Conditions: Facioscapulohumeral Muscular Dystrophy
Keywords: FSHD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 95
Healthy volunteers: no

Brief summary:
Study A083-02 is a multi-center, Phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of locally-acting ACE-083 in patients with Facioscapulohumeral muscular dystrophy (FSHD) to be conducted in two parts. Part 1 is open-label, dose-escalation and Part 2 is randomized, double-blind, and placebo-controlled.

Detailed description:
Part 1 (dose escalation, open-label) Part 1 will consist of up to 6 cohorts of patients and will evaluate multiple ascending dose levels of ACE-083 administered unilaterally or bilaterally to either the tibialis anterior (TA) or biceps brachii (BB) muscle(s). Patients in each cohort will be enrolled in a 4-week screening period before beginning treatment. A Safety Review Team (SRT) will meet to review data for each cohort when at least 4 patients within a cohort have completed their Day 43 visit prior to dose escalation of the next cohort. Study duration for Part 1 for each patient will be approximately 24 weeks, including a 4-week screening period, a 12-week treatment period, and an 8-week follow-up period after the last dose.

Part 2 (randomized, double-blind, placebo-controlled, with open-label extension) Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted to determine whether cohorts for one or both muscles will be pursued in Part 2, as well as the recommended dose level for each muscle. A total of up to 56 new patients (28 patients per muscle) may be enrolled and randomized (1:1) to receive either ACE-083 (n=14/muscle) or placebo (n=14/muscle) bilaterally to either the TA or BB muscles (but not both). Patients will receive blinded study drug once every three weeks for approximately 6 months (9 doses).

Patients who complete the double-blind treatment period will immediately roll over to open-label treatment with ACE-083, receiving the same dose of active drug, bilaterally in either the TA or BB muscle, once every three weeks for approximately 6 months (8 doses). In Part 2, the SRT will periodically review blinded safety data for each muscle treated.

Study duration for Part 2 for each patient will be approximately 15 months, including a 1-month screening period, a 12-month treatment period (6-month double-blind, placebo-controlled and a 6-month open-label extension), and a 2-month follow-up period after the last dose

Arms:
arm 1: ACE-083 150 mg TA unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein arm 2: ACE-083 200 mg TA unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein arm 3: ACE-083 200 mg TA bilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein arm 4: ACE-083 150 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein arm 5: ACE-083 200 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein arm 6: ACE-083 240 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein arm 7: Part 2, double-blind (DB) placebo-controlled (PC). Placebo TA bilaterally, once every 3 weeks for up to 9 doses.

Drug: Placebo Normal saline

Afterwards, participants were rolled over into the open-label portion and received ACE-083 240 mg TA bilaterally, once every 3 weeks for up to 8 doses.

Drug: ACE-083 Recombinant fusion protein arm 8: Part 2, double-blind placebo-controlled. ACE-083 240 mg TA bilaterally, once every 3 weeks for up to 9 doses.

Drug: ACE-083 Recombinant fusion protein

Afterwards, participants were rolled over into the open-label portion and received ACE-083 240 mg TA bilaterally, once every 3 weeks for up to 8 doses.

Drug: ACE-083 Recombinant fusion protein arm 9: Part 2, double-blind placebo-controlled. Placebo BB bilaterally, once every 3 weeks for up to 9 doses.

Drug: Placebo Normal saline

Afterwards, participants were rolled over into the open-label portion and received ACE-083 240 mg Biceps Brachii (BB) bilaterally, once every 3 weeks for up to 8 doses.

Drug: ACE-083 Recombinant fusion protein arm 10: Part 2, double-blind placebo-controlled. ACE-083 240 mg Biceps Brachii (BB) bilaterally, once every 3 weeks for up to 9 doses.

Drug: ACE-083 Recombinant fusion protein

Afterwards, participants were rolled over into the open-label portion and received ACE-083 240 mg Biceps Brachii (BB) bilaterally, once every 3 weeks for up to 8 doses.

Drug: ACE-083 Recombinant fusion protein

Interventions: intervention 1: ACE-083 intervention 2: ACE-083 or placebo
Intervention descriptions: intervention 1: Recombinant fusion protein. intervention 2: Recombinant fusion protein or normal saline.

Protocol document:
Prot_001.pdf: 
Official Title: A Phase 2 Randomized, Double‐Blind, Placebo‐Controlled Study of ACE‐083 in Patients with 
Facioscapulohumeral Muscular Dystrophy 
NCT Number:  NCT02927080 
Document Dates: Protocol Amendment/Version 4: 09‐Jan‐2019 
 


Clinical Study Protocol 
 
ACE-083 
Study A083-02 
Revision: 04 
 
 
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Page 1 of 64 
CONFIDENTIAL 
1. 
TITLE PAGE 
 
 
Protocol A083-02 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of 
ACE-083 in Patients with Facioscapulohumeral Muscular Dystrophy  
 
 
 
 
 
 
 
 
SPONSOR: 
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Tel: 617-649-9200 
Fax: 617-649-9988 
 
 
 
 
 
ORIGINAL PROTOCOL DATE: 
 
 
24 June 2016 
 
AMENDMENT 01 DATE: 
 
 
 
 
31 August 2016 
 
AMENDMENT 02 DATE: 
 
 
 
 
21 November 2017 
 
AMENDMENT 03 DATE: 
 
 
 
 
08 August 2018 
 
AMENDMENT 04 DATE: 
 
 
 
 
09 January 2019 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable Institutional Review Board (IRB)/Independent Ethics Committee (IEC).  Your acceptance of this document 
constitutes agreement that you will not disclose the information contained herein to others without written authorization from 
Acceleron Pharma Inc. 
 
 


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Signature Page 
 
Acceleron Pharma Approval 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
Investigator Agreement: I have read the protocol and agree to conduct the study as 
outlined in the protocol.  The study will be conducted in accordance to current United 
States Food and Drug Administration (FDA) regulations, International Council of 
Harmonization (ICH) Guidelines, Good Clinical Practices (GCP), the Declaration of 
Helsinki, and local ethical and legal requirements. 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
 
 
 
Institution Name and Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Medical Monitor 
 
 
  
 
 
 
 
 
Pharmacovigilance  
 
 
  
 
 
 
 
Pharmacovigilance 
Medpace Clinical Safety 
Medpace SAE Hotline-USA 
Tel: 866-336-0930 or 800-730-5779 ext. 2999 
Fax: 866-336-5320 
Email: medpace-safetynotification@medpace.com 
 
Medpace SAE Hotline-Europe 
Tel: + 49-89-89-55-718-44 
Fax: + 49-89-89-55-718-104 
Email: medpace-safetynotification@medpace.com 
 
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................4 
LIST OF TABLES ...........................................................................................................................8 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................9 
4. 
PROTOCOL SYNOPSIS ...........................................................................................11 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Background .................................................................................................................21 
5.2. 
Study Rationale ...........................................................................................................22 
6. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
7. 
STUDY DESIGN .......................................................................................................25 
7.1. 
Overview of Study Design ..........................................................................................25 
7.2. 
Justification for Dose Level ........................................................................................26 
7.3. 
Benefit/Risk Assessment ............................................................................................26 
8. 
STUDY POPULATION .............................................................................................27 
8.1. 
Inclusion Criteria ........................................................................................................27 
8.2. 
Exclusion Criteria .......................................................................................................28 
8.3. 
Screen Failures ............................................................................................................29 
9. 
DISCONTINUATION/WITHDRAWAL CRITERIA ...............................................30 
9.1. 
Discontinuation of Study Treatment ...........................................................................30 
9.2. 
Withdrawal from the Study ........................................................................................30 
9.3. 
Lost to Follow Up .......................................................................................................31 
10. 
TREATMENT OF PATIENTS ..................................................................................32 
10.1. 
Treatments Administered ............................................................................................32 
10.1.1. 
Individual Dose Modification Rules ...........................................................................33 
10.2. 
Safety Review Team (SRT) ........................................................................................33 
10.3. 
Concomitant Medications ...........................................................................................34 
10.4. 
Treatment Compliance ................................................................................................35 
10.5. 
Randomization and Blinding ......................................................................................35 
11. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................36 
11.1. 
Study Drug ..................................................................................................................36 


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11.2. 
Study Drug Packaging and Labeling ..........................................................................36 
11.3. 
Study Drug Storage .....................................................................................................36 
11.4. 
Study Drug Preparation ..............................................................................................36 
11.5. 
Study Drug Accountability .........................................................................................36 
11.6. 
Study Drug Handling and Disposal ............................................................................36 
12. 
STUDY PROCEDURES ............................................................................................37 
12.1. 
Written Informed Consent ..........................................................................................37 
12.2. 
Study Assessments......................................................................................................37 
12.3. 
Safety Assessments .....................................................................................................37 
12.4. 
Efficacy Assessments .................................................................................................37 
12.5. 
Pharmacokinetic and Pharmacodynamic Assessments ..............................................37 
13. 
SAFETY .....................................................................................................................38 
13.1. 
Definition of Adverse Events .....................................................................................38 
13.1.1. 
Adverse Event .............................................................................................................38 
13.1.1.1. 
Unexpected Adverse Events .......................................................................................38 
13.1.1.2. 
Events Not to Be Considered as Adverse Events .......................................................38 
13.1.1.3. 
Serious Adverse Event ................................................................................................38 
13.1.1.4. 
Events Not to Be Considered as Serious Adverse Events ..........................................39 
13.1.1.5. 
Suspected Unexpected Serious Adverse Reactions ....................................................39 
13.2. 
Severity .......................................................................................................................39 
13.3. 
Relationship to Study Drug ........................................................................................39 
13.4. 
Recording Adverse Events .........................................................................................40 
13.4.1. 
Documentation of Serious Adverse Events ................................................................40 
13.5. 
Reporting Adverse Events ..........................................................................................41 
13.6. 
Pregnancy ...................................................................................................................41 
13.7. 
Reporting Serious Adverse Events .............................................................................41 
13.7.1. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators ..........................................................42 
14. 
STATISTICS ..............................................................................................................43 
14.1. 
Analysis Populations ..................................................................................................43 
14.2. 
Statistical Analysis Considerations .............................................................................43 
14.2.1. 
Patient Demographics and Disposition .......................................................................43 
14.2.2. 
Drug Exposure ............................................................................................................43 


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14.2.3. 
Efficacy Data ..............................................................................................................43 
14.2.3.1. 
Part 1 ...........................................................................................................................43 
14.2.3.2. 
Part 2 ...........................................................................................................................44 
14.2.3.3. 
Exploratory .................................................................................................................45 
14.2.3.4. 
Pooled Analyses ..........................................................................................................45 
14.2.4. 
Safety Data ..................................................................................................................45 
14.2.5. 
Pharmacokinetic Data .................................................................................................45 
14.2.6. 
Anti-drug Antibody Data ............................................................................................46 
14.3. 
Determination of Sample Size ....................................................................................46 
14.4. 
Interim Analysis ..........................................................................................................46 
14.5. 
Deviation from Original Analysis Plan ......................................................................46 
15. 
ETHICS ......................................................................................................................47 
15.1. 
Institutional Review Board .........................................................................................47 
15.2. 
Ethical Conduct of the Study ......................................................................................47 
15.3. 
Patient Information and Consent ................................................................................47 
15.4. 
Patient Data Protection ...............................................................................................47 
16. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES .............................48 
16.1. 
Study Monitoring ........................................................................................................48 
16.2. 
Audits and Inspections ................................................................................................48 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................49 
17.1. 
Data Quality Control and Quality Assurance .............................................................49 
17.1.1. 
Investigator Responsibility .........................................................................................49 
17.1.2. 
Protocol Modifications ...............................................................................................49 
18. 
CONFIDENTIALITY ................................................................................................50 
19. 
PUBLICATION POLICY ..........................................................................................51 
20. 
PROTOCOL AMENDMENTS ..................................................................................52 
21. 
DATA HANDLING AND RECORDKEEPING .......................................................53 
21.1. 
Case Report Form Completion ...................................................................................53 
21.2. 
Retention of Records ..................................................................................................53 
22. 
REFERENCES ...........................................................................................................54 
23. 
APPENDICES ............................................................................................................55 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................56 


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APPENDIX 2. CLINICAL SAFETY LABORATORY ASSESSMENTS ................................62 
APPENDIX 3. MEDICAL RESEARCH COUNCIL MANUAL MUSCLE TESTING 
GRADING SCALE ....................................................................................................63 
APPENDIX 4. PERFORMANCE OF THE UPPER LIMB TEST .............................................64 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms .............................................................................9 
Table 3: 
Objectives and Endpoints ...........................................................................................23 
Table 4: 
Cohort Schedule for Study A083-02 ..........................................................................33 
Table 5: 
Schedule of Events for Part 1: Dose Escalation, Open-Label ....................................57 
Table 6: 
Schedule of Events for Part 2: Randomized, Double-Blind, Placebo-
Controlled with Open-Label Extension ......................................................................59 
Table 7: 
Clinical Safety Laboratory Assessments ....................................................................62 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BB 
Biceps brachii 
CK 
Creatine kinase 
CRF 
Case report form 
CTX 
C-terminal collagen crosslinks 
DLT 
Dose limiting toxicity 
DUX4 
Double homeobox protein 4 
ECG 
Electrocardiogram 
EMG 
Electromyography 
FDA 
Food and Drug Administration 
FSHD 
Facioscapulohumeral muscular dystrophy 
FSHD-HI 
Facioscapulohumeral muscular dystrophy-health index 
FST 
Follistatin 
GCP 
Good clinical practice 
GDF8 
Growth and differentiation factor 8 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IgG2 
Immunoglobulin G2 
IM 
Intramuscular 
IP 
Investigational product 
IRB 
Institutional review board 
MMT 
Manual muscle testing 
MRC 
Medical Research Council 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 


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Abbreviation or Specialist Term Explanation 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PUL 
Performance of the upper limb 
QMT 
 
Quantitative muscle testing 
RF 
Rectus femoris 
SAE 
Serious adverse event 
SD 
Standard deviation 
SRT 
Safety review team 
SUSAR 
Suspected unexpected serious adverse reaction 
TA 
Tibialis anterior 
TGF-β 
Transforming growth factor beta 
ULN 
Upper limit of normal 


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4. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Acceleron Pharma Inc., 128 Sidney Street, Cambridge, MA 02139 
Name of Investigational Product: ACE-083 
Name of Active Ingredient: ACE-083 is a recombinant fusion protein consisting of a modified 
form of human follistatin linked to a human IgG2 Fc domain. 
Title of Study: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in 
Patients with Facioscapulohumeral Muscular Dystrophy  
Study Centers: Approximately 30 centers 
Phase of Development: 2 
Objectives 
Part 1 
Primary: 
 To evaluate the safety and tolerability of ACE-083 in patients with 
facioscapulohumeral muscular dystrophy (FSHD) 
Secondary: 
 To determine the recommended dose level(s) of ACE-083 for Part 2 
 To evaluate change in muscle volume and intramuscular fat fraction of the injected 
muscle 
 To evaluate change in strength of the injected muscle 
 To estimate the systemic exposure of ACE-083 when administered as a local muscle 
injection 
Exploratory: 
 To evaluate changes in motor function related to the injected muscle  
 To evaluate changes in patient-reported measures of FSHD-health index (FSHD-HI)  
total score and subscale scores  
Part 2 
Primary: 
 To determine whether treatment with ACE-083 increases total muscle volume of the 
injected muscle in patients with FSHD 
      Secondary: 
 To determine whether treatment with ACE-083 decreases intramuscular fat fraction of 
the injected muscle  
 To determine whether treatment with ACE-083 increases strength of the injected 
muscle 
 To determine whether treatment with ACE-083 improves motor function (e.g., six 
minute walk test distance, performance of upper limb [PUL] mid-level/elbow 
dimension assessment) related to the injected muscle 


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 To evaluate changes in patient-reported measures of FSHD-HI total score and subscale 
scores  
 To evaluate the safety and tolerability of ACE-083 
 To estimate the systemic exposure of ACE-083 when administered as a local muscle 
injection 
     Exploratory (Part 2, open-label): 
 To assess the effect of treatment with ACE-083 on motor function as measured by the 
100-meter timed test (tibialis anterior groups) or PUL high level/shoulder dimension 
assessment (biceps brachii groups) 
Methodology 
This is a multicenter, Phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), 
efficacy, and pharmacokinetics (PK) of ACE-083 in patients with FSHD, to be conducted in two 
parts.  Part 1 is open-label, dose-escalation (3 months) and Part 2 is randomized, double-blind, 
placebo-controlled (6 months) followed by an open-label extension (6 months).  Patients who have 
signed the informed consent form (ICF) and meet the eligibility criteria will be enrolled into the 
study.   
Part 1 (dose escalation, open-label) 
Part 1 will consist of up to 6 cohorts of patients and will evaluate multiple ascending dose levels 
of ACE-083 in either the tibialis anterior (TA) or biceps brachii (BB) muscle.  Patients in each 
cohort will be enrolled in a 1-month screening period before beginning treatment.  
Cohorts 1a and 1b will be treated in parallel.  The dose level in Cohort 1a will be 150 mg (3 mL) 
administered by multiple injections unilaterally into the TA muscle, once every 3 weeks for up to 
5 doses.  Patients in Cohort 1b will be similarly treated in the BB muscle.  The estimated tissue 
exposure of ACE-083 (mg/g muscle) is expected to be similar for the TA and the BB, as the two 
muscles are relatively similar in size.   
For Cohorts 2a and 2b, the decision to enroll patients and the dose levels that will be administered 
will be based upon Safety Review Team (SRT) review of safety and, if necessary, imaging data 
collected in prior cohorts.  The planned dose level for Cohorts 2a and 2b is 200 mg, with a 
maximum possible dose level of 250 mg, to be selected following SRT review of data from prior 
cohorts. 
For Cohorts 3a and 3b, the decision to enroll patients, dose level (maximum 250 mg), muscle 
tested (TA and/or BB), and unilateral or bilateral dosing will be based upon SRT review of safety 
and imaging data collected in prior cohorts.  
The SRT will meet to review data for each cohort when at least 4 patients within a cohort have 
completed their Day 43 visit (SRT meetings for “a” and “b” cohorts can occur separately or 
together, depending on recruitment).  The SRT may recommend one or more of the following: 
treatment of the remaining patients at the current dose level; escalation to a higher dose level for 
the next cohort; an intermediate (lower) dose level; or no treatment of additional patients or 
cohorts.  Recommendations made by the SRT may be relevant to both the TA and BB or specific 
to one or the other muscle, as safety findings and dose escalation may be specific to each muscle. 
 
