time the subject signs the ICF through 
the safety follow-up visit (either at the end of the placebo-controlled treatment period or at 
the end of the OLE, as applicable). Any SAE that occurs after these time periods and that is 
believed to be related to study drug should be reported by the investigator (as described in 
Section 6.2.1.6). 
At every study visit, subjects will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to subject observations, AEs identified from any study data (eg, clinically 
significant laboratory values, physical examination findings, ECG changes) or identified 
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from review of other documents that are relevant to subject safety will be documented on the 
AE page in the eCRF. 
6.2.1.5 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes the following: 
x drug treatment 
x dose 
x event term 
x time of onset 
x investigator-specified assessment of severity and relationship to study drug 
x time of resolution of the event 
x seriousness 
x any required treatment or evaluations 
x outcome 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states (if unexpected 
worsening beyond normal disease progression based on investigator’s assessment) must also 
be reported. All AEs must continue to be followed to satisfactory resolution as described in 
Section 6.2.1.10. The Medical Dictionary for Regulatory Activities (MedDRA) will be used 
to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
Please refer to the ReDUX4 Emergency Guidance Document (31 March 2020) for reporting 
of AEs related to the COVID-19 pandemic.  
Reporting for AESIs is described in Section 6.2.1.3. 
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6.2.1.6 Reporting Serious Adverse Events 
The investigator must report any AE that meets the SAE criteria (Section 6.2.1.2) to
immediately (ie, within 24 hours after the site personnel first learn about the event) via 
electronic data capture (EDC). In the event that EDC entry is not possible (eg, system failure 
or access problems), the study site staff should complete the paper SAE report form and fax 
the form to
Pharmacovigilance within 24 hours of awareness or call the 
safety 
hotline to report. The study site staff should update the EDC system as soon as it is available.  
A full description of every SAE will need to be provided to
Pharmacovigilance. 
The following contact information should be used if reporting SAEs via fax or phone: 
Pharmacovigilance 
6.2.1.7 Suspected Unexpected Serious Adverse Reactions 
The sponsor will promptly evaluate all suspected unexpected serious adverse reactions 
(SUSARs) against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and applicable regulatory authorities based 
on applicable legislation. 
To determine reporting requirements for single AE cases, the sponsor will assess the 
expectedness of these events using the IB. 
The sponsor will compare the severity of each SUSAR and the cumulative event frequency 
reported for the study with the severity and frequency reported in the IB. 
Reporting requirements will also be based on the investigator’s assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. 
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6.2.1.8 Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 
Mild: 
An event that is usually transient in nature and generally does not interfere with 
normal activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal activities. 
Severe: 
An AE that is incapacitating and prevents normal activities. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of the onset and duration of each episode. 
6.2.1.9 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
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Not 
related: 
This relationship suggests that there is no association between the study drug 
and the reported event. 
 
Unlikely: 
This relationship suggests that the event is most likely produced by other 
factors such as the subject’s clinical condition, intercurrent illness, or 
concomitant drugs administered to the subject, and does not follow a known 
response pattern to the study drug, or the temporal relationship of the event to 
study drug administration makes a causal relationship unlikely. 
 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, ie, the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to the 
study drug but could also have been produced by other factors. 
 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the study drug seems likely. The event 
disappears or decreases on cessation or reduction of the dose of study drug. 
 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. The event reappears or worsens if the study 
drug is re-administered. 
 
 
6.2.1.10 Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. 
6.2.2 Laboratory Analyses 
Samples for serum chemistry, hematology, coagulation, and urinalysis will be collected at the 
time points specified in Table 13-1 and Table 13-2. Processing, storage, and shipping 
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procedures for all clinical laboratory samples are provided in a laboratory manual. Sample 
collection details are presented in Section 6.7. 
For the screening visit, subjects will be required to fast for at least 4 hours prior to laboratory 
blood samples being taken. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, radiological scans, vital sign measurements), including those 
that worsen from baseline (ie, prior to first dose in the placebo-controlled treatment period) 
and are felt to be clinically significant in the medical and scientific judgment of the 
investigator, are to be recorded as AEs or SAEs. However, any clinically significant safety 
assessments that are associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the subject’s condition, are not to be reported as AEs or 
SAEs. Clinically significant abnormal laboratory test results will be reviewed by the 
investigator and recorded as AEs or SAEs on the appropriate page in the eCRF.  
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Blood and other biological samples will be collected for the following clinical laboratory 
tests: 
Serum chemistry 
Glucose, sodium, potassium, calcium, inorganic phosphate, total protein, albumin, 
blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, creatine 
phosphokinase 
Hematology 
Hemoglobin (including mean corpuscular volume), mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, hematocrit, red blood cell count, total 
white blood cell count, platelet count 
Differential blood counts, including basophils, eosinophils, neutrophils, 
lymphocytes, and monocytes 
Coagulation 
International normalized ratio, prothrombin time, partial thromboplastin time 
Urinalysis 
Leucocytes, blood, nitrite, protein, urobilinogen, bilirubin, pH, specific gravity, 
ketones, glucose 
If there is a clinically significant positive result, urine will be sent for microscopy 
and/or culture. 
Pregnancy 
Serum β-hCG (all female subjects of child-bearing potential), serum 
follicle-stimulating hormone (suspected postmenopausal female subjects only 
[defined in Section 5.5.1]), urine pregnancy test 
Serology testing 
HbsAg, HCV antibody, HIV-1/HIV-2 antibodies 
Urine drug screen 
Cocaine, amphetamines, opiates (morphine), benzodiazepines, and cannabinoids 
 
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6.2.3 Medical History 
Medical history will be recorded at screening and will be reviewed at baseline to ensure no 
changes have occurred since the screening visit. Clinically relevant findings that are present 
prior to study drug initiation must be recorded on the Medical History page in the eCRF. 
Clinically relevant findings found after study drug initiation and meeting the definition of an 
AE (new AE or worsening of previously existing condition) must be recorded on the AE page 
in the eCRF. 
FSHD-specific history will be recorded at screening or at a subject’s next scheduled study 
visit, if not previously recorded.  
6.2.4 Vital Signs 
Vital sign (pulse rate, respiration rate, blood pressure, and temperature) assessments will be 
performed at the time points specified in Table 13-1 and Table 13-2. Assessments will be 
taken after the subject has been seated or recumbent for at least 5 minutes and before any 
12-lead ECG assessment or blood sampling is performed. 
6.2.5 Physical Examinations  
Physical examinations will be performed at the time points specified in Table 13-1 and 
Table 13-2.  
Physical examinations at the screening visit and the safety follow-up visit will include an 
evaluation of body systems, including but not limited to the following: skin; head, eyes, ears, 
nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph 
nodes; neurological system; and MSK system.  
Symptom-directed physical examinations can occur at any time during the study if triggered 
by AEs or if deemed necessary by the investigator.  
Weight (kg) will be recorded at screening and throughout the study at the time points 
specified in Table 13-1 and Table 13-2.  
Height (cm) will be recorded and body mass index (BMI) calculated at screening and once 
yearly during the OLE: BMI (kg/m2)=weight (kg)/(height [cm]/100)2. Weight and height will 
be measured with shoes off and preferably with the same balance at each visit. 
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6.2.6 Twelve-Lead Electrocardiograms 
Twelve-lead ECGs will be performed at the time points specified in Table 13-1 and 
Table 13-2. The primary ECG tracings will be locally read by the investigator. Any ECGs 
found to have abnormalities will be referred for a second opinion by a central reader. 
Twelve-lead ECGs will be performed after subjects have been recumbent for at least 
5 minutes. The ECGs should be performed after the measurement of vital signs and before 
any procedures that may affect heart rate (eg, blood sampling). 
At the screening visit, if QTcF exceeds 450 msec for males or 470 msec for females, the 
ECG will be repeated 2 more times, and the average of the 3 QTcF values will be used to 
determine the subject’s eligibility for the study.  
Any clinically significant changes from baseline should be reported as AEs or SAEs, if 
applicable. 
6.3 
Pharmacokinetic and Pharmacodynamic Assessments 
6.3.1 Pharmacokinetic Assessments 
During the placebo-controlled treatment period, blood samples will be collected to measure 
the plasma concentrations of losmapimod at Day 1 (baseline), Week 4, Week 16, and 
Week 36 at the following time points: immediately predose and 4 hours (±30 minutes) after 
administration of the study dose. Blood samples will also be taken, when feasible, after 
dosing during the Week 12, Week 24, and Week 48 visits, preferably ≥1 hour after dosing 
(Table 13-1). During the OLE, blood samples will be collected to measure the plasma 
concentration of losmapimod after dosing at each visit, preferably ≥1 hour after dosing 
(Table 13-2). 
For each plasma PK sample, approximately 3 mL of blood will be collected via an 
intravenous catheter placed in an antecubital vein in the arm into a 3 mL, lavender-capped 
vacutainer tube containing K2-EDTA. The indwelling catheter will be kept patent by saline 
flush after each blood sampling. The exact actual clock time of withdrawal of the blood 
sample will be recorded.  
Skeletal muscle biopsies will be taken at Day 1 (baseline; predose) and at Week 16 or 
Week 36 to assess the losmapimod concentrations in muscle during the placebo-controlled 
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treatment period (Table 13-1). Skeletal muscle biopsy procedures are described in Section 
6.1.1. 
Further detailed handling, processing, storage, and shipping procedures for plasma and 
skeletal muscle biopsy PK samples are described in laboratory manuals. 
6.3.2 Pharmacodynamic Assessments 
During the placebo-controlled treatment period, samples for assessing the target engagement 
estimates of losmapimod in peripheral blood will be collected at Day 1 (baseline) and 
Week 16 or Week 36 if it was not possible to collect the sample due to the COVID-19 
pandemic, at the following time points: immediately predose and 4 hours (±30minutes) after 
taking the study dose (Table 13-1).  
For drug target engagement measurements in skeletal muscle tissue during the 
placebo-controlled treatment period, each biopsy will be analyzed for pHSP27/total HSP27. 
Target engagement estimates of losmapimod in skeletal muscle biopsy will be taken at Day 1 
(baseline; predose) and at Week 16 or Week 36 (Table 13-1). Skeletal muscle biopsy 
procedures are described in Section 6.1.1. Target engagement in muscle will be compared to 
target engagement in blood collected on the same day. 
Further detailed handling, processing, storage, and shipping procedures for target 
engagement samples are described in a laboratory manual. 
6.4 
Other Assessments 
6.4.1 Reachable Work Space 
The RWS Microsoft Kinect-based movement sensor system will be used at the visits noted in 
Table 13-1 and Table 13-2 to determine the subjects’ RWS. 
The RWS is a 3D sensor-based system (using a single depth-ranging sensor) that can 
unobtrusively detect an individual’s RWS and reflects individual global upper extremity 
function, including shoulder and proximal arm. Previous and ongoing evaluation of the 
hardware and software system using a commercially available and cost-effective single 
sensor platform (Microsoft Kinect sensor) has demonstrated its high reliability, repeatability, 
face validity, feasibility, sensitivity to change, and promise as a COA for FSHD and other 
neuromuscular disorders (Han et al, 2015). 
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During the evaluation, subjects will be seated in front of the Microsoft Kinect sensor and will 
undergo a standardized upper extremity movement protocol under the supervision of a study 
clinical evaluator while looking at a TV monitor. The evaluation will be performed with and 
without weights and on both the right and left arms. The Kinect sensor will track the 3D 
upper limb trajectory and transform the movements into a body-centric coordinate system. 
Each individual’s RWS envelope will be reconstructed in a graphical output. Each side’s 
RWS envelope will be divided into 4 quadrants, with the shoulder joint serving as the origin. 
The absolute total RWS surface envelope area (m2) as well as areas for each of the quadrants 
will be calculated. Scaling of the data by each person’s arm length will allow normalization 
for comparison between subjects (Han et al, 2015). RWS includes the functional workspace, 
where patients are instructed to touch certain parts of their body and are rated on their ability 
to complete this task. 
Instructions for equipment assembly, setup, testing, and site certification; a manual of 
operation; and a quick reference guide will be described in a RWS manual. A central reader 
will be responsible for training, quality control, data analysis, and standardization of the 
RWS across all sites in the study. 
6.4.2 Timed Up and Go 
The classic and FSHD TUG test will be performed at the visits noted in Table 13-1 and 
Table 13-2. 
The TUG test is a simple test that is used to assess a person’s mobility and requires both 
static and dynamic balance. It measures the time that a person takes to rise from a chair, walk 
3 meters, turn around, walk back to the chair, and sit down. The optimized TUG test is the 
classic TUG but adds the component of getting up from a laying position on a bed-like table 
in the clinic at the start of the test and laying back down on his or her back at the end of the 
test. The test will be done twice per visit. 
A manual of operation, traditional TUG source documents, and FSHD TUG source document 
will be described in a TUG manual. A central reader will be responsible for training, quality 
control, data analysis, and standardization of the TUG and FSHD TUG across all sites in the 
study. 
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6.4.3 Dynamometry 
Dynamometry will be performed at the visits noted in Table 13-1 and Table 13-2. 
Quantitative isometric dynamometry (hand-held dynamometer) will be used to assess the 
skeletal muscle strength of study subjects in both the upper and lower limbs bilaterally. 
Shoulders, flexors and extensors in the elbow, knees, and ankles as well as the grip will be 
measured at each applicable visit. Isometric dynamometry measures the static muscle 
strength without any movement. 
Further details of the assessment will be provided in a study reference manual. All sites will 
use the same equipment and standardized testing procedure. 
6.4.4 Motor Function Measure Domain 1 
The MFM scale Domain 1 assessment will be performed at the visits noted in Table 13-1 and 
Table 13-2. 
The MFM scale assesses the severity of the motor deficit as determined by an experienced 
physical therapist (Bérard et al, 2005). The score is reproducible, the coefficients of the 
interrater reliability are good or excellent. Domain 1 of the MFM provides a clinician’s 
assessment of functional impairment for standing and transfers.  
Instructions for performing the MFM scale Domain 1 assessment will be provided in a study 
reference manual. 
6.4.5 FSHD Health Index 
The FSHD-HI will be performed at the visits noted in Table 13-1 and Table 13-2. 
The FSHD-HI is an FSHD-specific patient-reported measure of disease burden on activities 
of daily living, quality of life, and symptom prevalence and severity. It consists of a 
questionnaire with 116 items developed from qualitative interviews of patients followed by a 
national cross-sectional validation study. The measure consists of 14 subscales that measure a 
patient’s perception of their ambulation and mobility, hand function, shoulder and arm 
function, emotional health, back/chest/abdomen strength, fatigue, pain, eating function, 
ability to do activities, communication ability, satisfaction in social situations, performance in 
social situations, body image and cognition. Scoring is performed centrally by the developer. 
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6.4.6 Patients’ Global Impression of Change 
The PGIC will be performed at the visits noted in Table 13-1 and Table 13-2 to obtain the 
subjects’ rating of overall improvement. 
6.4.7 Genetic Confirmation of FSHD1 
Genetic testing for FSHD1 is highly sensitive and specific. The finding of a D4Z4 
contraction on chromosome 4q35 likely has a sensitivity of 93% and a specificity of 98% for 
the diagnosis of clinically defined FSHD. Healthy individuals possess at least 11 D4Z4 
repeats, yielding a DNA fragment >38 kb on standard genetic testing. Affected individuals 
possess between 1 and 10 repeats, yielding DNA fragments ranging from 10 to 38 kb in size. 
Measurement of the size of the residual D4Z4 sequence on 4q35 forms the basis for genetic 
testing in FSHD (Tawil et al, 2015). For this study, only subjects with 1 to 9 repeats will be 
enrolled. The number of repeats will be calculated by a diagnostic laboratory using the size 
of the D4Z4 bands on Southern blot testing. The site will enter the number of repeats into the 
IRT system. Subjects with 10 repeats will be excluded from the study because such 
individuals tend to have slower progression and are more variable due to the presence of 
genetic modifiers. 
Genetic confirmation must be obtained before the subject is randomized and before the 
baseline muscle biopsy is performed. Genetic confirmation can come from previous testing, 
if verified with appropriate documentation from an accredited laboratory. If genetic testing is 
necessary, the 4-week screening window and activities will not start until the results are 
obtained and verified by the principal investigator.  
Due to the stable transmission of repeat sizes within families, subjects with a clinical 
diagnosis of FSHD who have a first-degree relative with a genetically confirmed diagnosis of 
FSHD1 may be entered into the study for screening assessments including MRI. During 
screening, a confirmatory genetic diagnosis will be conducted. If genetic testing during 
screening is necessary, the 4-week screening window will not start until the results are 
obtained and verified by the principal investigator. 
Further detailed handling, processing, storage, and shipping procedures for genetic testing 
samples are described in a laboratory manual. 
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6.5 
Safety Review Committee 
As detailed in Section 11.1.1, a safety review committee (SRC) will review safety data from 
the study.  
6.6 
Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication. Any pregnancy that occurs 
during study participation must be reported as an SAE. Study staff should complete the paper 
Pregnancy Initial Report Form and fax the form to
Pharmacovigilance within 24 hours 
of awareness or call the
safety hotline to report.  
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To ensure subject safety, irrespective of the treatment received by the subject, any pregnancy 
occurring during study drug administration or until follow-up must be reported within 
24 hours of the investigator’s knowledge of the event to the sponsor. 
If a woman becomes pregnant while on study drug, the study drug must be discontinued 
immediately. The investigator must counsel the subject and discuss the potential risks to the 
pregnancy and the possible effects on the embryo or fetus. The pregnancy must be followed 
up to determine the outcome (including spontaneous miscarriage, elective termination, 
normal birth, or congenital abnormality) and status of mother and child, even if the subject 
was discontinued from the study. Pregnancy complications and elective terminations for 
medical reasons must be reported as an AE or SAE. Spontaneous miscarriages must be 
reported as an SAE. 
Any SAE occurring in association with a pregnancy, that is brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study drug must be promptly reported to
and Fulcrum 
Therapeutics. 
6.7 
Sample Collections 
Processing, storage, and shipping procedures for all clinical laboratory, PK, and target 
engagement samples are provided in a laboratory manual. 
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7 
Statistical and Analytical Plan 
Details regarding the statistical methods and definitions will be provided in statistical 
analysis plan(s) (SAP[s]). Separate SAPs will be prepared for each treatment period of the 
study. The SAP for the placebo-controlled treatment period will be finalized prior to database 
lock/freeze for the IA. 
Any deviations from the SAP(s) are to be justified in the clinical study reports. Statistical 
analyses will be performed using Version 9.3 or higher of SAS (SAS Institute, Cary, NC). 
Analyses will be generated separately for the placebo-controlled treatment period and the 
OLE.  
7.1 
Placebo-Controlled Treatment Period 
7.1.1 Primary Endpoint 
The primary endpoint of the placebo-controlled treatment period is the change from baseline 
in DUX4 activity in affected skeletal muscle at Week 16 or Week 36, as measured by 
QRT-PCR in a panel of DUX4-regulated gene transcripts. 
7.1.2 Secondary Endpoints 
The secondary endpoints of the placebo-controlled treatment period are as follows: 
x Safety and tolerability of losmapimod as defined by the following: 
o Type, frequency, severity, seriousness, and relationship of AEs to 
losmapimod 
o Incidence of AESIs 
o Number of subjects who prematurely discontinue study drug due to an AE 
o Frequency of clinically significant changes in laboratory test, ECG, vital 
sign, and physical examination results  
x Change from baseline in MFF, LMV, and MFI at Week 12, Week 24 (if applicable) 
and Week 48 
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x Plasma concentrations of losmapimod at Week 4, Week 12, Week 16, Week 24, Week 
36, and Week 48 
x Concentrations of losmapimod in skeletal muscle biopsy at steady state at Week 16 or 
Week 36 
x Target engagement parameters in blood, and skeletal muscle biopsy at Week 16 or 
Week 36 
7.1.3 Exploratory Endpoints 
The exploratory endpoints of the placebo-controlled treatment period are as follows: 
x Change from baseline in COAs, including 
o RWS with and without weights at Week 4, Week 12, Week 24, and 
Week 36 
o Classic and FSHD TUG at Week 4, Week 12, Week 24, and Week 36 
o Muscle strength by hand-held quantitative dynamometry at Week 4, 
Week 12, Week 24, Week 36, and Week 48 
o MFM Domain 1 at Week 12, Week 24, Week 36, and Week 48 
o FSHD-HI at Week 4, Week 12, Week 24, Week 36, and Week 48 
o PGIC at Week 4, Week 12, Week 16, Week 24, Week 36, and Week 48 
Change from baseline in inflammatory, immune, apoptotic, and other muscle disease 
transcripts may be conducted in muscle biopsy at Week 16 or Week 36 and in circulating 
proteins in plasma and serum at Week 4, Week 12, Week 16, Week 24, Week 36, and 
Week 48. 
7.2 
Open-Label Extension 
7.2.1 Primary Endpoint 
The primary endpoint of the OLE is to evaluate the safety and of losmapimod as defined by 
the following: 
x Type, frequency, severity, seriousness, and relationship of AEs to losmapimod 
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x Incidence of AESIs 
x Number of subjects who prematurely discontinue study drug due to an AE 
x Frequency of clinically significant changes in laboratory test, ECG, vital sign, and 
physical examination results 
7.2.2 Secondary Endpoints 
x Change from baseline in MFF, LMV, and MFI after long-term dosing (at 
every-24-week time points) 
x Plasma concentrations of losmapimod after long-term dosing (at every-12-week time 
points) 
7.2.3 Exploratory Endpoints 
The exploratory endpoints of the OLE are as follows: 
x Change from baseline in COAs after long-term dosing (at every-12-week time points), 
including 
o RWS with and without weights 
o Classic and FSHD TUG 
o Muscle strength by hand-held quantitative dynamometry 
o MFM Domain 1 
o FSHD-HI 
o PGIC 
x Change from baseline in inflammatory, immune, apoptotic, and other muscle disease 
transcripts in circulating proteins in plasma and serum after long-term dosing (at 
every-24-week time points) 
7.3 
Sample Size Calculations 
Assuming an effect size of 0.70, a sample size of 68 subjects (34 subjects per group) will be 
needed to provide 80% power with a 2-sided test at a 0.05 significance level to detect a 
difference between losmapimod and placebo in change from baseline in DUX4 activity in 
affected skeletal muscle after 16  or 36 weeks (depending upon when the muscle biopsy was 
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performed) during the placebo-controlled treatment period. Assuming that approximately 
10% of subjects will be non-evaluable, approximately 76 subjects will be randomly assigned 
at a 1:1 ratio to losmapimod and placebo (38 subjects per group).  
7.4 
Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Full analysis set (FAS): The FAS will consist of all subjects who are randomly assigned to 
receive double-blind study drug in the placebo-controlled treatment period. All analyses 
using the FAS will group subjects according to randomized treatment. The FAS is the main 
analysis population for key study endpoints (Section 7.6.1). For the secondary and 
exploratory endpoints, subjects who already transitioned into the OLE portion under protocol 
version 3.0 will be analyzed as randomized, in this analysis population. 
Per-protocol set (PPS): The PPS will consist of all FAS subjects who fulfill all 
inclusion/exclusion criteria and do not have any significant protocol deviations. All analyses 
using the PPS will group subjects according to randomized treatment. PPS analyses will be 
conducted for key study endpoints (Section 7.6.1) to assess robustness of key study 
inferences.  
Safety analysis set: The safety analysis set will consist of all subjects who receive any study 
drug. All analyses using the safety analysis set will group subjects according to treatment 
actually received. 
Pharmacokinetic analysis set: The PK analysis set will consist of all subjects who receive at 
least 1 dose of losmapimod and have evaluable PK data for losmapimod. 
Pharmacodynamic analysis set: The PD analysis set will consist of all subjects who receive at 
least 1 dose of losmapimod and have evaluable PD data for losmapimod. 
Open-label losmapimod (Pre-COVID-19) analysis set: This analysis set will consist of 
subjects who were already transitioned into open-label losmapimod under version 3.0 of the 
protocol. This analysis set will be used for sensitivity analysis, to assess 
secondary/exploratory endpoints in this subset of subjects. 
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Open-label analysis set: The open-label analysis set will consist of all subjects who complete 
24 weeks of treatment in the placebo-controlled treatment period and receive at least 1 dose 
of open-label losmapimod in the OLE. Safety and efficacy analyses in the OLE will be based 
on this analysis set. 
7.5 
Description of Subgroups to Be Analyzed 
Any planned subgroup analyses will be described in the SAP(s). 
7.6 
Statistical Analysis Methodology 
Continuous variables will be summarized using the mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized using frequency counts 
and percentages. Data will be listed in data listings. 
Details of the statistical analyses, methods, and data conventions are described in the SAP(s). 
All statistical tests will be 2-sided and performed using a 0.05 significance level. 
Details of multiplicity adjustment, if any, will be fully described in the SAP(s). 
7.6.1 Hypothesis Testing on Key Study Endpoints 
Hypothesis testing on key study endpoints will be conducted using the FAS.  
A sequential testing procedure will be used to control for Type I Error to test the following 
key study endpoints: 
x DUX4 change from baseline (Week 16 or Week 36) 
x LMV change from baseline (Week 48) 
x FSHD TUG (Week 48) 
The testing hierarchy will be provided in the SAP. Each endpoint will be tested at 
approximately 5% alpha in a hierarchical manner, using the final test-alpha obtained from 
O’Brien-Fleming Spending Function (Section 7.6.8). 
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7.6.2 Analysis of Primary Endpoints 
The primary endpoint of the placebo-controlled treatment period is the change from baseline 
in DUX4 activity in affected skeletal muscle at Week 16 or Week 36, as measured by 
QRT-PCR in a panel of DUX4-regulated gene transcripts. An analysis of covariance 
(ANCOVA) model will be used to analyze the change from baseline in DUX4 activity in 
affected skeletal muscle, with repeat number category and treatment group as fixed effects 
and baseline DUX4 activity in affected skeletal muscle as a covariate. Least-square (LS) 
mean, standard error, and 95% CI of the LS mean will be provided for each treatment group. 
The difference in LS means between treatment groups and the 95% CI of the difference will 
also be calculated. The final p-value will be compared against the significance level of 
approximately 0.05 (Section 7.6.8). All available data will be used. Details will be provided 
in the SAP(s).  
The FAS will be used for the primary analysis for the placebo-controlled treatment period.  
The analysis for the primary endpoint for the OLE is described in Section 7.6.6. 
7.6.3 Analysis of Secondary Endpoints 
Secondary endpoints (detailed in Section 7.1.2 and Section 7.2.2) will be summarized using 
descriptive statistics.  
Continuous endpoints with multiple post-baseline assessments will be analyzed using 
mixed-effect model for repeated measures (MMRM) methods including repeat number 
category, treatment group, visit, and treatment-by-visit interaction as fixed effects and 
baseline value as a covariate. Continuous endpoints with a single post-baseline assessment 
will be analyzed using ANCOVA methods, with repeat number category and treatment group 
as fixed effects and baseline value as a covariate. Secondary endpoints in the OLE will be 
summarized according to the treatment assigned at randomization. For all subjects, changes 
in measurements will be calculated relative to measurements obtained at baseline (ie, prior to 
first dose in the placebo-controlled treatment period).  
Further details of these endpoints are presented in Section 7.6.5, Section 7.6.6, and the 
SAP(s). 
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7.6.4 Analyses of Exploratory Endpoints 
Exploratory endpoints (detailed in Section 7.1.3 and Section 7.2.3) will be summarized using 
descriptive statistics. Confidence intervals will be included as appropriate. When appropriate, 
continuous exploratory endpoints will also be analyzed using ANCOVA or MMRM methods 
similar to those used for the primary and secondary endpoints. Any treatment group 
comparisons will be in the nature of hypothesis generation, and any statistical inference will 
not have any confirmatory value. Exploratory endpoints in the OLE will be summarized 
according to the treatment assigned at randomization. 
7.6.5 Pharmacokinetic and Pharmacodynamic Analyses 
Plasma PK concentrations at each time point for losmapimod will be presented in listings and 
summarized in tables. Losmapimod concentrations in skeletal muscle biopsy at each time 
point will also be presented in listings and summarized in tables. The summary tables will 
display the following descriptive statistics: n, mean, standard deviation, coefficient of 
variation, median, minimum, and maximum.  
The individual and mean plasma concentrations and the individual and mean concentrations 
in skeletal muscle biopsies will be presented by collection time in figures on linear scales. 
The target engagement estimates of losmapimod in peripheral blood and skeletal muscle 
biopsies will be presented in listings and summarized in tables. The summary tables will 
display the following descriptive statistics: n, mean, standard deviation, coefficient of 
variation, median, minimum, and maximum. Within-group LS means, the associated standard 
errors and 2-sided 95% CIs, treatment differences in LS means and the associated 2-sided 
95% CIs, and 2-sided p-values will be derived from the ANCOVA model and presented in the 
tables. 
Population PK and PK/PD models may be developed to address program objectives that 
require an integrative interpretation of these study results. These may include investigations 
of the nature of the PK/PD relationship and the use of these study results as part of a larger 
model-based data analysis. If population PK and PK/PD analyses are performed, those results 
will be reported separately from the results of this study. 
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7.6.6 Safety Analyses 
Safety data in the placebo-controlled treatment period will be analyzed using the safety 
analysis set and summarized by treatment group and visit (if applicable) using descriptive 
statistics. Safety data in the OLE will be analyzed using the open-label analysis set. 
Treatment-emergent AEs will be summarized by MedDRA system organ class and preferred 
term; separate summaries will be produced for treatment-related AEs, AESIs, SAEs, and 
discontinuations due to AEs. Laboratory tests, vital signs, findings from physical 
examinations, and ECGs will be summarized for changes over time during treatment using 
descriptive statistics.  
7.6.7 Other Analyses 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the placebo-controlled treatment period and by treatment 
assigned at randomization in the OLE.  
Efficacy data will be summarized at each scheduled visit in the OLE, and subjects will be 
grouped according to initial treatment assigned at randomization. 
Descriptive statistics will include the number of non-missing observations, mean, standard 
deviation, median, minimum, and maximum for quantitative data. For qualitative data, 
frequency counts and percentage will be determined. A full description of demographic 
variables will be included in the SAP(s).  
Individual subject demographics and baseline information will be provided in data listings.  
Medical history will be coded using MedDRA at the time of each database lock and will be 
summarized using the number of observations and percentages of subjects reporting each 
category and listed for each subject. 
A list of protocol deviations (major or minor) will be finalized prior to each database lock. 
7.6.8 Interim Analyses 
One IA will be performed when a minimum of 22 paired muscle biopsies are completed. A 
group sequential method (O’Brien-Fleming Spending Function) will be used to ensure an 
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overall significance level of 0.05 (double-sided) due to multiple looks at the DUX4 primary 
endpoint, if the IA is deemed necessary by the Sponsor. 
x With a sample size of approximately 22 subjects at IA, the test alpha at IA is 
approximately 0.001, and the final test alpha is 0.05. If the p-value from the test is 
<0.001, then the study may be stopped for efficacy, or continue as planned as decided 
by the Sponsor. Cumulative exit probability under the alternative hypothesis is 
approximately 2.3% and  approximately 82.3% at the IA and final analysis, 
respectively (SAS Version 9.4; nQuery 8 – Power and Sample Size for Group 
Sequential Trials, Version 8.5.1.0). 
x With a sample size of 32 subjects at IA, the test alpha at IA is approximately 0.004, 
and the final test alpha is 0.048. If the p-value from the test is <0.004, then the trial 
may be stopped for efficacy, or continue as planned as decided by Sponsor. 
Cumulative exit probability under the alternative hypothesis is approximately 13.9% 
and  approximately 82.2% at the IA and final analysis, respectively (SAS Version 9.4; 
nQuery 8 – Power and Sample Size for Group Sequential Trials, Version 8.5.1.0). 
The alphas at the time of the IA for sample sizes ranging from 22 to 32 are provided in 
Table 7-1: 
Table 7-1 
Alpha at Interim Analysis and Final Analysis for Different Sample Sizes 
at Interim Analysis (O’Brien-Fleming Method) 
Interim Analysis Sample Size 
Alpha at Interim Analysis 
Alpha at Final 
22 
0.000567 
0.049755 
23 
0.000736 
0.049685 
24 
0.000951 
0.049596 
25 
0.001203 
0.049493 
26 
0.001474 
0.049384 
27 
0.001803 
0.049253 
28 
0.002173 
0.049107 
29 
0.002556 
0.048959 
30 
0.003005 
0.048787 
31 
0.003496 
0.048602 
32 
0.004027 
0.048405 
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8 
Data Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) 
E6(R2) risk and quality processes described in the applicable procedural documents. The 
quality management approach to be implemented in this study will be documented and will 
comply with the current ICH guidance on quality and risk management. 
8.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports, ECG 
strips, etc. 
Study site personnel will enter subject data into Medidata RAVE® (the eCRF program). The 
analysis data sets will be a combination of these data and data from other sources (eg, 
laboratory data). 
Clinical data management will be performed in accordance with applicable
standards 
and data cleaning procedures to ensure the integrity of the data, eg, removing errors and 
inconsistencies in the data. Adverse event terms will be coded using MedDRA, an internal 
validated medical dictionary, and concomitant medications will be coded using the World 
Health Organization Drug Dictionary. 
After final database lock, each study site will receive a CD-ROM containing all of their site 
specific eCRF data as entered into the Medidata RAVE system for the study, including full 
discrepancy and audit history. Additionally, a CD-ROM copy of all of the study site’s data 
from the study will be created and sent to the sponsor for storage. 
will maintain a 
duplicate CD-ROM copy for their records. In all cases, subject initials will not be collected 
or transmitted to the sponsor. 
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9 
Ethics 
9.1 
Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an 
IRB/IEC before participation of human subjects in research studies. Before study onset, the 
protocol, informed consent, advertisements to be used for the recruitment of study subjects, 
and any other written information regarding this study to be provided to the subject or the 
subject’s legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC compliance with ICH harmonised tripartite guideline E6(R2): 
Good Clinical Practice (GCP) will be maintained by the site and will be available for review 
by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date on which approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
9.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
9.3 
Subject Information and Consent 
A written informed consent approved by the sponsor and by the IEC/IRB in compliance with 
applicable regulatory authority regulations shall be obtained from each subject before 
entering the study or performing any unusual or nonroutine procedure that involves risk to 
the subject. An informed consent template may be provided by the sponsor to investigative 
sites. If any institution-specific modifications to study-related procedures are proposed or 
made by the site, the consent should be reviewed by the sponsor or its designee or both 
before IRB/IEC submission. Once reviewed, the consent will be submitted by the 
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investigator to his or her IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating subjects must sign the 
revised form. 
Before recruitment and enrollment, each prospective subject or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject or legal guardian. 
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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, applicable regulatory authorities, or the IRB/IEC. 
To ensure privacy, directly identifying information of study subjects will not be attached to 
records or samples released to the sponsor and its service providers for research purposes. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. Additional confidentiality 
requirements and obligations will be set forth in the clinical trial agreement to be entered into 
by the sponsor, the principal investigator, and the institution.  
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required by 
applicable regulatory authorities. In addition, the investigator must provide to the sponsor a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year following the completion of the study. 
Neither the sponsor nor 
is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
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absence of specific arrangements, neither the sponsor nor 
s financially responsible for 
further treatment of the subject’s disease. 
10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 
and, for US sites, Title 21 of the Code of Federal Regulations by providing the following 
essential documents, including but not limited to: 
x IRB/IEC approval 
x Original investigator-signed investigator agreement page of the protocol 
x For US sites, Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572 
x For non-US sites, the investigator’s current curriculum vitae and/or other 
documentation evidencing qualifications, and any other documents that the IRB/IEC 
may request. For US sites, a curriculum vitae for the investigator and each 
subinvestigator listed on Form FDA 1572 
x Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required by applicable regulatory authorities. In 
addition, the investigators must provide to the sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the 
investigation and for 1 year after the completion of the study. 
x IRB/IEC-approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to be 
provided to the subject or legal guardian, and 
x Laboratory certifications and normal ranges for any local laboratories used by the site. 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6(R2). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of subjects begins. 
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10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the 
sponsor and/or IRB/IEC according to the time line and method outlined in the protocol. In 
addition, the investigator agrees to submit annual reports to the study site IRB/IEC as 
appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
10.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
10.9 Publications 
After completion of the study, the data will be submitted for reporting at a scientific meeting 
and for publication in a peer-reviewed scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
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Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. Further terms 
concerning publication will be set forth in the clinical trial agreement entered into by the 
sponsor, the principal investigator, any vendors, and the institution. 
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11 Study Management 
The administrative structure will include an SRC. 
11.1 Monitoring 
11.1.1 Safety Review Committee 
An SRC will be formed to review safety data for all subjects at regular intervals throughout 
the study.  
The SRC charter will describe the processes for unblinding subject- or study-level data if the 
SRC requests unblinding. Details on the composition of the SRC and the schedule of SRC 
meetings and data reviews will be presented in the SRC charter. 
11.1.2 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals, 
in addition to maintaining necessary telephone and letter contact. The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or a regulatory agency (eg, FDA or other regulatory agency) access to all 
study records. 
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The investigator should promptly notify the sponsor and 
of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before subjects can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from or a change of the protocol to eliminate an immediate hazard to study subjects 
without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the sponsor for agreement, 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant, additional risk to the subject. Significant 
deviations can include nonadherence to inclusion or exclusion criteria or nonadherence to 
FDA regulations or ICH GCP guidelines and will lead to the subject being withdrawn from 
the study (Section 4.2). A list of major protocol deviations will be compiled prior to the start 
of the study. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB/IEC should be notified of all protocol deviations in a timely manner. 
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11.3 Study Termination 
Although Fulcrum Therapeutics has every intention of completing the study, Fulcrum 
reserves the right to discontinue the study at any time for clinical or administrative reasons. 
Should termination of the study be required, the sponsor will promptly inform the 
investigator and the IRB/IEC and provide them with a detailed written explanation. Fulcrum 
and the investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests. The sponsor has no plans to provide study drug to subjects after study 
closure or termination. The obligations to provide study results for subjects and reports to 
IRB/IEC shall continue as required by applicable laws and regulations. 
At any time, the sponsor, the investigators, or the IRBs/IECs may terminate this study for 
reasonable cause. Conditions that may lead to reasonable cause and warrant termination 
include, but are not limited to the following: 
x Subject or investigator noncompliance 
x Unsatisfactory subject enrollment 
x Lack of adherence to protocol procedures 
x Lack of evaluable and/or complete data 
x Potentially unacceptable risk to study subjects 
x Decision to modify drug development plan 
x Decision by the regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes the safety follow-up visit).  
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports.  
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Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study reports. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study reports, the sponsor will provide the investigator with 
the full summary of the study results. The investigator is encouraged to share the summary 
results with the study subjects, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 
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Edwards RH, Round JM, Jones DA. Occasional Survey. Needle biopsy of skeletal muscle: a 
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Flanigan KM, Coffeen CM, Sexton L, et al. Genetic characterization of a large, historically 
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Ino H, Takahashi N, Terao T, et al. Safety, tolerability, pharmacokinetics, and 
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Lomas DA, Lipson DA, Miller BE et al. An oral inhibitor of p38 MAP kinase reduces plasma 
fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol. 
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Padua L, Aprile I, Frusciante R, et al. Quality of life and pain in patients with 
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Pascoe S, Costa M, Marks-Konczalik J, et al. Biological effects of p38 MAPK inhibitor 
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Ricci E, Galluzzi G, Deidda G, et al. Progress in the molecular diagnosis of 
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Statland JM, Shah B, Henderson D, et al. Muscle pathology grade for facioscapulohumeral 
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Statland JM, Odrzywolski KJ, Shah B, et al. Immunohistochemical characterization of 
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Tasca G, Pescatori M, Monforte M, et al. Different molecular signatures in magnetic 
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Tawil R, Forrester J, Griggs RC, et al. Evidence for anticipation and association of deletion 
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Tawil R, Kissel JT, Heatwole C, et al. Evidence-based guideline summary: evaluation, 
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Guideline Development, Dissemination, and Implementation Subcommittee of the American 
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Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015;85(4):357-64. 
Vanderplanck C, Ansseau E, Charron S, et al. The FSHD atrophic myotube phenotype is 
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Wang LH, Friedman SD, Shaw D, et al. MRI-informed muscle biopsies correlate MRI with 
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Watz H, Barnacle H, Hartley BF, et al. Efficacy and safety of the p38 MAPK inhibitor 
losmapimod for patients with chronic obstructive pulmonary disease: a randomised, 
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Whiddon JL, Langford AT, Wong CJ, et al. Conservation and innovation in the DUX4-family 
gene network. Nat Genet. 2017;49(6):935-40. 
Yang S, Lukey P, Beerahee M, et al. Population pharmacokinetics of losmapimod in healthy 
subjects and patients with rheumatoid arthritis and chronic obstructive pulmonary diseases. 
Clin Pharmacokinet. 2013;52(3):187-98. 
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Yao Z, Snider L, Balog J, et al. DUX4-induced gene expression is the major molecular 
signature in FSHD skeletal muscle. Hum Mol Genet. 2014;23(20):5342-52. 
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13 Appendices 
13.1 Appendix: Schedules of Events 
 