 


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Part 2 (randomized, double-blind, placebo-controlled, with open-label extension) 
Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted 
to determine whether cohorts for one or both muscles will be pursued in Part 2, as well as the 
recommended dose level for each muscle.  A total of up to 56 new patients (28 patients per 
muscle) may be enrolled and randomized (1:1) to receive either ACE-083 (n=14/muscle) or 
placebo (n=14/muscle) bilaterally to either the TA or BB muscles (but not both).  Patients will 
receive blinded study drug once every three weeks for approximately 6 months (9 doses).  
Patients who complete the double-blind treatment period will immediately roll over to open-label 
treatment of ACE-083, receiving the same dose of active drug, bilaterally in either the TA or BB 
muscle, once every three weeks for approximately 6 months (8 doses).  In Part 2, the SRT will 
periodically review blinded safety data for each muscle treated.  
Number of Patients (planned) 
Up to 36 patients will be enrolled in the dose escalation phase of the study (Part 1) and up to 56 
patients (14 active, 14 placebo per muscle) will be enrolled in Part 2, for a total of up to 
approximately 92 patients. 
Diagnosis and Main Criteria for Eligibility 
Inclusion Criteria: 
1. Age ≥ 18 years 
2. Genetically-confirmed FSHD1 or FSHD2 (or a first-degree relative with genetically 
confirmed FSHD1 or FSHD2) and clinical findings meeting FSHD criteria  
3. Part 1 TA cohorts:  
a. 6-minute walk distance (6MWD) ≥ 150 meters(without a brace) 
b. Left and/or right ankle dorsiflexion Medical Research Council (MRC) manual muscle 
testing (MMT) grade 3 to 4+, inclusive (Appendix 3)  
Note: Contralateral side may be MRC MMT grade 3 to 5  
Part 1 BB cohorts:  
a. Left and/or right elbow flexion MRC MMT grade 3 to 4+, inclusive (Appendix 3) 
Note: Contralateral side may be any MRC MMT grade  
Part 2 TA cohorts:  
a. 6MWD ≥ 150 and ≤ 500 meters (without a brace); a maximum of 20% of  enrolled 
patients with 6MWD ≥ 450 meters will be included 
b. Left and right ankle dorsiflexion MRC MMT grade 3 to 4+, inclusive (Appendix 3)  
Part 2 BB cohorts:  
a. Left and right elbow flexion MRC MMT grade 3 to 4+, inclusive (Appendix 3) 
4. Females of childbearing potential (defined as sexually mature women who have not 
undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal 
≥ 24 consecutive months) must have negative urine pregnancy test prior to enrollment and 
use highly effective birth control methods (abstinence, oral contraceptives, barrier method 
with spermicide, or surgical sterilization) during study participation and for 8 weeks 
following the last dose of ACE-083.  Hormonal birth control use must be stable for at least 


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14 days prior to Day 1.  Males must agree to use a condom during any sexual contact with 
females of childbearing potential while participating in the study and for 8 weeks 
following the last dose of ACE-083, even if he has undergone a successful vasectomy.  
Patients must be counseled concerning measures to be used to prevent pregnancy prior to 
the first dose of ACE-083. 
5. Ability to adhere to the study visit schedule/procedures, and to understand and comply 
with protocol requirements 
6. Signed written informed consent 
Exclusion Criteria: 
1. Current active malignancy (e.g., remission less than 5 years duration), with the exception 
of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 
squamous cell carcinomas of the skin  
2. Symptomatic cardiopulmonary disease, significant functional impairment, or other 
co-morbidities that in the opinion of the investigator would limit a patient’s ability to 
complete strength and/or functional assessments on study 
3. Renal impairment (serum creatinine ≥ 2 times the upper limit of normal [ULN]) 
4. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN 
5. Increased risk of bleeding (i.e., due to hemophilia, platelet disorders, or use of any 
anticoagulation/platelet modifying therapies up to 2 weeks prior to Study Day 1; low dose 
aspirin [≤ 100 mg daily] is permitted) 
6. Major surgery within 4 weeks prior to Study Day 1 
7. Chronic systemic corticosteroids (≥ 2 weeks) within 4 weeks before Study Day 1 and for 
duration of study; intra-articular/topical/inhaled therapeutic or physiologic doses of 
corticosteroids are permitted 
8. Androgens or growth hormone within 6 months before Study Day 1 and for duration of 
study; topical physiologic androgen replacement is permitted  
9. Any change in medications potentially affecting muscle strength or function within 4 
weeks of Study Day 1 and for duration of study (e.g., creatine, CoQ10, systemic 
beta-adrenergic agonists) 
10. Previous exposure to any investigational agent potentially affecting muscle volume, 
strength, or function within 5 half-lives of last dose or 4 weeks of Study Day 1 if half-life 
is unknown, or any prior exposure to ACE-083 
11. Significant change in physical activity or exercise (e.g., significant increase or decrease in 
intensity or frequency) within 8 weeks before Study Day 1 or inability to maintain the 
baseline level of physical activity throughout the study 
12. Any condition that would prevent MRI scanning or compromise the ability to obtain a 
clear and interpretable scan of the TA or BB muscles, as applicable (e.g., pacemaker, 
knee/hip replacement, or metallic implants) 
13. Known active substance abuse, including alcohol 
14. History of sensitivity to protein pharmaceuticals 
15. Female that is lactating/breast-feeding 


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Investigational Product, Dosage, and Mode of Administration 
ACE-083 drug product is provided as a lyophilized powder contained in stoppered and sealed 
glass vials.  Each single-use vial will be reconstituted with sterile water and contains 1.2 mL of 
ACE-083 solution for injection after reconstitution. ACE-083 drug product solution for injection 
contains ACE-083 at a nominal concentration of 50 mg/mL. 
Using electromyography (EMG) or ultrasound guidance, each dose of study drug will be 
administered into the non-tendinous portion of the TA or BB up to 5 equal-volume injections per 
muscle.  The use of EMG or ultrasound guidance will ensure that viable muscle is present at the 
injection site.  If the degree of atrophy or fibro-fatty infiltration poses administration challenges, 
injections of ACE-083 should be distributed at least 2 cm apart into viable muscle.  Injection site 
locations as well as measures to avoid adjacent nerves and blood vessels and prevent intravascular 
injection are outlined in the Investigational Product (IP) Handling Guide. 
For unilateral dosing (part 1 only), if disease involvement in the lower leg or upper arm is 
asymmetric, the side that is weakest should be injected provided the MRC criterion is met.  For 
bilateral dosing in Part 1, if only one side is weak (i.e., contralateral side is MRC grade 5), it is 
acceptable to enroll the patient and to inject only the weak side.  If a patient meets inclusion 
criteria for both the TA and BB, the investigator will choose one target muscle based on the 
patient’s clinical presentation as well as on cohort availability and ability to complete assessments 
for muscle volume (MRI), strength, and function.  
In Cohorts 1 and 2 of Part 1, each dose will be administered unilaterally into the same targeted 
muscle, once every 3 weeks for up to5 doses.  For optional Cohort 3, bilateral dosing may be 
explored (to be determined by SRT), with a maximum absolute dose level of 250 mg/muscle 
administered bilaterally every 3 weeks for 5 doses. 
For Part 2, ACE-083 or placebo (normal saline) will be administered every 3 weeks for 
approximately 6 months (9 doses). Patients who complete the double-blind treatment period will 
immediately roll over to open-label treatment of ACE-083, receiving the same dose of active drug, 
bilaterally in either the TA or BB muscle, once every three weeks for approximately 6 months 
(8 doses).  
The planned dose scheme for Part 1 is below.  
Part 1: N=Up to 36 (3-month, dose-escalation, non-randomized, open-label) 
Cohort 
Muscle 
Dose 
Level a 
ACE-083 
n 
1a 
Tibialis 
anterior 
150 mg  
6 
2a 
Tibialis 
anterior 
200 mg b 
6 
3a 
(optional) 
Tibialis 
anterior 
TBD b 
6 
 
Cohort 
Muscle 
Dose 
Level a 
ACE-083 
n 
1b 
Biceps 
brachii 
150 mg  
6 
2b 
Biceps 
brachii 
200 mg b 
6 
3b 
(optional) 
Biceps 
brachii 
TBD b 
6 
  a Injection into muscle once every three weeks  
  b Dose levels for Cohorts 2 and 3 to be determined by SRT, not to exceed 250 mg per muscle  
 


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The planned dose scheme for Part 2 is below.  
Part 2: N=Up to 56a (6-month, randomized, double-blind, placebo-controlled, with 6-month 
open-label extension) 
6-month, double-blind, placebo-controlled 
Muscle 
Dose Levelb 
ACE-083 
n 
Placebo 
n 
Tibialis 
anterior 
TBDc 
14 
14 
Biceps 
brachii 
TBDc 
14 
14 
 
6-month, open-label extension 
Muscle 
Dose 
Levelb 
ACE-083 
n 
Tibialis  
anterior 
TBDc 
28 
Biceps  
brachii 
TBDc 
28 
a N=14 active, 14 placebo per muscle.  
 b Injection into muscle once every three weeks 
c Based on review of Part 1, not to exceed 250 mg per muscle 
Individual Dose Modification Rules 
For an adverse event (AE, including injection site reaction) of Grade 3 or higher, regardless of 
relationship to study drug, treatment will be paused and the patient will be monitored weekly.  
Dosing may resume upon resolution of the AE to ≤ Grade 1 or baseline, at the discretion of the 
investigator.  Dose level should be reduced by one level (i.e., from 240 to 200 mg or from 200 to 
150 mg) for events related to study drug for the remainder of the study; treatment will be 
discontinued if event occurred at 150 mg dose. 
Duration of Study 
Study duration for a patient in Part 1 will be approximately 6 months, including a 1-month 
screening period, a 3-month treatment period, and a 2-month follow-up period after the last dose.  
Study duration for a patient in Part 2 will be approximately 15 months, including a 1-month 
screening period, a 12-month treatment period (6-month double-blind, placebo-controlled and a 
6-month open-label extension), and a 2-month follow-up period after the last dose.   
If a patient has a positive anti-drug antibody (ADA) result at the last visit, the patient will be asked 
to return for additional ADA testing approximately every three months, until a negative result is 
obtained or the result is considered to be stabilized. 
Reference Therapy, Dosage, and Mode of Administration 
The placebo (control agent) to be used in Part 2 of this study will be sterile normal saline (0.9% 
sodium chloride for injection).  Sterile normal saline will be supplied by the investigational site’s 
pharmacist.  The manufacturer’s directions for saline storage and handling are to be followed, as 
are standard clinical practices for ensuring sterility.  Saline-filled syringes will be prepared by 
unblinded study personnel and provided to blinded study personnel for administration. 


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Safety Assessment: 
Dose-Limiting Toxicity (DLT) Definition:  
 A serious adverse event (SAE), possibly or probably related to study drug 
OR 
 An adverse event (AE), injection site reaction, laboratory parameter abnormality, or 
vital sign abnormality, possibly or probably related to study drug, and either grade ≥ 3 
(National Cancer Institute-Common Terminology Criteria for Adverse Events 
[NCI-CTCAE], Version 4.03) or grade ≥ 2 and considered clinically significant. 
Part 1 Dose Escalation Stopping Rules (under SRT review):  
Dosing at current levels will continue unless the following condition occurs: 
 ≥ 2 DLTs of the same character in a cohort 
Safety Review Team (SRT): 
An SRT, comprised at minimum of a principal investigator, medical monitor, and an independent 
neuromuscular specialist, will review all collected safety data when at least 4 patients in a cohort 
have completed their Day 43 visit. 
The SRT will review safety data including but not limited to AEs, laboratory results (including 
hematology and chemistry), urinalysis results, and vital signs data to assess for DLTs and overall 
safety of each dose level within each muscle.  The SRT may request collection of additional data 
from currently enrolled patients.  Based on review of safety data, the SRT will make one or more 
of the following recommendations: 
 Continue enrollment in current cohorts 
 Open next cohort and treat   
 Discontinue one or more cohorts 
 Begin enrollment into Part 2 
 Discontinue the study 
SRT recommendations for dose escalation in Part 1 will be based in part upon the dose escalation 
stopping rules for each muscle.  If a stopping rule is met, a lower intermediate dose may be 
recommended or the previous dose level will be considered the maximally tolerated dose (MTD). 
The SRT may also decide to cease enrollment in the presence of AEs that do not meet dose 
stopping rules if the nature of these AEs is deemed a significant risk to patients in a given cohort. 
In addition, the SRT will recommend a dose level for each muscle in Part 2.  In Part 2, the SRT 
will periodically review blinded safety data for each muscle treated.  Further details on the role of 
the SRT during Part 2 are included in the SRT Guidelines.  
Assessments for Evaluation: 
Safety: AEs, injection site reactions, concomitant medications, clinical laboratory tests (including 
hematology, chemistry, and ADA), urinalysis, vital signs, and physical examination findings.   
Pharmacokinetics: ACE-083 serum concentrations 
Pharmacodynamics: selected laboratory biomarkers (e.g., total testosterone, estradiol, serum 
C-terminal collagen crosslinks [CTX]) 


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Efficacy: 
Muscle volume: Muscle volume and intramuscular fat fraction in the TA and BB by MRI  
Muscle strength: Muscle strength (maximum voluntary isometric contraction) of ankle 
dorsiflexion and elbow flexion measured by quantitative muscle testing (by handheld 
dynamometer [Part 1 and Part 2] and at selected sites by fixed system [Part 1])  
Motor function tests: TA muscle function by 10-meter walk/run, 100-meter timed test (Part 2, 
open-label), 4-stair climb, 6-minute walk test, and gait analysis; BB muscle function by 
performance of the upper limb (PUL) testing (Appendix 4) and by upper extremity-specific 
FSHD-HI subscale scores  
Patient-reported disease burden and health-related quality of life: Patient-reported measures of 
quality of life and self-assessments of disease burden by the FSHD-HI total score and subscale 
scores 
Statistical Methods: 
Sample Size Calculation:  
Part 1 
There is no formal sample size calculation for Part 1.  Six patients in each cohort will provide 
sufficient data to evaluate safety and a preliminary assessment of changes in muscle volume and 
muscle strength. 
Part 2   
The sample size calculation for Part 2 is based upon the percent change from baseline in total 
muscle volume of the injected TA muscle 3 weeks after the last dose.  A 10% difference between 
ACE-083-treated and placebo groups in the percent change in total muscle volume from baseline 
is considered to be clinically meaningful.  The standard deviation (SD) is assumed to be 
approximately 9% for each group, based on preliminary MRI data for the ACE-083-treated side 
from the initial TA cohort in Part 1.  Similar assumptions apply for treatment of the BB muscle.   
Assuming a 2-sided type 1 error rate of 0.10, a 10% difference in percent change from baseline 
between the ACE-083-treated and placebo groups in total muscle volume, a standard deviation of 
9% for each group, and a 1:1 randomization, 83% power is achieved with a total sample size of 
n=24 for the TA muscle (12 active, 12 placebo), based on a standard t-test.  
In addition, this sample size also provides 83% power to detect a 10% difference in 6MWD, based 
on a similar estimated SD of 9% and a 2-sided type 1 error rate of 0.1. 
In order to account for dropouts (up to 15%), 28 patients will be randomized to study treatment for 
each muscle (14 active, 14 placebo) to ensure that at least 12 patients per treatment group 
complete the double-blind treatment period. 
Analysis Populations: 
Full Analysis Set: Part 1: All patients enrolled in the study and have received at least one dose of 
study drug.  Part 2: All patients randomized in the study 
Safety Population: All patients enrolled/randomized in the study who have received at least one 
dose of study drug (including placebo) 


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Per Protocol Set: All patients enrolled/randomized in the study, who have received at least one 
dose of study drug (including placebo) with no major protocol violations and at least one post-
baseline efficacy evaluation 
Pharmacokinetics Population: All patients who have received at least one dose of study drug and 
have sufficient PK samples collected and assayed for PK analysis 
Statistical Analysis:  
Complete details regarding the statistical analyses outlined below will be presented in a separate 
statistical analysis plan.  For statistical analyses involving safety data, these will be done on the 
safety population.  For statistical analyses involving pharmacokinetic data, these will be done on 
the pharmacokinetics population.  For statistical analyses involving efficacy and/or 
pharmacodynamics data, these will be done using the full analysis set and per protocol set 
populations. 
Part 1: Safety, pharmacodynamic and efficacy data will be summarized by cohort.  For each 
efficacy parameter, the absolute and percent change from baseline in the injected TA or BB and, 
with the exception of motor function tests and FSHD-HI total score and subscale score data, the 
raw and percent change from baseline of the treated, untreated, and treated minus untreated TA or 
BB muscle will be presented over time for patients receiving unilateral dosing of ACE-083.   
For efficacy measurements that are collected multiple times during the 1-month screening period, 
changes observed during this time will serve as the control for each patient.  They will be 
summarized together with post-baseline data. 
Part 2: The primary efficacy parameter will be the percent change in total muscle volume from 
baseline of the injected TA or BB 3 weeks after the last dose of the double-blind treatment period.  
A repeated measures analysis of covariance model will be used to compare the two treatment 
groups (ACE-083 and placebo) using a 2-sided 0.10 significance level.  If the 3-week post last 
dose data from the double-blind treatment visit are missing, the last observation will be carried 
forward.  Additional techniques for handling missing data will also be evaluated as sensitivity 
analyses to the last observation carried forward approach. 
Other strength and functional measurements will be tested similarly.  Estimates of the effect of 
ACE-083 and corresponding 90% confidence intervals will be produced. 
Where applicable, pooling of patient data may be done within and across Part 1 and Part 2 the 
details of which will be described in the statistical analysis plan.  Pooling by the estimated local 
dose of ACE-083 in the injected muscle (i.e., mg ACE-083/g muscle) may also be performed. 
AEs will be coded using the Medical Dictionary for Regulatory Activities.  Incidence of 
treatment-emergent AEs will be presented by system organ class and preferred term.  AE 
incidence rates will be described by cohort and by muscle with and without regard to causality.  
The frequency of occurrence of overall toxicity, categorized by toxicity grades (NCI-CTCAE, 
Version 4.03) will be summarized.  Change from baseline in clinical laboratory parameters and 
vital signs will be summarized across time.  Shift tables will be presented for selected laboratory 
parameters, and vital signs.  Physical examination results will be presented in listings.  
Pharmacodynamic data will be listed and summarized by cohort for each scheduled time. 
Listings of individual patient serum ACE-083 concentrations, actual blood sampling times, and 
PK parameters including graphs of concentration versus time will be prepared by dose level.  PK 


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parameters of ACE-083 will be determined using the standard non-compartmental method. 
Descriptive statistics of PK parameters will be summarized by cohort. 
The results of ADA testing for ACE-083 versus time as well as results following further 
characterization of positive ADA samples will also be presented.  Exploratory analysis will be 
performed on the potential effect of ADA on ACE-083 PK exposure if ADA tests are determined 
to be positive. 