 
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Table 13-1 
Schedule of Events: Placebo-Controlled Treatment Period 
Procedure 
Screening 
Baseline 
Week 
4 
Week 
12 
Week 
16 
Week 
24  
Week 
36 
Week 48 
End of Placebo-
Controlled 
Treatment 
Period/Start of OLEa 
ET 
Visitb 
Safety Follow-Up 
7 Days After the 
Last Dose of 
Study Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
Visit Window (days)d 
–28 to –1 
Day 1 
r5 
r5 
r5 
r5 
±14aa  
±5  
 
r3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Confirm eligibility via 
inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Height and BMIe 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xf 
 
 
 
 
 
 
 
 
FSHD-specific historyg 
X 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, 
HIV1/HIV2) 
X 
 
 
 
 
 
 
 
 
 
Urine drug screenh 
X 
 
 
 
 
 
 
 
 
 
Genetic confirmation of FSHD1i 
X 
 
 
 
 
 
 
 
 
 
Serum β-hCGk 
X 
 
 
 
 
 
 
 
 
 
Serum follicle-stimulating 
hormonel 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighte 
X 
X 
 
 
  
 
 
X 
X 
X 
Vital signsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Procedure 
Screening 
Baseline 
Week 
4 
Week 
12 
Week 
16 
Week 
24  
Week 
36 
Week 48 
End of Placebo-
Controlled 
Treatment 
Period/Start of OLEa 
ET 
Visitb 
Safety Follow-Up 
7 Days After the 
Last Dose of 
Study Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
Physical examinationo 
X 
 
 
 
 
 
 
 
 
X 
Standard 12-lead ECGp 
X 
X 
X 
 
 
 
 
X 
X 
X 
Serum chemistry 
Xq 
X 
X 
X 
X 
X 
X  
X 
X 
X 
Hematology 
Xq 
X 
X 
X 
X 
X 
X  
X 
X 
X 
Blood sample for coagulationbb 
Xq 
 
 
 
 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
X 
X 
MSK MRIr 
X 
 
 
X 
 
 
 
X 
Xs 
 
Muscle needle biopsyt 
 
X 
 
 
X 
 
Xt  
 
 
 
PK samplingu 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Target engagement samplingv 
 
X 
 
  
X 
 
X  
  
 
 
 
 
RWS 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
TUG (classic and FSHD) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Manual dynamometry 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
MFM Domain 1 
 
X 
 
X 
 
X 
X 
X 
X 
 
FSHD-HI questionnaire 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
PGIC questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensationx 
 
X 
X 
X 
X 
Xy 
X 
X 
 
 
Study drug count 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Page 109 
Procedure 
Screening 
Baseline 
Week 
4 
Week 
12 
Week 
16 
Week 
24  
Week 
36 
Week 48 
End of Placebo-
Controlled 
Treatment 
Period/Start of OLEa 
ET 
Visitb 
Safety Follow-Up 
7 Days After the 
Last Dose of 
Study Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
Concomitant medicationsz 
Continuous from signing the ICF through the safety follow-up visit 
Concomitant treatments and 
procedures 
Continuous from signing the ICF through the safety follow-up visit 
Adverse event monitoring 
Continuous from signing the ICF through the safety follow-up visit 
Abbreviations: β-hCG, beta human chorionic gonadotropin; BMI, body mass index; ECG, electrocardiogram; ET, early termination; 
FSHD, facioscapulohumeral muscular dystrophy; FSHD-HI, Facioscapulohumeral Muscular Dystrophy Health Index; HBsAg, hepatitis B surface 
antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent form; MFM, Motor Function Measure; 
MRI, magnetic resonance imaging; MSK, musculoskeletal; OLE, open-label extension; PGIC, Patients’ Global Impression of Change; 
PK, pharmacokinetic(s); RWS, Reachable Work Space; STIR, short tau inversion recovery; TUG, Timed Up and Go.  
Note: Some procedures may not have been performed due to the COVID-19 pandemic. Please refer to the ReDUX4 Emergency Guidance 
document. 
a 
Prior to the COVID-19 pandemic, subjects who reached the Week 24 visit had the option to roll over into the OLE. For subjects who had already 
rolled over, their next clinic visits will follow the assessments for the Week 36 and Week 48 visit in the placebo-controlled portion of the study in 
the COVID-19 Pandemic Emergency protocol version 4.0; however, these specific subjects will not undergo the Week 36 biopsy. Those subjects 
who rolled over before the COVID-19 pandemic protocol version 4.0 was implemented will remain on open label treatment. Subjects who did not 
roll over prior to the COVID-19 pandemic will roll over when they reach Week 48. Subjects who roll over into the OLE should not complete the 
ET visit or safety follow-up visit from the placebo-controlled treatment period. 
b 
If a subject prematurely discontinues study treatment during the placebo-controlled treatment period, they will be encouraged to remain in the 
study and continue with all other aspects of the study. If a subject decides to prematurely discontinue study treatment during the 
placebo-controlled treatment period and not continue with all other aspects of the study, they will be considered to have withdrawn from the study. 
If a subject withdraws from the study during the placebo-controlled treatment period, they will be asked to complete an ET visit as soon as 
possible after the decision to terminate study participation and to complete the safety follow-up visit 7 (±3) days after their last dose of study drug. 
If the ET visit will be scheduled more than 7 days after the last dose of study drug, the safety follow-up and ET visits may be combined, with no 
duplication of assessments required. 
c 
The safety follow-up visit 7 (±3) days after the last dose of study drug should only be completed by subjects who are not rolling over into the 
OLE. 
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Protocol FIS-002-2019, Version 4.0 (COVID-19 Pandemic Emergency Amendment) 
 
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Page 110 
d 
Scheduled visits may be split over 2 days if required, with a maximum of 5 business days in between visits. Unscheduled visits may be performed 
if clinically indicated. Subjects can travel for MRI or muscle biopsy if needed, but the use of a study-approved MRI scanner should be consistent 
during the trial. 
e 
Weight and height will be measured with shoes off and preferably with the same balance at each visit. Body mass index will be calculated at 
Screening. 
f 
Medical history will be reviewed at baseline to ensure no changes have occurred since the screening visit.  
g 
FSHD-specific history will be recorded at screening or at a subject’s next scheduled study visit, if not previously recorded.  
h 
Urine drug screen for drugs of abuse including cocaine, amphetamines, opiates (morphine), benzodiazepines, and cannabinoids. 
i 
Genetic confirmation must be obtained before the subject is randomized and before the baseline muscle biopsy is performed; genetic confirmation 
can come from previous testing if verified with appropriate documentation from an accredited laboratory. Due to the stable transmission of repeat 
sizes within families, subjects with a clinical diagnosis of FSHD who have a first-degree relative with a genetically confirmed diagnosis of 
FSHD1 may be entered into the study for screening assessments, including MRI. During screening, a confirmatory genetic diagnosis will be 
conducted. If genetic testing is necessary, the 4-week screening window and activities will not start until the results are obtained and verified by 
the principal investigator. 
k 
Serum pregnancy tests will be performed at screening for all female subjects of child-bearing potential. 
l 
Serum follicle-stimulating hormone testing is required for suspected postmenopausal female subjects only. 
m 
Urine pregnancy tests will be performed for all female subjects of child-bearing potential before randomization at all other visits. If pregnancy is 
found, subjects must be terminated from the study effective immediately. 
n 
Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the subject has been seated or recumbent for at 
least 5 minutes and before any 12-lead ECG assessment or blood sampling is performed.  
o 
Physical examination at the screening visit and the safety follow-up visit include an evaluation of body systems, including but not limited to the 
following: skin; head, eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological 
system; and MSK system. Symptom-directed physical examinations can occur at any time during the study if triggered by adverse events or if 
deemed necessary by the investigator.  
p 
Twelve-lead ECGs will be performed after subjects have been recumbent for at least 5 minutes. Twelve-lead ECGs will be performed after the 
measurement of vital signs and before any procedures that may affect heart rate (eg, blood sampling). 
q 
For the screening visit, subjects will be required to fast for at least 4 hours prior to laboratory blood samples being taken. 
r 
Subjects will be screened for any contraindications to MRI as per clinic standard practice. 
s 
The MRI at the ET visit will not be repeated if an MRI was completed during the previous 8 weeks. 
t 
The choice of the muscle(s) to be biopsied in this study will be determined by the investigator, informed by skeletal muscle MRI during screening. 
The bilateral vastus lateralis, vastus medialis, lateral gastrocnemius, medial gastrocnemius, and tibialis anterior will be evaluated for eligibility by 
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10 April 2020 
 
Page 111 
MRI using a central reader. Only those muscles that are STIR positive with the predetermined range of muscle fat fraction will be eligible for 
biopsy. The 12 patients who rolled over at Week 24 will not undergo the Week 36 muscle biopsy. 
u 
Blood samples for PK will be collected at Day 1 (baseline), Week 4, Week 16, and Week 36 at the following time points: immediately predose and 
4 hours (±30 minutes) after administration of the study dose. Blood samples will also be taken, when feasible, after dosing during the Week 12, 
Week 24, and Week 48 visits, preferably ≥1 hour after dosing. 
v 
Blood samples for target engagement will be collected on Day 1 (baseline), and Week 16 or Week 36, at the following time points: immediately 
predose and 4 hours (±30 minutes) after administration of the study dose. 
x 
The appropriate amount of study drug supply (losmapimod or placebo) will be given to the subject at each applicable visit to allow for dosing 
until their next scheduled study visit plus additional tablets to cover the visit window. Study drug (losmapimod or placebo) will be administered as 
2 tablets taken twice daily and should be taken with food. Subject diaries may only be used for a portion of the placebo-controlled portion of the 
trial to record the date and time of each dose taken. This information may also be used to calculate compliance. Subjects will record the date and 
time of each dose of study drug taken (losmapimod or placebo) in the subject diary. Subjects may be provided additional study drug via courier 
service, as applicable.  
y 
Subjects who are rolling over into the OLE will be dispensed open label losmapimod at the time of the rollover visit. Subjects may be provided 
open label losmapimod via courier or shipping service, as applicable. 
z 
All medications taken within 28 days before screening through the safety follow-up visit will be recorded. 
aa 
Large window given to accommodate the COVID-19 pandemic.  
bb 
It is optional to perform coagulation studies prior to muscle biopsies. Refer to your institutional guidelines.  
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Protocol FIS-002-2019, Version 4.0 (COVID-19 Pandemic Emergency Amendment) 
 
10 April 2020 
 
Page 112 
Table 13-2 
Schedule of Events: Open-Label Extension (Visits will Occur Quarterly Until Study Drug 
Approval or Study Is Discontinued) 
Procedure 
Week 60 
Week 108 
Week 156 
Week 204 
Week 72 
Week 120 
Week 168 
Week 216 
Week 84 
Week 132 
Week 180 
Week 96 
Week 144 
Week 192 
ET 
Visita 
Safety Follow-Up 
7 Days After the 
Last Dose of Study 
Drug 
Visit Window (days)b 
r7 
r7
r7 
r7 
 
r3  
Weight, height, and BMIc 
 
X 
 
 
 
 
 
 
Urine pregnancy teste 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
Physical examinationg 
 
 
 
 
 
X 
Standard 12-lead ECGh 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
MSK MRIi 
 
X 
 
X 
Xj 
 
PK samplingk 
X 
X 
X 
X 
X 
 
 
 
RWS 
X 
X 
X 
X 
X 
X 
TUG (classic and FSHD) 
X 
X 
X 
X 
X 
X 
Manual dynamometry 
X 
X 
X 
X 
X 
X 
MFM Domain 1 
X 
X 
X 
X 
X 
 
FSHD-HI questionnaire 
X 
X 
X 
X 
X 
X 
PGIC questionnaire 
X 
X 
X 
X 
X 
X 
Clinic visit 
X 
X 
X 
X 
X 
X 
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Protocol FIS-002-2019, Version 4.0 (COVID-19 Pandemic Emergency Amendment) 
 
10 April 2020 
 
Page 113 
Procedure 
Week 60 
Week 108 
Week 156 
Week 204 
Week 72 
Week 120 
Week 168 
Week 216 
Week 84 
Week 132 
Week 180 
Week 96 
Week 144 
Week 192 
ET 
Visita 
Safety Follow-Up 
7 Days After the 
Last Dose of Study 
Drug 
Study drug dispensationm 
X 
X 
X 
X 
 
 
Study drug count 
X 
X 
X 
X 
X 
 
Concomitant medicationsn 
Continuous from signing the ICF through the safety follow-up visit 
Concomitant treatments and procedures 
Continuous from signing the ICF through the safety follow-up visit 
Adverse event monitoring 
Continuous from signing the ICF through the safety follow-up visit 
Abbreviations: BMI, body mass index; ECG, electrocardiogram; ET, early termination; FSHD, facioscapulohumeral muscular dystrophy; FSHD-HI, 
Facioscapulohumeral Muscular Dystrophy Health Index; ICF, informed consent form; MFM, Motor Function Measure; MRI, magnetic resonance 
imaging; MSK, musculoskeletal; OLE, open-label extension; PGIC, Patients’ Global Impression of Change; PK, pharmacokinetic(s); RWS, 
Reachable Work Space; TUG, Timed Up and Go.  
a 
If a subject prematurely discontinues study treatment during the OLE, they will be encouraged to remain in the study and continue with all other 
aspects of the study. If a subject decides to prematurely discontinue study treatment during the OLE and not continue with all other aspects of the 
study, they will be considered to have withdrawn from the study. If a subject withdraws from the study during the OLE, they will be asked to 
complete the ET visit as soon as possible after the decision to terminate study participation and to complete the safety follow-up visit 7 (±3) days 
after their last dose of study drug. If the ET visit will be scheduled more than 7 days after the last dose of study drug, the safety follow-up and ET 
visits may be combined, with no duplication of assessments required. 
b 
Scheduled visits may be split over 2 days if required, with a maximum of 5 business days in between visits. Unscheduled visits may be performed 
if clinically indicated. Subjects can travel for MRI or muscle biopsy if needed, but the use of a study-approved MRI scanner should be consistent 
during the trial. 
c 
Weight and height will be measured and BMI will be calculated once a year (ie, Week 48, Week 96, Week 144, etc.). Weight and height will be 
measured with shoes off and preferably with the same balance. 
e 
Urine pregnancy tests will be performed for all female subjects of child-bearing potential before dispensation of study drug. If pregnancy is found, 
subjects must be terminated from the study effective immediately. 
f 
Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the subject has been seated or recumbent for at 
least 5 minutes and before any 12-lead ECG assessment or blood sampling is performed.  
g 
Physical examination at the safety follow-up visit includes an evaluation of body systems, including but not limited to the following: skin; head, 
eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological system; and MSK 
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Protocol FIS-002-2019, Version 4.0 (COVID-19 Pandemic Emergency Amendment) 
 
10 April 2020 
 
Page 114 
system. Symptom-directed physical examinations can occur at any time during the study if triggered by adverse events or if deemed necessary by 
the investigator.  
h 
Twelve-lead ECGs will be performed after subjects have been recumbent for at least 5 minutes. Twelve-lead ECGs will be performed after the 
measurement of vital signs and before any procedures that may affect heart rate (eg, blood sampling). 
j 
The MRI at the ET visit will not be repeated if an MRI was completed during the previous 12 weeks. 
k 
Blood samples for PK will be collected after dosing at each clinic visit, preferably ≥1 hour after dosing. 
l 
 Blood samples may be used to aid in the discovery of potential biomarkers of FSHD disease activity and treatment effects.. Serum and plasma 
samples taken twice a year (ie, every 24 weeks [ Week 72, Week 96, Week 120, Week 144, Week 168, etc.]) will be used.  
m 
The appropriate amount of study drug supply (losmapimod) will be given to the subject at each applicable visit to allow for dosing until their next 
scheduled study visit plus additional tablets to cover the visit window or additional study drug will be provided to the subject via a courier, as 
applicable. Study drug (losmapimod) will be administered as 2 tablets taken twice daily and should be taken with food.  
n 
All medications taken within 28 days before screening through the safety follow-up visit will be recorded. 
 
 
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Protocol FIS-002-2019, Version 4.0 (COVID-19 Pandemic Emergency Amendment) 
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13.2 Appendix: Drugs Potentially Affecting Muscle Function 
Potential list of drug(s) or supplements that may affect muscle function includes, but is not 
limited to, the following: 
1. Statins 
2. Steroids 
3. Testosterone or other growth hormone agonists 
4. Beta-agonists 
5. Creatine 
6. Colchicine 
7. Benzylpenicillin 
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CONFIDENTIAL                                                                                                                                                      Page 1 of 1 
 
 
To: Principal Investigators and Study Coordinators of ReDUX4 
 
Re: Protocol V2.0 dated 30 Jul 2019 
 
 
 
This memo is being provided to sites in the USA, Canada, France and Spain to explain the gap in 
protocols between Protocol V1.0 and Protocol V3.0. 
 
Protocol FIS-002-2019 was first submitted as V1.0 dated 27 Mar 2019 for approval to all competent 
authorities and ethics committees.  This original version was submitted in all countries: USA, 
Canada, France, Spain, and Germany.  In the USA, Canada, France and Spain, the subsequent 
protocol version was Protocol V3.0 dated 27 Nov 2019.  Protocol V2.0 dated 30 Jul 2019 was only 
provided to Germany to submit for approvals.  Sites in the USA, Canada, France and Spain did not 
receive Protocol V2.0; therefore, there will be no documentation related to this version in the 
Investigator Site Files. Due to the addition of the open-label extension phase, Fulcrum decided to 
bypass submission of Protocol V2.0 in the USA, Canada, France and Spain and go directly to 
Protocol V3.0 and related ICF, which added the open-label extension.  Sites in the USA, Canada, 
France, and Spain received Protocol V3.0 dated 27 Nov 2019 directly.  
 
Please file this memo accordingly. 
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
SUMMARY OF CHANGES TO THE PROTOCOL
Protocol History
Version and Date of Protocol
Comments
Version 1.0, 27 March 2019
Original version
Version 2.0, 30 July 2019
x
Clarified benefit/risk ratio
x
Clarified exclusion criterion #18
x
Clarified unblinding procedure in the event 
of an emergency
x
Added instructions for missed doses and 
study drug compliance details
x
Added adverse events of special interest and 
stopping criteria for abnormal liver tests
x
Updated the process for calculating the 
number of D4Z4 repeats
x
Updated language for the analysis of the 
primary endpoint and secondary endpoints 
to match the statistical analysis plan
x
Clarified collection time points in the 
schedule of events
x
Updated language referencing regulatory 
authorities
x
Clarified that the sponsor has no plans to 
provide study drug to subjects after study 
closure or termination
Version 3.0, 27 November 2019
x
Added an open-label extension (OLE) to the 
protocol. Added language to differentiate 
the placebo-controlled treatment period part 
of the study versus the OLE part of the 
study. Clarified that baseline is prior to the 
first dose in the placebo-controlled 
treatment period.
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
x
Change from baseline in lean muscle tissue 
volume and fat fraction in FSHD1 subjects, 
as measured by musculoskeletal (MSK) 
magnetic resonance imaging (MRI),
changed from exploratory 
objective/endpoint to a secondary 
objective/endpoint and revised to include 
muscle fat infiltration (MFI).
x
Increased the number of randomized 
subjects from approximately 66 to 
approximately 76.
x
Clarified that for scheduled study visits that 
are split over 2 days, the visits may not be 
more than 5 business days apart.
x
Clarified that subjects can travel for MRI or 
muscle biopsy if needed, but the use of a 
study-approved MRI scanner should be 
consistent during the trial.
x
Clarified in inclusion criterion #3 that 
“appropriate documentation” is 
documentation from an accredited 
laboratory.
x
Clarified in inclusion criterion #4 that a 
RICCI score between 2 and 4 does not 
include subjects that use wheelchairs or 
walkers for any reason. 
x
Clarified in exclusion criterion #12 that that 
subjects should not be vaccinated with a live 
attenuated vaccine throughout the study.
x
Added clarifications on the identity of 
investigational product, study drug 
packaging, study drug accountability, and 
compliance.
x
Clarified pregnancy reporting.
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
x
Removed collection of blood sample for 
coagulation at the early termination visit and 
7-day safety follow up visit.
x
Clarified that a full physical examination 
will be performed at the screening visit and 
the 7-day safety follow up visit and a 
symptom directed physical examination will 
be performed at all other visits.
x
Added additional details for the safety and 
tolerability endpoint. Revised the secondary 
and exploratory endpoints to include 
specific time points.
x
Clarified that functional workspace is a part 
of the reachable workspace (RWS) 
assessment
Key changes to the current version of the protocol are summarized below: 
Change and Rationale
Affected Sections
An OLE was added to this protocol to assess long-
term safety, tolerability, and efficacy of 
losmapimod treatment in subjects with FSHD1.
Study Title; Sections 1 through 7; Figure 3-1; 
Table 13-1; Table 13-2
Added details on length of dosing in prior clinical 
studies.
Section 1.5
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
Change and Rationale
Affected Sections
The change from baseline in lean muscle tissue 
volume (clarified as lean muscle volume [LMV]) 
and fat fraction (clarified as muscle fat fraction 
[MFF]) in FSHD1 subjects, as measured by MSK 
MRI, was changed from an exploratory 
objective/endpoint to a secondary 
objective/endpoint and was revised to also include 
muscle fat infiltration (MFI). It is anticipated that 
changes in MRI will take longer to detect than 
changes in DUX4 expression on skeletal muscle 
biopsy. Evaluation of changes in MRI throughout 
the study will inform whether treatment with 
losmapimod could slow disease progression by 
protecting and/or restoring skeletal muscle and 
therefore was elevated to a secondary 
objective/endpoint.
Section 2; Section 7
Added text regarding exploratory biomarker 
testing to the study design.
Section 3.1.1
Clarified that for scheduled visits that are split 
over 2 days, the visits must be no more than 
5 business days apart.
Section 3.1.1; Table 13-1
Clarified that subjects can travel for MRI or 
muscle biopsy if needed, but the use of a 
study-approved MRI scanner should be consistent 
during the trial.
Section 3.1.1; Table 13-1
Clarified in the study design that the change from 
baseline in aberrant DUX4 activity will be 
evaluated in skeletal muscle.
Section 3.1.1
Revised the schematic of study design for the 
placebo-controlled treatment to reflect the 
increased number of randomized subjects and the 
OLE.
Figure 3-1
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
Change and Rationale
Affected Sections
The number of randomized subjects was increased 
from 66 (33 subjects per group) to 76 (38 subjects 
per group) to assess for a somewhat smaller effect 
size, to allow more patients to participate, and to 
allow for better assessment of potential efficacy 
trends in MRI endpoints. Based on current 
estimates, an effect size of 0.70 will enable 
assessment of change for a sample size of 
68 subjects (34 subjects per group) plus an 
additional 10% of subjects with no evaluable data 
for a total of 76 subjects (38 subjects per group).
Section 3.1.1; Figure 3-1; Section 4.1; 
Section 7.3
Clarified the rationale for the study design.
Section 3.2.2
Clarified that study drug should be taken with 
food.
Section 3.1.1; Table 13-1
Clarified that genetic confirmation must be 
obtained before the subject is randomized and 
before the baseline muscle biopsy is performed. 
Clarified that genetic confirmation documentation 
must come from an accredited laboratory.
Section 4.1.1; Section 6.4.7; Table 13-1
Added text to inclusion criterion #4 to clarify that 
for subjects with a RICCI score between 2 and 4, 
subjects who use a wheelchair or walker for any 
activity are not permitted to enroll in the study;
this is to ensure that the enrolled population can 
complete all assessments. Added this clarification,
as well as clarification that the RICCI score will 
be assigned according to the worst clinical 
assessment on physical examination, to 
Section 6.4.8 and Table 13-1. Also added a RICCI
score assessment at Week 24 in Table 13-1.
Section 4.1.1; Section 6.4.8; Table 13-1
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
Change and Rationale
Affected Sections
Added to exclusion criterion #12 that subjects 
should not be vaccinated with a live attenuated 
vaccine throughout the study.
Section 4.1.2
Details on the identity of investigational product 
and study drug packaging were added.
Section 5.3; Section 5.4.1
Clarified study drug accountability, stating that 
during the study each subject will be provided a 
sufficient quantity of study drug to allow for 
dosing until their next scheduled study visit plus 
additional tablets to cover the visit window.
Section 5.4.1; Section 5.4.2; Table 13-1
Clarified that the investigator, study staff, 
subjects, and monitor will remain blinded to the 
treatment until study closure. The sponsor and/or 
its designee will remain blinded to the treatment 
until after all subjects have completed the Week 
24 visit (or have discontinued) and the database 
from the placebo-controlled treatment period has 
been locked for statistical analyses, after which 
time they will be unblinded.
Section 5.6
Revised the language for determining treatment 
compliance and removed this language from 
Table 13-1.
Section 5.7; Table 13-1
Clarified that muscle biopsy tissues will be used 
to measure other gene transcripts and may be used 
to measure proteins related to the pathology of 
FSHD as part of exploratory biomarker endpoints.
Section 6.1.1
Clarified that baseline is prior to the first dose in 
the placebo-controlled treatment period.
Section 6.2.2; Section 7.6.2
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
Change and Rationale
Affected Sections
Moved medical history assessment to its own 
section. Added that FSHD-specific history will 
also be assessed.
Section 6.2.3; Table 13-1
Clarified that a full physical examination will be 
performed at the screening visit and the 7-day 
safety follow-up visit and that symptom-directed 
physical examinations can occur at any time 
during the study.
Section 6.2.5; Table 13-1
Updated the text that biopsy tissue evaluated for 
drug target engagement will not be stimulated 
with sorbitol.
Section 6.3.2
Clarified that RWS includes the functional 
workspace, where patients are instructed to touch 
certain parts of their body and are rated on their 
ability to complete this task. 
Section 6.4.1
Clarified that pregnancy should be reported using 
the paper Pregnancy Initial Report Form rather 
than following SAE reporting procedures.
Section 6.6
Clarified that separate statistical analysis plans 
(SAPs) will be prepared for each treatment period 
of the study and that analyses will be generated 
separately for the placebo-controlled treatment 
period and the OLE.
Section 7
Revised the secondary endpoints to include the 
MSK MRI endpoint and to add additional detail 
for the safety and tolerability endpoint. Revised 
the secondary and exploratory endpoints to 
include specific time points.
Section 7.1.2; Section 7.1.3
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
Change and Rationale
Affected Sections
Revised text to indicate that details of a 
multiplicity adjustment, if any, will be fully 
described in the SAP(s).
Section 7.6
Added text for the analysis of target engagement 
to describe that within-group least-square (LS) 
means, the associated standard errors and 2-sided 
95% CIs, treatment differences in LS means and 
the associated 2-sided 95% CIs, and 2-sided p-
values will be derived from the analysis of 
covariance model and presented in the tables.
Section 7.6.4
Added that a list of protocol deviations (major or 
minor) will be finalized prior to each database 
lock.
Section 7.6.6
Removed the collection of a blood sample for 
coagulation from early termination and safety 
follow-up visits in the placebo-controlled 
treatment period as coagulation results are only 
needed prior to a muscle biopsy.
Table 13-1
Added study drug dispensation at Week 24 for 
subjects who are rolling over into the OLE.
Table 13-1
Clarified that body mass index will be calculated 
at the screening visit.
Table 13-1
Clarified that the choice of the muscle(s) to be 
biopsied in this study will be determined by the 
investigator, informed by skeletal muscle MRI 
during screening and that only those muscles that 
are short tau inversion recovery (STIR) positive 
with the predetermined range of MFF will be 
eligible for biopsy.
Table 13-1
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Fulcrum Therapeutics
Losmapimod
Protocol FIS-002-2019, Version 3.0
27 November 2019
Change and Rationale
Affected Sections
Added language to clarify which parts of the 
study will be performed as part of the 
placebo-controlled treatment period versus the 
OLE.
Throughout
Typographical and administrative changes were 
also made to improve the clarity of the document.
Throughout
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Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-002-2019, version 2.0  
24 July 2019 
SUMMARY OF CHANGES TO THE PROTOCOL 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1, 27 March 2019 
Original version 
Version 2.0 24 July 2019 
x 
Clarified benefit/risk ratio 
x 
Clarified exclusion criterion #18 
x 
Added instructions for missed doses and 
study drug compliance details. 
x 
Added adverse events of special interest and 
stopping criteria for abnormal liver tests 
x 
Updated the process for calculating the 
number of D4Z4 repeats 
x 
Updated language for the analysis of the 
primary endpoint and secondary endpoints 
to match the statistical analysis plan 
x 
Clarified collection time points in the 
schedule of events 
x 
Updated language referencing regulatory 
authorities 
 
Key changes to the current version of the protocol are summarized below.  
Change and Rationale 
Affected Sections 
Clarification of benefit/risk ratio in regard to 
adverse events expected for the class of P38 
inhibitors and adverse events reported in 
specific populations studied. 
Section 1.5 
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Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-002-2019, version 2.0  
24 July 2019 
Change and Rationale 
Affected Sections 
Clarified the participation in concurrent clinical 
trials in exclusion criterion #18. Patients will be 
excluded if they are currently participating in a 
prospective study with an investigational 
product, whether it concerns an experimental 
drug or a medical device. However, concurrent 
participation in natural history studies 
(non-drug, non-device studies) may be 
acceptable if confirmed in writing by the 
sponsor.  
Section 4.1.2 
Added instructions for missing a dose of study 
drug 
Section 5.2 
Added study drug compliance details. 
Section 5.7; Table 13-1 
Added adverse events of special interest 
(AESIs) and described liver tests and stopping 
criteria to be consistent with the investigator’s 
brochure. Added AESIs as a secondary endpoint 
and to safety analyses. 
Section 3.1; Section 6.2.1.3; Section 6.2.1.5; 
Section 7.2; Section 7.7.5 
Updated the process for calculating the number 
of D4Z4 repeats, which will be calculated by a 
diagnostic laboratory. The site will enter the 
number of repeats into the IRT system. 
Removed reference to using a calculator from 
Inclusion Criterion #3 
Section 4.1.1; Section 6.4.7 
Updated text in Section 3.1, Section 6.3.1, and 
footnote “q” in the schedule of events table to 
clarify that PK samples collected Weeks 12 and 
24 should be obtained after dosing, preferably 
≥1 hour after dosing. 
Section 3.1; Section 6.3.1; Table 13-1 
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Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-002-2019, version 2.0 
24 July 2019 
Change and Rationale 
Affected Sections 
Updated text in Section 6.4.9 and footnote “s” in 
the schedule of events table to clarify that serum 
and plasma samples collected at Weeks 4, 12, 
16, and 24 can be obtained predose or postdose. 
Section 6.4.9; Table 13-1 
Updated text in the analysis of the primary 
endpoint to match the statistical analysis plan 
and updated text in the analysis of secondary 
endpoints to state that endpoints with multiple 
post-baseline assessments are to be analyzed 
using a mixed-effect model for repeated 
measures to match the statistical analysis plan. 
Section 7.7.1; Section 7.7.2 
Updated language referencing regulatory 
authorities  
Section 9.3; Section 10.1; Section 10.2; 
Section 10.3 
Typographical and administrative changes were 
also made to improve the clarity of the 
document. 
Throughout 
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SAP_001.pdf: 
Fulcrum 
Losmapimod 
Protocol: FIS-002-2019 
Clinical Study Report 
 
16.1.9 
Documentation of Statistical Methods 
This section contains the following document: 
Final Statistical Analysis Plan version 1.0 dated 28 May 2020 
 
1


F ulcr u m T her a pe utics  
 
FI S -0 0 2 -2 0 1 9  
 
A P h ase 2, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, 4 8 -Wee k,  
P ar allel -Gr o u p St u dy of t he Effic acy a n d S afety of L os m a pi m o d i n Tre ati n g 
S u bjects wit h F aci osc a p ul o h u mer al M usc ul ar Dystr o p hy ( F S H D) wit h O pe n -
L a bel E xte nsi o n ( O L E)  
 
2 8 M ay 2 0 2 0  
 
Fi nal  Statistical A nal ysis Pla n  
( Place b o-C o ntr olle d Treat me nt Peri o d)  
 
Versi o n 1. 0  
 
Pre pare d b y:  
 
 
Iss u e d b y: 
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Lea d Bi ostatisticia n, Bi ostatistics  
 
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U p o n re vie w of t his d oc u me nt, t he u n dersi g ne d a p pr o ves t he statistical a nal ysis pla n. T he 
a nal ysis met h o ds is acce pta ble a n d t he ta ble, listi n g, a n d fi g ure pr o d ucti o n ca n be gi n.  
 
 
A p pr o ve d b y:  _ _ _
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Date:  _ _ _/ _ _ _/ _ _ _  
 
 
 
 
 
Direct or, Bi o metrics  
 
 
F ulcr u m T hera pe utics  
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Fulcrum Therapeutics 
 
Final Statistical Analysis Plan, Version 1.0 
 
FIS-002-2019 
 
Date Issued: 28May2020 
 
  
 
 
 
II
DOCUMENT REVISION HISTORY 
 
Version 
Date 
Details 
0.5 
06Dec2019 
Stable Draft Version 
0.6 
07Jan2020 
1) Update derivation of DUX4-related 
endpoints in 15.1, 15.2, and 15.3. 
2) Removed section on inclusion and exclusion 
(Section 6.4) since no details are collected 
from screen failures. 
3) Removed 16.2.3.2 in Section 15.6. 
4) Updated number of 16.2.3.1 to 16.2.3 in 
Section 15.6. 
0.7 
05Feb2020 
1) Updated section 8.1. Composite DUX4 score 
will now be provided by Q2 Lab Solutions. 
2) Updated Appendices 15.1-15.5 to now 
contain assay validation, gene subset 
selection criteria/process, and derivation of 
DUX4 Score. 
0.8 
05May2020 
1) Added details on the analysis for 
neurological examination results in Section 
9.4 Physical Examination. 
2) Added presentation of FSHD specific history 
in Section 6.2. 
3) Updated Section 4.7 on sample size 
computation based on Version 3.0 of the 
protocol. 
4) Added details about inclusion of open-label 
extension phase but a separate SAP will be 
created for this. 
5) Updated SAP according to protocol Version 
4.0 (COVID-19 Pandemic Emergency 
Amendment) 
a. Extended randomized placebo-
controlled period from 24 to 48 
weeks in Section 3.1, 3.2, 4.4, 4.8, 
7.2.1, 8, 9, and 11. 
b. Added Open-label Losmapimod (Pre-
COVID-19) Analysis Set in Section 
4.9.6 and 8.Muscle biopsy to support 
the primary endpoint is updated to be 
performed on Week 16 or 36 for 
those subjects unable to have the 
biopsy at Week 16 due to the 
COVID-19 pandemic. 
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Fulcrum Therapeutics 
 
Final Statistical Analysis Plan, Version 1.0 
 
FIS-002-2019 
 
Date Issued: 28May2020 
 
  
 
 
 
III
c. Added interim analysis to be 
performed after a minimum of 22 
paired muscle biopsies have been 
collected. 
d. Added hypothesis testing on primary 
and select secondary and exploratory 
endpoints in Section 8.1. 
e. Removed measurement of the 
metabolite GSK198602 in Section 2, 
3.2 and 10. 
f. Updated Appendix 15.6 to include 
the latest schedule of events. 
g. Updated Appendices 15.7-15-9 to 
include the additional outputs and 
additional column to identify the 
outputs needed for topline and IA 
deliveries. 
 
1.0 
28May2020 
Approved version 
 
4


Fulcrum Therapeutics 
 
Final Statistical Analysis Plan, Version 1.0 
 
FIS-002-2019 
 
Date Issued: 28May2020 
 
  
 
 
 
IV
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. VII 
1. 
INTRODUCTION............................................................................................................. 1 
2. 
OBJECTIVES ................................................................................................................... 1 
2.1. PRIMARY OBJECTIVES ........................................................................................................ 1 
2.2. SECONDARY OBJECTIVES ................................................................................................... 2 
2.3. EXPLORATORY OBJECTIVES ............................................................................................... 2 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 2 
3.2. STUDY ENDPOINTS ............................................................................................................. 4 
3.2.1. 
Primary Endpoint........................................................................................................ 4 
3.2.2. 
Secondary Endpoints .................................................................................................. 4 
3.2.3. 
Exploratory Endpoints ................................................................................................ 5 
3.3. TREATMENTS ...................................................................................................................... 6 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 6 
4.1. REPORTING CONVENTIONS ................................................................................................. 6 
4.2. HANDLING OF MISSING DATA ............................................................................................ 7 
4.3. BASELINE, STUDY DAY, AND CHANGE FROM BASELINE DEFINITIONS ................................ 7 
4.4. VISIT WINDOWS ................................................................................................................. 8 
4.5. MULTIPLE VALUES ............................................................................................................. 8 
4.6. SUBGROUP .......................................................................................................................... 8 
4.7. SAMPLE SIZE ...................................................................................................................... 9 
4.8. RANDOMIZATION, STRATIFICATION, AND BLINDING .......................................................... 9 
4.9. ANALYSIS SET .................................................................................................................. 10 
4.9.1. 
Full Analysis Set (FAS) ............................................................................................. 10 
4.9.2. 
Per Protocol Set (PPS) ............................................................................................. 10 
4.9.3. 
Safety Analysis Set .................................................................................................... 10 
4.9.4. 
Pharmacokinetics Analysis Set ................................................................................. 10 
4.9.5. 
Pharmacodynamics Analysis Set .............................................................................. 11 
4.9.6. 
Open-label Losmapimod (Pre-COVID-19) Analysis Set .......................................... 11 
5. 
SUBJECT DISPOSITION ............................................................................................. 11 
5.1. DISPOSITION ..................................................................................................................... 11 
5.2. PROTOCOL DEVIATIONS ................................................................................................... 11 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 11 
6.1. DEMOGRAPHICS ................................................................................................................ 11 
6.2. BASELINE DISEASE CHARACTERISTICS ............................................................................. 12 
6.3. MEDICAL HISTORY ........................................................................................................... 12 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 13 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 13 
7.1.1. 
Prior Medications ..................................................................................................... 14 
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7.1.2. 
Concomitant Medications ......................................................................................... 14 
7.2. STUDY TREATMENTS ........................................................................................................ 14 
7.2.1. 
Extent of Exposure .................................................................................................... 14 
7.2.2. 
Treatment Compliance .............................................................................................. 15 
8. 
EFFICACY ANALYSIS ................................................................................................. 15 
8.1. HYPOTHESIS TESTING PROCEDURE FOR KEY STUDY ENDPOINTS ..................................... 15 
8.2. CHANGE FROM BASELINE IN DUX4 ACTIVITY IN SKELETAL MUSCLE AT WEEK 16 OR 
WEEK 36 .................................................................................................................................... 16 
8.2.1. 
SENSITIVITY ANALYSES OF PRIMARY ENDPOINT .......................................................... 17 
8.3. MSK MRI MUSCLE FAT FRACTION, LEAN MUSCLE VOLUME AND MUSCLE FAT 
INFILTRATION ............................................................................................................................. 18 
8.4. CLINICAL OUTCOME ASSESSMENTS ................................................................................. 19 
8.4.1. 
Reachable Work Space With and Without Weights .................................................. 19 
8.4.2. 
Classic and FSHD TUG............................................................................................ 19 
8.4.3. 
Manual Dynamometry .............................................................................................. 20 
8.4.4. 
MFM Domain 1......................................................................................................... 21 
8.4.5. 
FSHD-HI ................................................................................................................... 21 
8.4.6. 
PGIC ......................................................................................................................... 22 
8.5. INFLAMMATORY, IMMUNE, APOPTOTIC, AND MUSCLE DISEASE TRANSCRIPTS ................ 22 
9. 
SAFETY ANALYSIS...................................................................................................... 22 
9.1. ADVERSE EVENTS ............................................................................................................. 22 
9.1.1. 
Incidence of TEAEs ................................................................................................... 23 
9.1.2. 
Relationship of TEAEs to Study Drug ....................................................................... 24 
9.1.3. 
Severity of TEAE ....................................................................................................... 24 
9.1.4. 
Serious TEAEs .......................................................................................................... 25 
9.1.5. 
TEAEs Leading to Treatment Discontinuation ......................................................... 25 
9.1.6. 
TEAEs Leading to Study Withdrawal ....................................................................... 25 
9.1.7. 
Death ......................................................................................................................... 25 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 25 
9.2.1. 
Hematology ............................................................................................................... 26 
9.2.2. 
Serum Chemistry ....................................................................................................... 26 
9.2.3. 
Urinalysis .................................................................................................................. 27 
9.2.4. 
Other Laboratory Tests ............................................................................................. 27 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 27 
9.4. PHYSICAL EXAMINATION ................................................................................................. 27 
9.5. ELECTROCARDIOGRAM ..................................................................................................... 29 
10. 
PHARMACOKINETICS ............................................................................................... 30 
11. 
PHARMACODYNAMICS............................................................................................. 30 
12. 
INTERIM ANALYSIS ................................................................................................... 31 
13. 
SAFETY REVIEW COMMITTEE (SRC) ................................................................... 32 
14. 
REFERENCES ................................................................................................................ 33 
15. 
APPENDICES ................................................................................................................. 34 
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VI
15.1. 
THE STEPS FROM RAW QPCR CT TO STATISTICAL ANALYSIS ...................................... 35 
15.2. 
VALIDATION OF THE QPCR ASSAY ............................................................................... 36 
15.3. 
QPCR NORMALIZATION ............................................................................................... 37 
15.4. 
DERIVATION OF DUX4 SCORE FROM DELTA CT........................................................... 38 
15.5. 
SELECTION OF 6 GENE TRANSCRIPTS ............................................................................. 39 
15.6. 
DERIVATION OF MRI COMPOSITE SCORE ...................................................................... 40 
15.7. 
SCHEDULE OF STUDY PROCEDURES .............................................................................. 42 
15.7.1. 
SCHEDULE OF STUDY PROCEDURES: PLACEBO-CONTROLLED TREATMENT PERIOD .. 42 
15.7.2. 
SCHEDULE OF STUDY PROCEDURES: OPEN-LABEL EXTENSION (VISITS WILL OCCUR 
QUARTERLY UNTIL STUDY DRUG APPROVAL OR STUDY IS DISCONTINUED) ............................. 47 
15.8. 
LIST OF PLANNED SUMMARY TABLES ........................................................................... 50 
15.9. 
LIST OF PLANNED DATA LISTINGS ................................................................................ 63 
15.10. 
LIST OF PLANNED FIGURES ........................................................................................ 65 
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VII 
List of Abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BID 
twice daily 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
CI 
confidence interval 
COA 
clinical outcome assessment 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
DUX4 
double homeobox 4 
ECG 
electrocardiogram 
FAS 
full analysis set 
FSHD 
facioscapulohumeral muscular dystrophy 
FSHD-HI 
FSHD Health Index 
IRT 
Interactive Response Technology 
LMV 
lean muscle volume 
LOCF 
Last Observation Carried Forward 
LS 
least-squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFF 
muscle fat fraction 
MFI 
muscle fat infiltration 
MFM 
Motor Function Measure 
MRI 
Magnetic Resonance Imaging 
MMRM 
Mixed Effect Model for Repeated Measures 
MSK 
musculoskeletal 
OL 
open-label 
OLE 
open-label extension 
PGIC 
Patient’s Global Impression of Change 
PO 
orally 
PPS 
per protocol set 
PT 
preferred term 
RWS 
Reachable Workspace 
RSA 
relative surface area 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis Software 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
SRC 
Safety Review Committee 
TEAE 
treatment-emergent adverse events 
TUG 
Timed Up and Go 
WHODD 
World Health Organization drug dictionary 
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Fulcrum Therapeutics 
 
Final Statistical Analysis Plan, Version 1.0 
 
FIS-002-2019 
 
Date Issued: 28May2020 
 
  
 
 
 
1
1. Introduction 
 
This study is being conducted under the sponsorship of Fulcrum Therapeutics (Fulcrum) in 
accordance with applicable standard operating procedures. Statistical analyses are being conducted 
under contract with
 Inc., in collaboration with Fulcrum. 
 