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5. 
INTRODUCTION 
5.1. 
Background 
ACE-083 is a recombinant fusion protein consisting of a modified form of human follistatin 
(FST) linked to a human IgG2 Fc domain.  Follistatin is a member of the transforming growth 
factor (TGF)-β superfamily, a large family of structurally related cytokine-like proteins and cell 
surface receptors that play pivotal roles in the development, differentiation, and maturation of 
virtually all cells and tissues.1  Follistatin has been shown to be a potent activin antagonist 
through its role as a natural ligand trap, functioning as a key regulator of activin activity in body 
tissues.2  Growth and differentiation factor 8 (GDF8), also known as myostatin, is a powerful 
negative regulator of skeletal muscle development and growth.3  Inhibition of the modulating 
effects of both activin and myostatin on skeletal muscle growth has been identified as a 
promising therapeutic approach for degenerative diseases of skeletal muscle.4  Unlike myostatin, 
in which the expression and site of action is primarily restricted to skeletal muscle, activin is 
produced in many different tissues and mediates a wide range of biologic processes in animals 
and humans, throughout all stages of development.5  The challenge for therapeutic intervention 
in muscle diseases, therefore, has been in the selective inhibition of activin/myostatin activity 
only in the target tissue (i.e., skeletal muscle) in order to prevent or minimize undesirable off-
target effects due to broad systemic inhibition of activin.  ACE-083 has been engineered and 
developed as a locally-active ligand trap of activin and myostatin in addition to other ligands.  
The properties of ACE-083 are such that the drug remains primarily within the muscle(s) 
injected to increase mass and strength of the particular muscle(s).  
As described in the ACE-083 Investigator’s Brochure (IB), a number of nonclinical 
pharmacology studies have been conducted with ACE-083 to define the ligand-binding 
properties of the molecule and assess its anabolic effects on skeletal muscle in normal animals 
and in a mouse model of muscle disease.  Preclinical studies in normal mice and rats have 
demonstrated increased muscle mass as a result of increased fiber hypertrophy and not 
hyperplasia.  This ACE-083-induced muscle hypertrophy has also been shown to translate to 
functional improvement in muscle strength in normal mice.  ACE-083 has also been evaluated in 
a well-established mouse model of human Duchenne muscular dystrophy as representative of a 
degenerative muscle disorder.  ACE-083 treatment in these mice resulted in significant increases 
in the mass of the injected muscle.  These studies provide evidence that local inhibition of 
activin/myostatin by ACE-083 can increase muscle mass even in animals with a degenerative 
skeletal muscle disease. 
In addition, Study A083-01, a phase 1, double-bind, placebo-controlled, dose-ranging study 
designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of local 
muscle injections of ACE-083 in healthy postmenopausal women has been completed.  
Forty-two subjects have received ACE-083 at dose levels of 50 mg to 200 mg administered as 
single or multiple injections into either the right rectus femoris or right tibialis anterior muscle.  
ACE-083 was generally safe and well tolerated in this study with no serious adverse events or 
grade ≥ 3 events reported.  A significant dose-dependent change in volume of the injected 
muscle was been seen in the treated versus placebo group.  


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5.2. 
Study Rationale 
The initial proposed indication for ACE-083 is facioscapulohumeral muscular dystrophy 
(FSHD), which is the third most common muscular dystrophy and has an autosomal dominant 
pattern of inheritance in most patients compared to a less common sporadic form which affects 
approximately 10-30% of patients.6,7  FSHD has a prevalence of 1:15,000-1:20,000.6,7 FSHD is 
characterized by complex genetic mechanisms relating to the double homeobox protein 4 gene 
(DUX4).  DUX4 is normally repressed through epigenetic mechanisms in somatic cells and is 
derepressed in FSHD leading to toxic damage to skeletal muscle cells.  The DUX4 gene is 
located in the D4Z4 microsatellite array in the 4q35 region.  In FSHD1, one D4Z4 allele is 
contracted (1 to 10 repeat units) and has been in associated with DNA hypomethylation and 
chromatin structural changes.  FSHD2 accounts for about 5% of FSHD cases and has been 
characterized by hypomethylation of both normal D4Z4 alleles.  Mutations in the SMCHD1 gene 
resulting in changes in the D4Z4 chromatin structure have been linked to FSHD2.  Both types 
are phenotypically indistinguishable.8  Other rare atypical variants of the disease can also 
manifest in the setting of a genetic diagnosis.  
FSHD patients typically present in their second decade of life and live a normal lifespan.  The 
disease is clinically characterized by slowly progressive focal asymmetric areas of muscle 
weakness involving the facial, scapular, upper arm, lower leg, and abdominal muscles.  Biceps 
and triceps involvement can affect upper arm flexion and extension limiting ability to lift objects 
and perform activities of daily living.  Weakness of the tibialis anterior (TA), a commonly 
affected lower extremity muscle in FSHD patients, often results in impaired dorsiflexion and foot 
drop.  Foot drop can lead to gait instability and falls requiring the use of braces, walking devices, 
and wheelchairs.  About 20% of FSHD patients become non-ambulatory.  Other clinical 
complications associated with FSHD may involve respiratory muscle weakness, resulting in 
pulmonary complications, retinovascular disease, chronic pain, and hearing loss.9  Laboratory 
and muscle biopsy findings are often non-specific and therefore are not required for diagnosis. 
Elevations in creatine kinase (CK) can be seen but are often normal in asymptomatic patients.  
Muscle biopsy can show variable changes in muscle fiber size (both hypertrophy and atrophy) 
and inflammatory cellular infiltrates.10 
The management of the disease is based on supportive care including pain management, physical 
therapy, walking devices or braces, and surgical procedures including those to stabilize the 
scapula and improve shoulder function.  There is an extremely high unmet need for drug 
development in FSHD as there is no approved disease-modifying therapy for this unrelenting 
disease.  Clinical trials have evaluated multiple systemic treatments including prednisone, 
albuterol, strength training, and a myostatin inhibitor without definitive positive results.8  Given 
the frequent involvement of isolated muscles such as the TA and biceps brachii (BB), the 
localized action of ACE-083 could provide meaningful improvements in a patient’s muscle 
strength, function, and quality of life.  


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6. 
OBJECTIVES AND ENDPOINTS 
Table 3: 
Objectives and Endpoints 
Part 1 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability of 
ACE-083 in patients with FSHD 
 
Presence and nature of AEs including 
injection site reactions and changes in 
clinical laboratory parameters. 
Secondary 
 
To determine the recommended dose level(s) of 
ACE-083 for Part 2 
 
To evaluate changes in muscle volume and 
intramuscular fat fraction of the injected muscle 
 
To evaluate changes in strength of the injected 
muscle  
 
To estimate the systemic exposure of ACE-083 
when administered as a local muscle injection 
 
Recommendation from SRT 
 
 
Percent change from baseline in total muscle 
volume of the injected muscle 
 
 
Percent and absolute change from baseline in 
intramuscular fat fraction of the injected 
muscle 
 
Percent change from baseline in strength 
measurements 
 
Systemic exposure by changes in serum 
concentrations over time  
Exploratory 
 
To evaluate changes in motor function related to 
the injected muscle 
 
To evaluate changes in patient-reported measures 
of FSHD-HI total score and subscale scores  
 
Percent change from baseline in functional 
assessments  
 
Percent change from baseline in FSHD-HI 
total score 
 
Percent change from baseline in FSHD-HI 
subscale scores 
 
 
 


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Part 2 
Objectives 
Endpoints 
Primary 
 
To determine whether treatment with ACE-083 
increases total muscle volume of the injected 
muscle in patients with FSHD 
 
Percent change from baseline in total muscle 
volume of the injected muscle 
Secondary 
 
To determine whether treatment with ACE-083 
decreases intramuscular fat fraction of the 
injected muscle 
 
To determine whether treatment with ACE-083 
increases strength of the injected muscle 
 
To determine whether treatment with ACE-083 
improves motor function related to the injected 
muscle 
 
 
 
 
To determine whether treatment with ACE-083 
improves patient-reported measures of FSHD-HI 
total score and subscale scores  
 
To evaluate safety and tolerability of ACE-083 
 
 
 
To estimate the systemic exposure of ACE-083 
when administered as a local muscle injection 
 
Percent and absolute change from baseline in 
intramuscular fat fraction of the injected 
muscle  
 
Percent change from baseline in strength 
measurements 
 
Percent change from baseline in functional 
assessments (e.g., six minute walk test 
distance [tibialis anterior groups], 
performance of upper limb [PUL] mid-
level/elbow dimension assessment [biceps 
brachii groups])   
 
Percent and absolute change from baseline in 
FSHD-HI total score as well as percent and 
absolute change in FSHD-HI subscale scores 
 
Presence and nature of AEs including 
injection site reactions and changes in 
clinical laboratory parameters 
 
Systemic exposure by changes in serum 
concentrations over time  
Exploratory (Part 2, open-label) 
 
To assess the effect of treatment with ACE-083 
on selected motor function tests 
 
Percent change from baseline in 100-meter 
timed test (tibialis anterior groups) and PUL 
high-level/shoulder dimension assessment 
(biceps brachii groups) 


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7. 
STUDY DESIGN 
7.1. 
Overview of Study Design 
Study A083-02 is a multicenter, Phase 2 study to evaluate the safety, tolerability, 
pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with 
FSHD to be conducted in two parts.  Part 1 is open-label, dose-escalation (3 months) and Part 2 
is randomized, double-blind, placebo-controlled (6 months) with an open-label extension 
(6 months).  Patients who have signed the informed consent form (ICF) and meet the eligibility 
criteria will be enrolled into the study. Up to 36 patients will be enrolled in Part 1 and up to 56 
patients (14 active, 14 placebo per muscle) will be enrolled in Part 2, for a total of up to 
approximately 92 patients. 
Study duration for a patient in Part 1 of the study will be approximately 6 months, including a 1-
month screening period, a 3-month treatment period, and a 2-month follow-up period after the 
last dose.  Study duration for a patient in Part 2 of the study will be approximately 15 months, 
including a 1-month screening period, a 12-month treatment period (6-month double-blind, 
placebo-controlled and a 6-month open-label extension), and a 2-month follow-up period after 
the last dose.   
If a patient has a positive anti-drug antibody (ADA) result at the last visit, the patient will be 
asked to return for additional ADA testing approximately every three months, until a negative 
result is obtained or the result is considered to be stabilized. 
Part 1 (dose escalation, open-label) 
Part 1 will consist of up to 6 cohorts of patients and will evaluate multiple ascending dose levels 
of ACE-083 in either the tibialis anterior (TA) or biceps brachii (BB) muscle.  Patients in each 
cohort will be enrolled in a 1-month screening period before beginning treatment.  
Cohorts 1a and 1b will be treated in parallel.  The dose level that will be administered in Cohort 
1a will be 150 mg (3 mL) administered by multiple injections unilaterally into the TA muscle, 
once every 3 weeks for up to 5 doses.  Patients in Cohort 1b will be similarly treated in the BB 
muscle.  The estimated tissue exposure of ACE-083 (mg/g muscle) is expected to be similar for 
the TA and the BB, as the two muscles are relatively similar in size.   
For Cohorts 2a and 2b, the decision to enroll patients and the dose levels that will be 
administered will be based upon Safety Review Team (SRT) review of safety and, if necessary, 
imaging data collected in prior cohorts.  The planned dose level for Cohorts 2a and 2b is 200 mg, 
with a maximum possible dose level of 250 mg, to be selected following SRT review of data 
from prior cohorts. 
For Cohorts 3a and 3b, the decision to enroll patients, dose level (maximum 250 mg), muscle 
tested (TA and/or BB), and unilateral or bilateral dosing will be based upon SRT review of 
safety and imaging data collected in prior cohorts.  
The SRT will meet to review data for each cohort when at least 4 patients within a cohort have 
completed their Day 43 visit (SRT meetings for a and b cohorts can occur separately or together, 
depending on recruitment).  The SRT may recommend one or more of the following: treatment 
of the remaining patients at the current dose level; escalation to a higher dose level for the next 


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cohort; an intermediate (lower) dose level or no treatment of additional patients or cohorts.  
Recommendations made by the SRT may be relevant to both the TA and BB or specific to one or 
the other muscle, as safety findings and dose escalation may be specific to each muscle.  
Part 2 (randomized, double-blind, placebo-controlled, with open-label extension) 
Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted 
to determine whether cohorts for one or both muscles will be pursued in Part 2, as well as the 
recommended dose level for each muscle.  A total of up to 56 new patients (28 patients per 
muscle) may be enrolled and randomized (1:1) to receive either ACE-083 (n=14/muscle) or 
placebo (n=14/muscle) bilaterally to either the TA or BB muscles (but not both).  Patients will 
receive study drug once every three weeks for approximately 6 months (9 doses).   
Patients who complete the double-blind treatment period will immediately roll over to open-label 
treatment of ACE-083, receiving the same dose of active drug, bilaterally in either the TA or BB 
muscle, once every three weeks for approximately 6 months (8 doses).  In Part 2, the SRT will 
periodically review blinded safety data for each muscle treated. 
7.2. 
Justification for Dose Level 
ACE-083 was administered into either the rectus femoris (RF) or TA muscle of healthy 
post-menopausal women in the Phase 1 Study A083-01 at absolute dose levels per muscle of up 
to 200 mg (RF) or 150 mg (TA) as either a single dose or repeated dose every 3 weeks.  An 
estimated ACE-083 exposure (mg/g muscle) within the muscle was calculated for each patient 
using the dose administered to each patient and the size of each patient’s RF as measured at 
baseline by MRI.  Exposures of approximately 1.2 to 1.6 mg drug/g muscle every 3 weeks for 2 
doses in the RF resulted in the desired effect of an approximately 15% increase in muscle 
volume.  These exposures were considered safe and generally well tolerated following review of 
safety information.  
Considering the overall similarity in size for the TA and BB muscles, as well as the potential for 
muscle atrophy and fibro-fatty infiltration in FSHD patients, a starting dose level of 150 mg for 
both the TA and BB is considered appropriate and safe based on the Phase 1 clinical trial results.  
This starting dose level will protect patient safety and also ensure that the initial exposures 
achieved within the muscle have the potential to impact efficacy endpoints.  All subsequent dose 
levels (higher or lower) will be determined/confirmed following review of study data and 
recommendations from the SRT.  A maximum absolute dose/muscle of 250 mg following dose 
escalation has been chosen based on administration feasibility and volume constraints.  
7.3. 
Benefit/Risk Assessment 
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of ACE-083 is provided in the IB.  


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8. 
STUDY POPULATION 
8.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening: 
Inclusion Criteria: 
1. Age ≥ 18 years 
2. Genetically-confirmed FSHD1 or FSHD2 (or a first-degree relative with genetically 
confirmed FSHD1 or FSHD2) and clinical findings meeting FSHD criteria  
3. Part 1 TA cohorts:  
a. 6-minute walk distance ≥ 150 meters (without a brace)  
b. Left and/or right ankle dorsiflexion Medical Research Council (MRC) 
manual muscle testing (MMT) grade 3 to 4+, inclusive (Appendix 3)  
Note: Contralateral side may be MRC MMT grade 3 to 5  
Part 1 BB cohorts:  
a. Left and/or right elbow flexion MRC MMT grade 3 to 4+, inclusive 
(Appendix 3) 
Note: Contralateral side may be any MRC MMT grade  
Part 2 TA cohorts:  
a. 6MWD ≥ 150 and ≤ 500 meters (without a brace); a maximum of 20% of  
enrolled patients with 6MWD ≥ 450 meters will be included 
b.  Left and right ankle dorsiflexion MRCMMT grade 3 to 4+, inclusive 
(Appendix 3)  
Part 2 BB cohorts:  
a. Left and right elbow flexion MRC MMT grade 3 to 4+, inclusive 
(Appendix 3) 
4. Females of childbearing potential (defined as sexually mature women who have not 
undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal 
≥ 24 consecutive months) must have negative urine pregnancy test prior to enrollment 
and use highly effective birth control methods (abstinence, oral contraceptives, barrier 
method with spermicide, or surgical sterilization) during study participation and for 8 
weeks following the last dose of ACE-083.  Hormonal birth control use must be stable for 
at least 14 days prior to Day 1.  Males must agree to use a condom during any sexual 
contact with females of childbearing potential while participating in the study and for 8 
weeks following the last dose of ACE-083, even if he has undergone a successful 
vasectomy.  Patients must be counseled concerning measures to be used to prevent 
pregnancy prior to the first dose of ACE-083. 


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5. Ability to adhere to the study visit schedule/procedures, and to understand and comply 
with protocol requirements 
6. Signed written informed consent 
8.2. 
Exclusion Criteria 
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:  
1. Current active malignancy (e.g., remission less than 5 years duration), with the exception 
of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 
squamous cell carcinomas of the skin  
2. Symptomatic cardiopulmonary disease, significant functional impairment, or other 
co-morbidities that in the opinion of the investigator would limit a patient’s ability to 
complete strength and/or functional assessments on study 
3. Renal impairment (serum creatinine ≥ 2 times the upper limit of normal [ULN]) 
4. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN 
5. Increased risk of bleeding (i.e., due to hemophilia, platelet disorders, or use of any 
anticoagulation/platelet modifying therapies up to 2 weeks prior to Study Day 1; low 
dose aspirin (< 100 mg daily) is permitted) 
6. Major surgery within 4 weeks prior to Study Day 1 
7. Chronic systemic corticosteroids (≥ 2 weeks) within 4 weeks before Study Day 1 and for 
duration of study; intra-articular/topical/inhaled therapeutic or physiologic doses of 
corticosteroids are permitted 
8. Androgens or growth hormone within 6 months before Study Day 1 and for duration of 
study; topical physiologic androgen replacement is permitted  
9. Any change in medications potentially affecting muscle strength or function within 4 
weeks of Study Day 1 and for duration of study (e.g., creatinine, CoQ10, systemic beta-
adrenergic agonists) 
10. Previous exposure to any investigational agent potentially affecting muscle volume, 
strength, or function within 5 half-lives of last dose or 4 weeks of Study Day 1 if half-life 
is unknown, or any prior exposure to ACE-083 
11. Significant change in physical activity or exercise (e.g., significant increase or decrease 
in intensity) within 8 weeks before Study Day 1 or inability to maintain the baseline level 
of physical activity throughout the study 
12. Any condition that would prevent MRI scanning or compromise the ability to obtain a 
clear and interpretable scan of the TA or BB muscles, as applicable (e.g., pacemaker, 
knee/hip replacement, or metallic implants) 
13. Known active substance abuse, including alcohol 
14. History of sensitivity to protein pharmaceuticals 


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15. Female that is lactating/breast-feeding 
8.3. 
Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 additional times.  The interval between rescreenings should be at least 4 
weeks after the end of the 4-week screening period (i.e., the earliest re-consent may occur is 8 
weeks after the prior consent was signed).  Each time rescreening is performed; the individual 
must sign a new ICF and will be assigned a new identification number.  If a test is repeated 
within the screening window, the patient does not need to sign a new ICF. 