The Clinical, Data Management, and Biostatistics departments at 
will work diligently and 
collaboratively with Fulcrum to ensure that the data collected and analyzed for this study are of 
the highest quality possible. This will be accomplished in part by having thorough edit checks 
written, programmed, and updated as needed. 
 
This Statistical Analysis Plan (SAP) is based on the protocol version 4.0 (COVID-19 Pandemic 
Emergency Amendment), dated 10Apr2020. This SAP is for the randomized, placebo-controlled 
treatment period. A separate SAP will be written for the open-label extension (OLE). 
 
Facioscapulohumeral muscular dystrophy (FSHD) is a rare disabling disease with an estimated 
worldwide population prevalence of between 1:15,000 and 1:20,000 (Statland and Tawil, 2014), 
or approximately 16,000 to 21,000 affected individuals in the United States. FSHD is characterized 
by descending progressive skeletal muscle weakness affecting the face, shoulders, arms, and trunk, 
followed by weakness of the distal lower extremities and pelvic girdle. FSHD is caused by aberrant 
overexpression of the double homeobox 4 (DUX4) gene, a homeobox transcription factor. DUX4 
is located within D4Z4 macrosatellite repeats on chromosome 4q35 and is not normally expressed 
in adult skeletal muscle when the number of repeats is >10. Approximately 95% of patients with 
FSHD have type 1 (FSHD1), in which the D4Z4 repeat array is contracted to 1 to 10 units on one 
allele (Lemmers et al, 2010; Statland and Tawil, 2014). FSHD patients carrying a smaller number 
of repeats (1 to 3 units) are, on average, more severely affected (Tawil et al, 1996). 
 
There are currently no approved disease-modifying treatments for FSHD. Fulcrum is developing 
losmapimod, a selective p38α/β inhibitor, which is predicted to reduce DUX4 in affected skeletal 
muscle. It is anticipated that the proposed human dose of losmapimod for FSHD at 15 mg orally 
(PO) twice daily (BID) will provide drug concentrations in skeletal muscles sufficient to 
significantly inhibit p38α/β and reduce aberrant expression of DUX4. 
 
The term study drug that is being used throughout this document refers to losmapimod and/or 
placebo. 
 
2. Objectives 
2.1. 
Primary Objectives 
 
The primary objective of the placebo-controlled treatment period is to evaluate the efficacy of 
losmapimod in inhibiting or reducing expression of DUX4, the root cause of FSHD, as measured 
by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies from FSHD1 subjects. 
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2.2. 
Secondary Objectives 
 
The secondary objectives of the placebo-controlled treatment period are: 
• To evaluate the safety and tolerability of losmapimod in FSHD1 subjects. 
• To evaluate the change from baseline in muscle fat fraction (MFF), lean muscle volume 
(LMV) and muscle fat infiltration (MFI) in FSHD1 subjects, as measured by 
musculoskeletal (MSK) magnetic resonance imaging (MRI); 
• To evaluate the plasma concentrations of losmapimod in FSHD1 subjects; 
• To evaluate the levels of losmapimod in skeletal muscle in FSHD1 subjects; and 
• To evaluate losmapimod target engagement in blood and in skeletal muscle in FSHD1 
subjects. 
 
2.3. 
Exploratory Objectives 
 
The exploratory objectives of the placebo-controlled treatment period are: 
• To evaluate the change from baseline in the following clinical outcome assessments 
(COAs): 
o Reachable Work Space (RWS) with and without weights 
o Classic and FSHD Timed Up and Go (TUG) 
o Muscle strength by hand-held quantitative dynamometry 
o Motor function Measure (MFM) Domain 1 
o FSHD Health Index (FSHD-HI) 
o Patients’ Global Impression of Change (PGIC) 
• To evaluate the change from baseline of inflammatory, immune, apoptotic, and muscle 
disease transcripts in muscle biopsy and circulating proteins in plasma and serum. 
 
3. Investigational Plan 
3.1. 
Overall Study Design and Plan 
 
This study will be conducted in 2 parts: a randomized, double-blind placebo-controlled treatment 
period for 48 weeks, followed by a losmapimod open-label treatment period with a study 
population of males and females between 18 and 65 years of age at enrollment, inclusive, who 
have confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the D4Z4 
array on chromosome 4; a clinical severity score of 2 to 4 (RICCI score; range 0-5), inclusive, at 
screening; and a MRI eligible muscle for biopsy, as determined by a central reader. 
 
During the placebo-controlled treatment period, approximately 76 subjects with FSHD1 will be 
randomized 1:1 to receive 15 mg PO of losmapimod (n=38) or placebo (n=38) tablets BID for 48 
weeks. At the time of the latest protocol amendment (Version 4.0; 10Apr2020), enrollment was 
completed, a total of 80 subjects have been enrolled.  
 
Once subjects reach Week 48, they will have the option to roll over into the open-label extension, 
with all subjects receiving 15 mg losmapimod PO BID. Subjects who wish to roll over into the 
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open-label extension must complete all procedures from the Week 48 end of placebo-controlled 
treatment period/start of open-label extension visit. Prior to the COVID-19 pandemic, subjects 
who reached the Week 24 visit had the option to roll over into the OLE. Subjects who have already 
rolled over to the OLE prior to the COVID-19 pandemic (n=12) will remain on open label 
treatment. Their next clinic visits will follow the assessments for the Week 36 and Week 48 visits 
in the placebo-controlled portion of the study in the COVID-19 Pandemic Emergency protocol 
version 4.0. These subjects will not undergo the Week 36 biopsy. Subjects who did not roll over 
prior to the COVID-19 pandemic, and thus are still on the randomized treatment, will continue on 
the randomized treatment and roll over into the OLE at the Week 48 visit. Please see the COVID-
19 Pandemic Emergency protocol version 4.0 for further details. 
 
The placebo-controlled treatment period will include a 4-week screening period and a 24 or 48-
week placebo-controlled treatment period. Subjects who rolled over to the OLE portion of the 
study prior to the COVID-19 pandemic (under protocol version 3.0) have completed a 4-week 
screening period followed by a 24-week placebo-controlled treatment period.  
 
Blood samples for pharmacokinetics (losmapimod concentrations) endpoints will be collected at 
Day 1, Week 4, Week 16, and Week 36 at the following timepoints: immediately pre-dose and 4 
hours (±30 minutes) after administration of the study drug. Blood samples for target engagement 
will be collected at Day 1 and Week 16 or Week 36 at the following timepoints: immediately pre-
dose and 4 hours (±30 minutes) after administration of the study drug. Musculoskeletal MRIs will 
be performed at screening, Week 12, Week 24, and Week 48. Muscle biopsies will be taken at Day 
1 and Week 16, or at Day 1 and Week 36 if the muscle biopsy could not be performed at Week 16 
due to the COVID-19 pandemic.  
 
Safety and tolerability will be evaluated based on the assessment of adverse events (AEs), AEs of 
special interest (AESIs), serious adverse events (SAEs), laboratory tests, electrocardiogram 
(ECGs), vital signs, and physical examinations. 
 
A schematic of the study design of the placebo-controlled treatment period is presented in Figure 
3-1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 3-1: Schematic of Study Design 
 
 
Abbreviations: BID, twice daily; MRI, magnetic resonance imaging; OLE, open-label extension 
 
 
During the open-label extension, subjects will be asked to attend clinic visits approximately 
every 12 weeks, and MRI will take place every 24 weeks. Study drug (open-label losmapimod) 
will be administered BID and should be taken with food. Subjects will remain in the open-label 
extension until study drug approval or until the study is discontinued by the Sponsor. All subjects 
who complete or discontinue from treatment will be asked to complete a 7-day safety follow-up 
period. 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
 
The primary endpoint of the placebo-controlled treatment period is the change from baseline in 
DUX4 activity in affected skeletal muscle at Week 16 or Week 36, as measured by QRT-PCR in 
a panel of DUX4-regulated gene transcripts. 
3.2.2. 
Secondary Endpoints 
 
The secondary endpoints of the placebo-controlled treatment period are as follows: 
• Safety and tolerability of losmapimod as defined by the following: 
o Type, frequency, severity, seriousness, and relationship of AEs to losmapimod; 
o Incidence of AESI; 
o Number of subjects who prematurely discontinue study drug due to an AE; and 
o Frequency of clinically significant changes in laboratory test, ECG, vital sign, and 
physical examination results 
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• Change from baseline in MFF, LMV, and MFI at Week 12, Week 24 (if applicable) and 
Week 48; 
• Plasma concentrations of losmapimod at Week 4, Week 12, Week 16, Week 24, Week 36, 
and Week 48; 
• Concentrations of losmapimod in skeletal muscle biopsy at steady state at Week 16 or 
Week 36;   
• Target engagement parameters in blood, and skeletal muscle biopsy at Week 16 or Week 
36. 
3.2.3. 
Exploratory Endpoints 
 
The exploratory endpoints of the placebo-controlled period are as follows: 
• Change from baseline in COAs, including 
o RWS with and without weights at Week 4, Week 12, Week 24,  Week 36, and Week 
48 
o Classic and FSHD TUG at Week 4, Week 12, Week 24,  Week 36, and Week 48 
o Muscle strength by hand-held dynamometry at Week 4, Week 12, Week 24, Week 
36, and Week 48 
o MFM Domain 1 at Week 12, Week 24, Week 36, and Week 48 
o FSHD-HI at Week 4, Week 12, Week 24, Week 36, and Week 48 
o PGIC at Week 4, Week 12, Week 16, Week 24, Week 36, and Week 48 
• Change from baseline in inflammatory, immune, apoptotic, and muscle disease transcripts 
may be conducted in muscle biopsy at Week 16 or Week 36 and in circulating proteins in 
plasma and serum at Week 4, Week 12, Week 16, Week 24, Week 36, and Week 48. 
 
 
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3.3. 
Treatments   
 
Study drug tablets in the placebo-controlled treatment period (losmapimod or placebo) and the 
open-label extension (losmapimod) will be dispensed to subjects at the visits detailed in Table 13-
1 and Table 13-2 of the protocol, respectively.  
 
During the placebo-controlled treatment period, subjects will receive either 15 mg losmapimod 
BID or placebo BID.  In the open-label extension, all subjects will receive 15 mg losmapimod 
BID. As 7.5 mg losmapimod tablets will be used in this study, subjects will be taking 2 tablets, PO 
BID. The study drug should be taken with food, with the date and time of each dose taken recorded 
in the subject’s diary. 
 
4. General Statistical Considerations 
4.1. 
Reporting Conventions 
 
All data summaries, unless otherwise noted, will be presented by treatment group: 
• Losmapimod 15 mg BID 
• Placebo BID 
 
The following conventions will be used for all the data presentations and analyses unless otherwise 
specified. 
 
Appropriate descriptive statistics will be computed and displayed for both continuous and 
categorical variables. For continuous and quantitative variables, summaries will include n (number 
of subjects with non-missing data), mean, standard deviation (SD), Q1 (first quartile), Q3 (third 
quartile), median, minimum and maximum. Reporting conventions for descriptive statistics will 
follow the 
Standard TLF Guidelines. For categorical variables, summaries will include the 
number and percentage of subjects who are in a particular category. Percentages will be computed 
based on the number of non-missing data points for patients in the applicable analysis set. 
Reporting of percentages will follow the
tandard TLF Guidelines.  
 
A total column will be presented for all demographic, baseline characteristic, baseline disease 
characteristic, protocol deviation, and prior and concomitant medication summaries. 
 
All data will be listed by treatment group, FSHD repeat number category, subject ID, Ricci score, 
sex and visit date, if available. Any repeat assessments or additional assessments, along with any 
unscheduled visits, will be presented in the listings. Sort order of data listings will be treatment 
group, FSHD repeat number category, subject ID, and visit date, if available. 
Statistical tests will be 2-sided and will be conducted at the significance level provided in Table 
12-1), unless otherwise specified. P-values will be reported to 4 decimal places, with p-values less 
than 0.0001 reported as “<0.0001”.  
 
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All analyses will be performed using Statistical Analysis Software (SAS®, release 9.4 or higher). 
A separate document as an appendix to this SAP will contain the tables, listings, and figure (shells). 
 
4.2. 
Handling of Missing Data 
 
Missing data for primary efficacy endpoint will be handled as specified in the sensitivity analyses 
Section 8.2.1.  
All missing and partial dates for the prior/concomitant medications and adverse events will be 
handled as outlined in Sections 7.1 and 9.1, respectively. 
In categorical summaries, a missing category will be included if and only if any data for the given 
endpoint is missing.   
Missing values for other individual data points will remain as missing, unless otherwise, stated. 
 
4.3. 
Baseline, Study Day, and Change from Baseline Definitions 
 
Unless indicated otherwise, baseline will be defined as the last non-missing evaluation on or before 
the day of first dose of study drug. In the event that the last non-missing evaluation and the study 
drug administration happen on the same day, timing of the evaluation will be used to determine 
the pre- or post-dose. If timing is not available, the evaluation is considered pre- or post-dose based 
on the schedule of events for that assessment.  For example, AEs and concomitant medication are 
considered post-baseline evaluations.  
 
For muscle biopsies, any assessment taken on the first day of study drug exposure will be 
considered baseline, irrespective of timing to study drug. 
 
Relative study days will be calculated as: 
 
(assessment date – dose administration date) + 1  
 
if the assessment date is on the same day or after the dosing date, otherwise: 
 
(assessment date – dose administration date).  
 
Study day will be presented on all listings where appropriate.  
 
Change from baseline will be computed as (post-baseline assessment value - baseline assessment 
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4.4. 
Visit Windows 
 
In general, data for assessments that are collected by scheduled visits will be mapped to visits that 
appear in the schedule of assessments per the protocol using the actual study day of assessment. 
Data mapped to scheduled visits will include all data collected up to the reporting cut-off date and 
may include withdrawal visits and unscheduled visits.  
 
Visit windows will be continuous from the midpoint between two consecutive study visits and will 
be dependent on the schedule of assessments for each variable independently. The exception is the 
Week 16 analysis window, which has been extended to allow for potentially delayed visit due to 
COVID-19 pandemic. An example of the Vital Signs visit window is given in Table 4-1. Visit 
windows for each variable will be constructed in the same manner. 
 
Table 4-1: Visit Windows 
 
Study Visit 
Scheduled Day 
Analysis Window 
Baseline 
1 
<=1 
Week 4 
28 
>1 to <=56 
Week 12 
84 
>56 to <=98 
Week 16 
112 
>98 to <=154 
Week 24 
168 
>154 to <=210 
Week 36 
252 
>210 to <=294 
Week 48 
336 
>294 to <=378 
 
4.5. 
Multiple Values 
 
For summaries displayed by visit, multiple values for a given assessment within a time window 
will be handled as follows:  
 
• Efficacy: The nearest non-missing value to the nominal timepoint will be assigned to the 
visit. If two values are equidistant from the nominal timepoint then the latest value will 
be selected. 
• Safety: The first non-missing value to the nominal timepoint will be assigned to the visit. 
 
For the PK and biomarker data, if the assay is believed to have failed for an assessment due to 
technical reasons, the sample will be re-run and the last/latest assessment date/time that is available 
will be used for the data analysis. 
 
4.6. 
Subgroup 
 
A subgroup analysis will be performed for the following subsets at baseline: 
1) Repeat category (1 to 3 repeats, 4 to 9 repeats) 
2) Clinical severity score (RICCI score 2 to 3, 3.5 to 4) 
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3) Sex (Male, Female) 
4) Fat Fraction at biopsy site. This is an average of results from 2 Readers. 
a. > 10 to <=20% 
b. >20 to <=40% 
5) Mean DUX4 score (DUX4 Score 1) at baseline values partitioned by 3 thresholds:  
a. >=Q1 (first quartile of observed mean DUX4 score (DUX4 Score 1) at baseline) 
b. >=Q2 (median of observed mean DUX4 score (DXU4 Score 1) at baseline) 
c. >=Q3 (third quartile of observed mean DUX4 score (DXU4 Score 1) at baseline) 
6) Subjects completing 'RWS protocol with above shoulder movements’ at baseline 
7) Subjects who completed 'RWS protocol with above shoulder movements’ all through the 
study 
8) Subjects completing the classical TUG, without an assisted device, at baseline 
9) Subjects completing the FSHD TUG, without an assisted device, at baseline 
10) MFFtot, LMVtot and MFItot with thresholds at the median of observed baseline data 
11) Subjects with non-censored laboratory observations for DUX4 score at baseline. 
  
 
Endpoints for which the subgroup analysis will be performed are indicated in subsequent sections.  
 
4.7. 
Sample Size 
 
Assuming an effect size of 0.70, a sample size of 68 subjects (34 subjects per group) will be needed 
to provide 80% power with a 2-sided test at a 0.05 significance level to detect a difference between 
losmapimod and placebo in change from baseline in DUX4 activity in affected skeletal muscle 
after 16 weeks or 36 weeks (depending upon when the muscle biopsy was performed) during the 
placebo-controlled treatment period. Assuming that approximately 10% of subjects will be 
non-evaluable, approximately 76 subjects will be randomly assigned at a 1:1 ratio to losmapimod 
and placebo (38 subjects per group).  
 
4.8. 
Randomization, Stratification, and Blinding 
 
Subjects will be randomly assigned at the baseline visit (Day 1) to receive losmapimod (active 
drug) or placebo using a 1:1 allocation ratio. Randomization will be stratified to ensure that the 
treatment allocation is balanced across FSHD repeat number categories (ie, 1 to 3 repeats versus 
4 to 9 repeats). An Interactive Response Technology (IRT) system will be used to administer study 
drug according to the randomization schedule.  
 
The placebo-controlled treatment period will be performed in a double-blind fashion. The 
investigator, study staff, subjects, sponsor, and monitor will remain blinded to the treatment until 
study closure. The sponsor and/or its designee will remain blinded to the subject-level treatment 
assignment until after all subjects have completed the Week 48 visit (or have discontinued) and 
the database from the placebo-controlled treatment period has been locked for statistical analyses, 
after which time they will unblinded. The study drug and its matching placebo are 
indistinguishable and will be packaged in the same way. There are no tolerability issues that are 
expected to potentially unblind the assigned study drug. 
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During the open-label extension, no blinding will be performed (subjects will receive open-label 
losmapimod); however, subjects will remain blinded to their original treatment assignment from 
the placebo-controlled treatment period for the duration of the study. The Sponsor and/or its 
designee may be unblinded after all subjects have completed the Week 48 visit (or have 
discontinued) and the database from the placebo-controlled treatment period has been locked for 
statistical analyses.  
 
4.9. 
Analysis Set 
 
The following analysis sets will be used in the statistical analyses. 
 
4.9.1. Full Analysis Set (FAS) 
 
The FAS will consist of all subjects who are randomly assigned to receive double-blind study drug 
in the placebo-controlled treatment period. All analyses using the FAS will group subjects 
according to randomized treatment. The FAS is the main analysis population for the key study 
endpoints. For the secondary and exploratory endpoints, subjects who already transitioned into the 
OLE portion under protocol version 3.0 will be analyzed as randomized, in this analysis 
population. 
 
4.9.2. Per Protocol Set (PPS) 
 
The PPS will consist of all FAS subjects who fulfill all inclusion/exclusion criteria and do not have 
any significant protocol deviations. All analyses using the PPS will group subjects according to 
randomized treatment. PPS analyses will be conducted for key study endpoints to assess robustness 
of key study inferences. 
 
4.9.3. Safety Analysis Set 
 
The Safety Analysis Set will consist of all subjects who receive any study drug. All analyses using 
the Safety Analysis Set will group subjects according to treatment actually received. 
 
4.9.4. Pharmacokinetics Analysis Set 
 
The PK Analysis Set will consist of all subjects who receive at least 1 dose of losmapimod and 
have evaluable PK data for losmapimod. 
 
 
 
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4.9.5. Pharmacodynamics Analysis Set 
 
The PD Analysis Set will consist of all subjects who receive at least 1 dose of losmapimod and 
have evaluable PD data for losmapimod. 
 
4.9.6. Open-label Losmapimod (Pre-COVID-19) Analysis Set 
 
This analysis set will consist of subjects who were already transitioned into open-label losmapimod 
under version 3.0 of the protocol. This analysis set will be used for sensitivity analysis, to assess 
secondary/exploratory endpoints in this subset of subjects. 
5. Subject Disposition 
5.1. 
Disposition 
 
Subject disposition will be summarized for the FAS. A disposition of subjects includes the number 
and percentage of subjects for the following categories:  
• Subjects who were randomized 
• Subjects who completed the treatment 
• Subjects who discontinued the treatment 
• Subjects who completed the study 
• Subjects who discontinued from the study 
 
The reason for study discontinuation will also be summarized. 
 
A summary of the subjects included in each analysis set will be presented.  
 
All percentages will be based on the number of subjects in the FAS. 
 
Subject disposition data will also be presented in a listing. 
 
5.2. 
Protocol Deviations 
 
Significant protocol deviations will be summarized by deviation type for all FAS subjects. A listing 
of all protocol deviations will be provided as well. Prior to DBL, the listing for protocol deviations 
will be determined in a blinded manner. 
 
6. Demographics and Baseline Characteristics 
6.1. 
Demographics 
A summary of demographics and baseline characteristics will be presented. The demographic 
characteristics will consist of age (years), sex, race, and ethnicity. The baseline characteristics will 
consist of baseline height (cm), baseline weight (kg), and baseline body mass index (BMI) 
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(kg/m^2). Body mass index is calculated as (body weight in kilograms) / (height in meters)2. Age, 
baseline height, baseline weight, and baseline BMI will be summarized using descriptive statistics. 
The number and percentage of subjects by sex (Male, Female), race (White, African American, 
Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and Other) 
and ethnicity (Hispanic or Latino, Not Hispanic or Latino) will also be reported. Percentages will 
be based on the total number of subjects in the FAS. A separate presentation may be done for the 
Safety Analysis Set. 
 
Subject demographic and baseline characteristics will also be presented in a listing. 
 
6.2. 
Baseline Disease Characteristics 
 
Baseline disease characteristics include the following parameters: 
• FSHD repeat number (1, 2, 3, 4, 5, 6, 7, 8, and 9) 
• FSHD repeat category (1 to 3 repeats, 4 to 9 repeats) 
• Clinical severity score (RICCI score 2, 2.5, 3, 3.5, 4) 
• FSHD history 
o Age of symptom (years) 
o First symptom 
▪ Weakness 
▪ Difficulty smiling 
▪ Reaching over head 
▪ Walking 
▪ Running 
▪ Keeping up with peers 
▪ Pain 
▪ Others 
o Age at diagnosis (years) 
o Pain related to FSHD 
 
Percentages will be based on the total number of subjects in the FAS. Listings will be presented 
for the FAS. A separate presentation may be done for the Safety Analysis Set. 
 
6.3. 
Medical History 
 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.0 or higher. The number and percentage of subjects with any medical history will be 
summarized by treatment group and overall and presented by system organ class (SOC) and 
preferred term (PT). Percentages will be calculated based on the number of subjects in the FAS. 
 
Subject medical history data including specific details will also be presented in a listing. 
 
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7. Treatments and Medications 
7.1. 
Prior and Concomitant Medications 
 
All medications used within 28 days prior to the date of screening through safety follow-up will 
be collected on the CRF (case report form). All medications will be coded according to the World 
Health Organization Drug Dictionary (WHODD Global B3 Mar 2019 or higher). 
 
A prior medication is defined as any medication that is taken prior to the first dose of study drug 
and stopped before the date of study drug administration. A concomitant medication is defined as 
any medication that is taken on or after the date of study drug administration regardless when the 
medication is started up to 7 days after the last dose date. 
 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete medication 
start and stop dates will be imputed as follows: 
 
Missing start dates (where UK, UKN, and UNKN indicate unknown or missing day, month, and 
year, respectively): 
 
• UK-MMM-YYYY: If the month and year are different from the month and year of 
administration of study drug, assume 01-MMM-YYYY. If the month and year are the same as 
the administration of study drug month and year and the end date (after any imputation) is on 
or after the administration of study drug, then assume the first day of the month of the 
administration of study drug. If the month and year are the same as month and year of the study 
drug administration and the end date (after any imputation) is prior to the study drug 
administration, then assume the first day of the month of the administration of the study drug 
for the start date; 
• DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of the study drug 
administration, assume DD-JAN-YYYY/01-JAN-YYYY of the collected year. If the year is 
the same as study drug administration year and the end date (after any imputation) is on or 
after the study drug administration, then assume the date of the study drug administration. If 
the year is the same as the study drug administration and the end date (after any imputation) is 
prior to the first dose of study drug, then assume the first day of the month of the administration 
of the study drug for the start date. 
 
Missing stop dates (where UK, UKN, and UNKN indicated unknown or missing day, month, and 
year, respectively): 
 
• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
DD-UKN-YYYY: Assume DD-DEC-YYYY; 
• 
UK-UKN-YYYY: Assume 31-DEC-YYYY. 
 
If the start date is completely missing and end date is not prior to the study drug administration, 
then the medication will be classified as concomitant. If the start date is completely missing and 
the end date is within 30 days prior to the first dose of study drug, then the medication will be 
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classified as prior. If the end date is missing, then the medication will be classified as ongoing. 
Medications for which the start and end dates are missing will be classified as concomitant. 
 
Prior and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) classification level 4 and preferred drug name, respectively. When ATC classification level 
4 is missing, the next available ATC level will be used as ATC level 4.  
 
Summaries will be performed using the Safety Analysis Set.  
 
Data on prior and concomitant medications will also be presented in a listing. 
 
7.1.1. Prior Medications 
 
The total number of prior medications and the number and percentage of subjects with at least one 
prior medication will be summarized by treatment group and overall. The number and percentage 
of all prior medications will be summarized by treatment group and overall and presented by 
Anatomical Therapeutic Chemical (ATC) level 4 and PT. All summaries will be performed using 
the FAS. 
 
7.1.2. Concomitant Medications 
 
The total number of concomitant medications and the number and percentage of subjects with at 
least one concomitant medication will be summarized by treatment group and overall. The number 
and percentage of all concomitant medications will be summarized by treatment group and overall 
and presented by Anatomical Therapeutic Chemical (ATC) level 4 and PT. All summaries will be 
performed using the Safety Analysis Set. 
7.2. 
Study Treatments 
7.2.1. Extent of Exposure 
 
Duration of exposure is defined as the total number of days a subject is exposed to study drug and 
will be presented as the total number of days from the first dose date (Day 1) to the last dose date 
(ie, calculated as the date of last dose minus the date of first dose + 1). If the last dose date is 
missing, or if a subject is lost to follow-up, but the drug accountability log confirms that the subject 
has taken study drug, the visit date following the last completed drug accountability log will be 
used.  
 
The exposure to study drug will also be characterized by cumulative dose, which is defined as the 
cumulative number of tablets taken.  
 
The duration of exposure to study drug by treatment group will be summarized for all subjects in 
the Safety Analysis Set and will be presented in a table using summary statistics. The duration of 
exposure will then be classified into one of the following categories: < 8 weeks, >= 8 weeks, >= 
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16 weeks, >= 24 weeks, >=36 weeks and >=48 weeks and will be presented as the number and 
percentage of subjects in each duration category. Percentages will be computed from the number 
of subjects in the Safety Analysis Set.  
 
The total cumulative dose in mg will be defined as the total number of tablets taken across all study 
days times 7.5 mg. Average daily dose will be defined as cumulative dose divided by total days 
on study drug. The average daily dose and cumulative dose will be summarized using summary 
statistics. 
 
A summary of each subject’s exposure will also be presented in a listing.  
7.2.2. Treatment Compliance  
 
Study drug compliance will be calculated for each subject by taking into account whether a subject 
takes all doses of study drug as instructed. The number of tablets taken will be calculated by 
subtracting the number of tablets returned from the number of tablets dispensed.  
 
The study drug compliance (%) for each visit will be calculated by dividing the total number of 
tablets taken up to the next visit by the total number of tablets prescribed at each visit and then 
multiplying by 100. Compliance (%) = [(total number of tablets dispensed – total number of tablets 
returned) / (number of days in visit interval * number of tablets prescribed per day)] * 100. The 
overall study drug compliance (%) will be calculated by dividing the total number of tablets taken 
at all visits by the total number of tablets prescribed for all visits and then multiplying by 100. 
 
The overall study drug compliance will be summarized by treatment group.  
 
The number and percentage of subjects in different percentage compliance categories (<80%, 
>=80% to <120%, and >= 120% compliant) will be presented. Percentages will be calculated from 
the number of subjects in the Safety Analysis Set.  
 
8. Efficacy Analysis 
 
Efficacy endpoints will be analyzed using the FAS. The primary efficacy endpoint will also be 
performed on the PPS and will be considered supportive of the primary analyses on the FAS. As 
part of sensitivity analysis, a separate analysis will be done of efficacy endpoints using the Open-
label Losmapimod (Pre-COVID-19) Analysis Set. 
 
8.1. 
Hypothesis Testing Procedure for Key Study Endpoints  
 
A fixed sequential testing procedure will be used to control for the experiment-wise Type I Error 
to test the following key study endpoints as ordered below: 
• DUX4 change from baseline at Week 16 or Week 36 [DUX4 Score 1. See Section 8.2] 
• LMV change from baseline at Week 48 [Total LMV, composite of assessments from 
multiple muscles. See Section 8.3] 
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• FSHD TUG change from baseline at Week 48 [average completion time of FSHD TUG. 
See Section 8.4.2] 
 
At each step in this sequential ordering, statistical significance for the endpoint will be claimed 
only if the p-value for the test is less than the final alpha obtained from the O’Brien-Fleming 
Spending Function (Table 12-1) and the p-values for the tests for all previous endpoints in the list 
are also less than the final alpha provided. 
 
The testing hierarchy will be as follows: 
• If the p-value for the test of the comparison of DUX4 change from baseline between the 
two treatment groups is less than the final alpha, then the comparison of the LMV change 
from baseline will be conducted. If the p-value from this comparison is also less than the 
final alpha, then the comparison of the FSHD TUG change from baseline will be 
conducted. 
• Once a p-value is greater than or equal to the final alpha for the current endpoint being 
evaluated, then only the tests for the preceding endpoints will be considered significant. 
• The formal statistical tests for any of the endpoints will be considered statistically 
nonsignificant when the test has a p-value of greater than or equal to final alpha. However, 
nominal p-values will still be provided for these endpoints. 
 
8.2. 
Change from Baseline in DUX4 Activity in Skeletal Muscle at Week 16 or Week 36 
 
A subset of DUX4-gene transcripts will be measured in skeletal muscle biopsies, using a validated 
QRT-PCR assay, to assess the treatment effect of losmapimod over placebo on aberrant DUX4 
activity. A mean DUX4 score (DUX4 Score 1) will be derived for each patient, at each time point 
based on normalized gene expression values for the panel of pre-selected genes.DUX4 Score 1 is 
a mean of normalized (delta-CT) for the pre-selected panel of 6 genes, by subject, for each 
timepoint. 
 
The quantification of gene expression and normalization of qPCR are conducted at a central 
laboratory (Q2 Lab Solutions) in a blinded fashion, with no access to treatment assignment 
information. A total of six DUX4-regulated gene transcripts (CCNA1; KHDC1L; MBD3L2; 
PRAMEF6; SLC34A2; ZSCAN4) have been pre-selected for inclusion in the mean DUX4 score. 
DUX4 Score 1 will be used for the primary analysis. A second and third composite scores (DUX4 
Score 2 and DUX4 Score 3, respectively) will be used for sensitivity analysis. For details on assay 
validation, gene subset selection criteria/process, and derivation of DUX4 Score, see Appendices 
15.1 – 15.5.  
 
DUX4 score 1 will be summarized as change from baseline to either Week 16 or Week 36. Study 
subjects can only have one post-baseline biopsy (either Week 16 or Week 36, but not both). If the 
pre-treatment or on-treatment DUX-4 results are unavailable, then the assessment is considered 
missing. See Section 8.2.1 for details of missing data handling for DUX4 Score. 
 
For each treatment, descriptive statistics of aberrant DUX4 activity will be presented at Baseline 
and post-baseline (Week 16 or Week 36) as well as change from baseline. An ANCOVA model 
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will be used to analyze the change from baseline in DUX4 activity in affected skeletal muscle, 
which is the response variable, with repeat number category and treatment group as fixed effects 
and baseline DUX4 activity in affected skeletal muscle as a covariate. Within-group least-squares 
(LS) means, the associated standard errors (SEs) and 2-sided 95% CIs, treatment differences in LS 
means and the associated 2-sided 95% CIs and 2-sided p-values will be derived from the model 
and presented in the table. If the model-based p-value of the treatment difference in the change 
from baseline is less than the final alpha provided in Table 12-1, the difference between two 
treatment groups will be determined to be statistically significant.  
 
Similar methods will be used to analyze the change from baseline in DUX4 activity within 
subgroups identified in Section 4.6 to evaluate consistency of treatment effects across the 
subgroups. For the repeat category subgroup analysis, the repeat category will be excluded as fixed 
effect from the model. 
 
The LS mean change from baseline by visit of the DUX4 activity will be graphically presented. 
 
8.2.1. Sensitivity Analyses of Primary Endpoint 
 
Missing Data: The following sensitivity analyses will be conducted on the primary efficacy 
endpoint to assess the impact of missing data on study conclusions: 
 
• Last Observation Carried Forward (LOCF): Post-baseline missing DUX4 score 
will be imputed using baseline DUX4 score for each subject with missing data. Patients 
who are missing the baseline assessment will be excluded from the analysis. 
 
• Placebo Mean Imputation: Post-baseline missing DUX4 score will be imputed using 
mean post-baseline score calculated from the placebo arm. Patients who are missing 
the baseline assessment will be excluded from the analysis. 
 
• 
Observed worst case imputation: For subjects with missing baseline DUX4, 
imputation will be done using the smallest baseline DUX4 score among subjects with 
non-missing data. For subjects missing post-baseline DUX4, imputation will be done 
using the highest DUX4 score among subjects with non-missing data.   
 
DUX4 by timepoint: The primary endpoint will be analyzed separately for Week 16 and Week 
36 to assess the impact of biopsy timing on study conclusions. 
 
COVID-19 related treatment disruptions: Subjects may be diagnosed with COVID-19 and 
proceed on a quarantine or have no access to study treatment for a prolonged duration. These 
subjects will be excluded from analysis of the primary endpoint, to assess the impact of COVID-
19 related treatment disruptions on the study conclusions.  
 
Excluding cross-over subjects: Subjects who already transitioned into open label losmapimod 
based on the prior protocol version will be excluded from the analysis. 
 
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DUX4 change excluding subjects with censored laboratory observations at baseline: 
Subjects with censored observations at baseline for any of the transcripts in the panel of 6 
DUX4-regulated transcripts will be excluded from the analysis. 
8.3. 
MSK MRI Muscle Fat Fraction, Lean Muscle Volume and Muscle Fat Infiltration 
 
Measurement of the extent of skeletal muscle tissue replacement by fat in FSHD patients will be 
done through automatic skeletal muscle segmentation for the 3D muscle volumes and fat fraction 
analysis via robust algorithms using Dixon imaging. This will be assessed at Screening, Week 12, 
and Week 48.  
 
A. Composite measures: Composite variables, incorporating pre-selected muscles, will be 
derived for longitudinal analysis of muscle fat fraction, lean muscle volume and muscle fat 
infiltration (MFFtot, LMVtot, and MFItot respectively), as described in Appendix 15.6. The 
scores will be derived by scientists at the MRI Service Provider (AMRA Medical Inc.) in 
a blinded fashion, with no access to treatment assignment information. 
 
For each treatment, descriptive statistics of MFFtot , LMVtot, and MFItot per visit as well as 
changes from baseline will be presented. A Mixed Effect Model for Repeated Measures 
(MMRM) model will be used to analyze the change from baseline in each composite MRI 
score, with repeat number category, treatment group, visit, and treatment-by-visit 
interactions as fixed effects and baseline value of the parameter as a covariate. Within-
group LS mean changes from baseline, the associated SEs and 2-sided 95% CIs, treatment 
differences in LS mean changes from baseline at Weeks 12 and 48 and the associated 2-
sided 95% CIs and 2-sided p-values will be derived from the MMRM model and will be 
provided in the summary table.  An unstructured covariance matrix will be used to model 
the correlation among repeated measurements within each subject.  If models using 
unstructured covariance do not converge, an AR(1) covariance structured will be used 
instead. LMVtot is the key endpoint for hypothesis testing. 
 
B. Individual Muscles: For each muscle location, a similar method will be used to analyze 
muscle fat fraction (%), lean muscle volume (L), and muscle fat infiltration (%) per visit 
as well as changes from baseline.  
 
The LS mean change from baseline by visit of the MSK MRI muscle fat fraction, lean muscle 
volume, and muscle fat infiltration will be graphically presented. 
 
The change from baseline in the composite parameters will also be summarized by subgroups 
identified in Section 4.6 to evaluate consistency of treatment effects across the subgroups. 
 
 
 
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8.4. 
Clinical Outcome Assessments 
8.4.1. Reachable Work Space With and Without Weights 
 
The reachable work space (RWS) is a 3-dimensional sensor-based system (using a single depth-
ranging sensor) that can unobtrusively detect an individual’s RWS and reflects an individual global 
upper extremity function, including shoulder and proximal arm. The evaluation will be performed 
with and without weights and on both the right and left arms at Baseline, Week 4, Week 12, Week 
24, Week 36, Week 48 and Safety Follow-up.  
 
The absolute total RWS surface envelope area (m2) as well as areas for each of the quadrants will 
be calculated and provided by a vendor in a blinded fashion, with no access to treatment 
assignment information. The reachable workspace relative surface area (RSA) represents the 
portion of the unit hemisphere that is covered by an individual’s hand movement. 
 
For each treatment, descriptive statistics of RSA results per visit as well as the change from 
baseline will be presented by quadrant, for total upper quadrants (Q1+Q3) and total area 
(Q1+Q2+Q3+Q4) for the assessment with weights and without weights, and by dominant and non-
dominant arm. An MMRM model will be used to analyze the change from baseline in total area 
with repeat number category, treatment group, visit, and treatment-by-visit interactions as fixed 
effects and baseline value of the total area as a covariate. A separate model will be run with and 
without weights and for the dominant and non-dominant hand. Within-group LS mean changes 
from baseline, the associated SEs and 2-sided 95% CIs, treatment differences in LS mean changes 
from baseline at post-baseline visits and the associated 2-sided 95% CIs and 2-sided p-values will 
be derived from the MMRM model and will be provided in the summary table.  An unstructured 
covariance matrix will be used to model the correlation among repeated measurements within each 
subject. If models using unstructured covariance do not converge, an AR(1) covariance structured 
will be used instead. Similar methods will be used to analyze the change from baseline in RSA for 
each quadrant.   
 
Summary tables will be generated, showing percentage of subjects with RWS decline of >=5%, 
>=2% at each post-baseline timepoint. 
 
See Section 4.6, #6 and #7, for sub-group analyses to be conducted on this endpoint. 
 
The functional work space (FWS) will also be summarized using number and percentages of 
subjects belonging to the categories of normal or low speed. The detected time within each target 
will be presented in a listing. 
 
8.4.2. Classic and FSHD TUG 
 
The TUG test is used to assess a person’s mobility and requires both static and dynamic balance. 
It measures the time that a person takes to rise from a chair, walk 3 meters, turn around, walk back 
to the chair, and sit down. The FSHD TUG test is the classic TUG but adds the component of 
getting up from a laying position on a bed-like table in the clinic at the start of the test and laying 
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back down on his or her back at the end of the test. The FSHD TUG will capture total completion 
time and completion times for each segment (supine to sit, stand-walk-sit, and sit to supine). Each 
test will be done twice per visit and will be assessed at Baseline, Week 4, Week 12, Week 24, 
Week 36, Week 48, and Safety Follow-up. The average of Trial 1 and Trial 2 assessments at each 
visit will be derived for both the classic TUG completion time and each of the FSHD TUG 
completion times (ie, supine to sit, stand-walk-sit, sit to supine, and total) and will be used for the 
analysis. 
 
For each treatment, descriptive statistics of classic TUG average completion time and FSHD TUG 
average completion times in seconds per visit as well as the change from baseline will be provided 
in tables. The average completion time of the FSHD TUG is a key study endpoint, for 
hypothesis testing. Descriptive statistics of FSHD TUG average completion times will be 
presented for each segment (supine to sit, stand-walk-sit, sit to supine, and total). An MMRM 
model will be used to analyze the change from baseline in classic TUG average completion time 
with repeat number category, treatment group, visit, and treatment-by-visit interactions as fixed 
effects and baseline value of classic TUG average completion time as a covariate. Within-group 
LS mean changes from baseline, the associated SEs and 2-sided 95% CIs, treatment differences in 
LS mean changes from baseline at post-baseline visits and the associated 2-sided 95% CIs and 2-
sided p-values will be derived from the MMRM model and will be provided in the summary table.  
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements within each subject. If models using unstructured covariance do not converge, an 
AR(1) covariance structured will be used instead.  Similar methods will be used to analyze the 
change from baseline in FSHD TUG average completion times. 
 
Similar analysis will also be conducted for each of the individual components of the FSHD TUG. 
 
The change from baseline in the classic and FSHD TUG average completion times will also be 
summarized by subgroups #8 and #9, respectively,  identified in Section 4.6 to evaluate 
consistency of treatment effects across the subgroups. 
 
8.4.3. Manual Dynamometry 
 
Qualitative isometric dynamometry (hand-held dynamometer) will be used to assess the skeletal 
muscle strength of study subjects in both the upper and lower limbs bilaterally. Shoulders, flexors 
and extensors in the elbow, knees, and ankles as well as the grip bilaterally will be measured at 
each applicable visit. Isometric dynamometry measures the static muscle strength without any 
movement. This will be assessed at Baseline, Week 4, Week 12, Week 24, Week 36, Week 48, 
and Safety Follow-up. 
 
For each treatment, descriptive statistics of average and maximum weight in kilogram per visit as 
well as the change from baseline will be presented by overall and according to assessment (right 
shoulder abductors, left shoulder abductors, right elbow flexors, left elbow flexors, right elbow 
extensors, left elbow extensors,  right knee extension, left knee extension, right knee flexion, left 
knee flexion, right ankle dorsiflexors, left ankle dorsiflexors, right hand grip, and left hand grip). 
An MMRM model will be used to analyze the change from baseline in average weight with repeat 
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number category, treatment group, visit, and treatment-by-visit interactions as fixed effects and 
baseline value of average weight as a covariate. Within-group LS mean changes from baseline, the 
associated SEs and 2-sided 95% CIs, treatment differences in LS mean changes from baseline at 
post-baseline visits and the associated 2-sided 95% CIs and 2-sided p-values will be derived from 
the MMRM model and will be provided in the summary table.  An unstructured covariance matrix 
will be used to model the correlation among repeated measurements within each subject. If models 
using unstructured covariance do not converge, an AR(1) covariance structured will be used 
instead.  Similar methods will be used to analyze the change from baseline in maximum weight. 
 
Similar analysis will be done for total average manual dynamometry for: (a.) all muscles 
combined; (b.) upper extremity strength, in the shoulders and elbows combined; and (c.) lower 
extremity strength, which includes right knee extension, left knee extension, right knee flexion, 
left knee flexion, right ankle dorsiflexors, and left ankle dorsiflexors muscles combined. 
 
8.4.4. MFM Domain 1 
 
The MFM scale assesses the severity of the motor deficit. It provides a clinician’s assessment of 
functionality impairment for standing and transfers. Domain 1 has 13 items in version 1 and 15 
items in version 3 of the protocol with each item scored from 0 to 3. The MFM Domain 1 score 
corresponds to the sum of the item scores divided by the maximum score for this dimension and 
multiplied by 100 (ie, sum of scores/39*100 for 13 items questionnaire and sum of scores/45*100 
for the 15 items questionnaire). This will be assessed at Baseline, Week 12, Week 24, Week 36, 
and Week 48. 
 
For each treatment, descriptive statistics of the MFM Domain 1 scores (individual item scores and 
Domain 1 score) per visit as well as the change from baseline will be presented. An MMRM model 
will be used to analyze the change from baseline in MFM Domain 1 score with repeat number 
category, treatment group, visit, and treatment-by-visit interactions as fixed effects and baseline 
score as a covariate. Within-group LS mean changes from baseline, the associated SEs and 2-sided 
95% CIs, treatment differences in LS mean changes from baseline at post-baseline visits and the 
associated 2-sided 95% CIs and 2-sided p-values will be derived from the MMRM model and will 
be provided in the summary table.  An unstructured covariance matrix will be used to model the 
correlation among repeated measurements within each subject. If models using unstructured 
covariance do not converge, an AR(1) covariance structured will be used instead. 
8.4.5. FSHD-HI 
 
The FSHD-HI is an FSHD-specific patient-reported measure of disease burden on activities of 
daily living, quality of life, and symptom prevalence and severity. It consists of a questionnaire 
with 116 items developed from qualitative interviews of patients. The measure consists of 14 
subscales that measure a patient’s perception of their ambulation and mobility, hand function, 
shoulder and arm function, emotional health, back/chest/abdomen strength, fatigue, pain, eating 
function, ability to do activities, communication ability, satisfaction in social situations, 
performance situations, body image and cognition. The 116 items are combined into a total score, 
the score is then transformed onto a percentage scale, with 100 representing maximal disability, 
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and lower scores representing decreasing disability. This FSHD-HI total score will be calculated 
by a separate vendor. This score, along with the 14 subscale scores will be assessed at Baseline, 
Week 4, Week 12, Week 24, Week 36, Week 48, and Safety Follow-up. 
 
For each treatment, descriptive statistics of the FSHD-HI total and subscale scores per visit as well 
as the change from baseline will be presented. An MMRM model will be used to analyze the 
change from baseline in FSHD-HI total score with repeat number category, treatment group, visit, 
and treatment-by-visit interactions as fixed effects and baseline score as a covariate. Within-group 
LS mean changes from baseline, the associated SEs and 2-sided 95% CIs, treatment differences in 
LS mean changes from baseline at post-baseline visits and the associated 2-sided 95% CIs and 2-
sided p-values will be derived from the MMRM model and will be provided in the summary table.  
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements within each subject. If models using unstructured covariance do not converge, an 
AR(1) covariance structured will be used instead. Similar methods will be used to analyze the 
change from baseline in FSHD-HI subscale scores. 
 
8.4.6. PGIC 
 
The PGIC will be assessed to obtain the subject’s rating of overall improvement. The rating 
includes the following: 1= Very much improved, 2= Much improved, 3= Minimally improved, 4= 
No change, 5= Minimally worse, 6= Much worse, 7=Very much worse. This will be assessed at 
Week 4, Week 12, Week 16, Week 24, Week 36, Week 48, and Safety Follow-up. 
 
Responses of 1= Very much improved, 2= Much improved, and 3= Minimally improved will be 
considered as improved and responses of 4 = No change, 5 = Minimally worse, 6= Much worse, 
and 7=Very much worse will be considered as not improved. For each treatment, descriptive 
statistics of PGIC values and PGIC response categories will be presented.   
 
8.5. 
Inflammatory, Immune, Apoptotic, and Muscle Disease Transcripts 
 
The analysis of these exploratory endpoints will be described in a separate document. 
 
9. Safety Analysis 
 
All summaries of safety data will use the Safety Analysis Set and will be presented by treatment. 
9.1. 
Adverse Events 
 
A treatment-emergent AE (TEAE) is defined as an AE that meets any of the following conditions: 
• begins on or after the first dose of study drug and before the stop of study drug + 7 days; 
• begins before the first dose of study drug and worsens in severity on or after the first dose 
of study drug and before the stop of study drug + 7 days; 
• is completely missing an onset date and end date; 
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• is completely missing an onset date and the end date is on or after the first dose of study 
drug. 
 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be imputed 
as follows: 
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
• 
UK-MMM-YYYY: If the AE month and year are different from the month and year of the 
first dose of study drug, assume 01-MMM-YYYY. If the month and year are the same as 
the first dose of study drug month and year and the AE end date (after any imputation) is 
on or after the first dose of study drug, then assume the date of the first dose of study drug. 
If the AE month and year are the same as the first dose of study drug month and year and 
the AE end date (after any imputation) is prior to the first dose of study drug, then assume 
the end date for the onset date.  
• 
DD-UKN-YYYY/UK-UKN-YYYY: If the AE year is different from the year of first dose 
of study drug, assume DD-JAN-YYYY/01-JAN-YYYY of the collected year. If the AE 
year is the same as the first dose of study drug year and the AE end date (after any 
imputation) is on or after the first dose of study drug, then assume the date of the first dose 
of study drug. If the year is the same as the first dose of study drug and the AE end date 
(after any imputation) is prior to the first dose of study drug, then assume the end date for 
the onset date.  
 
Missing end dates (where UK and UKN indicate unknown or missing day and month respectively):  
• UK-MMM-YYYY: Assume the last day of the month; 
• DD-UKN-YYYY: Assume DD-DEC-YYYY; 
• UK-UKN-YYYY: Assume 31-DEC-YYYY. 
 
All AEs will be classified by SOC and PT according to the MedDRA version 22.0 or higher. 
 
An overview summary of the number and percentage of subjects with any TEAE, serious TEAE, 
study drug-related TEAE, study drug-related serious TEAE, TEAE leading to treatment 
discontinuation, TEAE leading to study withdrawal, and AE leading to death will be provided by 
treatment group. In addition, the number and percentage of subjects with AESI will be presented. 
Adverse events of special interest for this study include liver tests that meet the criteria for potential 
drug-induced liver injury (DILI), in accordance with the US Food and Drug Administration (FDA) 
“Guidance for Industry-Drug-Induced Liver Injury: Premarketing Clinical Evaluation”. Further 
details of liver tests and criteria are described in Section 9.2.2. 
 
9.1.1. Incidence of TEAEs 
 
Summaries of the total number of TEAEs and the number and percentage of subjects with at least 
one TEAE will be provided by treatment group. The number and percentage of subjects and the 
number of events will also be presented by SOC and PT. At each level of subject summarization, 
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a subject is counted once within each PT if the subject reported one or more events. Percentages 
will be based on the number of subjects in the Safety Analysis Set. The number of events will be 
summarized by treatment group.  
 
The summary of TEAEs will also be presented in descending order from the SOC with the highest 
total incidence (that is, summed across all treatment groups) to the SOC with the lowest total 
incidence. If the total incidence for any two or more SOCs is equal, the SOCs will be presented in 
alphabetical order. Within each SOC, the PTs will be presented in alphabetical order. 
 