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9. 
DISCONTINUATION/WITHDRAWAL CRITERIA  
The reason for treatment discontinuation / study withdrawal must be recorded in the 
corresponding patient’s case report form (CRF).  The investigator must notify the sponsor and 
medical monitor when a patient has been discontinued or withdrawn from the study.   
All patients who are discontinued/withdrawn from the study prior to the end of treatment visit 
should complete the tests and evaluations (excluding the MRI if it has been done within 4 weeks 
of study withdrawal) scheduled for the end of treatment visit (Day 106/ET for Part 1, Day 
358/ET for Part 2) at the time of discontinuation/withdrawal and will be asked to return to the 
clinic to complete the remaining follow-up visit assessment. 
9.1. 
Discontinuation of Study Treatment  
Reasons that may lead to discontinuation of study treatment include: 
 Treatment completed  
 Adverse event 
 Patient request (withdrawal of consent) 
 Death 
 Lost to follow-up 
 Pregnancy 
 Protocol deviation 
 Study terminated by sponsor1 
9.2. 
Withdrawal from the Study  
Reasons that may lead to a patient’s withdrawal from the study include:  
 Patient’s request 
 Screen failure 
 Patient’s unwillingness or inability to comply with the protocol  
 Death 
 Lost to follow-up 
 Study terminated by sponsor1 
 Adverse event  
                                                 
1 the sponsor may terminate study treatment or a dose level after consultation with the investigator and the SRT at 
any time for safety or administrative reasons.  The sponsor will terminate the study if the occurrence of SAEs or 
other findings suggests unacceptable risk to the health of the patients.   


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9.3. 
Lost to Follow Up  
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted after three attempts by the study site.  Every attempt should 
be made to collect all data on discontinued patients. 
 
 
 


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10. 
TREATMENT OF PATIENTS 
10.1. 
Treatments Administered 
Using electromyography (EMG) or ultrasound guidance, each dose of study drug will be 
administered into the non-tendinous portion of the TA or BB as a series of up to 5 equal-volume 
injections.  The use of EMG or ultrasound guidance will ensure that viable muscle is present at 
the injection site.  If the degree of atrophy or fibro-fatty infiltration poses administration 
challenges, injections of ACE-083 should be distributed at least 2 cm apart into viable muscle. 
Injection site locations as well as measures to avoid adjacent nerves and blood vessels and 
prevent intravascular injection are outlined in the Investigational Product (IP) Handling Guide. 
For unilateral dosing, if disease involvement in the lower leg or upper arm is asymmetric, the 
side that is weakest should be injected provided the MRC criterion is met.  For bilateral dosing in 
Part 1, if only one side is weak (i.e., contralateral side is MRC grade 5), it is acceptable to enroll 
the patient and to inject only the weak side.  If a patient meets inclusion criteria for both the TA 
and BB, the investigator will choose one target muscle based on the patient’s clinical 
presentation as well as on cohort availability and ability to complete assessments for muscle 
volume (MRI), strength, and function. 
In Part 1, Cohorts 1 and 2, each dose will be administered unilaterally into the same targeted 
muscle, once every 3 weeks for up to 5 doses.  For optional Cohort 3, bilateral dosing may be 
explored (determined by SRT), with a maximum absolute dose level of 250 mg/muscle 
administered bilaterally, every 3 weeks for 5 doses. 
For Part 2, ACE-083 or placebo (normal saline) will be administered every 3 weeks for 
approximately 6 months (9 doses).  Patients who complete the double-blind treatment period will 
immediately roll over to open-label treatment of ACE-083, receiving the same dose of active 
drug, bilaterally in either the TA or BB muscle, once every three weeks for approximately 6 
months (8 doses). 
The planned dose scheme for Part 1 and 2 is shown below.  


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Table 4: 
Cohort Schedule for Study A083-02 
Part 1: N= Up to 36 (3-month, dose-escalation, non-randomized, open-label) 
Cohort 
Muscle 
Dose 
Level a 
ACE-083 
n 
1a 
Tibialis 
anterior 
150 mg  
6 
2a 
Tibialis 
anterior 
200 mg b 
6 
3a 
(optional) 
Tibialis 
anterior 
TBD b 
6 
 
Cohort 
Muscle 
Dose 
Level a 
ACE-083 
n 
1b 
Biceps 
brachii 
150 mg  
6 
2b 
Biceps 
brachii 
200 mg b 
6 
3b 
(optional) 
Biceps 
brachii 
TBD b 
6 
a Injection into muscle once every three weeks 
b Dose level for Cohorts 2 and 3 to be determined by SRT, not to exceed 250 mg per muscle  
 
Part 2: N=Up to 56a (6-month, randomized, double-blind, placebo-controlled and 6-month 
open-label extension) 
6-month, double-blind, placebo-controlled 
Muscle 
Dose 
Level b 
ACE-083 
n 
Placebo 
n 
Tibialis 
anterior 
TBDc 
14 
14 
Biceps 
brachii 
TBDc 
14 
14 
6-month open-label extension 
Muscle 
Dose 
Level b 
ACE-083 
n 
Tibialis 
anterior 
TBDc 
28 
Biceps 
brachii 
TBDc 
28 
a N=14 active, 14 placebo per muscle.  
b Injection into muscle once every three weeks 
c  Based on review of Part 1, not to exceed 250 mg per muscle 
10.1.1. 
Individual Dose Modification Rules 
For an adverse event (AE, including injection site reactions) of Grade 3 or higher, regardless of 
relationship to study drug, treatment will be paused and the patient will be monitored weekly.  
Dosing may resume upon resolution of the AE to ≤ Grade 1 or baseline, and dose level may be 
reduced to the prior dose level deemed safe by SRT, at the discretion of the investigator.  Dose 
level should be reduced by one level (i.e., from 240 to 200 mg or from 200 to 150 mg) for events 
related to study drug for the remainder of the study; treatment will be discontinued if event 
occurred at 150 mg dose.  If dosing does not resume within 6 weeks of the last dose given, the 
patient will be discontinued from treatment.  
10.2. 
Safety Review Team (SRT) 
Dose-Limiting Toxicity (DLT) Definition:  
 A serious adverse event (SAE), possibly or probably related to study drug 
OR 


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 An adverse event (AE), injection site reaction, laboratory parameter abnormality, or 
vital sign abnormality, possibly or probably related to study drug, and either grade ≥ 3 
(National Cancer Institute-Common Terminology Criteria for Adverse Events 
[NCI-CTCAE], Version 4.03) or grade ≥ 2 and considered clinically significant. 
Part 1 Dose Escalation Stopping Rules (under SRT review):  
Dosing at current levels will continue unless the following condition occurs: 
 ≥ 2 DLTs of the same character in a cohort 
Safety Review Team (SRT): 
An SRT, comprised at minimum of a principal investigator, medical monitor, and an independent 
neuromuscular specialist, will review all collected safety data when at least 4 patients in a cohort 
have completed their Day 43 visit. 
The SRT will review safety data including but not limited to AEs, laboratory results (including 
hematology and chemistry), urinalysis results, and vital signs data to assess for DLTs and overall 
safety of each dose level within each muscle.  The SRT may request collection of additional data 
from currently enrolled patients.  Based on review of safety data, the SRT will make one or more 
of the following recommendations: 
 Continue enrollment in current cohorts 
 Open next cohort and treat   
 Discontinue one or more cohorts 
 Begin enrollment into Part 2 
 Discontinue the study 
SRT recommendations for dose escalation in Part 1 will be based in part upon the dose escalation 
stopping rules for each muscle.  If a stopping rule is met, a lower intermediate dose may be 
recommended, or the previous dose level will be considered the maximally tolerated dose 
(MTD).  The SRT may also decide to cease enrollment in the presence of AEs that do not meet 
dose stopping rules if the nature of these AEs is deemed a significant risk to patients in a given 
cohort.  In addition, the SRT will recommend a dose level for each muscle in Part 2.  In Part 2, 
the SRT will periodically review blinded safety data for each muscle treated. Further details on 
the role of the SRT during Part 2 are included in the SRT Guidelines.  
10.3. 
Concomitant Medications 
During screening and throughout the study, patients may take stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol.  If there is an immediate 
clinical need during the study to prescribe a new medication or a new dosage of an existing 
medication for either a new or chronic condition, concurrent therapy may be administered at the 
discretion of the investigator.  Androgens or growth hormone (topical physiologic androgen 
replacement is permitted) and any change in medications potentially affecting muscle strength or 
function (e.g., creatinine, CoQ10, systemic beta-adrenergic agonists) are prohibited.  The 
investigator may consult the medical monitor regarding what constitutes a stable dose or a 


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chronic condition.  Information regarding concomitant medications will be collected beginning at 
study screening and will include all medications taken within 4 weeks prior to Study Day 1.   
10.4. 
Treatment Compliance 
Each dose of study drug will be administered as an injection at the clinical site by the study staff 
and will be documented in the study record.  Monitoring for patient compliance with the 
treatment regimen is therefore unnecessary. 
10.5. 
Randomization and Blinding 
Part 1: This is an open-label, dose escalation phase that does not require randomization. 
If a patient discontinues the study for reasons other than a safety issue related to ACE-083 and 
the patient had not completed the Day 43 visit, the patient may be replaced.  The replacement 
patient will receive the same treatment as the patient replaced.  Both the replacement and 
originally allocated patient numbers will be unique numbers. 
Part 2: Patients who have signed the informed consent and meet all eligibility criteria will be 
stratified by baseline MRC MMT grade (3 to 4- and 4- to 4+) of the weaker side and then 
randomized to receive ACE-083 (at a dose level determined by Part 1) or placebo.  Patients with 
a MRC MMT grade 4-may be stratified with either grade 3 to 3+ patients or 4 to 4+ patients 
depending on the computer-generated randomization scheme.  These patients will only be 
included in the stratum assigned during randomization.  The randomization scheme will be 
computer generated and will be prepared by a statistical group designated by the sponsor.  If a 
patient discontinues the study for reasons other than a safety issue related to ACE-083 and the 
patient had not completed the Day 43 visit, the patient may be replaced.  The replacement patient 
will receive the same treatment as the patient replaced.  Both the replacement and originally 
allocated patient numbers will be unique numbers. 
Among study personnel, only the pharmacist or his/her designee who prepares the study drug 
(ACE-083 or placebo), an unblinded clinical monitor designated by the sponsor, and the 
analytical laboratory will be unblinded to the patient treatment assignments.  All other study 
personnel (including but not limited to investigators, study coordinators, nursing staff, and 
clinical monitors) and all patients will remain blinded to the study treatment assignments.  The 
sponsor and the sponsor’s representatives will also remain blinded to the study treatment 
assignments.  
In the event of a medical emergency for an individual patient in which knowledge of the study 
drug is critical to the patient’s medical management, the investigator may break the blind for that 
patient.  However, prior to breaking the blind, every effort must be made by the investigator to 
first discuss the need to break the blind with the medical monitor.  Further, it must be determined 
by the investigator that breaking the treatment blind is necessary information for the medical 
management of that patient.  If the blind is broken prior to the end of treatment visit, the patient 
must be withdrawn from the study and complete the tests and evaluations scheduled for the end 
of treatment visit (Day 106/ET for Part 1 and Day 358/ET for Part 2) and will be asked to return 
to the clinic to complete the remaining follow-up visit assessments. 


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11. 
STUDY DRUG MATERIALS AND MANAGEMENT 
11.1. 
Study Drug 
Study drug is either ACE-083 or placebo.  ACE-083 is a recombinant fusion protein consisting 
of a modified form of human follistatin linked to a human IgG2 Fc domain.  Placebo will be 
sterile normal saline (0.9% sodium chloride for injection). 
11.2. 
Study Drug Packaging and Labeling 
ACE-083 drug product is provided as a lyophilized powder contained in stoppered and sealed 
glass vials.  Each single-use vial will be reconstituted with sterile water and contains 1.2 mL of 
ACE-083 solution for injection after reconstitution.  ACE-083 drug product solution for injection 
contains ACE-083 at a nominal concentration of 50 mg/mL.  Sterile normal saline for placebo 
will be supplied by the investigational site’s pharmacist. 
11.3. 
Study Drug Storage 
ACE-083 should be stored at °C until use.  The manufacturer’s directions for saline storage 
are to be followed, as are standard clinical practices for ensuring sterility. 
11.4. 
Study Drug Preparation 
Please refer to the IP Handling Guideline, provided separately, for detailed study drug handling, 
administration, and storage instructions.  The manufacturer’s directions for saline handling are to 
be followed, as are standard clinical practices for ensuring sterility. 
11.5. 
Study Drug Accountability 
Accountability for study drug is the responsibility of the investigator.  Investigational clinical 
supplies must be received by a designated person at the clinical site and kept in a secured 
location.  The clinical site must maintain accurate records demonstrating dates and amounts of 
study drug received, to whom it was dispensed (patient-by-patient accounting), and accounts of 
any study drug accidentally or deliberately destroyed or returned. 
Unless otherwise notified, all vials of study drug, both used and unused, must be saved for drug 
accountability purposes.  The used vials may be discarded, per the institution’s standard practice, 
after a drug accountability assessment has been completed by the clinical monitor.  At the end of 
the study, the sponsor will provide direction for the outcome of all unused vials.  Following the 
sponsor’s instructions, the investigator must either return all unused vials of study drug to the 
sponsor or destroy them at the clinical site.  In either case, the outcome must be documented on 
the drug accountability log. 
11.6. 
Study Drug Handling and Disposal 
Please refer to the IP Handling Guideline, provided under separate cover, for detailed study drug 
handling, administration, storage, and disposal instructions. 


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12.
STUDY PROCEDURES
12.1. 
Written Informed Consent
Patients will be required to sign an independent ethics committee (IEC)/institutional review 
board (IRB)-approved ICF prior to any study-related procedures, including screening 
evaluations. 
12.2. 
Study Assessments 
For each patient, all study procedures should be conducted according to the Schedule of Events 
(Appendix 1) and following the study-specific recommendations included in the Study Manual. 
12.3. 
Safety Assessments 
Safety assessments include monitoring of adverse events (AEs), injection site reactions, 
concomitant medications, clinical laboratory assessments (including hematology, chemistry, and 
ADA), urinalysis, vital signs, and physical examination findings.  
Please refer to Appendix 2 for the Clinical Laboratory Assessments that will be performed 
during this study. 
12.4. 
Efficacy Assessments 
Muscle volume: Muscle volume and intramuscular fat fraction in the TA and BB by MRI 
Muscle strength: Muscle strength (maximum voluntary isometric contraction) of ankle 
dorsiflexion and elbow flexion measured by quantitative muscle testing (by handheld 
dynamometer [Part 1 and Part 2] and at selected sites by fixed system [Part 1])  
Motor function tests: TA muscle function by 10-meter walk/run, 100-meter timed test (Part 2, 
open-label), 4-stair climb, 6-minute walk test, and gait analysis; BB muscle function by 
performance of the upper limb (PUL) testing (Appendix 4) and by upper extremity-specific 
FSHD-HI subscale scores  
Patient-reported disease burden and health-related quality of life: Patient-reported measures of 
quality of life and self-assessments of disease burden by the FSHD-HI total score and subscale 
scores 
12.5. 
Pharmacokinetic and Pharmacodynamic Assessments 
Pharmacokinetic assessment includes ACE-083 serum concentrations. PK samples for patients 
taking concomitant medications may be analyzed for changes in cytochrome P450 enzymes. 
Pharmacodynamic assessments include selected laboratory biomarkers (e.g., total testosterone, 
estradiol, serum C-terminal collagen crosslinks [CTX]). 


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13. 
SAFETY 
13.1. 
Definition of Adverse Events 
13.1.1. 
Adverse Event  
For this protocol, an adverse event (AE) is any untoward medical occurrence in a clinical 
investigational study where a patient is administered a study drug (i.e., on or after the Cycle 1 
Day 1 dose), which does not necessarily have a causal relationship with this treatment.  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study drug whether or 
not it is considered related to the study drug.  
Abnormal laboratory and other abnormal investigational findings (e.g., physical exam, ECG) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to treatment discontinuation, or are otherwise considered clinically relevant by the investigator.  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.  In the case of a fatality, the cause of death 
is considered as the AE, and the death is considered as its outcome. 
13.1.1.1. Unexpected Adverse Events 
An unexpected AE is an AE that is not described in nature or severity in the IB under the  
Reference Safety Information. 
13.1.1.2. Events Not to Be Considered as Adverse Events 
Pre-existing medical conditions/signs/symptoms present before the screening period that do not 
worsen in severity or frequency during the study are defined as baseline medical conditions, and 
are not to be considered AEs. 
13.1.1.3. Serious Adverse Event  
An SAE is any AE (on or after the Cycle 1 Day 1 dose), occurring at any dose, regardless of 
causality, that: 
 Results in death 
 Is life-threatening: life-threatening means that the patient was at immediate risk of 
death from the reaction as it occurred (i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form) 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
however, a hospitalization for an elective procedure will not be considered a SAE  
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event: an important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered 
an SAE when, based upon appropriate medical judgment, it may jeopardize the 


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patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions for SAEs.  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.  
13.1.1.4. Events Not to Be Considered as Serious Adverse Events 
Elective hospitalizations to administer or to simplify study treatment or perform procedures are 
not considered SAEs.  Unexpected complications and/or prolongation of elective hospitalization 
should be recorded as AEs.  
13.1.1.5. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and the investigator identifies as related to the investigational product or procedure. 
Acceleron follows procedures for the expedited reporting of SUSARs consistent with global 
regulations and associated guidances.    
13.2. 
Severity 
Investigators must evaluate the severity/intensity of AEs according to the CTCAE Version 4.03, 
preferentially using the graded scales.  If the severity/intensity of a particular AE is not 
specifically graded, the investigator should apply the general guidelines for determination of 
Grade 1 through Grade 5 as listed in the CTCAE v4.03 cover page (reproduced below), using 
their best medical judgment: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (e.g. preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.) 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living (e.g. bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden) 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
13.3. 
Relationship to Study Drug 
Investigators must also assess the causal relationship of each AE to study drug.  Factors for the 
assessment of causal relationship include, but are not limited to, temporal relationship between 
the AE and the administration of study drug, known side effects of study drug, medical history, 
concomitant therapy, course of the underlying disease and pertinent study procedures.  


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Probably: 
A causal relationship is clinically/biologically highly plausible and there is a 
plausible time sequence between onset of the AE and administration of study 
drug and there is a reasonable response on withdrawal. 
Possibly: 
A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of study 
drug. 
Unlikely: 
A causal relationship is improbable and another documented cause of the AE 
is most plausible. 
Not Related: A causal relationship can be definitively excluded and another documented 
cause of the AE is most plausible. 
13.4. 
Recording Adverse Events 
It is the responsibility of the investigator to document all AEs that occur during the study. 
Patients will be evaluated and questioned generally for AEs during the course of the study.  The 
investigator must report in detail all adverse signs and symptoms which are either volunteered by 
patients or observed during or following the course of investigational product administration on 
the appropriate CRF page.  All clearly related signs, symptoms, and abnormal diagnostic 
procedure results should be recorded as a single diagnosis.  All untoward medical occurrences 
arising after signing of the ICF until a patient is dosed on Cycle 1 Day 1 are to be documented on 
the medical history CRF.  All AEs occurring on or after the Cycle 1 Day 1 dose through the End 
of Study visit (Day 141 for Part 1 and Day 393 for Part 2) are to be reported and documented on 
the AE CRF.  
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the AE CRF.  Any clinically relevant changes in laboratory assessments, or other 
clinical findings as described in Section 13.1 , are considered AEs and must be recorded on the 
AE CRF. AEs are to be followed for resolution as described in in Section 13.5.  
It is important that each AE report include a description of the event, duration (onset and 
resolution dates), severity, relationship with ACE-083, any other potential causal factors, any 
treatment given, or other action taken (including dose delay or discontinuation of study drug) and 
outcome.  In addition, SAEs should be identified and the appropriate seriousness criteria 
documented.  AEs categorized as SAEs must also be documented using an SAE Report Form as 
described in Section 13.4.1.  
Specific guidance can be found in the CRF Completion Guidelines provided by the Sponsor or 
designee. 
13.4.1. 
Documentation of Serious Adverse Events 
All SAEs that occur after the first study drug administration on Cycle 1 Day 1 until the /End of 
Study visit (Day 141 for Part 1 and Day 393 for Part 2) are to be documented on the AE CRF.   
For all SAEs, an SAE Report Form must be completed with as much information as possible and 
submitted within the time frame described in Section 13.7.  When new significant information is 
obtained as well as when the outcome of an event is known, the investigator should record the 


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information on a new SAE Report Form.  In all instances, the investigator should follow up with 
patients until the outcome of the SAE is known. 
13.5. 
Reporting Adverse Events 
As described in Section 13.4 , all AEs must be recorded in the CRF up until the last follow-up 
visit.  All patients who received at least one dose of study drug, whether they completed the 
treatment period or not, should complete the end of treatment procedures.    
All AEs will be followed until clinical database lock (or resolution if it occurs before database 
lock).  All SAEs will undergo active follow-up until the event(s) have returned to baseline status, 
have stabilized, or until the investigator and sponsor have agreed that follow-up is no longer 
necessary.  Follow-up data for SAEs obtained after clinical database lock will be incorporated 
into the study drug safety database.  If a patient experiences an SAE that is considered to be 
related to study treatment at any time after the study, it must be reported to the sponsor. 
13.6. 
Pregnancy 
Female patients who are of childbearing potential at the time of consent or who become of 
childbearing potential during study participation must agree to use a highly effective method of 
birth control for the duration of the study and for 8 weeks after the last dose of ACE-083.  
Male patients and their partners must be using a highly effective method of birth control for the 
duration of the study and for 8 weeks after last dose of ACE-083.  
All pregnancies occurring during the study and up to 8 weeks after the last dose of ACE-083 
must be reported immediately to the investigator.  The investigator must report all pregnancies to 
the sponsor within 24 hours of notification.  A pregnant female participant must discontinue 
study drug immediately.  Monitoring of the patient should continue until conclusion of the 
pregnancy.  If the pregnancy ends for any reason before the anticipated date, the investigator 
should notify Medpace Clinical Safety.  At the completion of the pregnancy, the investigator will 
document the outcome of the pregnancy.  If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e. postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), the investigator should follow the procedures 
for reporting an SAE.  
13.7. 
Reporting Serious Adverse Events 
If an SAE occurs during the reporting period, the investigator must immediately (i.e., within a 
maximum 24 hours after becoming aware of the event) inform the CRO by telephone, fax, or 
e-mail. 
All written reports should be transmitted using the study-specific SAE Report Form, which must 
be completed by the investigator following specific completion instructions.  Names, addresses, 
telephone and fax numbers for SAE reporting are located on the SAE Report Form and in the 
completion instructions provided in the Study Manual.  When an SAE (or follow-up information) 
is reported by telephone, a written report must be sent immediately thereafter by fax or e-mail.  
Reporting procedures and timelines for follow-up information are the same as for the initially 
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Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
therapy).  In all cases, the information provided in the SAE Report Form must be consistent with 
the data that are recorded in the corresponding sections of the CRF. 
The investigator/reporter must respond to any request for follow-up information or to any 
question the Sponsor or designee may have on the AE within the same timelines as described for 
initial reports.  This is necessary to permit a prompt assessment of the event by the Sponsor and 
(as applicable) to allow the Sponsor to meet regulatory timelines associated with expedited 
reporting obligations. 
Requests for follow-up will usually be made by the responsible clinical monitor or medical 
monitor, or in exceptional circumstances by a pharmacovigilance representative who may 
contact the investigator directly to obtain clarification on a particularly critical event. 
13.7.1. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators 
The sponsor will send appropriate safety notifications to health authorities in accordance with 
applicable laws and regulations. 
The investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs involving his/her patients to the IEC or institutional review board (IRB) that 
approved the study. 
In accordance with International Conference on Harmonization (ICH) GCP guidelines, the 
sponsor will inform the investigator of “findings that could adversely affect the safety of 
patients, impact the conduct of the study, or alter the IEC’s/IRB’s approval/favorable opinion to 
continue the study.”  
The sponsor will inform the investigator of AEs that are serious, unexpected and are considered 
to be related to study drug (SUSARs).  The investigator should place copies of these Safety 
Reports in the Investigator Site File.  National regulations with regard to Safety Report 
notifications to investigators will be followed. 
When specifically required by regulations and guidelines, the sponsor will provide appropriate 
Safety Reports directly to the concerned lead IEC/IRB and will maintain records of these 
notifications.  When direct reporting by the sponsor is not clearly defined by national or 
site-specific regulations, the investigator will be responsible for promptly notifying the 
concerned IEC/IRB of any Safety Reports and for filing copies of all related correspondence in 
the Investigator Site File. 
For studies covered by the European Union Clinical Trials Directive 2001/20/EC, the Sponsor’s 
responsibilities regarding the reporting of SAEs/SUSARs will be carried out in accordance with 
that Directive and with the related Detailed Guidances. 


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14.
STATISTICS
14.1. 
Analysis Populations
Full Analysis Set: Part 1 - All patients enrolled in the study and have received at least one dose 
of study drug. Part 2 - All patients randomized in the study 
Safety Population: All patients enrolled/randomized in the study who have received at least one 
dose of study drug (including placebo) 
Per Protocol Set: All patients enrolled/randomized in the study, who have received at least one 
dose of study drug (including placebo) with no major protocol violations and at least one post 
baseline efficacy evaluation 
Pharmacokinetics Population: All patients who have received at least one dose of study drug and 
have sufficient PK samples collected and assayed for PK analysis 
14.2. 
Statistical Analysis Considerations 
A review of the available data from Part 1 will be conducted prior to enrolling patients into 
Part 2.  Safety and changes in efficacy parameters will be reviewed across cohorts and muscles 
to determine which dose levels, dose regimens, and muscles will be explored in Part 2.  Further 
details will be described in a separate statistical analysis plan. 
14.2.1. 
Patient Demographics and Disposition  
Individual patient demographic data will be listed by patient. 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be provided for 
continuous demographic variables (age, weight, height, and BMI) and frequency counts will be 
tabulated for categorical demographic variables (gender, race, ethnicity) by treatment and overall 
for each study part (Part 1 and Part 2).  Age will be calculated based on birth date and informed 
consent date. 
Individual patient disposition data will be listed by patient. 
Frequency counts will be tabulated for disposition data and will consist of the number of patients 
completing the study (Yes / No) along with frequency counts of primary reason for 
discontinuation (provided there is at least one patient who discontinued).  Summaries will be 
provided by treatment and overall for each study part (Part 1 and Part 2). 
14.2.2. 
Drug Exposure 
Individual study drug administration data will be listed by patient.  Descriptive statistics of study 
drug exposure will be presented. 
14.2.3. 
Efficacy Data 
14.2.3.1. Part 1 
MRI 


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MRI variables will include total muscle volume (TMV) [mm3], intramuscular fat fraction (FF) 
[%] and other calculated volume and mass parameters.  
Muscle strength 

(For TA muscle): Ankle dorsiflexion peak force value which is the maximum of three
measurements from the hand-held dynamometer or fixed system,

(For BB muscle): Elbow flexion peak force value which is the maximum of three
measurements from the hand-held dynamometer or fixed system
For each parameter in unilateral cohorts, the raw data as well as the absolute and percent change 
from baseline in the treated TA or BB muscle, untreated TA or BB muscle, and the treated minus 
untreated TA or BB muscle will be summarized for each scheduled time point.  For dose cohorts 
where the administration is bilateral, descriptive statistics of raw data, absolute and percent 
change from baseline will be provided by side treated [right and left] as well as the mean of the 
right and left sides for MRI and muscle strength parameters.     
Baseline is defined as the last non-missing value prior to first dose of ACE-083.  Theoretically, 
this should be the Day 1 pre-dose value.  Such summaries will also be done for raw data and 
change from baseline for each primary efficacy parameter. 
Estimates of the effect of ACE-083 on each efficacy parameter and corresponding 90% 
confidence intervals will be produced for the percent change data described above.  For muscle 
strength parameters, the percent change from the screening to the baseline value will serve as the 
control for each cohort. 
Additional analyses may be performed as appropriate. 
14.2.3.2. Part 2 
Primary 
The primary efficacy endpoint is the percent change in total muscle volume three weeks post last 
dose of the double-blind treatment period from baseline, where baseline is defined as the last 
non-missing value prior to first dose of study drug. 
The percent change in total muscle volume at each visit from baseline of the injected TA or BB 
will be summarized using descriptive statistics.  Descriptive statistics will be provided by side 
treated [treated and untreated] as well as the mean of the right and left sides (if bilateral 
treatment).  The effect of ACE-083 on the percent change in total muscle volume from baseline 
of the injected TA or BB three weeks post last dose of the double-blind treatment period versus 
placebo will be tested using a repeated analysis of covariance model using a two-sided 0.10 
significance level.  If such data is missing, the last observation will be carried forward.  
Additional techniques for handling missing data will also be evaluated as sensitivity analyses to 
the last observation carried forward approach.  
Additional analyses may be performed as appropriate. 
Secondary 
MRI 


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MRI variables will include intramuscular fat fraction (FF) (%) and other calculated volume and 
mass parameters.  
Muscle strength 
Muscle strength parameters are defined similarly as that for Part 1.  For each muscle strength 
parameter, descriptive statistics of the raw data, absolute and the percent change from baseline 
will be summarized for each scheduled timepoint.  Baseline is defined as the last non-missing 
value prior to dosing.  Descriptive statistics will be provided by side treated [treated and 
untreated] as well as the mean of the right and left sides (if bilateral treatment).  
Estimates of the effect of ACE-083 versus placebo for the percent change in muscle strength 
from baseline along with the corresponding 90% confidence interval will be provided.  A 
statistical model appropriate for this data will be used to generate the point estimates and 90% 
confidence intervals for these parameters as well as to perform a test of the effect of ACE-083 on 
these parameters versus placebo. 
Additional analyses may be performed as appropriate. 
Muscle function data will be summarized descriptively.  Other analyses may be performed as 
appropriate. 
FSHD-HI total and subscale scores will be summarized using descriptive statistics.  Other 
analyses may be performed as appropriate. 
14.2.3.3. Exploratory 
Muscle function data and FSHD-HI total score and subscale scores assessed from Part 1 and 
100-meter timed test and high-level/shoulder dimension PUL results from Part 2 open-label will 
be summarized descriptively.  Other analyses may be performed as appropriate. 
14.2.3.4. Pooled Analyses 
Where applicable, pooling of patient data may be done within and across Part 1 and Part 2, the 
details of which will be described in the statistical analysis plan.  Pooling by the estimated local 
dose of ACE-083 in the injected muscle (i.e., mg ACE-083/g muscle) may also be performed. 
14.2.4. 
Safety Data 
AEs will be coded using the Medical Dictionary for Regulatory Activities.  Incidence of 
treatment-emergent AEs will be presented by system organ class SOC and preferred term.  AE 
incidence rates will be described by cohort and by muscle with and without regard to causality. 
The frequency of occurrence of overall toxicity, categorized by toxicity grades (NCI-CTCAE, 
Version 4.03) will be summarized.  Change from baseline in clinical laboratory parameters and 
vital signs will be summarized across time. Shift tables will be presented for selected laboratory 
parameters, and vital signs.  Physical examination results will be presented in listings.  
14.2.5. 
Pharmacokinetic Data 
Listing of individual patient serum ACE-083 concentrations, actual blood sampling times, and 
PK parameters including graphs of concentration versus time will be prepared by dose level.  PK 


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parameters of ACE-083 will be determined using the standard non-compartmental method.  
Descriptive statistics of PK parameters will be summarized by cohorts. 
14.2.6. 
Anti-drug Antibody Data 
The results of ADA testing for ACE-083 versus time will be listed and summarized.  Exploratory 
analysis will be performed on the potential effect of ADA on ACE-083 PK exposure if ADA 
tests are determined to be positive.   
14.3. 
Determination of Sample Size 
There is no formal sample size calculation for Part 1.  Six patients in each cohort will provide 
sufficient data to evaluate safety and a preliminary assessment of changes in muscle volume and 
muscle strength.  
The sample size calculation for Part 2 is based upon the percent change from baseline in total 
muscle volume of the injected TA muscle 3 weeks after the last dose.  A 10% difference between 
ACE-083-treated and placebo groups in the percent change in total muscle volume from baseline 
is considered to be clinically meaningful.  The standard deviation (SD) is assumed to be 
approximately 9% for each group, based on preliminary MRI data for the ACE-083-treated side 
from the initial TA cohort in Part 1.  Similar assumptions apply for treatment of the BB muscle.   
Assuming a 2-sided type 1 error rate of 0.10, a 10% difference in percent change from baseline 
between ACE-083-treated and placebo groups in total muscle volume, a standard deviation of 
9% for each group, and a 1:1 randomization, 83% power is achieved with a total sample size of 
n=24 for the TA muscle (12 active, 12 placebo), based on a standard t-test.  
In addition, this sample size also provides 83% power to detect a 10% difference in 6-minute 
walk test distance, based on a similar estimated SD of 9% and a 2-sided type 1 error rate of 0.10. 
In order to account for dropouts (up to 15%), 28 patients will be randomized to study treatment 
for each muscle (14 active, 14 placebo) to ensure that at least 12 patients per treatment group 
complete the double-blind treatment period.  
14.4. 
Interim Analysis 
For Part 1, periodic reviews of the available safety and tolerability will be done to assist dose 
escalation decisions.   
For Part 2, no interim analyses are planned. 
14.5. 
Deviation from Original Analysis Plan 
A formal statistical analysis plan for the analysis and presentation of data from this study will be 
prepared before the database lock.  Deviations from the statistical analyses outlined in this 
protocol will be indicated in this plan; any further modifications will be noted in the final clinical 
study report. 


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15. 
ETHICS 
15.1. 
Institutional Review Board 
The investigator will submit this protocol, any protocol modifications, and the patient ICF to be 
used in this study to the appropriate IRB/IEC for review and approval.  A letter confirming 
IRB/IEC approval of the protocol and ICF as well as a statement that the IRB/IEC is organized 
and operates according to GCP and the applicable laws and regulations, must be forwarded to the 
sponsor prior to the enrollment of patients into the study.  A copy of the approved ICF will also 
be forwarded to the sponsor.  Appropriate reports on the progress of the study will be made to 
the IEC and the sponsor by the principal investigator in accordance with applicable 
governmental regulations and in agreement with the policy established by the sponsor.  
15.2. 
Ethical Conduct of the Study  
The sponsor and the investigator must comply with all instructions, regulations, and agreements 
in this protocol and in the applicable ICH and GCP guidelines, and must also conduct the study 
in accordance with local regulations.  
15.3. 
Patient Information and Consent  
Informed written consent is required from each patient prior to any testing under this protocol, 
including screening tests and evaluations.  The ICF, as specified by the study center’s IEC, must 
follow the Protection of Human Patients regulations listed in the Code of Federal Regulations, 
Title 21, Part 50.  The principles of informed consent in the Declaration of Helsinki should be 
implemented in this clinical study and should comply with local and national regulations.  The 
consent forms must be in a language fully comprehensible to the prospective subject.  
Information should be given in both oral and written form whenever possible and deemed 
appropriate by the IEC.  
The background of the proposed study and the benefits and risks of the procedures and study 
must be explained to the patients.  It is the responsibility of the investigator to obtain consent and 
to provide the patient with a copy of the signed and dated ICF.  Confirmation of a patient’s 
informed consent must also be documented in the patient’s medical record prior to any testing 
under this protocol, including screening tests and evaluations.  
All ICFs used in this study must be approved by the appropriate IEC and by the sponsor or 
designee.  The ICF must not be altered without the prior agreement of the relevant IEC and the 
sponsor.  
15.4. 
Patient Data Protection  
Prior to any testing under this protocol, including screening tests and evaluations, patients must 
authorize the release and use of protected health information, as required by local law.  
The patient will not be identified by name in the CRF or in any study reports.  These reports will 
be used for research purposes only.  The sponsor, its designee, and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the patient’s 
personal medical data confidential. 


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16. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES 
16.1. 
Study Monitoring 
The clinical monitor will arrange to visit the clinical sites at regular intervals during the study. 
The monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, drug accountability, compliance with regulatory 
requirements, and continued adequacy of the clinical sites and their facilities.  During these 
visits, CRFs and other data related to the study will be reviewed and any discrepancies or 
omissions will be resolved.  The clinical monitor will be given access to study–relevant source 
documents (including medical records) for purposes of source data verification. 
16.2. 
Audits and Inspections 
The investigators and clinical sites will permit trial-related monitoring, audits, IEC review, and 
regulatory inspections as requested by FDA or other health authorities and the sponsor or 
designee.  In addition to CRFs, the clinical site will permit direct access to source 
data/documents (i.e., original medical records, laboratory reports, hospital documents, progress 
reports, signed ICFs, etc.).  During and/or after completion of the study, quality assurance 
officers named by the sponsor or the regulatory authorities may wish to perform on-site audits.  
The investigator is expected to cooperate with any audit and provide assistance and 
documentation (including source data) as requested. 
 


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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1. 
Data Quality Control and Quality Assurance 
17.1.1. 
Investigator Responsibility 
The investigator is responsible for ensuring the study is conducted according to the protocol, 
Code of Federal Regulations, GCP, and applicable regulatory requirements.  The investigator’s 
responsibilities are outlined in these documents and must include the responsibility to obtain a 
signed informed consent prior to patient participation in the study. 
17.1.2. 
Protocol Modifications 
The investigator should not modify the protocol without agreement from the sponsor and prior 
review or approval by the IEC, unless an emergency situation requires protocol modification to 
ensure the safety of patients.  Any deviations from the protocol should be documented by the 
investigator or designee. 