An additional summary will be presented by PT only. This summary will be presented in 
descending order from the PT with the highest total incidence to the PT with the lowest total 
incidence. 
 
All AEs will also be presented in a listing. 
 
9.1.2. Relationship of TEAEs to Study Drug 
 
A summary of TEAEs by maximum relationship to study drug will be presented in a table by 
incidence of occurrence. The investigator will provide an assessment of the relationship of the 
event to the study drug. The possible relationships are “Unlikely Related”, “Possibly Related”, 
“Probably Related”, and “Definitely Related”. In the TEAE by maximum relationship table, if a 
subject reports multiple occurrence of the same TEAE, only the most related occurrence will be 
summarized. Percentages will be based on the number of subjects in the Safety Analysis Set. All 
AEs that have a missing relationship will be presented in the summary table as “Definitely 
Related” but will be presented in the data listing with a missing relationship. 
 
The AE data will be categorized and presented by SOC, PT, and relationship in the same manner 
to that described in Section 9.1.1. 
 
9.1.3. Severity of TEAE 
 
A summary of TEAEs by maximum severity will be presented in a table. The severity that will be 
presented represents the most extreme severity captured on the CRF page. The possible severities 
are “Mild”, “Moderate”, and “Severe”. In the TEAE by maximum severity table, if a subject 
reported multiple occurrences of the same TEAE, only the most severe occurrence will be 
summarized. AEs that are missing severity will be presented in tables as “Severe” but will be 
presented in the data listing with a missing severity. Percentages will be based on the number of 
subjects in the Safety Analysis Set. 
 
The AE data will be categorized and presented by SOC, PT, and severity in the same manner to 
that described in Section 9.1.1. 
 
 
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9.1.4. Serious TEAEs 
 
The seriousness of an AE should be assessed independently by the Investigator from the severity 
of the AE. An SAE is defined as any untoward medical occurrence that at any dose results in death, 
is life-threatening, is a congenital anomaly/birth defect, requires in-patient hospitalization or 
prolongation, or results in significant disability. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered SAEs when, based upon medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed above. 
SAE data will be presented by SOC and PT in the same manner to that described in Section 9.1.1.  
 
9.1.5. TEAEs Leading to Treatment Discontinuation 
 
A summary of TEAEs that caused treatment discontinuation will be presented in a table. At each 
level of subject summarization, a subject is counted once if the subject reported one or more events. 
Percentages will be based on the number of subjects in the Safety Analysis Set.  
 
 
TEAE leading to treatment discontinuation data will be presented by SOC and PT in the same 
manner to that described in Section 9.1.1. 
 
9.1.6. TEAEs Leading to Study Withdrawal 
 
A summary of TEAEs that lead to study discontinuation will be presented in a table. At each level 
of subject summarization, a subject is counted once if the subject reported one or more events. 
Percentages will be based on the number of subjects in the Safety Analysis Set.  
 
TEAE leading to study discontinuation data will be presented by SOC and PT in the same manner 
to that described in Section 9.1.1. 
 
9.1.7. Death 
 
A summary of TEAEs where the answer to ‘Outcome’ in the AE form is ‘Death Related to Adverse 
Event’ will be presented in a table. Percentages will be based on the number of subjects in the 
Safety Analysis Set.  
 
Death data will be presented by SOC and PT in the same manner to that described in Section 9.1.1. 
9.2. 
Clinical Laboratory Evaluations 
 
Laboratory assessments will be performed by a central laboratory. All summaries will be based on 
the units provided by the central laboratory (ie, no conversion will be done).  
 
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9.2.1. Hematology 
 
The following laboratory tests will be included: hemoglobin (including mean corpuscular volume), 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red blood 
cell count, total white blood count, platelet count, differential blood counts, including basophils, 
eosinophils, neutrophils, lymphocytes, and monocytes.  
 
Summary tables presenting observed values and changes from baseline will be presented for 
hematologic tests with numeric values by treatment group for subjects in the Safety Analysis Set. 
Changes from baseline to each scheduled post-baseline visit will be presented. All hematology 
data by subject will also be presented in a listing. 
 
The clinical assessment of ‘Low’, ‘Normal’, or ‘High’ relative to the reference range will be 
summarized in shift tables comparing the baseline results to maximum value post-baseline for 
those subjects with results at both visits.  
 
All hematology data by subject will be presented in a listing. 
 
9.2.2. Serum Chemistry 
 
The following laboratory tests will be included:  glucose, sodium, potassium, calcium, inorganic 
phosphate, total protein, albumin, blood urea nitrogen, creatinine, total bilirubin, alkaline 
phosphatase, 
aspartate 
aminotransferase, 
gamma-glutamyl 
transferase, 
and 
creatinine 
phosphokinase.  
 
Summary tables presenting observed values and changes from baseline will be presented for serum 
chemistry tests with numeric values by treatment group for subjects in the Safety Analysis Set. 
Changes from baseline to each scheduled post-baseline visit will be presented. All chemistry data 
by subject will also be presented in a listing. 
 
The clinical assessment of ‘Low’, ‘Normal’, or ‘High’ relative to the reference range will be 
summarized in shift tables comparing the baseline results to maximum value post-baseline for 
those subjects with results at both visits.  
 
Results indicating liver-related abnormalities (i.e., ALT, AST, Total Bilirubin, and/or Alkaline 
Phosphatase) will also be summarized separately. A newly notable laboratory abnormality is 
defined as an abnormality observed post baseline that meets the notable criteria in Table 9-1 and 
that did not exist at baseline. Subjects can still meet the criteria for a newly notable laboratory 
abnormality if the baseline value is missing. The table below displays the general variables and 
thresholds of interest. Subjects are considered to have notable laboratory abnormalities if his/her 
response falls within the specified definitions at least once during the treatment period.  
 
 
 
 
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Table 9-1: 
Notable Criteria for Laboratory Data Abnormalities – Liver Function Tests 
Laboratory 
Variable 
SI 
Units 
AST 
>3 x ULN 
ALT 
>3 x ULN 
Total Bilirubin  
>2 x ULN 
Alkaline Phosphatase (ALP) 
<2 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN and ALP < 2 x ULN 
(potential DILI or Hy’s law case) 
 
 
All chemistry data by subject will be presented in a listing. 
 
9.2.3. Urinalysis 
 
The following laboratory tests will be included: leukocytes, blood, nitrite, protein, urobilinogen, 
bilirubin, pH, specific gravity, ketones, and glucose.  
 
Summary tables presenting observed values and changes from baseline will be presented for 
urinalysis tests with numeric values by treatment group for subjects in the Safety Analysis Set. 
Changes from baseline to each scheduled post-baseline visit will be presented. 
 
All urinalysis data by subject will be presented in a listing. 
 
9.2.4. Other Laboratory Tests 
 
The following coagulation tests will also be reported: International normalized ratio, prothrombin 
time, and partial thromboplastin time. These parameters will be presented and summarized in the 
same manner to that described in Section 9.2.1. 
 
9.3. 
Vital Sign Measurements 
 
Summary tables will be presented for vital sign data, including pulse rate, respiration rate, blood 
pressure, and temperature by treatment for subjects in the Safety Analysis Set. Observed results at 
each visit will be presented. Change from baseline to each post-dose assessment will also be 
presented. All vital sign data by subject will also be presented in a listing. 
 
9.4. 
Physical Examination 
 
A table will summarize physical examination results by treatment for the Safety Analysis Set. 
Status of a body system and any finding associated with the body system as normal, abnormal, or 
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not done will be captured at screening and safety follow-up. Physical examination results for all 
subjects will also be presented in a listing.  
 
A separate table will be presented for the summary of neurological examination results. The scores 
collected in the CRF which is in ordinal scales will be converted into numeric scales according to 
the convention provided below. 
 
MMT score as collected in the CRF 
Numeric Scale 
0 
0 
1 
1 
2 
2 
3- 
2.67 
3 
3 
4- 
3.67 
4 
4 
4+ 
4.33 
5- 
4.67 
5 
5 
 
A total and average of the numeric score will be derived for upper extremity, lower extremity, and 
all muscle groups.  
 
The following are the components of the upper extremity: 
• Deltoid MRC Score Right  
• Deltoid MRC Score Left 
• Shoulder Abduction MRC Score Right  
• Shoulder Abduction MRC Score Left 
• Triceps MRC Score Right 
• Triceps MRC Score Left 
• Biceps MRC Score Right  
• Biceps MRC Score Left 
• Wrist Extension MRC Score Right  
• Wrist Extension MRC Score Left 
• Wrist Flexion MRC Score Right  
• Wrist Flexion MRC Score Left 
• Finger Extension MRC Score Right  
• Finger Extension MRC Score Left 
• Finger Flexion MRC Score Right  
• Finger Flexion MRC Score Left 
• Grip MRC Score Right  
• Grip MRC Score Left 
 
The following are the components of the lower extremity: 
• Hip Flexion MRC Score Right  
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• Hip Flexion MRC Score Left 
• Knee Extension MRC Score Right  
• Knee Extension MRC Score Left 
• Knee Flexion MRC Score Right  
• Knee Flexion MRC Score Left 
• Hip Abduction MRC Score Right  
• Hip Abduction MRC Score Left 
• Hip Adduction MRC Score Right  
• Hip Adduction MRC Score Left 
• Ankle Dorsiflexion MRC Score Right  
• Ankle Dorsiflexion MRC Score Left 
• Plantarflexion MRC Score Right  
• Plantarflexion MRC Score Left 
 
Total score in the upper extremity is derived as the sum of numeric scores of muscles included in 
the upper extremity. Total score in the lower extremity is derived as the sum of numeric scores of 
muscles included in the lower extremity. Total score in all muscle groups is the sum of numeric 
scores of muscles in the upper and lower extremities plus the numeric score in neck flexion and 
neck extension. 
 
Average score in the upper extremity is the sum of numeric scores of muscles included in the upper 
extremity divided by 18.  Average score in the lower extremity is the sum of numeric scores of 
muscles included in the lower extremity divided by 14.  Average score in all muscle groups is the 
sum of numeric scores of muscles in the upper and lower extremities and numeric scores in neck 
flexion and neck extension divided by 34. 
 
Neurological examination results for all subjects will also be presented in a listing.  
 
9.5. 
Electrocardiogram 
 
All subjects will have a standard 12-lead ECG performed during the study as clinically indicated.  
Electrocardiogram data for all subjects will also be presented in a listing. 
 
Descriptive summaries will be provided for the ECG data including ventricular rate (bpm), PR 
interval (msec), QRS duration (msec), QT interval (msec), and QTcF interval (msec) by treatment 
group for subjects in the Safety Analysis Set. In addition, number and percentage of subjects with 
normal sinus rhythm will also be presented in a table. Observed results at each visit will be 
presented. Change from baseline to each post-dose assessment will also be presented.  
 
The number and percentage of subjects with an overall evaluation of ‘Normal’, ‘Abnormal, Not 
Clinically Significant’, or ‘Abnormal, Clinically Significant’ will be presented for baseline, Week 
4, Week 48, End of Treatment, and Safety Follow-up. 
 
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A categorical summary of QTcF values and change from baseline at each visit will be presented 
by number and percentage for the Safety Analysis Set. Categories for reporting absolute QTcF 
interval are defined as: >450 to 480 msec, >480 to 500 msec, and >500 msec. Change from baseline 
in QTc interval is classified as: >30 to 60 msec increase from baseline and >60 msec increase from 
baseline.  
 
ECG data for all subjects will also be presented in a listing. 
 
10. Pharmacokinetics 
By-subject listing of pharmacokinetic blood sample and muscle sample collection times as well as 
derived sampling time deviations will be provided.  Losmapimod plasma and muscle 
concentrations will be summarized using descriptive statistics (n, mean, standard deviation, 
minimum, median, maximum, coefficient of variation) by scheduled time point.  Concentrations 
that are below the limit of quantitation (BLQ) will have a value of LLOQ value divided by 2 in 
the computation of descriptive statistics. Mean concentration-time data will be graphically 
presented. All data presentation will use the PK Analysis Set. 
Predose samples that are missing will be assigned as missing. 
Concentrations assigned a value of missing will be omitted from the calculation of descriptive 
statistics.  A concentration value of zero will be included for the computation of arithmetic mean.  
If 50% or more of the values are BLQ at one scheduled time point, the arithmetic mean will be 
reported as BLQ. 
The individual and mean plasma concentrations and the individual and mean concentrations in 
skeletal muscle biopsies will be presented by scheduled time point in figures on linear scales. 
 
 
11. Pharmacodynamics  
 
For each treatment, descriptive statistics of natural log (ln) transformed pHSP27 concentrations in 
blood will be presented at Baseline, Week 16, and Week 36 as well as change from baseline at 
Week 16 and Week 36.  An MMRM model will be used to analyze the change from baseline in 
ln-transformed pHSP27 in blood with repeat number category, treatment group, visit, and 
treatment-by-visit interactions as fixed effects and baseline value of ln-transformed pHSP27 in 
blood as a covariate. Within-group LS mean changes from baseline, the associated SEs and 2-
sided 95% CIs, treatment differences in LS mean changes from baseline at post-baseline visits and 
the associated 2-sided 95% CIs and 2-sided p-values will be derived from the MMRM model and 
will be provided in the summary table.  An unstructured covariance matrix will be used to model 
the correlation among repeated measurements within each subject. If models using unstructured 
covariance do not converge, an AR(1) covariance structured will be used instead. Similar methods 
will be used to analyze the change from baseline in ln-transformed values of total pHSP27 and ln-
transformed values of pHSP27 to total HSP27 ratio in blood. Similar methods will be used to 
analyze the change from baseline within subgroups identified in Section 4.6 (#1 - #3) to evaluate 
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consistency of treatment effects across the subgroups. For the repeat category subgroup analysis, 
the repeat category will be excluded as fixed effect from the model. 
 
Point estimates (i.e., LS means) will be back transformed using the exponential function to 
tabularly and graphically present the ratio of postbaseline to baseline in pHSP27.  Percent change 
from baseline, calculated as the difference in the ratio of postbaseline to baseline minus 1 times 
100, will also be tabularly and graphically presented.   
Population PK and PK/PD models may be developed to address program objectives that require 
an integrative interpretation of these study results. These may include investigations of the nature 
of the PK/PD relationship and the use of these study results as part of a larger model-based data 
analysis. If population PK and PK/PD analyses are performed, those results will be reported 
separately from the results of this study. 
12. Interim Analysis 
 
Initially, no interim analysis for efficacy was planned. However, based on protocol version 4.0 
(COVID-19 Pandemic Emergency Amendment) dated 10Apr2020, an interim analysis was 
included to provide timely data to inform the further development of losmapimod for the treatment 
of FSHD. 
 
 One IA will be performed when a minimum of 22 paired muscle biopsies are completed. A group 
sequential method (O’Brien-Fleming Spending Function) will be used to ensure an overall 
significance level of 0.05 (double-sided) due to multiple looks at the DUX4 primary endpoint, if 
the IA is deemed necessary by the Sponsor. 
 
• With a sample size of approximately 22 subjects at IA, the test alpha at IA is approximately 
0.001, and the final test alpha is 0.05. If the p-value from the test is <0.001, then the study 
may be stopped for efficacy, or continue as planned as decided by the Sponsor. Cumulative 
exit probability under the alternative hypothesis is approximately 2.3% and approximately 
82.3% at the IA and final analysis, respectively (SAS Version 9.4; nQuery 8 – Power and 
Sample Size for Group Sequential Trials, Version 8.5.1.0). 
 
• With a sample size of 32 subjects at IA, the test alpha at IA is approximately 0.004, and 
the final test alpha is 0.048. If the p-value from the test is <0.004, then the trial may be 
stopped for efficacy, or continue as planned as decided by Sponsor. Cumulative exit 
probability under the alternative hypothesis is approximately 13.9% and approximately 
82.2% at the IA and final analysis, respectively (SAS Version 9.4; nQuery 8 – Power and 
Sample Size for Group Sequential Trials, Version 8.5.1.0). 
 
The alpha at the time of the IA for sample size ranging from 22 to 32 are provided in Table 12-1 
 
 
 
 
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Table 12-1 Alpha at Interim Analysis and Final Analysis for Different Sample Sizes at 
Interim Analysis (O’Brien Fleming Method) 
 
Interim Analysis Sample Size 
Alpha at Interim Analysis 
Alpha at Final 
22 
0.000567 
0.049755 
23 
0.000736 
0.049685 
24 
0.000951 
0.049596 
25 
0.001203 
0.049493 
26 
0.001474 
0.049384 
27 
0.001803 
0.049253 
28 
0.002173 
0.049107 
29 
0.002556 
0.048959 
30 
0.003005 
0.048787 
31 
0.003496 
0.048602 
32 
0.004027 
0.048405 
 
 
The DUX4, PK, demographics, disposition data and sub-group analysis on the DUX4 endpoint 
(Section 4.6, #1 to #5 and #11)will be presented to the Sponsor as group-level summaries of the 
unblinded data with associated p-values. The respective tables are indicated in the List of Planned 
Summary Tables.  
 
13. Safety Review Committee (SRC) 
 
A SRC will be appointed for the study. The primary responsibility of the SRC will be to act in an 
advisory capacity to the Sponsor to safeguard the interests of trial patients by monitoring patient 
safety, assess patient risk versus benefit, and assess data quality and general evaluation of the trial 
progress. Its activities will be delineated in a SRC charter that will define the membership, 
responsibilities and the scope and frequency of data reviews. The SRC may have an organizational 
meeting prior to commencement of the trial. The SRC will have meetings where it will review 
blinded data during a closed session. These meetings will be planned at regular intervals. They 
may convene ad hoc meetings based on rates of SAEs if safety concerns arise during the trial. 
After its assessment, the SRC will recommend continuation, modification or termination of the 
clinical trial. 
The blinded team will prepare the safety tables, listings and/or figures using the dummy 
randomization and materials/kits schedule. 
 
 
 
 
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14. References 
 
Han J, Kurillo G, Abresch R, et al. Reachable Workspace in Facioscapulohumeral muscular 
dystrophy (FSHD) by Kinect. Muscle Nerve. 2015 February ; 51(2): 168-175 
 
Lemmers RJ, Wohlgemuth M, Frants RR, et al. Contractions of D4Z4 on 4qB subtelomeres do 
not cause facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2004;75:1124-30. 
Lemmers RJ, van der Vliet PJ, Klooster R, et al. A unifying genetic model for 
Facioscapulohumeral Muscular Dystrophy. Science. 2010;329(5999):1650-3. 
Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an 
FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat 
Genet. 2012;44(12):1370-4. 
Ruiz-Cortes X, Ortiz-Corredor F, Mendoza-Pulido C, Reliabilty of home-based, motor function 
measure in hereditary neuromuscular diseases. Journal of International Medical Research. 2017, 
Vol. 45 (I) 261-271 
Statland JM and Tawil R. Risk of functional impairment in facioscapulohumeral muscular 
dystrophy. Muscle Nerve. 2014;49(4):520-7. 
Statland JM, Shah B, Henderson D, et al. Muscle pathology grade for facioscapulohumeral 
muscular dystrophy biopsies. Muscle Nerve. 2015;52(4):521-6. 
Statland JM, Odrzywolski KJ, Shah B, et al. Immunohistochemical characterization of 
facioscapulohumeral muscular dystrophy muscle biopsies. J Neuromuscul Dis. 2015; 2(3):291-9. 
Tawil R, Forrester J, Griggs RC, et al. Evidence for anticipation and association of deletion size 
with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol. 
1996;39 (6):744–48. 
Tawil R, Kissel JT, Heatwole C, et al. Evidence-based guideline summary: Evaluation, diagnosis, 
and management of facioscapulohumeral muscular dystrophy: Report of the Guideline 
Development, Dissemination, and Implementation Subcommittee of the American Academy of 
Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular 
& Electrodiagnostic Medicine. 2015;85(4):357-64. 
 
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15. Appendices 
 
 
 
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15.1. The Steps from Raw QPCR Ct to Statistical Analysis 
 
1. Raw Cts from qPCR are determined for DUX4 regulated genes using a validated assay 
(Fluidigm), described in Appendix 15.2. 
2. The raw Cts from the genes are normalized to reference (housekeeping) genes using the 
process described in Appendix 15.3. The document also describes the method for 
selecting the reference genes. 
3. A mean DUX4 score is created for each subject using the normalized data, at baseline 
and post-baseline, using the derivation described in Appendix 15.4. 
a. Six DUX4-regulated gene transcripts were selected, a priori, to be in a mean 
DUX4 score. The process of selection of these 6 genes is detailed in Appendix 
15.5. 
4. An ANCOVA regression model is then used to test the hypothesis for change in the 
composite score between treatment arms.  
 
 
 
 
 
 
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15.3.  QPCR Normalization 
 
 
 
 
  
 
 
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15.4. Derivation of DUX4 Score from Delta CT 
Select only rows pertaining to the following 6 gene transcripts: CCNA1; KHDC1L; MBD3L2; 
PRAMEF6; SLC34A2; ZSCAN4 
 
DUX4 Score 1: Mean 
Take the mean of delta-CT values across all 6 transcripts, by subject, by timepoint 
 
DUX4 Score 2: Standardized Z-Score Composite 
Step 1 (Pre-Treatment data only): (By gene transcript) 
I. 
Calculate Mean (measure of average) of delta CT 
II. 
Calculate standard deviation (measure of variability) of delta CT  
 
Step 2 (Pre-treatment and post-treatment: By gene transcript; by subject) 
I. 
Use variability obtained in Step 1 to calculate standardized score per gene transcript, per 
patient:  
 
𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑𝑖𝑧𝑒𝑑 𝑆𝑐𝑜𝑟𝑒
= (𝑁𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑒𝑑 𝐷𝑒𝑙𝑡𝑎 𝐶𝑡 𝑉𝑎𝑙𝑢𝑒−𝑀𝑒𝑎𝑛) ÷ 𝑆𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝐷𝑒𝑣𝑖𝑎𝑡𝑖𝑜𝑛 
 
a. Rationale: Standardize all gene measures to the same scale; reduce the impact of 
highly variable genes in the final composite measure 
 
II. 
Calculate  mean of standardized scores for each patient, across all genes, by visit.  
a. Each patient’s final score is the mean standardized score across multiple 
transcripts. 
b. This “composite score” is then used in the analysis for change from baseline. 
 
DUX4 Score 3: Median 
Take the median of delta-CT values across all 6 transcripts, by subject, by timepoint 
 
 
 
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15.5. Selection of 6 gene transcripts 
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15.6. 
Derivation of MRI Composite Score 
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Page 1/2
Input to the Statistical Plan for FSHD analysis 
Muscle categorization 
Each muscle is categorized into one of three categories1: 
A. ‘Normal’ muscles are normal appearing (low MFI and MFF, muscle likely unaffected by disease) 
B. ‘Affected’ muscles have a likely disease involvement (intermediate MFI and MFF) 
C. ‘End-stage’ corresponds to that more than 50% of the muscle tissue has been replaced by fat, and most of the functional capacity is likely lost 
Muscle category 
MFF criteria 
 
MFI criteria 
A. Normal 
MFF < 50% 
AND 
MFI < 10% 
B. Affected 
MFF < 50% 
AND 
MFI ≥ 10% 
C. End-stage 
MFF ≥ 50% 
- 
- 
Quality control of measurements 
Trained anatomical imaging experts evaluate the signal quality in each muscle. If a muscle is not analyzable, that muscle is marked as not analyzable 
and no measurements will be extracted from it. For cross-sectional analysis minor quality issues are accepted, but not for longitudinal analysis. Hence, 
as seen below, we’ll use different statistical inclusion parameters depending on if we are doing a cross-sectional or longitudinal analysis. 
Statistical inclusion parameters 
The muscle categorization and quality control results are summarized in 3 statistical inclusion parameters which will be provided for each muscle: 
• 
Statistical Inclusion Category: Can take the values A, B or C, which correspond to ‘Normal’, ‘Affected’ and ‘End-stage’. Abbreviated SIcat in 
equations. 
• 
Statistical Inclusion Cross-sectional: Can take the values 0 or 1 (0 if there are major signal quality issues indicating unreliable measurement, 
1 otherwise). Abbreviated SIcross in equations. 
• 
Statistical Inclusion Longitudinal: Can take the values 0 or 1 (0 if there are any signal quality issues, including minor, 1 otherwise). 
Abbreviated SIlong in equations. 
Note: In general, if a SI parameter is ‘Unable to Assess’, ‘NA’ or ‘0’, that muscle should be excluded from the corresponding data analysis. . As for 
other muscle measurements, the SI parameters will have a corresponding ‘Quality Issues’ column – these columns may be ignored. 
Whole-body combined measurements 
Cross-sectional analysis 
MRI-based measurements from multiple muscles is combined to obtain global measurements of disease affection for correlation to disease severity or 
functional test scores in cross-sectional data: 
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15.7. 
Schedule of Study Procedures 
15.7.1. 
Schedule of Study Procedures: Placebo-Controlled Treatment Period 
 
  
Procedure 
Screening 
Baselin
e 
Wee
k 
4 
Wee
k 
12 
Week 
16 
Wee
k 24  
Wee
k 36 
Week 48 
End of Placebo-
Controlled 
Treatment 
Period/Start of 
OLEa 
ET 
Visit
b 
Safety Follow-
Up 
7 Days After the 
Last Dose of 
Study Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
Visit Window (days)d 
–28 to –1 
Day 1 
5 
5 
5 
5 
±14aa
  
±5  
 
3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Confirm eligibility via 
inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Height and BMIe 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xf 
 
 
 
 
 
 
 
 
FSHD-specific historyg 
X 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, 
HIV1/HIV2) 
X 
 
 
 
 
 
 
 
 
 
Urine drug screenh 
X 
 
 
 
 
 
 
 
 
 
Genetic confirmation of 
FSHD1i 
X 
 
 
 
 
 
 
 
 
 
Serum β-hCGk 
X 
 
 
 
 
 
 
 
 
 
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Procedure 
Screening 
Baselin
e 
Wee
k 
4 
Wee
k 
12 
Week 
16 
Wee
k 24  
Wee
k 36 
Week 48 
End of Placebo-
Controlled 
Treatment 
Period/Start of 
OLEa 
ET 
Visit
b 
Safety Follow-
Up 
7 Days After the 
Last Dose of 
Study Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
Serum follicle-stimulating 
hormonel 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighte 
X 
X 
 
 
  
 
 
X 
X 
X 
Vital signsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationo 
X 
 
 
 
 
 
 
 
 
X 
Standard 12-lead ECGp 
X 
X 
X 
 
 
 
 
X 
X 
X 
Serum chemistry 
Xq 
X 
X 
X 
X 
X 
X  
X 
X 
X 
Hematology 
Xq 
X 
X 
X 
X 
X 
X  
X 
X 
X 
Blood sample for coagulationbb 
Xq 
 
 
 
 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
X 
X 
MSK MRIr 
X 
 
 
X 
 
 
 
X 
Xs 
 
Muscle needle biopsyt 
 
X 
 
 
X 
 
Xt  
 
 
 
PK samplingu 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Target engagement samplingv 
 
X 
 
  
X 
 
X  
  
 
 
 
 
RWS 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
TUG (classic and FSHD) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Manual dynamometry 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
MFM Domain 1 
 