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18. 
CONFIDENTIALITY 
To maintain patient privacy, all CRFs, study drug accountability records, study reports and 
communications will identify the patient by the assigned patient identification number.  The 
investigator will grant clinical monitor(s) and auditor(s) from the sponsor or designee and 
regulatory authorities’ access to the patient’s original medical records for verification of data 
gathered on the CRFs and to audit the data collection process.  The patient’s confidentiality will 
be maintained and will not be made publicly available.  The patient’s medical information will 
only be released to the extent permitted by the applicable laws and regulations.  
All information regarding the investigational product supplied by the sponsor to the investigator 
is privileged and confidential information.  The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the sponsor.  It 
is understood that there is an obligation to provide the sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used towards the 
development of the investigational product and may be disclosed to regulatory authorities, other 
investigators, corporate partners, or consultants as required. 
 
 
 


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19.
PUBLICATION POLICY
All information concerning study drug is considered confidential and shall remain the sole 
property of the sponsor.  The investigator(s) agrees to use this information only in conducting the 
study and shall not use it for any other purposes without the sponsor’s written approval.  The 
investigator(s) agrees not to disclose the sponsor’s confidential information to anyone except to 
persons involved in the study that need such information to assist in conducting the study, and 
then only on like terms of confidentiality and non-use. 
It is understood by the investigator(s) that the information developed from this clinical study will 
be used by the sponsor in connection with the development of study drug, and therefore may be 
disclosed as required to regulatory agencies.  To allow for the use of the information derived 
from clinical studies, it is understood that there is an obligation to provide the sponsor with 
complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except as specified in a separate, 
written, agreement between the sponsor and the investigator(s). 


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20. 
PROTOCOL AMENDMENTS 
Protocol amendments that impact patient safety, change the scope of the investigation, or affect 
the scientific quality of the study must be approved by the IEC and submitted to the appropriate 
regulatory authorities before implementation.  
In the event that the protocol needs to be modified immediately to eliminate an apparent hazard 
to a patient, the sponsor will implement the protocol change and subsequently amend the 
protocol and notify the regulatory authorities and/or the IEC, as appropriate. 
 


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21.
DATA HANDLING AND RECORDKEEPING
21.1. 
Case Report Form Completion 
CRFs will be completed for each enrolled patient. It is the investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data reported in the patient’s CRF.  Source 
documentation supporting the CRF data should indicate the patient’s participation in the study 
and should document the dates and details of study procedures, AEs, and patient status.  
Investigators will maintain copies of the CRFs at the clinical site.  For patients who discontinue 
or terminate from the study, the CRFs will be completed as much as possible, and the reason for 
the discontinuation or termination clearly and concisely specified on the appropriate CRF. 
21.2. 
Retention of Records 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirements.  Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product, or according to applicable regulatory requirements.  If the investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility.  The Sponsor must be notified in writing if a custodial change occurs. 


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22. 
REFERENCES 
1. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev 2000;14:627-44. 
2. Welt C, Sidis Y, Keutmann H, Schneyer A. Activins, inhibins, and follistatins: from 
endocrinology to signaling. A paradigm for the new millennium. Exp Biol Med (Maywood) 
2002;227:724-52. 
3. Lee SJ, Lee YS, Zimmers TA, et al. Regulation of muscle mass by follistatin and activins. 
Mol Endocrinol 2010;24:1998-2008. 
4. Tsuchida K, Nakatani M, Hitachi K, et al. Activin signaling as an emerging target for 
therapeutic interventions. Cell Commun Signal 2009;7:15. 
5. Xia Y, Schneyer AL. The biology of activin: recent advances in structure, regulation and 
function. J Endocrinol 2009;202:1-12. 
6. Flanigan KM, Coffeen CM, Sexton L, Stauffer D, Brunner S, Leppert MF. Genetic 
characterization of a large, historically significant Utah kindred with facioscapulohumeral 
dystrophy. Neuromuscul Disord 2001;11:525-9. 
7. Deenen JC, Arnts H, van der Maarel SM, et al. Population-based incidence and prevalence of 
facioscapulohumeral dystrophy. Neurology 2014;83:1056-9. 
8. Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. 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. Neurology 
2015;85:357-64. 
9. Stubgen JP, Stipp A. Facioscapulohumeral muscular dystrophy: a prospective study of 
weakness and functional impairment. J Neurol 2010;257:1457-64. 
10. Facioscapulohumeral Muscular Dystrophy. University of Washington, Seattle, 1999 Mar 8 
[Updated 2014 Mar 20]. (Accessed at http://www.ncbi.nlm.nih.gov/books/NBK1443/.) 
11. Personius KE, Pandya S, King WM, Tawil R, McDermott MP. Facioscapulohumeral 
dystrophy natural history study: standardization of testing procedures and reliability of 
measurements. The FSH DY Group. Phys Ther 1994;74:253-63. 
12. Mayhew A, Mazzone ES, Eagle M, et al. Development of the Performance of the Upper 
Limb module for Duchenne muscular dystrophy. Dev Med Child Neurol 2013;55:1038-45. 
 
 


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23.
APPENDICES


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APPENDIX 1. SCHEDULE OF EVENTS 


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Table 5: 
Schedule of Events for Part 1: Dose Escalation, Open-Label 
Screening Period 
Treatment Period 
Follow-Up Period 
Day -28 
Day -7 
(±3d)15 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Day 
106/ET2 
(±3d)15 
Day 
141/EOS 
(±3d)15 
Day 11 
Day 2 
Day 8 
(±1d)15 
Day 221 
(±1d)15 
Day 431 
(±3d)15 
Day 641 
(±3d)15 
Day 851 
(±3d)15 
Day 86 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
X 
X 
Urine pregnancy test3 
X 
X 
X 
X 
X 
Medical history 
X 
X 
X 
MMT assessment (MRC) 
X 
Genetic testing16 
X 
Physical examination4 
X 
X 
X 
X 
X 
X 
X 
Injection site examination5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology7 
X 
X 
X 
X 
X 
X 
X 
Chemistry7 
X 
X 
X 
X 
X 
X 
X 
Urinalysis7 
X 
X 
X 
X 
X 
PD Biomarkers 
X 
X 
X 
X 
X 
X 
X 
Anti-drug antibody 
X 
X 
X 
X 
X 
X 
X 
X8 
Serum PK9 
0, 2, 4, 
6 h 
X 
X 
X 
X 
X 
0, 2, 4, 
6 h 
X 
X 
X 
ECG (12 lead) 
X 
Bilateral MRI10 
X 
X 
X 
X 
Strength (QMT – by fixed system)11 
X 
X 
X 
X 
X 
X 
Strength (QMT – by handheld device)11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lower Leg Functional Assessments12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Upper Arm Functional Assessments13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSHD-Health Index 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration14 
X 
X 
X 
X 
X 


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Clinical Study Protocol 
Study A083-02 
Revision: 04 
09 January 2019 
Acceleron Pharma Inc. 
Page 58 of 64 
CONFIDENTIAL 
1   Study procedures must be done prior to administration of study drug.  Reference the Study Manual for the order of study procedures. Laboratory samples and functional/strength assessments may be collected up to 24 hours prior to 
administration of study drug.  Time of study drug administration is the time of the first injection.  
2   Patients who discontinue prior to the Day 106/ET visit should complete the Day 106/ET visit at the time of discontinuation and return for the remaining follow-up period visit.  If an MRI has been completed within 4 weeks of 
discontinuation, it does not need to be repeated as part of the Day 106/ET visit procedures.  
3 Pregnancy test for women of childbearing potential to be performed and negative result confirmed before dosing.  
4   Full physical examination (skin, head, eyes, ears, nose, throat and neck, lymph nodes, cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neurological) at screening and Day 106/ET; limited physical examination 
(skin, cardiovascular, respiratory, musculoskeletal, and neurological assessments) for Days 1, 22, 43, 64, 85. 
5   Injection site examination including but not limited to evaluating erythema, pain, bruising, bleeding, and other signs of discomfort or skin reaction to be completed at least 30 minutes after injection.
6 Vital signs (weight, heart rate, systolic and diastolic blood pressure) must be taken prior to administration of study drug on dosing days.  Height is collected only at screening. 
7 Tests defined in Appendix 2, Table 7.  
8     If a patient has a positive ADA result at Day 141, the patient will be asked to return to the clinical site for additional follow-up approximately every 3 months until a negative or stable result is obtained. 
9    PK samples on a dosing day have a ±15 minute window for post-dose sample collection, based on time of first injection.  Pre-dose samples may be collected up to 4 hours prior to dosing.  Day 2 and 86 sample collection should be 
24 hours post dose ±3 hours. 
10    MRI assessments should be completed within 5 days prior to the scheduled dose administration.  MRI assessments during the follow up period (Day 106/ET and Day 141) have a ± 5 day window. 
11  Maximum voluntary isometric contraction testing (MVICT) of both TA and BB muscles will be conducted for all cohorts at screening visits and Day 141 only using a handheld dynamometer, only the muscle under study will be 
tested (i.e., TA or BB).  Both sides will be tested for all visits (right and left). 
12  TA cohort only: 10-meter walk/run, 4-stair climb, 6-minute walk test, and gait analysis; lower leg assessments will be collected for the BB cohorts at screening visits and Day 141 only.  
13  BB cohort only: PUL testing (middle domain) testing; PUL testing (middle domain) will also be performed on patients in TA cohorts at screening visits and Day 141 only.  Non-ambulatory patients in the BB cohort can opt out of 
the TA screening tests.  
14  Study drug administration should occur within 21 days (± 3 days) of the previous dose. 
15 All visit day windows should be considered relative to the date of the previous dose of study drug. Actual visit days may be different than planned (e.g., Day 8, Day 22) due to windows on visits and potential dosing delays.  
16 Genetic testing for FSHD1/FSHD2 to be performed at screening if patient has not already had testing performed or previous results cannot be used to determine eligibility.  Genetic testing for FSHD1/FSHD2 to be performed during 
the study if first degree relative is used for study eligibility but patient has not had testing previously performed or if patient’s genetic documentation is inadequate with respect to FSHD1 D4Z4 fragment size or repeat number 


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Clinical Study Protocol 
Study A083-02 
Revision: 04 
09 January 2019 
Acceleron Pharma Inc. 
Page 59 of 64 
CONFIDENTIAL 
Table 6: 
Schedule of Events for Part 2: Randomized, Double-Blind, Placebo-Controlled with Open-Label Extension 
Screening 
Double-Blind, Placebo-Controlled 
Open-Label 
ET17 
EOS18,20 
Cycle(s)  
-- 
-- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10, 15 
16 
11, 12, 
13; 
14, 17 
-- 
-- 
Planned Day(s)  
-28
to -
21 
-7
(±3d) 
11 
2 
8 
(±1d)2 
221  
(±1d)2 
431 
 (±3d)2 
641  
(±3d)2 
851 
(±3d)2 
86 
1061 
(±3d)2 
1271 
(±3d)2 
1481 
(±3d)2 
1691 
(±3d)2 
(190, 295)1 
(±3d)2 
3161 
(±3d)2 
(211, 
232, 253; 
274, 
337)1 
(±3d)2 
358 
(±3d)
2
393 
(±3d)2 
Informed consent 
X 
Inclusion/exclusio
n criteria 
X 
Urine pregnancy 
test3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
X 
X 
Genetic testing4 
X 
Full physical 
examination5 
X 
X 
X 
X 
X 
Limited physical 
examination6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site 
examination7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD Biomarkers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-drug 
antibody 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
Serum PK10 
0, 
2, 
4, 
6 h 
X 
X 
0, 2, 4, 6 
h 
X 
X 
X 
X 
ECG (12 lead) 
X 
X 
4 h19 
X 
Bilateral MRI11 
X 
X 
X 
X 
X 
X 


ACE-083 
Clinical Study Protocol 
Study A083-02 
Revision: 04
09 January 2019 
Acceleron Pharma Inc. 
Page 60 of 64 
CONFIDENTIAL 
Screening 
Double-Blind, Placebo-Controlled 
Open-Label 
ET17 
EOS18,20 
Cycle(s)  
-- 
-- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10, 15 
16 
11, 12, 
13; 
14, 17 
-- 
-- 
Planned Day(s)  
-28
to -
21 
-7
(±3d) 
11 
2 
8 
(±1d)2 
221  
(±1d)2 
431 
 (±3d)2 
641  
(±3d)2 
851 
(±3d)2 
86 
1061 
(±3d)2 
1271 
(±3d)2 
1481 
(±3d)2 
1691 
(±3d)2 
(190, 295)1 
(±3d)2 
3161 
(±3d)2 
(211, 
232, 253; 
274, 
337)1 
(±3d)2 
358 
(±3d)
2
393 
(±3d)2 
Strength (QMT – 
by handheld 
device)12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lower Leg 
Functional 
Assessments13 
TA 
& 
BB 
TA & 
BB 
TA 
TA 
TA 
TA 
TA 
TA 
TA 
TA 
TA & BB 
Day 190 
TA Day 
295 
TA 
TA 
TA & 
BB 
Upper Arm 
Functional 
Assessments14 
BB 
& 
TA 
BB & 
TA 
BB 
BB 
BB 
BB 
BB 
BB 
BB 
BB 
BB & TA 
Day 190 
BB Day 
295 
BB 
BB 
BB & 
TA 
FSHD-Health 
Index 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of 
adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization15 
X 
Study drug 
administration16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MMT assessment 
(MRC) 
X 
X 
X 
X 


ACE-083 
Clinical Study Protocol 
Study A083-02 
Revision: 04
09 January 2019 
Acceleron Pharma Inc. 
Page 61 of 64 
CONFIDENTIAL 
1 Study procedures must be done prior to administration of study drug.  Reference the Study Manual for the order of study procedures. Laboratory samples and functional/strength assessments may be collected up to 24 hours prior to 
administration of study drug.  Time of study drug administration is the time of the first injection.  The Day 1 visit is timed relative to the Screening Day -28 to Day -21 visit.  The Day -7 visit is timed relative to the scheduled Day 1 
visit. 
2  All visit day windows should be considered relative to the date of the previous dose of study drug.  Actual visit days may be different than planned (e.g., Day 8, Day 22) due to windows on visits and potential dosing delays.  
3 Pregnancy test for women of childbearing potential to be performed and negative result confirmed before dosing.  
4 Genetic testing for FSHD1/FSHD2 to be performed at screening if patient has not already had testing performed or previous results cannot be used to determine eligibility.  Genetic testing for FSHD1/FSHD2 to be performed during 
the study if first degree relative is used for study eligibility but patient has not had testing previously performed or if patient’s genetic documentation is inadequate with respect to FSHD1 D4Z4 fragment size or repeat number 
5 Full physical examination includes skin, head, eyes, ears, nose, throat and neck, lymph nodes, cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neurological  
6 Limited physical examination includes skin, cardiovascular, respiratory, musculoskeletal and neurological assessments 
7 Injection site examination including but not limited to evaluating erythema, pain, bruising, bleeding, and other signs of discomfort or skin reaction to be completed at least 30 minutes after injection.
8 Vital signs (weight, heart rate, systolic and diastolic blood pressure) must be taken prior to administration of study drug on dosing days.  Height is collected only at screening. 
9 Tests defined in Appendix 2, Table 7.  
10 PK samples on a dosing day have a ±15 minute window for post-dose sample collection, based on the time of the first injection.  Pre-dose samples may be collected up to 4 hours prior to dosing.  Day 2 and 86 sample collection 
should be 24 hours post dose ±3 hours. 
11 MRI assessments should be completed within 5 days prior of the scheduled dose administration.  MRI assessments during the follow up period (Day 358/ET and Day 393/EOS) have a ± 5 day window 
12 Maximum voluntary isometric contraction testing (MVICT) of both TA and BB muscles will be conducted for all cohorts at screening visits, Day 190 and Day 393/EOS At all other visits, only the muscle under study will be tested 
(i.e., TA or BB).  Both sides will be tested for all visits (right and left). 
13 TA cohort only: 10-meter walk/run, 4-stair climb, 6-minute walk test, and gait analysis are performed at all visits: 100-meter timed test begins at Day 169 and continues throughout open-label visits; lower leg assessments will be 
collected for the BB cohorts at screening visits, Day 190 and Day 393/EOS only.  
14 BB cohort only: PUL mid-level/elbow dimension performed at all visits; additional PUL high level/shoulder dimension begins at Day 169 and continues throughout open-label visits; PUL testing will also be performed on patients 
in TA cohorts at screening visits (mid level), Day 190 (high and mid-level) and Day 393/EOS (high and mid-level) only. 
Non-ambulatory patients in the BB cohort can opt out of the TA assessments.  
15 Randomization should occur within 24 hours prior to Day 1 dose.   
16 Study drug administration should occur within 21 days (± 3 days) of the last dose. 
17 Patients who discontinue prior to the Day 358/ET visit should complete the Day 358/ET visit at the time of discontinuation and return for the remaining follow-up period visit.  If an MRI has been completed within 4 weeks of 
discontinuation, it does not need to be repeated as part of the Day 358/ET visit procedures. 
18 If a patient has a positive ADA result at Day 393/EOS, the patient will be asked to return to the clinical site for additional follow-up approximately every 3 months until a negative or stable result is obtained. 
19 ECG is to be conducted ±1 hour of the 4h PK sample. 
20 If subjects enroll directly into a separate extension study and will receive additional treatment with ACE-083, they do not need to complete the EOS visit.  For these subjects, their final Study Visit in this protocol will be the ET visit. 


ACE-083 
Clinical Study Protocol 
Study A083-02 
Revision: 04
09 January 2019 
Acceleron Pharma Inc. 
Page 62 of 64 
CONFIDENTIAL 
APPENDIX 2. CLINICAL SAFETY LABORATORY ASSESSMENTS 
Table 7: 
Clinical Safety Laboratory Assessments 
Type of Assessment 
Details 
Hematology 
Hemoglobin, hematocrit, platelet count, red blood cell count, white blood cell 
(WBC) count, and WBC differential 
Chemistry 
AST, ALT, lactate dehydrogenase (LDH) and isoenzymes 1-5, gamma-glutamyl 
transpeptidase (GGT), blood urea nitrogen (BUN), creatinine, creatine kinase 
(CK), myoglobin, aldolase, sodium, potassium, glucose, albumin, total bilirubin  
Urine 
Urinalysis by dipstick analysis (pH, specific gravity, protein, myoglobin, 
glucose, ketones, blood, leukocyte esterase, and nitrite) 


Clinical Study Protocol 
ACE-083 
09 January 2019 
Acceleron Pharma Inc. 
Page 63 of 64 
CONFIDENTIAL 
Study A083-02 
Revision: 04 
APPENDIX 3. MEDICAL RESEARCH COUNCIL MANUAL MUSCLE 
TESTING GRADING SCALE 
Grading Scale for Manual Muscle Testing (MMT)11 
MMT 
Grade 
Description 
5 
Normal strength 
5-
Uncertain muscle weakness
4+ 
Inability to resist against maximal pressure throughout range of motion
4 
Ability to resist against moderate pressure throughout range of motion
4-
Ability to resists against minimal pressure throughout range of motion
3+ 
Ability to move through full range of motion against gravity and to resist against
minimal pressure through partial range of motion, then contraction breaks abruptly
3 
Ability to move through full range of motion against gravity
3-
Ability to move through greater than one half range of motion against gravity
2+ 
Ability to move through less than one half range of motion against gravity
2 
Ability to move through full range of motion with gravity eliminated
2-
Ability to move in any arc of motion with gravity eliminated
1 
A flicker of movement is seen or felt in the muscle
0 
No contraction palpable


ACE-083 
09 January 2019 
Acceleron Pharma Inc. 
Page 64 of 64 
CONFIDENTIAL 
Clinical Study Protocol 
Study A083-02 
Revision: 04
APPENDIX 4. PERFORMANCE OF THE UPPER LIMB TEST 
Performance of the Upper Limb12 

SAP_000.pdf: 
Official Title: A Phase 2 Randomized, Double‐Blind, Placebo‐Controlled Study of ACE‐083 in Patients with 
Facioscapulohumeral Muscular Dystrophy 
NCT Number:  NCT02927080 
Document Dates: SAP version 1: 21‐Aug‐2019 


Confidential and Proprietary 
1 
Acceleron Pharma Inc. 
 
 
 
Statistical Analysis Plan 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study 
of ACE-083 in Patients with Facioscapulohumeral Muscular 
Dystrophy 
Sponsor: 
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Tel: +1 617-649-9200 
Fax: +1 617-576-0479 
Investigational Product: 
ACE-083 
Protocol Number: 
A083-02 
EudraCT Number: 
2016-003257-15 
Version Number: 
1.0 
Date: 
21 August 2019 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, especially unpublished data, is the property of 
Acceleron Pharma Inc. (or under its control), and therefore provided to you in confidence for 
review by you and/or your staff. It is understood that this information will not be disclosed to 
others without written authorization from Acceleron.




A083-02 
Statistical Analysis Plan 
Confidential and Proprietary 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................5 
2. 
STUDY OBJECTIVES ................................................................................................5 
2.1. 
Primary Objective .........................................................................................................5 
2.2. 
Secondary Objectives ...................................................................................................5 
2.3. 
Exploratory Objectives .................................................................................................6 
3. 
OVERALL STUDY DESIGN ......................................................................................7 
3.1. 
Part 1 .............................................................................................................................7 
3.2. 
Part 2 .............................................................................................................................8 
4. 
STATISTICAL METHODS .........................................................................................9 
4.1. 
General Method ............................................................................................................9 
4.1.1. 
Sample Size Determination ..........................................................................................9 
4.1.2. 
Computing Environment ..............................................................................................9 
4.1.3. 
Treatment Description ..................................................................................................9 
4.1.4. 
Definitions of Baseline ...............................................................................................10 
4.1.5. 
Data Handling Conventions ........................................................................................11 
4.2. 
Analysis Population ....................................................................................................12 
4.3. 
Subject Disposition .....................................................................................................13 
4.4. 
Demographic and Baseline Characteristics ................................................................14 
4.4.1. 
Demographics .............................................................................................................14 
4.4.2. 
Baseline Characteristics ..............................................................................................14 
4.5. 
Prior and Concomitant Medications/Therapy .............................................................17 
4.6. 
Study Drug Exposure ..................................................................................................17 
4.6.1. 
Extent of Exposure .....................................................................................................17 
4.7. 
Efficacy Data ..............................................................................................................18 
4.7.1. 
Variables .....................................................................................................................18 
4.7.1.1. 
MRI .............................................................................................................................18 
4.7.1.2. 
Muscle Strenght ..........................................................................................................19 
4.7.1.3. 
Motor Function ...........................................................................................................20 
4.7.1.4. 
Patient Reported Outcome Variables..........................................................................23 
4.7.2. 
Analyses ......................................................................................................................23 
4.7.2.1. 
Part 1 ...........................................................................................................................23 


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Statistical Analysis Plan 
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4.7.2.2. 
Part 2 ...........................................................................................................................25 
4.7.2.3. 
Part 2 Open-Label Extension ......................................................................................43 
4.7.2.4. 
Subgroup Analyses (Part 2 Only) ...............................................................................45 
4.7.2.5. 
Other Analyses ............................................................................................................47 
4.8. 
Pharmacodynamic Data ..............................................................................................48 
4.8.1. 
Variables .....................................................................................................................48 
4.8.2. 
Analyses ......................................................................................................................48 
4.8.2.1. 
Part 1 ...........................................................................................................................48 
4.8.2.2. 
Part 2 ...........................................................................................................................48 
4.9. 
Safety Data ..................................................................................................................48 
4.9.1. 
Adverse Events ...........................................................................................................48 
4.9.2. 
Clinical Laboratory Evaluations .................................................................................50 
4.9.3. 
Anti-Drug Antibodies .................................................................................................51 
4.9.4. 
Other Safety Data .......................................................................................................51 
4.10. 
Pharmacokinetic Data .................................................................................................51 
5. 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE 
PROTOCOL ...............................................................................................................52 
6. 
PROGRAMMING SPECIFICATIONS .....................................................................53 
7. 
APPENDICES ............................................................................................................56 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................57 
 
LIST OF TABLES 
Table 1: 
Planned Doses to Be Administered for Part 1 ..............................................................7 
 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical techniques to be used to analyze data for study protocol A083-02.  The purpose of 
the SAP is to ensure the credibility of the study findings by pre-specifying the statistical 
approaches to the analysis of study data prior to database lock. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
Part 1 
 To evaluate the safety and tolerability of ACE-083 in patients with 
facioscapulohumeral disease (FSHD) 
Part 2 
 To determine whether treatment with ACE-083 increases total muscle volume of the 
injected muscle in patients with FSHD 
2.2. 
Secondary Objectives 
Part 1 
 To determine the recommended dose level(s) of ACE-083 for Part 2 
 To evaluate changes in muscle volume and intramuscular fat fraction of the injected 
muscle 
 To evaluate changes in strength of the injected muscle 
 To estimate the systemic exposure of ACE-083 when administered as a local muscle 
injection 
Part 2 
 To determine whether treatment with ACE-083 decreases intramuscular fat fraction 
of the injected muscle 
 To determine whether treatment with ACE-083 increases strength of the injected 
muscle 
 To determine whether treatment with ACE-083 improves motor function related to 
the injected muscle 
 To evaluate changes in patient-reported measures of FSHD-HI total score and 
subscale scores 
 To evaluate safety and tolerability of ACE-083 
 To estimate the systemic exposure of ACE-083 when administered as a local muscle 
injection 


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2.3. 
Exploratory Objectives  
Part 1 
 To evaluate changes in motor function related to the injected muscle 
 To evaluate changes in patient-reported measures of FSHD-HI total score and 
subscale scores. 
 


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3. 
OVERALL STUDY DESIGN 
This study is a two-part multicenter, phase 2 study to evaluate the safety, tolerability, 
pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with 
FSHD.  Part 1 is open-label dose-escalation and Part 2 is randomized, double blind, placebo-
controlled with an open-label extension.   
Patients who participate in Part 1 are not eligible to participate in Part 2. 
The total study duration for individual patients in Part 1 will be approximately 6 months, which 
includes a 1-month screening period, a 3-month treatment period, and a 2-month follow-up 
period after the last dose.  The total study duration for individual patients in Part 2 will be 
approximately 15 months, which includes a 1-month screening period, a 12-month treatment 
period (6-month double-blind, placebo-controlled followed by a 6-month open-label extension), 
and a 2-month follow-up period after the last dose. 
3.1. 
Part 1 
Part 1 will consist of up to 6 cohorts of patients and will evaluate multiple ascending dose levels 
of ACE-083 in either the tibialis anterior (TA) or biceps brachii (BB) muscle.  Patients in each 
cohort will be enrolled in a 1-month screening period before beginning treatment. 
Table 1 below outlines the planned doses to be administered. 
6-month intervals thereafter. 
The primary endpoint analysis will be performed when all participants have completed their 
post-Treatment Period PVR assessment. 
A detailed charter will outline all activities of the DMC (including, but not limited to, type of 
data to be reviewed, DMC responsibilities, and frequency of meetings). 
Table 1: 
Planned Doses to Be Administered for Part 1 
Cohort 
Dosing 
Days 
Muscle 
Planned 
Dose 
Level 
Type of 
Administration 
ACE-083 
n 
1a 
1, 22, 43, 64, 
and 85 
Tibialis 
Anterior 
150 mg 
Unilateral 
6 
2a 
1, 22, 43, 64, 
and 85 
Tibialis 
Anterior 
200 mg 
Unilateral 
6 
3a 
1, 22, 43, 64, 
and 85 
Tibialis 
Anterior 
200 mg 
Bilateral 
6 
Total Number of Patients (Planned) 
18 
 


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Cohort 
Dosing 
Days 
Muscle 
Planned 
Dose 
Level 
Type of 
Administration 
ACE-083 
n 
1b 
1, 22, 43, 64, 
and 85 
Biceps 
brachii 
150 mg 
Unilateral 
6 
2b 
1, 22, 43, 64, 
and 85 
Biceps 
brachii 
200 mg 
Unilateral 
6 
3b 
1, 22, 43, 64, 
and 85 
Biceps 
brachii 
240 mg 
Unilateral 
6 
Total Number of Patients (Planned) 
18 
Periodic reviews of selected blinded safety and imaging data will be reviewed by the Safety 
Review Team (SRT) in accordance with the SRT Guidelines.  
3.2. 
Part 2 
Prior to the initiation of Part 2, a review of the safety and efficacy data from Part 1 will be done 
in order to determine whether one or both the TA and BB muscles will be studied as well as the 
recommended dose level for each muscle.  Up to 56 patients (28 patients per muscle) will be 
enrolled and randomized (1:1 ratio) to receive either ACE-083 (n=14/muscle) or placebo 
(n=14/muscle) bilaterally to either the TA or BB muscles (but not both).  Patients will receive 
study drug once every three weeks for approximately 6 months (9 doses).  If a patient 
discontinues the study for reasons other than a safety issue related to investigational study drug 
and the patient had not completed the Day 43 visit, the patient may be replaced.  The 
replacement patient will receive the same treatment as the patient replaced. 
Patients who complete the double-blind treatment period will immediately roll over to open-label 
treatment with ACE-083.  All patients will receive ACE-083 administered at the same dose as in 
the double-blind period.  They will receive bilateral injections, in the same muscles that study 
drug was administered to during the double-blind period, once every three weeks for 
approximately 6 months (8 doses).  In Part 2, the SRT will periodically review blinded safety 
data for each muscle treated. 
A stratified randomization schedule will be prepared under the direction of the Sponsor with the 
stratification factors of: “Muscle” (values are “Tibialis anterior (TA)” and “Biceps brachii 
(BB)”) and “MRC-MMT Grade” (values are “3 to 4-” and “4- to 4+”).  Stratification by baseline 
MRC-MMT grade will be that of the weaker side.  Patients whose weaker MRC-MMT grade is 
“4-“ will be randomly assigned to either the “3 to 4-“ or the “4- to 4+” stratum based on the 
Interactive Response Technology (IRT) system.  Because Part 2 is multicenter, an IRT system 
will be used to randomize patients sequentially across clinical sites.   
Similar to Part 1, periodic reviews of selected blinded safety and imaging data will be reviewed.  
Further details concerning the frequency and timing of SRT reviews of Part 2 data are described 
in the SRT Guidelines. 
 
 


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4. 
STATISTICAL METHODS 
4.1. 
General Method 
The Full Analysis Set consists of all randomized participants treated with correct treatment 
assignment. 
4.1.1. 
Sample Size Determination 
There was no formal sample size calculation for Part 1.  Six patients in each cohort will provide 
sufficient data to evaluate safety and a preliminary assessment of changes in muscle volume and 
muscle strength.   
The sample size calculation for Part 2 is based upon the percent change from baseline in total 
muscle volume of the injected TA muscle 3 weeks after the last dose.  A 10% difference between 
ACE-083-treated and placebo groups in the percent change in total muscle volume from baseline 
is considered to be clinically meaningful.  The standard deviation (SD) is assumed to be 
approximately 9% for each group, based on preliminary MRI data for the ACE-083-treated side 
from the initial TA cohort in Part 1.  Similar assumptions apply for the treatment of the BB 
muscle. 
Assuming a 2-sided type I error rate of 0.10, a 10% difference in percent change from baseline 
between ACE-083-treated and placebo groups in total muscle volume, a standard deviation of 
9% for each group, and a 1:1 randomization, 83% power is achieved with a total sample size of 
24 for the TA muscle (12 active, 12 placebo), based on a standard t-test. 
In addition, this sample size also provides 83% power to detect a 10% difference in 6-minute 
walk test distance, based on a similar estimated SD of 9% and a 2-sided type 1 error rate of 0.10. 
In order to account for dropouts (up to 15%), 28 patients will be randomized to study treatment 
for each muscle (14 active, 14 placebo) to ensure that at least 12 patients per treatment group 
complete the double-blind treatment period. 
4.1.2. 
Computing Environment 
The analysis of clinical data from both Parts 1 and 2 will be performed under the direction of the 
Acceleron Pharma Biostatistics Department, using SAS® (version 9.4 or higher) and R. 
4.1.3. 
Treatment Description  
Treatment descriptions as well as abbreviations used in tables, listings, and figures are described 
below: 
Part 1 
Unless otherwise stated, tables and figures will be presented as shown below: 
Part 1 – Tibialis Anterior 
ACE-083 150 mg 
Unilateral 
ACE-083 200 mg 
Unilateral 
ACE-083 200 mg 
Bilateral 
Overall 
 
 


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Part 1 – Biceps Brachii 
ACE-083 150 mg 
Unilateral 
ACE-083 200 mg 
Unilateral 
ACE-083 240 mg 
Unilateral 
Overall 
Listings will contain only the treatment groups shown with no “Overall” group. 
Part 2 
Unless otherwise stated, tables and figures will be presented using one or more of the following 
as shown below, depending on what is being summarized/analyzed. 
Part 2 – Double-blind period 
Tibialis Anterior 
Biceps Brachii 
Placebo ACE-083 Overall Placebo ACE-083 Overall 
Part 2 – Open-label period –by treatment group sequence 
Tibialis Anterior 
Biceps Brachii 
ACE-083ACE-083 PlaceboACE-083 ACE-083ACE-083 PlaceboACE-083 
Part 2 – Open-label period – Pooled across treatment group sequence 
Tibialis Anterior Biceps Brachii 
ACE-083 
ACE-083 
Listings will contain the treatment groups shown above however, there will be no “Overall” 
group. 
4.1.4. 
Definitions of Baseline 
Part 1 and Part 2 (Double-blind phase) 
For MRI, PD, and safety data, baseline is defined as the last non-missing assessment prior to the 
first dose of study drug administration.  Theoretically, this is the Day 1 pre-dose assessment.  For 
patients that are randomized (applicable to patients participating in Part 2) but do not receive any 
study drug administration, the date of randomization will be the baseline reference. 
For motor function data (lower leg and upper arm functional assessments), strength (QMT by 
handheld device), gait, and FSHD-HI data whose pre-treatment assessments are performed up to 
three times prior to the first dose, the baseline is defined as the average of the non-missing 
values.  Theoretically, this would be at the Screening Day -28, Screening Day -7, and Day 1 
visits.  The first dose date will serve as the reference from which the non-missing pre-treatment 
values would be identified. For patients that are randomized (applicable to patients participating 
in Part 2) but do not receive any study drug administration, the date of randomization will be the 
baseline reference.   The last non-missing assessment prior to the first dose of study drug 
administration will also be determined for this data and will be available for sensitivity analyses 
for any analyses of changes from baseline as appropriate. 
 
 


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Part 2 (Open-label extension) 
For assessments performed in the open-label extension where data prior to the start of the open-
label extension is collected at both Day 169 and 190, the baseline is defined as the mean of the 
assessments performed at Day 169 and Day 190.  Should one of these assessments be missing, 
the other assessment would be used as the baseline.   
For assessments performed in the open-label extension where data prior to the open-label 
extension is only collected at Day 190 (e.g. MRI, FSHD-HI, strength), then the baseline would 
be the Day 190 assessment.   
4.1.5. 
Data Handling Conventions 
Unless otherwise stated or indicated: 
 Individual data for all patients will be presented in data listings, sorted by “Study 
Part” (Part 1 or Part 2), “Treatment Group”, and “Patient Number”; 
 For any parameter analyzed, only observations from visits and/or time points planned 
in the protocol will be used in descriptive statistics.  An exception to this rule is for a 
baseline assessment.  Should an unscheduled assessment be taken after the scheduled 
baseline assessment but before the first dose of study medication, then the 
unscheduled assessment may be used as the baseline; 
 For variables where the Day 1 assessment is defined as the baseline, should an 
individual patient have a Day 1 assessment after having received their first dose, then 
an unscheduled assessment may be used as the baseline, provided that the 
unscheduled assessment was done prior to first dose. 
 For variables where the baseline is defined as the mean of Day -28, Day -7, and Day 
1, should an individual patient have a Day 1 assessment taken after having received 
their first dose, then only the Day -28, Day -7, and any unscheduled assessment will 
be used to determine the average for the baseline (as described in Section 4.1.4), 
provided that the unscheduled assessment was done prior to first dose. 
 For the determination of baseline PUL, only data on the patient’s preferred side will 
be used.  For example, if the patient’s preferred side is “Left” and any individual PUL 
assessment at any of the Day -28, Day -7, and Day 1 timepoints is recorded as having 
been done on the “Right” or performed as “Both”, that individual assessment will not 
be used in the determination of the baseline PUL for that patient. 
 With the exception of what is described in the preceeding bullet, unscheduled 
assessements will not be collectively summarized in summary tables or figures; 
however, these data will appear in individual patient listings. 
 For adverse events where the assessment of “Relationship to study drug” is missing, it 
will be assumed that the adverse event is “Probably Related” to study drug. 
 For selected efficacy data, tests of statistical hypotheses and estimation using the end-
of-treatment visit or the Day 190 visit (Part 2 double-blind component), multiple 
imputation for missing data will be performed.  There will be no imputations 
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Additional techniques for handling missing data may also be considered and 
evaluated.   
 If a patient has a Day 190 assessment performed after having received the Day 190 
dose (first dose in the open-label phase), then the Day 190 assessment for that patient 
will be included in statistical analyses of Day 190 data only if the difference between 
the Day 190 assessment and the Day 190 dose date is less than or equal to 7 days. 
 Descriptive statistics for quantitative parameters will be provided using number of 
observations (N), mean, standard deviation (SD), standard error of the mean (SEM), 
median, minimum and maximum; 
 Should it be necessary to convert duration in days to duration in months, the duration 
in days will be divided by 30.417 (365/12) to calculate duration in months. 
 Descriptive statistics for qualitative parameters will be provided using frequencies 
(N) and percentages (%). 
 If the result of a continuous variable contains nonnumeric values (e.g. ‘<X’ or ‘>X’), 
the imputed values used for the descriptive statistics will be determined by 
considering the following rules: 
 If the value is ‘<X’, the value used will be X/2; 
 If the value is ‘>X’, the value used will be X. 
 Concerning the determination of absolute and percent change from baseline for data 
such as MRI and muscle strength where assessments are reported separately for the 
left and right sides and the average absolute and/or percent change from baseline is 
needed, the absolute and/or percent change is determined for the left and right sides 
separately and then averaged.  The “average” represents the “average” absolute (or 
percent) change from baseline for the left and right sides.  For MRI and muscle 
strength data, should a patient have an MRI and/or strength assessment on one side 
(i.e. right side) but not the other side at an individual timepoint, the value for the 
average absolute (or percent) change from baseline for that patient and timepoint will 
be the absolute (or percent) change from the side from which the MRI and/or strength 
assessment was obtained. 
4.2. 
Analysis Population 
The analysis populations include the following: 
 Full Analysis Set: Part 1 – All patients enrolled in the study receiving at least one 
dose of ACE-083. Part 2 – All patients randomized; 
 Safety Set: All patients enrolled/randomized in the study who have received at least 
one dose of study drug (includes placebo); 
 Per Protocol Set: All patients enrolled/randomized in the study who have received at 
least one dose of study drug (includes placebo) with no major protocol violations. 
 Major protocol violations include: 