X 
 
X 
 
X 
X 
X 
X 
 
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Procedure 
Screening 
Baselin
e 
Wee
k 
4 
Wee
k 
12 
Week 
16 
Wee
k 24  
Wee
k 36 
Week 48 
End of Placebo-
Controlled 
Treatment 
Period/Start of 
OLEa 
ET 
Visit
b 
Safety Follow-
Up 
7 Days After the 
Last Dose of 
Study Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
FSHD-HI questionnaire 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
PGIC questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensationx 
 
X 
X 
X 
X 
Xy 
X 
X 
 
 
Study drug count 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medicationsz 
Continuous from signing the ICF through the safety follow-up visit 
Concomitant treatments and 
procedures 
Continuous from signing the ICF through the safety follow-up visit 
Adverse event monitoring 
Continuous from signing the ICF through the safety follow-up visit 
Abbreviations: β-hCG, beta human chorionic gonadotropin; BMI, body mass index; ECG, electrocardiogram; ET, early termination; 
FSHD, facioscapulohumeral muscular dystrophy; FSHD-HI, Facioscapulohumeral Muscular Dystrophy Health Index; HBsAg, hepatitis B surface 
antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent form; MFM, Motor Function Measure; 
MRI, magnetic resonance imaging; MSK, musculoskeletal; OLE, open-label extension; PGIC, Patients’ Global Impression of Change; 
PK, pharmacokinetic(s); RWS, Reachable Work Space; STIR, short tau inversion recovery; TUG, Timed Up and Go.  
Note: Some procedures may not have been performed due to the COVID-19 pandemic. Please refer to the ReDUX4 Emergency Guidance 
document. 
a 
Prior to the COVID-19 pandemic, subjects who reached the Week 24 visit had the option to roll over into the OLE. For subjects who had already 
rolled over, their next clinic visits will follow the assessments for the Week 36 and Week 48 visit in the placebo-controlled portion of the study in 
the COVID-19 Pandemic Emergency protocol version 4.0; however, these specific subjects will not undergo the Week 36 biopsy. Those subjects 
who rolled over before the COVID-19 pandemic protocol version 4.0 was implemented will remain on open label treatment. Subjects who did not 
roll over prior to the COVID-19 pandemic will roll over when they reach Week 48. Subjects who roll over into the OLE should not complete the 
ET visit or safety follow-up visit from the placebo-controlled treatment period. 
b 
If a subject prematurely discontinues study treatment during the placebo-controlled treatment period, they will be encouraged to remain in the 
study and continue with all other aspects of the study. If a subject decides to prematurely discontinue study treatment during the 
placebo-controlled treatment period and not continue with all other aspects of the study, they will be considered to have withdrawn from the study. 
If a subject withdraws from the study during the placebo-controlled treatment period, they will be asked to complete an ET visit as soon as 
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possible after the decision to terminate study participation and to complete the safety follow-up visit 7 (±3) days after their last dose of study drug. 
If the ET visit will be scheduled more than 7 days after the last dose of study drug, the safety follow-up and ET visits may be combined, with no 
duplication of assessments required. 
c 
The safety follow-up visit 7 (±3) days after the last dose of study drug should only be completed by subjects who are not rolling over into the 
OLE. 
d 
Scheduled visits may be split over 2 days if required, with a maximum of 5 business days in between visits. Unscheduled visits may be performed 
if clinically indicated. Subjects can travel for MRI or muscle biopsy if needed, but the use of a study-approved MRI scanner should be consistent 
during the trial. 
e 
Weight and height will be measured with shoes off and preferably with the same balance at each visit. Body mass index will be calculated at 
Screening. 
f 
Medical history will be reviewed at baseline to ensure no changes have occurred since the screening visit.  
g 
FSHD-specific history will be recorded at screening or at a subject’s next scheduled study visit, if not previously recorded.  
h 
Urine drug screen for drugs of abuse including cocaine, amphetamines, opiates (morphine), benzodiazepines, and cannabinoids. 
i 
Genetic confirmation must be obtained before the subject is randomized and before the baseline muscle biopsy is performed; genetic confirmation 
can come from previous testing if verified with appropriate documentation from an accredited laboratory. Due to the stable transmission of repeat 
sizes within families, subjects with a clinical diagnosis of FSHD who have a first-degree relative with a genetically confirmed diagnosis of 
FSHD1 may be entered into the study for screening assessments, including MRI. During screening, a confirmatory genetic diagnosis will be 
conducted. If genetic testing is necessary, the 4-week screening window and activities will not start until the results are obtained and verified by 
the principal investigator. 
k 
Serum pregnancy tests will be performed at screening for all female subjects of child-bearing potential. 
l 
Serum follicle-stimulating hormone testing is required for suspected postmenopausal female subjects only. 
m 
Urine pregnancy tests will be performed for all female subjects of child-bearing potential before randomization at all other visits. If pregnancy is 
found, subjects must be terminated from the study effective immediately. 
n 
Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the subject has been seated or recumbent for at 
least 5 minutes and before any 12-lead ECG assessment or blood sampling is performed.  
o 
Physical examination at the screening visit and the safety follow-up visit include an evaluation of body systems, including but not limited to the 
following: skin; head, eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological 
system; and MSK system. Symptom-directed physical examinations can occur at any time during the study if triggered by adverse events or if 
deemed necessary by the investigator.  
p 
Twelve-lead ECGs will be performed after subjects have been recumbent for at least 5 minutes. Twelve-lead ECGs will be performed after the 
measurement of vital signs and before any procedures that may affect heart rate (eg, blood sampling). 
q 
For the screening visit, subjects will be required to fast for at least 4 hours prior to laboratory blood samples being taken. 
r 
Subjects will be screened for any contraindications to MRI as per clinic standard practice. 
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s 
The MRI at the ET visit will not be repeated if an MRI was completed during the previous 8 weeks. 
t 
The choice of the muscle(s) to be biopsied in this study will be determined by the investigator, informed by skeletal muscle MRI during screening. 
The bilateral vastus lateralis, vastus medialis, lateral gastrocnemius, medial gastrocnemius, and tibialis anterior will be evaluated for eligibility by 
MRI using a central reader. Only those muscles that are STIR positive with the predetermined range of muscle fat fraction will be eligible for 
biopsy. The 12 patients who rolled over at Week 24 will not undergo the Week 36 muscle biopsy. 
u 
Blood samples for PK will be collected at Day 1 (baseline), Week 4, Week 16, and Week 36 at the following time points: immediately predose and 
4 hours (±30 minutes) after administration of the study dose. Blood samples will also be taken, when feasible, after dosing during the Week 12, 
Week 24, and Week 48 visits, preferably ≥1 hour after dosing. 
v 
Blood samples for target engagement will be collected on Day 1 (baseline), and Week 16 or Week 36, at the following time points: immediately 
predose and 4 hours (±30 minutes) after administration of the study dose. 
x 
The appropriate amount of study drug supply (losmapimod or placebo) will be given to the subject at each applicable visit to allow for dosing 
until their next scheduled study visit plus additional tablets to cover the visit window. Study drug (losmapimod or placebo) will be administered as 
2 tablets taken twice daily and should be taken with food. Subject diaries may only be used for a portion of the placebo-controlled portion of the 
trial to record the date and time of each dose taken. This information may also be used to calculate compliance. Subjects will record the date and 
time of each dose of study drug taken (losmapimod or placebo) in the subject diary. Subjects may be provided additional study drug via courier 
service, as applicable.  
y 
Subjects who are rolling over into the OLE will be dispensed open label losmapimod at the time of the rollover visit. Subjects may be provided 
open label losmapimod via courier or shipping service, as applicable. 
z 
All medications taken within 28 days before screening through the safety follow-up visit will be recorded. 
aa 
Large window given to accommodate the COVID-19 pandemic.  
bb 
It is optional to perform coagulation studies prior to muscle biopsies. Refer to your institutional guidelines.  
 
 
 
 
 
 
 
 
 
 
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15.7.2. 
Schedule of Study Procedures: Open-Label Extension (Visits will Occur Quarterly Until Study Drug 
Approval or Study is Discontinued) 
 
Procedure 
Week 60 
Week 108 
Week 156 
Week 204 
Week 72 
Week 120 
Week 168 
Week 216 
Week 84 
Week 132 
Week 180 
Week 96 
Week 144 
Week 192 
ET 
Visita 
Safety Follow-Up 
7 Days After the 
Last Dose of Study 
Drug 
Visit Window (days)b 
7 
7 
7 
7 
 
3  
Weight, height, and BMIc 
 
X 
 
 
 
 
 
 
 
 
Urine pregnancy teste 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
Physical examinationg 
 
 
 
 
 
X 
Standard 12-lead ECGh 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
MSK MRIi 
 
X 
 
X 
Xj 
 
PK samplingk 
X 
X 
X 
X 
X 
 
 
 
RWS 
X 
X 
X 
X 
X 
X 
TUG (classic and FSHD) 
X 
X 
X 
X 
X 
X 
Manual dynamometry 
X 
X 
X 
X 
X 
X 
MFM Domain 1 
X 
X 
X 
X 
X 
 
FSHD-HI questionnaire 
X 
X 
X 
X 
X 
X 
PGIC questionnaire 
X 
X 
X 
X 
X 
X 
Clinic visit 
X 
X 
X 
X 
X 
X 
Study drug dispensationm 
X 
X 
X 
X 
 
 
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Procedure 
Week 60 
Week 108 
Week 156 
Week 204 
Week 72 
Week 120 
Week 168 
Week 216 
Week 84 
Week 132 
Week 180 
Week 96 
Week 144 
Week 192 
ET 
Visita 
Safety Follow-Up 
7 Days After the 
Last Dose of Study 
Drug 
Study drug count 
X 
X 
X 
X 
X 
 
Concomitant medicationsn 
Continuous from signing the ICF through the safety follow-up visit 
Concomitant treatments and procedures 
Continuous from signing the ICF through the safety follow-up visit 
Adverse event monitoring 
Continuous from signing the ICF through the safety follow-up visit 
Abbreviations: BMI, body mass index; ECG, electrocardiogram; ET, early termination; FSHD, facioscapulohumeral muscular dystrophy; FSHD-HI, 
Facioscapulohumeral Muscular Dystrophy Health Index; ICF, informed consent form; MFM, Motor Function Measure; MRI, magnetic resonance 
imaging; MSK, musculoskeletal; OLE, open-label extension; PGIC, Patients’ Global Impression of Change; PK, pharmacokinetic(s); RWS, 
Reachable Work Space; TUG, Timed Up and Go.  
a 
If a subject prematurely discontinues study treatment during the OLE, they will be encouraged to remain in the study and continue with all other 
aspects of the study. If a subject decides to prematurely discontinue study treatment during the OLE and not continue with all other aspects of the 
study, they will be considered to have withdrawn from the study. If a subject withdraws from the study during the OLE, they will be asked to 
complete the ET visit as soon as possible after the decision to terminate study participation and to complete the safety follow-up visit 7 (±3) days 
after their last dose of study drug. If the ET visit will be scheduled more than 7 days after the last dose of study drug, the safety follow-up and ET 
visits may be combined, with no duplication of assessments required. 
b 
Scheduled visits may be split over 2 days if required, with a maximum of 5 business days in between visits. Unscheduled visits may be performed 
if clinically indicated. Subjects can travel for MRI or muscle biopsy if needed, but the use of a study-approved MRI scanner should be consistent 
during the trial. 
c 
Weight and height will be measured and BMI will be calculated once a year (ie, Week 48, Week 96, Week 144, etc.). Weight and height will be 
measured with shoes off and preferably with the same balance. 
e 
Urine pregnancy tests will be performed for all female subjects of child-bearing potential before dispensation of study drug. If pregnancy is found, 
subjects must be terminated from the study effective immediately. 
f 
Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the subject has been seated or recumbent for at 
least 5 minutes and before any 12-lead ECG assessment or blood sampling is performed.  
g 
Physical examination at the safety follow-up visit includes an evaluation of body systems, including but not limited to the following: skin; head, 
eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological system; and MSK 
system. Symptom-directed physical examinations can occur at any time during the study if triggered by adverse events or if deemed necessary by 
the investigator.  
h 
Twelve-lead ECGs will be performed after subjects have been recumbent for at least 5 minutes. Twelve-lead ECGs will be performed after the 
measurement of vital signs and before any procedures that may affect heart rate (eg, blood sampling). 
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j 
The MRI at the ET visit will not be repeated if an MRI was completed during the previous 12 weeks. 
k 
Blood samples for PK will be collected after dosing at each clinic visit, preferably ≥1 hour after dosing. 
l 
 Blood samples may be used to aid in the discovery of potential biomarkers of FSHD disease activity and treatment effects.. Serum and plasma 
samples taken twice a year (ie, every 24 weeks [ Week 72, Week 96, Week 120, Week 144, Week 168, etc.]) will be used.  
m 
The appropriate amount of study drug supply (losmapimod) will be given to the subject at each applicable visit to allow for dosing until their next 
scheduled study visit plus additional tablets to cover the visit window or additional study drug will be provided to the subject via a courier, as 
applicable. Study drug (losmapimod) will be administered as 2 tablets taken twice daily and should be taken with food.  
n 
All medications taken within 28 days before screening through the safety follow-up visit will be recorded. 
 
 
 
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15.8. 
List of Planned Summary Tables 
 
 
TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.1.1 
Subject Disposition 
FAS 
U 
5.1 
Standard 
 
Y 
Table 
14.1.2 
Protocol Deviations 
FAS 
U 
5.2 
Standard 
 
 
Table 
14.1.3.1 
Demographics 
FAS 
U 
6.1 
Standard 
Y 
Y 
Table 
14.1.3.2 
Demographics 
Safety Analysis Set R 
6.1 
Standard 
 
 
Table 
14.1.4.1 
Baseline Disease Characteristics 
FAS 
U 
6.2 
Standard 
Y 
 
Table 
14.1.4.2 
Baseline Disease Characteristics 
Safety Analysis Set R 
6.2 
Standard 
 
 
Table 
14.1.5 
Medical History 
FAS 
U 
6.3 
Standard 
 
 
Table 
14.1.6.1 
Prior Medications 
Safety Analysis Set U 
7.1.1 
Standard 
 
 
Table 
14.1.6.2 
Concomitant Medications 
Safety Analysis Set R 
7.1.2 
Standard 
 
 
Table 
14.1.7.1 
Study Drug Exposure 
Safety Analysis Set U 
7.2.1 
Standard 
 
 
Table 
14.1.7.2 
Drug Compliance 
Safety Analysis Set U 
7.2.2 
Standard 
 
 
Table 
14.2.1.1 
Summary of Losmapimod Concentrations by Scheduled 
Time and Specimen Type 
PK Analysis Set 
U 
10 
Efficacy 
 
Y 
Table 
14.2.1.1.1 
Summary of Losmapimod Concentrations by Scheduled 
Time and Specimen Type 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
10 
Efficacy 
 
 
Table 
14.2.1.2.1 
Summary of Target Engagement Estimates in Blood 
PD analysis set 
U 
11 
Efficacy 
Y 
 
Table 
14.2.1.2.2 
Summary of Target Engagement Estimates in Blood by 
Baseline Repeat Category 
PD analysis set 
U 
11 
Efficacy 
 
 
Table 
14.2.1.2.3 
Summary of Target Engagement Estimates in Blood by 
Baseline Clinical Severity Score 
PD analysis set 
R 
11 
Efficacy 
 
 
Table 
14.2.1.2.4 
Summary of Target Engagement Estimates in Blood by Sex PD analysis set 
R 
11 
Efficacy 
 
 
Table 
14.2.1.2.3.1 
Summary of Target Engagement Estimates 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
10 
Efficacy 
 
 
Table 
14.2.2.1.1 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
FAS 
U 
8.1 
Efficacy 
Y 
Y 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.2.1.2 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Baseline Repeat Category 
FAS 
U 
8.1 
Efficacy 
Y 
Y 
Table 
14.2.2.1.3 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Baseline DUX4 Score 1 
FAS 
R 
8.1 
Efficacy 
Y 
Y 
Table 
14.2.2.1.4 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Sex 
FAS 
R 
8.1 
Efficacy 
Y 
Y 
Table 
14.2.2.1.5 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Fat Fraction at Biopsy Site 
FAS 
R 
8.1 
Efficacy 
Y 
Y 
Table 
14.2.2.1.6 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Total DUX4 Score (DUX4 Score 1) 
FAS 
R 
8.1 
Efficacy 
Y 
Y 
Table 
14.2.2.1.7 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Subjects Who Completed RWS Protocol With Above 
Shoulder Movements at Baseline 
FAS 
R 
8.1 
Efficacy 
Y 
 
Table 
14.2.2.1.8 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Subjects Who Completed RWS Protocol With Above 
Shoulder Movements All Through the Study 
FAS 
R 
8.1 
Efficacy 
Y 
 
Table 
14.2.2.1.9 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Subjects Who Completed the Classical TUG, Without 
an Assisted Device, at Baseline 
FAS 
R 
8.1 
Efficacy 
Y 
 
Table 
14.2.2.1.10 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Subjects Who Completed the FUG TUG, Without an 
Assisted Device, at Baseline 
FAS 
R 
8.1 
Efficacy 
Y 
 
Table 
14.2.2.1.11 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Median MFFtot at Baseline 
FAS 
R 
8.1 
Efficacy 
Y 
 
Table 
14.2.2.1.12 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Median LMVtot at Baseline 
FAS 
R 
8.1 
Efficacy 
Y 
 
Table 
14.2.2.1.13 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
by Median MFItot at Baseline 
FAS 
R 
8.1 
Efficacy 
Y 
 
Table 
14.2.2.1.14 
Change from Baseline in DUX4 Activity (DUX4 Score 1)  
by Subjects  with Non-Censored Laboratory Observations 
for DUX4 Score at Baseline 
FAS 
R 
8.1 
Efficacy 
Y 
Y 
Table 
14.2.2.2 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
PPS 
R 
8.1 
Efficacy 
Y 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.2.2.1 
Change from Baseline in DUX4 Activity (DUX4 Score 1) 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.2.1 
Sensitivity Analysis:  Change from Baseline (DUX4 Score 
1) in DUX4 Activity 
FAS (LOCF) 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.2.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) 
PPS (LOCF) 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.3.1 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) 
FAS (Placebo Mean 
Imputation) 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.3.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) 
PPS (Placebo Mean 
Imputation) 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.4.1 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) 
FAS (Observed 
Worst Case 
Imputation) 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.4.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) 
PPS (Observed 
Worst Case 
Imputation) 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.5.1 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) by Timepoint 
FAS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.5.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) by Timepoint 
PPS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.6.1 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) by  COVID-19 Related Treatment 
Disruptions 
FAS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.6.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) by  COVID-19 Related Treatment 
Disruptions 
PPS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.7.1 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) 
FAS (Excluding 
Cross-over 
Subjects) 
R 
8.1 
Efficacy 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.2.2.7.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) 
PPS (Excluding 
Cross-over 
Subjects) 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.8.1 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) Excluding Subjects with 
Censored Laboratory Observations at Baseline 
FAS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.8.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 1) Excluding Subjects with 
Censored Laboratory Observations at Baseline 
PPS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.9.1 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 2)  
FAS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.9.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 2)  
PPS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.10.1 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 3)  
FAS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.2.2.10.2 
Sensitivity Analysis:  Change from Baseline in DUX4 
Activity (DUX4 Score 3)  
PPS 
R 
8.1 
Efficacy 
 
 
Table 
14.2.3.1.1.1 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) 
FAS 
U 
8.2 
Efficacy 
Y 
 
Table 
14.2.3.1.1.1.1 Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.2 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Baseline Repeat Category 
FAS 
U 
8.2 
Efficacy 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.3.1.1.3 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Baseline Clinical Severity Score 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.4 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Sex 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.5 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Fat Fraction at Biopsy Site 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.6 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot)  by Baseline DUX4 Score 1 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.7 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Subjects Who Completed RWS Protocol With 
Above Shoulder Movements at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.8 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Subjects Who Completed RWS Protocol With 
Above Shoulder Movements All Through the Study 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.9 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Subjects Who Completed the Classical TUG, 
Without an Assisted Device, at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.10 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Subjects Who Completed the FUG TUG, 
Without an Assisted Device, at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.11 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Median MFFtot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.12 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Median LMVtot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.13 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Median MFItot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.1.14 
Change from Baseline in Composite Muscle Fat Fraction 
(MFFtot) by Subjects with Censored Laboratory 
Observations for DUX4 Score at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.1.2 
Change from Baseline in  Muscle Fat Fraction by 
Individual Muscles 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.1 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) 
FAS 
U 
8.2 
Efficacy 
Y 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.3.2.1.1.1 Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.2 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Baseline Repeat Category 
FAS 
U 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.3 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Baseline Clinical Severity Score 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.4 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Sex 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.5 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Fat Fraction at Biopsy Site 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.6 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Baseline DUX4 Score 1 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.7 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Subjects Who Completed RWS Protocol With 
Above Shoulder Movements at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.8 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Subjects Who Completed RWS Protocol With 
Above Shoulder Movements All Through the Study 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.9 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Subjects Who Completed the Classical TUG, 
Without an Assisted Device, at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.10 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Subjects Who Completed the FUG TUG, 
Without an Assisted Device, at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.11 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Median MFFtot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.12 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Median LMVtot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.1.13 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Median MFItot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
64


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FIS-002-2019 
 
   
            Date Issued: 28May2020 
 
  
 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.3.2.1.14 
Change from Baseline in Composite Lean Muscle Volume 
(LMVtot) by Subjects with Censored Laboratory 
Observations for DUX4 Score at Baseline by Median 
MFItot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.2.2 
Change from Baseline in Lean Muscle Volume by 
Individual Muscles 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.1 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) 
FAS 
U 
8.2 
Efficacy 
Y 
 
Table 
14.2.3.3.1.1.1 Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.2 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Baseline Repeat Category 
FAS 
U 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.3 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Baseline Clinical Severity Score 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.4 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Sex 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.5 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Fat Fraction at Biopsy Site 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.6 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Baseline DUX4 Score 1 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.7 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Subjects Who Completed RWS Protocol With 
Above Shoulder Movements at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.8 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Subjects Who Completed RWS Protocol With 
Above Shoulder Movements All Through the Study 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.9 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Subjects Who Completed the Classical TUG, 
Without an Assisted Device, at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.10 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Subjects Who Completed the FUG TUG, 
Without an Assisted Device, at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
65


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FIS-002-2019 
 
   
            Date Issued: 28May2020 
 
  
 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.3.3.1.11 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Median MFFtot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.12 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Median LMVtot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.13 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Median MFItot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.1.14 
Change from Baseline in Composite Muscle Fat Infiltration 
(MFItot) by Subjects with Censored Laboratory 
Observations for DUX4 Score at Baselineby Median 
MFItot at Baseline 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.3.3.2 
Change from Baseline in Muscle Fat Infiltration by 
Individual Muscles 
FAS 
R 
8.2 
Efficacy 
 
 
Table 
14.2.4.1.1 
Change from Baseline in Reachable Work Space (RWS) 
Relative Surface Areas 
FAS 
U 
8.3.1 
Efficacy 
 
 
Table 
14.2.4.1.1.1 
Change from Baseline in Reachable Work Space (RWS) 
Relative Surface Areas 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.1 
Efficacy 
 
 
Table 
14.2.4.1.1.2 
Change from Baseline in Reachable Work Space (RWS) 
Relative Surface Areas by Subjects Who Completed RWS 
Protocol With Above Shoulder Movements at Baseline 
FAS 
U 
8.3.1 
Efficacy 
 
 
Table 
14.2.4.1.1.3 
Change from Baseline in Reachable Work Space (RWS) 
Relative Surface Areas by Subjects Who Completed RWS 
Protocol With Above Shoulder Movements All Through 
the Study 
FAS 
U 
8.3.1 
Efficacy 
 
 
Table 
14.2.4.1.2 
Summary of Reachable Work Space (RWS) with >=5% 
Decline from Baseline by Visit  
FAS 
U 
8.3.1 
Efficacy 
 
 
Table 
14.2.4.1.3 
Summary of Reachable Work Space (RWS) with >=2% 
Decline from Baseline by Visit  
FAS 
U 
8.3.1 
Efficacy 
 
 
Table 
14.2.4.1.4 
Summary of Functional Work Space 
FAS 
U 
8.3.1 
Efficacy 
 
 
Table 
14.2.4.2.1 
Change from Baseline in Classic Timed Up and Go (TUG) 
Average Completion Time 
FAS 
U 
8.3.2 
Efficacy 
 
 
66


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FIS-002-2019 
 
   
            Date Issued: 28May2020 
 
  
 
 
 
58
TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.4.2.1.1 
Change from Baseline in Classic Timed Up and Go (TUG) 
Average Completion Time 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.2 
Efficacy 
 
 
Table 
14.2.4.2.1.2 
Change from Baseline in Classic Timed Up and Go (TUG) 
Average Completion Time by Subjects Who Completed the 
Classical TUG, Without an Assisted Device, at Baseline 
FAS 
U 
8.3.2 
Efficacy 
 
 
Table 
14.2.4.2.2.1 
Change from Baseline in FSHD Timed Up and Go (TUG) 
Average Completion Times 
FAS 
U 
8.3.2 
Efficacy 
 
 
Table 
14.2.4.2.2.1.1 Change from Baseline in FSHD Timed Up and Go (TUG) 
Average Completion Times 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.2 
Efficacy 
 
 
Table 
14.2.4.2.2.2 
Change from Baseline in FSHD Timed Up and Go (TUG) 
Average Completion Times by Subjects Who Completed 
the FSHD TUG, Without an Assisted Device, at Baseline 
FAS 
U 
8.3.2 
Efficacy 
 
 
Table 
14.2.4.2.3 
Change from Baseline in FSHD Timed Up and Go (TUG) 
Average Completion Times by Segment 
FAS 
U 
8.3.2 
Efficacy 
 
 
Table 
14.2.4.3.1 
Change from Baseline in Average Dynamometry Result 
FAS 
U 
8.3.3 
Efficacy 
 
 
Table 
14.2.4.3.1.1 
Change from Baseline in Average Dynamometry Result 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.3 
Efficacy 
 
 
Table 
14.2.4.3.2 
Change from Baseline in Maximum Dynamometry Result 
FAS 
U 
8.3.3 
Efficacy 
 
 
Table 
14.2.4.3.2.1 
Change from Baseline in Maximum Dynamometry Result 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.3 
Efficacy 
 
 
Table 
14.2.4.3.3 
Change from Baseline in Total Average Dynamometry 
Result; All Muscles Combined, Upper Extremity, Lower 
Extremity 
FAS 
U 
8.3.3 
Efficacy 
 
 
Table 
14.2.4.4.1 
Shift in Motor Function Measure (MFM) Individual 
Component Score 
FAS 
U 
8.3.4 
Efficacy 
 
 
67


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FIS-002-2019 
 
   
            Date Issued: 28May2020 
 
  
 
 
 
59
TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.2.4.4.1.1 
Shift in Motor Function Measure (MFM) Individual 
Component Score 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.4 
Efficacy 
 
 
Table 
14.2.4.4.2 
Change from Baseline in Motor Function Measure (MFM) 
Domain 1 
FAS 
U 
8.3.4 
Efficacy 
 
 
Table 
14.2.4.4.2.1 
Change from Baseline in Motor Function Measure (MFM) 
Domain 1 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.4 
Efficacy 
 
 
Table 
14.2.4.5 
Change from Baseline in FSHD Health Index (FSHD-HI)  
FAS 
U 
8.3.5 
Efficacy 
 
 
Table 
14.2.4.5.1 
Change from Baseline in FSHD Health Index (FSHD-HI)  
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.5 
Efficacy 
 
 
Table 
14.2.4.6.1 
Patients’ Global Impression of Change (PGIC) Improved 
and Not Improved 
FAS 
U 
8.3.6 
Efficacy 
 
 
Table 
14.2.4.6.1.1 
Patients’ Global Impression of Change (PGIC) Improved 
and Not Improved 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.6 
Efficacy 
 
 
Table 
14.2.4.6.2 
Patients’ Global Impression of Change (PGIC) 
FAS 
U 
8.3.6 
Efficacy 
 
 
Table 
14.2.4.6.2.1 
Patients’ Global Impression of Change (PGIC) 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
8.3.6 
Efficacy 
 
 
Table 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety Analysis Set U 
9.1 
Safety 
Y 
 
Table 
14.3.1.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.1 
Safety 
 
 
Table 
14.3.1.2 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term  
Safety Analysis Set U 
9.1.1 
Safety 
 
 
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            Date Issued: 28May2020 
 
  
 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.3.1.2.1 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term  
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.1.1 
Safety 
 
 
Table 
14.3.1.3 
Treatment-Emergent Adverse Events by Relationship to 
Study Drug 
Safety Analysis Set U 
9.1.2 
Safety 
 
 
Table 
14.3.1.3.1 
Treatment-Emergent Adverse Events by Relationship to 
Study Drug 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.1.2 
Safety 
 
 
Table 
14.3.1.4 
Treatment-Emergent Adverse Events by Maximum 
Severity 
Safety Analysis Set U 
9.1.3 
Safety 
 
 
Table 
14.3.1.4.1 
Treatment-Emergent Adverse Events by Maximum 
Severity 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.1.3 
Safety 
 
 
Table 
14.3.1.5 
Treatment-Emergent Adverse Events Leading to Treatment 
Discontinuation by System Organ Class and Preferred 
Term 
Safety Analysis Set R 
9.1.5 
Safety 
 
 
Table 
14.3.1.5.1 
Treatment-Emergent Adverse Events Leading to Treatment 
Discontinuation by System Organ Class and Preferred 
Term 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.1.5 
Safety 
 
 
Table 
14.3.1.6 
Treatment-Emergent Adverse Events Leading to Study 
Withdrawal by System Organ Class and Preferred Term 
Safety Analysis Set R 
9.1.6 
Safety 
 
 
Table 
14.3.1.6.1 
Treatment-Emergent Adverse Events Leading to Study 
Withdrawal by System Organ Class and Preferred Term 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.1.6 
Safety 
 
 
Table 
14.3.2.1 
Serious Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Analysis Set R 
9.1.4 
Safety 
 
 
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            Date Issued: 28May2020 
 
  
 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.3.2.1.1 
Serious Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.1.4 
Safety 
 
 
Table 
14.3.2.2 
Adverse Events Leading to Death by System Organ Class 
and Preferred Term 
Safety Analysis Set R 
9.1.7 
Safety 
 
 
Table 
14.3.2.2.1 
Adverse Events Leading to Death by System Organ Class 
and Preferred Term 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.1.7 
Safety 
 
 
Table 
14.3.4.1.1 
Change from Baseline in Hematology 
Safety Analysis Set U 
9.2.1 
Safety 
 
 
Table 
14.3.4.1.1.1 
Change from Baseline in Hematology 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.2.1 
Safety 
 
 
Table 
14.3.4.1.2 
Shift from Baseline in Hematology 
Safety Analysis Set U 
9.2.1 
Safety 
 
 
Table 
14.3.4.1.2.1 
Shift from Baseline in Hematology 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.2.1 
Safety 
 
 
Table 
14.3.4.2.1 
Change from Baseline in Chemistry  
Safety Analysis Set R 
9.2.2 
Safety 
 
 
Table 
14.3.4.2.1.1 
Change from Baseline in Chemistry  
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.2.2 
Safety 
 
 
Table 
14.3.4.2.2 
Shift from Baseline in Chemistry 
Safety Analysis Set R 
9.2.2 
Safety 
 
 
Table 
14.3.4.2.2.1 
Shift from Baseline in Chemistry 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.2.2 
Safety 
 
 
Table 
14.3.4.2.3 
Summary of Clinically Notable Laboratory Results by Visit 
- Chemistry (Liver) 
Safety Analysis Set U 
9.2.2 
Safety 
 
 
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            Date Issued: 28May2020 
 
  
 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.3.4.2.3.1 
Summary of Clinically Notable Laboratory Results by Visit 
- Chemistry (Liver) 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.2.2 
Safety 
 
 
Table 
14.3.4.3 
Change from Baseline in Coagulation 
Safety Analysis Set R 
9.2.3 
Safety 
 
 
Table 
14.3.4.3.1 
Change from Baseline in Coagulation 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.2.3 
Safety 
 
 
Table 
14.3.4.4 
Change from Baseline in Urinalysis 
Safety Analysis Set R 
9.2.3 
Safety 
 
 
Table 
14.3.4.4.1 
Change from Baseline in Urinalysis 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.2.3 
Safety 
 
 
Table 
14.3.5.1 
Change from Baseline in Vital Signs by Visit 
Safety Analysis Set U 
9.3 
Safety 
 
 
Table 
14.3.5.1.1 
Change from Baseline in Vital Signs by Visit 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.3 
Safety 
 
 
Table 
14.3.5.2.1 
Physical Examination 
Safety Analysis Set U 
9.4 
Safety 
 
 
Table 
14.3.5.2.1.1 
Physical Examination 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.4 
Safety 
 
 
Table 
14.3.5.2.2 
Neurological Examination Results 
Safety Analysis Set U 
9.4 
Safety 
 
 
Table 
14.3.5.2.2.1 
Neurological Examination Results 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.4 
Safety 
 
 
Table 
14.3.5.3.1 
Change from Baseline in Electrocardiogram Results 
Safety Analysis Set U 
9.5 
Safety 
 
 
Table 
14.3.5.3.1.1 
Change from Baseline in Electrocardiogram Results 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.5 
Safety 
 
 
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FIS-002-2019 
 
   
            Date Issued: 28May2020 
 
  
 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Table 
14.3.5.3.2 
Electrocardiogram Interpretation by Visit 
Safety Analysis Set U 
9.5 
Safety 
 
 
Table 
14.3.5.3.2.1 
Electrocardiogram Interpretation by Visit 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.5 
Safety 
 
 
Table 
14.3.5.3.3 
Summary of QTc Values 
Safety Analysis Set U 
9.5 
Safety 
 
 
Table 
14.3.5.3.3.1 
Summary of QTc Values 
Open-label 
losmapimod (Pre-
COVID-19) 
Analysis Set 
R 
9.5 
Safety 
 
 
 
 
15.9. 
List of Planned Data Listings 
 
TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Listing 
16.2.1 
Subject Disposition 
All Screened 
Subjects 
U 
5.1 
Standard 
 
 
Listing 
16.2.2 
Protocol Deviations 
FAS 
U 
5.2 
Standard 
 
 
Listing 
16.2.3 
Analysis Set 
All Screened 
Subjects 
U 
5.1 
Standard 
 
 
Listing 
16.2.4.1 
Demographics and Baseline Disease Characteristics 
FAS 
U 
6.1 
Standard 
 
 
 
 
Listing 
16.2.4.3 
Medical History 
FAS 
U 
6.3 
Standard 
 
 
Listing 
16.2.4.4 
Prior and Concomitant Medications 
Safety Analysis Set U 
7.1.1 and 
7.1.2 
Standard 
 
 
Listing 
16.2.4.5 
Physical Examination 
Safety Analysis Set U 
9.4 
Safety 
 
 
Listing 
16.2.4.6 
Neurological Examination Result 
Safety Analysis Set U 
9.4 
Safety 
 
 
Listing 
16.2.5.1 
Study Drug Accountability 
Safety Analysis Set U 
7.2.1 
Standard 
 
 
Listing 
16.2.5.2 
Study Drug Administration 
Safety Analysis Set U 
7.2.2 
Standard 
 
 
Listing 
16.2.5.3.1 
Individual Losmapimod Concentration  
PK Analysis Set 
U 
10 
Efficacy 
 
 
72
PPD


Fulcrum Therapeutics 
 
 
       
 
 
 
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FIS-002-2019 
 
   
            Date Issued: 28May2020 
 
  
 
 
 
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TLF 
Table 
Number 
Title 
Analysis Set 
Unique (U)/ 
Repeat (R) 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
Listing 
16.2.5.3.2 
Target Engagement Estimates 
PD Analysis Set 
U 
10 
Efficacy 
 
 
Listing 
16.2.6.1.1 
DUX4 Activity (Normalized Delta CT Value) 
FAS 
U 
8.1 
Efficacy 
 
 
Listing 
16.2.6.1.2 
DUX4 Score 
FAS 
U 
8.1 
Efficacy 
 
 
Listing 
16.3.6.2 
Fat Fraction, Lean Muscle Tissue Volume, and Muscle Fat 
Infiltration  
FAS 
U 
8.2 
Efficacy 
 
 
Listing 
16.3.6.3.1.1 
Reachable Work Space 
FAS 
U 
8.3.1 
Efficacy 
 
 
Listing 
16.3.6.3.1.2 
Functional Work Space 
FAS 
U 
8.3.1 
Efficacy 
 
 
Listing 
16.3.6.3.2.1 
Classic Timed Up and Go (TUG) 
FAS 
U 
8.3.2 
Efficacy 
 
 
Listing 
16.3.6.3.2.2 
Optimized Timed Up and Go (TUG) 
FAS 
U 
8.3.2 
Efficacy 
 
 
Listing 
16.3.6.3.3 
Muscle Strength by Handheld Quantitative Dynamometry 
FAS 
U 
8.3.3 
Efficacy 
 
 
Listing 
16.3.6.3.4 
Motor Function Measure (MFM) Domain 1 
FAS 
U 
8.3.4 
Efficacy 
 
 
Listing 
16.3.6.3.5 
Facioscapulohumeral Muscular Dystrophy Health Index 
(FSHD-HI) 
FAS 
U 
8.3.5 
Efficacy 
 
 
Listing 
16.3.6.3.6 
Patient Global Impression of Change (PGIC) 
FAS 
U 
8.3.6 
Efficacy 
 
 
Listing 
16.2.7.1 
Adverse Events 
Safety Analysis Set U 
9.1 
Safety 
 
 
Listing 
16.2.7.2 
Serious Adverse Events 
Safety Analysis Set R 
9.1 
Safety 
 
 
Listing 
16.2.7.3 
Adverse Events Leading to Treatment Discontinuation 
Safety Analysis Set R 
9.1 
Safety 
 
 
Listing 
16.2.7.4 
Adverse Events Leading to Study Withdrawal 
Safety Analysis Set R 
9.1 
Safety 
 
 
Listing 
16.2.7.5 
Deaths 
Safety Analysis Set R 
9.1 
Safety 
 
 
Listing 
16.2.8.1 
Laboratory Results – Hematology  
Safety Analysis Set U 
9.2.1 
Safety 
 
 
Listing 
16.2.8.2.1 
Laboratory Results – Chemistry  
Safety Analysis Set R 
9.2.2 
Safety 
 
 
Listing 
16.2.8.2.2 
Laboratory Results of Subjects with Incidence of ALT/AST 
>3 x ULN and Total Bilirubin >2 X ULN and ALP <2 x 
ULN 
Safety Analysis Set R 
9.2.2 
Safety 
 
 
Listing 
16.2.8.3 
Laboratory Results – Urinalysis  
Safety Analysis Set R 
9.2.3 
Safety 
 
 
Listing 
16.2.8.4 
Laboratory Results – Coagulation  
Safety Analysis Set R 
9.2.4 
Safety 
 
 
Listing 
16.2.8.5 
Vital Sign Results 
Safety Analysis Set U 
9.3 
Safety 
 
 
Listing 
16.2.8.6 
Electrocardiogram Results  
Safety Analysis Set U 
9.5 
Safety 
 
 
 
 
73


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            Date Issued: 28May2020 
 
  
 
 
 
65
15.10. List of Planned Figures 
 
 
Figure 
Number 
Title 
Analysis Set 
Unique 
(U)/ 
Repeat 
(R) 
SAP 
Section 
Efficacy/ 
Safety/ 
Standard 
Topline 
IA 
14.2.1 
LS Mean (+/- SE) Change from Baseline in 
DUX4 Activity by Visit 
FAS 
U 
8.2 
Efficacy 
14.2.2.1 
LS Mean (+/- SE) Change from Baseline in 
Muscle Fat Fraction by Visit 
FAS 
R 
8.2 
Efficacy 
14.2.2.2 
LS Mean (+/- SE) Change from Baseline in 
Lean Muscle Volume by Visit 
FAS 
R 
8.2 
Efficacy 
14.2.2.3 
LS Mean (+/- SE) Change from Baseline in 
Muscle Fat Infiltration by Visit 
FAS 
R 
8.2 
Efficacy 
14.2.3 
Mean (+/- SE) Plasma Concentrations by 
Treatment by Visit 
PK Analysis Set 
U 
10 
Efficacy 
14.2.4.1 
LS Mean (+/- SE) in Target Engagement 
Estimates by Treatment by Visit 
PD Analysis Set 
R 
10 
Efficacy 
 
 
14.2.4.2 
Mean Percent Change from Baseline in Target 
Engagement Estimates by Visit 
PD Analysis Set 
U 
10 
Efficacy 
 
 
 
 
74


 
Confidential 
Fulcrum Therapeutics 
 
FIS-002-2019 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week,  
Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating Subjects with 
Facioscapulohumeral Muscular Dystrophy (FSHD) with Open-Label Extension (OLE) 
 
25Feb2021 
 
Final Statistical Analysis Plan Addendum 
(Placebo-Controlled Treatment Period) 
 
 
Prepared by: 
 
 
 
 
Issued by: 
_____________  
 
 
Date:  ___/___/___ 
 
 
 
 
Lead Biostatistician, Biostatistics 
 
Reviewed by: ___
______________  
 
 
Date:  ___/___/___ 
 
 
 
 
Senior Reviewer, Director, Biostatistics 
 
Upon review of this document, including the shells, the undersigned approves the statistical 
analysis plan. The analysis methods and data presentation are acceptable, and the table, listing, 
and figure production can b
 
 
Approved by: ____________________________  
 
 
Date:  ___/___/___ 
 
 
 
 
VP, Biometrics 
 
 
Fulcrum Therapeutics 
 
 
 
 
 
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Fulcrum Therapeutics 
 
Final Statistical Analysis Plan Addendum 
 
FIS-002-2019 
 
Date Issued: 24Feb2021 
 
  
 
 
 II
 
TABLE OF CONTENTS 
1. 
INTRODUCTION............................................................................................................. 1 
2. 
ANALYSIS SET ................................................................................................................ 1 
2.1. 
PHARMACODYNAMICS ANALYSIS SET ................................................................. 1 
2.2. 
PER PROTOCOL ANALYSIS SET ............................................................................... 1 
3. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 1 
3.1. 
REPORTING CONVENTIONS...................................................................................... 1 
3.2. 
SUBGROUP ...................................................................................................................... 1 
4. 
TREATMENT COMPLIANCE ...................................................................................... 2 
5. 
EFFICACY ANALYSIS ................................................................................................... 2 
5.1. 
MIXED EFFECTS MODEL FOR REPEATED MEASURES .................................... 2 
5.2. 
CHANGE FROM BASELINE IN DUX4 ACTIVITY IN SKELETAL MUSCLE AT 
WEEK 16 OR WEEK 36 .................................................................................................. 2 
5.3. 
MSK MRI MUSCLE FAT FRACTION, LEAN MUSCLE VOLUME AND 
MUSCLE FAT INFILTRATION .................................................................................... 3 
5.4. 
REACHABLE WORK SPACE WITH AND WITHOUT WEIGHTS ........................ 4 
5.5. 
FSHD TUG ........................................................................................................................ 4 
5.6. 
PGIC................................................................................................................................... 5 
6. 
PHARMACODYNAMICS ANALYSIS ......................................................................... 5 
REFERENCES .............................................................................................................................. 5 
 
 
PPD


Fulcrum Therapeutics 
 
Final Statistical Analysis Plan Addendum 
 
FIS-002-2019 
 
Date Issued: 24Feb2021 
 
  
 
 
 1
1. Introduction 
 
The purpose of this addendum to the final statistical analysis plan (SAP), dated 28May2020, is to 
describe the additional analyses that will be performed as well as to provide details on the analyses 
that will no longer be performed. In addition, this document will also correct some typos in both 
SAP and protocol. 
 
2. Analysis Set 
2.1. 
Pharmacodynamics Analysis Set 
 
The Pharmacodynamic Analysis Set definition is updated to: 
 
 The PD Analysis Set will consist of all subjects who receive at least 1 dose of study drug and have 
evaluable PD data. 
2.2. 
Per Protocol Analysis Set 
 
The following are considered as significant protocol deviations in the study that may have a 
substantial impact on the primary endpoint. Thus, subjects in Full Analysis Set who satisfy any 
of the following criteria will be excluded from the Per Protocol Analysis Set. 
1) Study drug compliance of below 80% before the post-baseline muscle biopsy assessment, 
which is either on Week 16 or Week 36. 
2) Certain major protocol deviation identified from the protocol deviation tracker before 
database lock.  
3) Certain prohibited medications.  
4) Violation of inclusion/exclusion criteria.  
 
3. General Statistical Considerations 
3.1. 
Reporting Conventions 
 
Presentation of continuous and quantitative variables will also include standard errors (SE). 
3.2. 
Subgroup  
 
For the subgroup analysis, RWS will be presented according to protocol type instead of just 
presenting subjects who have above shoulder movements. 
1. Protocol Type (High or Low - for Subjects Who Completed RWS Protocol With Above 
Shoulder Movements or Below Shoulder Movements at Baseline).  
2. Protocol Type (High or Low - for Subjects Who Completed RWS Protocol With Above 
Shoulder Movements or Below Shoulder Movements All Through the Study). 
 


Fulcrum Therapeutics 
 
Final Statistical Analysis Plan Addendum 
 
FIS-002-2019 
 
Date Issued: 24Feb2021 
 
  
 
 
 2
Subgroup no. 8, subjects completing the classical TUG, without an assisted device at baseline, will 
be updated to also consider subjects with assisted device at baseline. Hence, the subgroup 
presentation will be based according to use or non-use of assisted device at baseline for subjects 
who completed the classical TUG. 
 
In the same manner, subgroup no. 9, subjects completing the FSHD TUG, without an assisted 
device, at baseline, will be updated to consider subjects with assisted device at baseline. Hence, 
the subgroup presentation will be based according to use or non-use of assisted device at baseline 
for subjects who completed the FSHD TUG. 
 
Subgroup no. 10, MFFtot, LMVtot and MFItot with thresholds at the median of observed baseline 
data, will be based on the Longitudinal Reference Value at Screening. 
 
4. Treatment Compliance 
 
Additional categories for compliance will be included and the existing categories will be updated 
as follows: 
 
<40% 
 
40-<60% 
 
60-<80% 
 
80-<120% 
 
>120% 
5. Efficacy Analysis  
5.1. 
Mixed Effects Model for Repeated Measures 
 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
 
5.2. 
Change from Baseline in DUX4 Activity in Skeletal Muscle at Week 16 or Week 36 
 
Fold change will be presented in Table 14.2.2.1.1 (Change from Baseline in DUX4 Activity 
(DUX4 Score 1) Full Analysis Set, Table 14.2.2.1.2 (Change from Baseline in DUX4 Activity 
(DUX4 Score 1) by Baseline Repeat Category Full Analysis Set), Table 14.2.2.1.6 (Change from 
Baseline in DUX4 Activity (DUX4 Score 1) by Baseline DUX4 Score 1 Full Analysis Set), and 
Table 14.2.2.2.5.1 (Sensitivity Analysis: Change from Baseline in DUX4 Activity (DUX4 Score 
1) by Timepoint Full Analysis Set). Fold change is the difference in the natural log (ln) transformed 
values of DUX 4 Score 1 at Week 36 or Week 16 DUX4 Score 1 and Baseline; then using the 
exponential function to return the computation to the original scale. The summary of fold change 
will include n, mean, SD, SE, median, minimum, maximum, and geometric mean. Geometric mean 
is derived as the arithmetic mean of the ln-transformed values of fold change of DUX4 Score 1; 
then using the exponential function to return the computation to the original scale. For the repeat 
category subgroup analysis, the repeat category will be excluded as fixed effect from the model. 
 


Fulcrum Therapeutics 
 
Final Statistical Analysis Plan Addendum 
 
FIS-002-2019 
 
Date Issued: 24Feb2021 
 
  
 
 
 3
In addition, an ANCOVA model will be used to analyze the change from baseline in the ln-
transformed value of DUX4 Score 1, with repeat number category and treatment group as fixed 
effects and ln-transformed baseline DUX4 Score 1 in affected skeletal muscle as a covariate. Then, 
the point estimates which include within-group least-squares (LS) means and 2-sided 95% CIs will 
be back transformed using the exponential function to return the values to the original scale as the 
ratio of means and the associated 2-sided 95% CIs.  
 
An additional sensitivity analysis will be done using the highest two expression transcripts. The 
DUX4 Score 1 of highest two expression transcript is derived as the mean of 2 genes or more (if 
there is a tie in values) with the highest expressing values at baseline. Similar methods in Section 
8.2 of the SAP will be used to analyze the change from baseline in the DUX4 activity of highest 
two expression transcripts 
 
5.3. 
MSK MRI Muscle Fat Fraction, Lean Muscle Volume and Muscle Fat Infiltration 
 
The cross-sectional composite scores will be used to correlate the results with Clinical Outcome 
Assessments (i.e. TUG and RWS).  Only summary statistics will be presented for these parameters. 
 
The cross-sectional results will be further presented by extremity i.e. upper extremity, lower 
extremity, and total results. The convention that will be used to get extremity equivalent of the 
cross-sectional results is provided in Table 5-3. 
 
 
Table 5-3. Extremity Equivalent of MRI Cross-sectional Results. 
 
MRI Cross-sectional Results 
Equivalent Extremity 
FSHD TUG Cross-sectional
Lower extremity (LE)
RWS Right Cross-sectional
Right upper extremity (RUE)
RWS Left Cross-sectional
Left upper extremity (LUE)
RUE + LUE
Upper extremity (UE)
LE + RUE + LUE
Total
 
 
In addition, Spearman correlation coefficients will be used to assess relationships between the by 
extremity MRI results and classical and FSHD TUG and RWS results by visit. The Spearman 
correlation coefficient and p-value will be calculated within each treatment and presented in a 
table. This will also be graphically presented using scatterplots. Specifically, the following 
relationships will be assessed: 
 
 
LE vs. FSHD-TUG 
 
LE vs. Classical TUG 
 
RUE vs. RWS 
 
LUE vs. RWS 
 
UE vs. RWS 


Fulcrum Therapeutics 
 
Final Statistical Analysis Plan Addendum 
 
FIS-002-2019 
 
Date Issued: 24Feb2021 
 
  
 
 
 4
 
TOTAL vs. FSHD-TUG 
 
TOTAL vs. Classical TUG 
 
TOTAL vs. RWS 
 
The longitudinal composite scores are used to measure the change from baseline at each post-
baseline visit. This is the result that will be used in the MMRM model. 
 
 
5.4. 
Reachable Work Space With and Without Weights 
 
The % change/year in RSA will be analyzed. A linear mixed-effects model will be used to analyze 
the total RSA, with treatment group as a fixed effect, and intercept, time and treatment-by-time 
interaction as random effects, and with adjustment for repeat number category and region (EU, 
USA, and Canada). Within-group LS mean of slope and the associated SEs, intercept and the 
associated SE, differences in the LS mean of slope and the associated 2-sided 95% CIs and 2-sided 
p-values will be derived from the linear mixed-model and will be provided in the summary table. 
In addition, the % change/year will be presented and will be derived as [(slope*365)/baseline]*100 
where baseline is the LS mean of the intercept. Difference in  % change/year between treatments 
will also be presented. 
 
A separate model will be run with and without weights and for the dominant and non-dominant 
hand. An unstructured covariance matrix will be used to model the correlation among repeated 
measurements within each subject. Similar methods will be used to analyze the change from 
baseline in RSA for each quadrant. 
  
The analysis related to functional work space (FWS) will no longer be done. According to the 
vendor, majority of the sessions were collected on normal speed and the table on FWS to show 
subjects belonging to normal or low speed will not give much information. In addition, the listing 
to show the detected will also be removed since this data was removed by the vendor. 
 
 
5.5. 
FSHD TUG 
 
An MMRM model will also be used to analyze the change from baseline in the sum of the 3 FSHD 
TUG segments average completion time with repeat number category, treatment group, visit, and 
treatment-by-visit interaction as fixed effects and baseline value as a covariate. Within-group LS 
mean changes from baseline, the associated SEs and 2-sided 95% CIs, treatment differences in LS 
mean changes from baseline at post-baseline visits and the associated 2-sided 95% CIs and 2-sided 
p-values will be derived from the MMRM model and will be provided in the summary table. An 
unstructured covariance matrix will be used to model the correlation among repeated 
measurements within each subject. If models using unstructured covariance do not converge, an 
AR(1) covariance structure will be used instead. 


Fulcrum Therapeutics 
 
Final Statistical Analysis Plan Addendum 
 
FIS-002-2019 
 
Date Issued: 24Feb2021 
 
  
 
 
 5
5.6. 
PGIC 
 
The PGIC will be further analyzed. An MMRM model will be used to analyze the PGIC with 
repeat number category, treatment group, visit, and treatment-by-visit interaction as fixed effects. 
Within-group LS mean changes from baseline, the associated SEs and 2-sided 95% CIs, treatment 
differences in LS mean changes from baseline at post-baseline visits and the associated 2-sided 
95% CIs and 2-sided p-values will be derived from the MMRM model and will be provided in the 
summary table.  An unstructured covariance matrix will be used to model the correlation among 
repeated measurements within each subject. If models using unstructured covariance do not 
converge, an AR(1) covariance structure will be used instead. 
 
In addition, a spaghetti plot will be presented to show the PGIC score within subject over time. 
 
 
 
6. Pharmacodynamics Analysis  
 
An ANCOVA model instead of MMRM model will be used to analyze the target engagement 
parameters. 
 
 
References 
 
Han J, Kurillo G, Abresch R, et al. Reachable Workspace in Facioscapulohumeral muscular 
dystrophy (FSHD) by Kinect. Muscle Nerve. 2015 February ; 51(2): 168-175 
 
Hatch M, Kim K., et al. Longitudinal Study of Upper Extremity Reachable Workspace in 
Fascioscapulohumeral Muscular Dystrophy. Neuromuscular Disorders. S0960-8966(18)31376-2 
 
Kenward M and  Roger J, Small Sample Inference for Fixed Effects from Restricted Maximum 
Likelihood. Biometrics. 119 Sep. Vol 53 No. 3 
 
 
 
PPD