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 Patients who discontinue the study prior to the Cycle 3 Day 43 visit; these patients 
are replaced per protocol 
 Patients whose Day 1 MRI or Day 190 MRI was done 7 or more days following 
study drug administration 
 Patients whose functional assessments (i.e. 10mW/R, mid-level PUL, 6MWT, 
4-stair climb) at Day 1 or Day 190 were done 7 or more days following study 
drug administration 
 Patients who did not receive the full study drug administration planned per 
protocol at all injection sites on any or both sides (right or left) for 2 or more 
consecutive visits for reasons other than dose reductions for the safety of the 
patient or feasibility concern (i.e., the site intended to administer the full dose but 
was unable). 
Should the statistical analysis populations be identical (e.g., Full Analysis Set = Per Protocol 
Set), statistical analyses will not be duplicated or repeated. 
4.3. 
Subject Disposition 
Individual patient disposition data will be listed. 
Frequency counts will be tabulated for disposition data and will include the following: 
 Number of patients enrolled [Part 1 only], 
 Number of patients randomized [Part 2 only], 
 Number (%) of patients completing the study [Part 1 only], 
 Number (%) of patients completing the double-blind treatment period [Part 2 only] 
 A patient is said to have completed the double-blind treatment period if the 
patient completed up to and including the Day 190 visit. 
 Number (%) of patients entered into the open-label period [Part 2 only] 
 Number (%) of patients completing the open-label treatment period [Part 2 only] 
 A patient is said to have completed the open-label treatment period if the patient 
completed up to and including the Day 337 visit. 
 Number (%) of patients that rollover to the extension study, A083-04 
 Patients that rollover to the extension study consist only of patients participating 
in Part 2 of this study who complete both the double-blind treatment period AND 
the open-label treatment period who will not have the Day 393/EOS visit.  These 
patients’ final study visit will be the Day 358/ET visit. 
 Number (%) of patients that do not rollover to the extension study A083-04 
 Patients that do not rollover to the extension study will have both the Day 358/ET 
and Day 393/EOS visits completed. 


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 Number (%) of patients discontuing from the study prior to completing both the 
double-blind period and the open label period [Part 2 only] 
 Number (%) of patients that discontinued during the double-blind period  
 Number (%) of patients that discontinued during the open-label period  
 Number (%) of patients for primary reason for discontinuation will also be 
provided [provided there is at least one patient who discontinued]. 
Summaries will be provided by treatment and overall for each study part (Part 1 and Part 2). 
4.4. 
Demographic and Baseline Characteristics 
4.4.1. 
Demographics 
Individual demographic data will be listed. 
Descriptive statistics (N, mean, SD, median, minimum and maximum) will be provided for 
continuous demographic variables (age, weight, height, and BMI) and frequency counts will be 
tabulated for categorical demographic variables (gender, race, ethnicity) by treatment and overall 
for each study part (Part 1 and Part 2).  Age will be calculated based on birth date and informed 
consent date. 
4.4.2. 
Baseline Characteristics 
Baseline characteristics of the patient population consist of selected items from the FSHD 
disease history, MRI, MRC-MMT, and functional test data.  Such data includes the following: 
 FSHD disease diagnosis  
 The disease diagnosis values are either FSHD1 or FSHD2 
 D4Z4 fragment size (kilobases) 
 The D4Z4 fragment sizes will be grouped into the following categories:  ≤ 18 kb; 
19-28 kb; > 28 kb (These categories roughly correspond with categories based on 
number of D4Z4 repeats.) 
 Scapular fixation surgery 
 This is a categorical variable whose possible values are “Right”, “Left”, “Both”, 
or “No History”. 
 This is derived off of the responses to the question “Did the patient have history 
of scapular fixation surgery” (responses are “Yes” or “No”) and if “Yes”, then the 
choice of either “Right”, “Left”, or “Both” would be selected.   
 A value of “No History” would be the case where the answer to the question “Did 
the patient have history of scapular fixation surgery” is “No”. 
 Wears any lower limb orthotics/braces 
 This is a categorical variable whose values are “Right”, “Left”, “Both”, or “Does 
not wear”. 


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 This is derived off of the responses to the question “Does the patient currently 
wear any lower limb orthotics/braces” (responses are “Yes” or “No”) and if 
“Yes”, then the choice of either “Right”, “Left”, or “Both” would be selected. 
 A value of “Does not wear” would be the case where the answer to the question 
“Does the patient currently wear any lower limb orthotics/braces?” is “No”. 
 Walking device use 
 Values are “Yes” or “No” 
 First degree relatives with FSHD 
 Values are “Yes” or “No” 
 Exercise program 
 This is a categorical variable whose values are “Aerobic 1-2 times per week”, 
“Aerobic 3-4 times per week”, “Aerobic 5+ times per week”, “Resistance training 
1-2 times per week”, “Resistance training 3-4 times per week”, “Resistance 
training 5+ times per week”, “Both aerobic and resistance training 1-2 times per 
week”, “Both aerobic and resistance training 3-4 times per week”, “Both aerobic 
and resistance training 5+ times per week”, and “No exercise program” 
 This is derived off of the responses to the question “Does the patient have a 
regular exercise program” (responses are “Yes” or “No”) and if “Yes”, then the 
choices of how many times a week overall (1-2, 3-4, or 5+) and the type of 
exercise (Aerobic, Resistance training, or Both) would be selected. 
 Age at onset of symptoms (years) 
 Age at diagnosis (years) 
 Duration since onset of symptoms (years) 
 Duration since onset of symptoms = Age (years) – Age at onset of symptoms 
(years) 
 Duration since diagnosis (years) 
 Duration since diagnosis = Age (years) – Age at diagnosis (years) 
 Total muscle volume (mm3) 
 See Section 4.7.1 for definition. 
 Total muscle mass (g) 
 See Section 4.7.1 for definition. 
 Calculated contractile muscle volume (mm3) 
 See Section 4.7.1 for definition. 
 Calculated contractile muscle mass (g) 
 See Section 4.7.1 for definition. 


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 Fat fraction (%) 
 6-minute walk distance (m) 
 Time to complete 10 meter walk/run (s) 
 PUL composite time (s) 
 MRC-MMT grade category 
Part 1 
 MRC-MMT grades will be grouped into the following categories:  [3 to 4-], [4 to 4+], 
[5- to 5] 
 For unilateral dose cohorts, summaries to be provided will be the side treated and will 
either be that of elbow flexion (for those receiving study drug in the BB muscle), 
ankle dorsiflexion (for those receiving study drug in the TA muscle), or knee 
extension (for those receiving study drug in the TA muscle). 
 For those receiving study drug bilaterally, each side will be summarized  
 Elbow flexion (for those receiving study drug in the BB muscle) 
 Ankle dorsiflexion (for those receiving study drug in the TA muscle) 
 Knee extension (for those receiving study drug in the TA muscle). 
Part 2 
 MRC-MMT grade classification:   [3 to 4-] and [4 to 4+]. 
 MRC-MMT grades will also be summarized (frequency with percents) by the 
weakest grade for each of the following: 
 Elbow flexion (BB patients) – possible values are 3, 3+, 4-, 4, 4+ 
 Ankle dorsiflexion (TA patients) – possible values are 3, 3+, 4-, 4, 4+ 
 Knee extension (TA patients) – possible values are 2-, 2, 2+, 3-, 3, 3+, 4-, 4, 4+, 5-, 5. 
 MRC-MMT SCORE which represents the conversion of the MRC-MMT grade to the 
decimal version as follows:  5 = 5.0, 5- = 4.67, 4+ = 4.33, 4 = 4.0, 4- = 3.67, 3+ = 
3.33, 3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 1 = 1.0. 
 For unilateral dose cohorts, summaries to be provided will be for the side treated 
and will either be that of elbow flexion (for those receiving study drug in the BB 
muscle) or ankle dorsiflexion (for those receiving study drug in the TA muscle). 
 For bilateral dose cohorts, this will be determined for each side (left and right) 
and then averaged.  Only the “average” will be presented in the summary table. 
 Dose of ACE-083 expressed as (mg/g calculated total muscle mass) 
 Dose of ACE-083 expressed as (mg/g calculated contractile muscle mass) 
The table below outlines how to derive the dose of ACE-083 expressed as either mg/g total 
muscle, or mg/g contractile muscle: 


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Dose of ACE-083 Expressed as 
mg/g Calculated Total Muscle Mass 
mg/g Calculated Contractile Muscle Mass 
Unilateral  
Cohorts 
Dose injected (mg) / (Baseline CCMV 
{mm3}* [1.06/1000] + Baseline CIMFV 
{mm3} * [0.9/1000]) 
Dose injected (mg) / (Baseline CCMV 
{mm3}* [1.06/1000]) 
Bilateral  
Cohorts 
Step 1: For each side (right and left), compute 
the following:  Dose injected (mg) /(Baseline 
CCMV {mm3}* [1.06/1000] + Baseline 
CIMFV {mm3}* [0.9/1000]) 
Step 2: Compute average of the Dose of ACE-
083 expressed as mg/g total muscle for each 
side using the information obtained from Step 
1. 
Step 1: For each side (right and left), 
compute the following:  Dose injected (mg) 
/(Baseline CCMV {mm3}* [1.06/1000]) 
Step 2: Compute average of the Dose of 
ACE-083 expressed as mg/g contractile 
muscle for each side using the information 
obtained from Step 1. 
CCMV = Calculated contractile muscle volume; CIMFV = Calculated intramuscular fat volume 
Note: For unilateral cohorts, this will be determined only for the side that is treated. 
This data will be summarized using appropriate descriptive statistics.   
4.5. 
Prior and Concomitant Medications/Therapy 
Prior and concomitant medications recorded during the study will be listed.  These will be coded 
with the WHO Drug Dictionary (Version 2016-09). 
Medications will be assigned as prior or concomitant based on the following rules: 
 If both the start and stop date exist and are before the first dose date of study drug, the 
medication will be classified as a prior medication. 
 If the start date is on or after the first dose date of study drug, the medication will be 
classified as a concomitant medication. 
 If the start date is before the first dose date of study drug and the stop date is after the 
first dose date of study drug or the medication is ongoing, the medication will be 
classified as prior and concomitant. 
 If the start date is missing and the stop date is before the first dose of study drug, the 
medication will be classified as prior. 
 If the start date is missing and the stop date is after the first dose of study drug or the 
medication is ongoing, the medication will be classified as concomitant. 
 If the start and stop dates are missing, the medication will be classified as 
concomitant. 
4.6. 
Study Drug Exposure 
4.6.1. 
Extent of Exposure 
A listing of individual patient dosing data will be provided. 
Study drug exposure will be summarized descriptively by cohort (Part 1) and by treatment group 
for each muscle (Part 2) for the safety population.  Such summaries will include the total number 


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of treatment cycles, the number and percentage of patients with dose delay and reduction.  If no 
patients experience dose delay and reduction, then no such summaries will be provided. 
The total number of cycles will be summarized by presenting the number and percentage of 
patients in each category.  Categories refer to the total number of treatment cycles.  For Part 1, 
the possible values of the total number of treatment cycles are:  “1”, “2”, “3”, “4”, and “5”.  For 
Part 2 (double-blind period), the possible values of the total number of treatment cycles over the 
course of the double-blind treatment period is:  “1”, “2”, “3”, “4”, “5”, “6”, “7”, “8”, or “9”.  For 
Part 2 (open-label extension), the possible values of the total number of treatment cycles over the 
course of the open-label extension is: “1”, “2”, “3”, “4”, “5”, “6”, “7”, or “8”. 
The total study drug exposure in weeks will also be summarized and will be derived according to 
the following formula: Exposure (weeks) = [(Last dose date – First dose date) +21] / 7. 
For Part 1, summaries of the total study drug exposure in weeks will be provided by cohort using 
descriptive statistics.  The summary table will include a pooled summary across cohorts within 
each muscle treated. 
For Part 2, summaries of the total study drug exposure in weeks will be provided by treatment 
group for each muscle treated. 
4.7. 
Efficacy Data 
4.7.1. 
Variables 
4.7.1.1. 
MRI 
MRI variables consist of the following: 
Variable 
Unit 
Formula for derivation or SAS variable name/expression from SDTM FA 
Total muscle volume 
(TMV) 
mm3 
TMV = Contractile muscle tissue volume (SAS variable FASTRESN in SDTM 
FA where FATESTCD = “MVOL”) + Intramuscular fat volume (SAS variable 
FASTRESN in SDTM FA where FATESTCD=”IFATVOL”) 
Intramuscular fat 
volume (IMFV) 
mm3 
SAS variable FASTRESN in SDTM FA where FATESTCD=”IFATVOL” 
Contractile muscle 
volume (CMV) 
mm3 
SAS variable FASTRESN in SDTM FA where FATESTCD=”MVOL” 
Fat fraction (FF) 
% 
SAS variable FASTRESN in SDTM FA where FATESTCD=”FATF” 
Contractile muscle 
fraction (CMF) 
% 
CMF = 100 – FF 
Calculated contractile 
muscle volume 
(CCMV) 
mm3 
CCMV = TMV * CMF/100 
Calculated 
intramuscular fat 
volume (CIMFV) 
mm3 
CIMFV = TMV * FF/100 
Contractile muscle 
mass (CMM) 
g 
CMM = CMV * 1.06/1000 


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Variable 
Unit 
Formula for derivation or SAS variable name/expression from SDTM FA 
Intramuscular fat mass 
(IMFM) 
g 
IMFM = IMFV * 0.9/1000 
Total muscle mass 
(TMM) 
g 
TMM = CMM + IMFM 
Calculated contractile 
muscle mass (CCMM) 
g 
CCMM = CCMV * 1.06/1000 
Calculated 
intramuscular fat mass 
(CIMFM) 
g 
CIMFM = CIMFV * 0.9/1000 
Calculated total 
muscle mass (CTMM) 
g 
CTMM = CCMM + CIMFM 
4.7.1.2. 
Muscle Strength 
Muscle strength variables consist of the following: 
 For cohorts where treatment is administered unilaterally 
 Ankle dorsiflexion (maximum voluntary isometric contraction [MVIC]) for the 
treated TA muscle [TA cohorts] 
a. 
MVIC = maximum force (from 3 measurements) from the hand-held 
dynamometer. 
b. 
The treated TA muscle can be either the right or left side.  The treated and 
untreated sides will remain the same for the individual patient throughout 
the study. 
 Elbow flexion (MVIC) for the treated BB muscle [BB cohorts] 
a. 
MVIC = maximum force (from 3 measurements) from the hand-held 
dynamometer. 
b. 
The treated BB muscle can be either the left or right side.  The treated and 
untreated sides will remain the same for the individual patient throughout 
the study. 
 For cohorts where treatment is administered bilaterally 
 Maximum (of 3 measurements) right ankle dorsiflexion (MVIC) [TA cohorts] 
 Maximum (of 3 measurements) left ankle dorsiflexion (MVIC) [TA cohorts] 
 Maximum (of 3 measurements) right elbow flexion (MVIC) [BB cohorts] 
 Maximum (of 3 measurements) left elbow flexion (MVIC) [BB cohorts] 
For each of the MRI and muscle strength variables listed above, the absolute and percent change 
from baseline will be determined for each side (“Treated”, “Untreated”, and “Treated – 
Untreated” sides for unilateral dose cohorts; “Left”, and “Right” sides for bilateral dose cohorts) 
and time.  In addition, for bilateral dose cohorts, the average of the absolute change from 
baseline as well as the average of the percent change from baseline for the left and right sides 
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4.7.1.3. 
Motor Function  
4.7.1.3.1. Lower Leg Function Assessments  
10-Meter Walk/Run Test 
 Time to complete 10-meter walk/run (seconds) 
4-Stair Climb  
 Ascending 
 Time to ascending stairs (sec.) 
 Number and percentage of patients belonging to the following grades: 
1. Unable to climb 4 standard stairs 
2. Climbs 4 standard stairs “marking time” (climbs one foot at a time, with both feet on a 
step before moving to next step), uses both arms on one or both handrails 
3. Climbs 4 standard stairs “marking time” (climbs one foot at a time, with both feet on a 
step before moving to next step), using one arm on one handrail 
4. Climbs 4 standard stairs “marking time” (climbs one foot at a time, with both feet on a 
step before moving to next step), not needing handrail 
5. Climbs 4 standard stairs alternating feet, needs handrail for support 
6. Climbs 4 standard stairs alternating feet, not needing handrail support 
7. Not Done 
 Descending  
 Time to descending stairs (sec.) 
 Number and percentage of patients belonging to the following grades: 
1. Unable to descend 4 standard stairs 
2. Descends 4 standard stairs “marking time” (climbs one foot at a time, with both feet on a 
step before moving to next step), uses both arms on one or both handrails 
3. Descends 4 standard stairs “marking time” (climbs one foot at a time, with both feet on a 
step before moving to next step), using one arm on one handrail 
4. Descends 4 standard stairs “marking time” (climbs one foot at a time, with both feet on a 
step before moving to next step), not needing handrail 
5. Descends 4 standard stairs alternating feet, needs handrail for support 
6. Descends 4 standard stairs alternating feet, not needing handrail support 
7. Not Done 
 
 


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 6-Minute Walk Test 
 Cumulative distance traveled at 6 minutes (meters) 
 Cumulative distance traveled at 1 minute (meters) 
 Cumulative distance traveled at 2 minutes (meters) 
 Cumulative distance traveled at 3 minutes (meters) 
 Cumulative distance traveled at 4 minutes (meters) 
 Cumulative distance traveled at 5 minutes (meters) 
 Gait Assessments 
 General measures: Ambulation distance (meters), Ambulation time (ms), 
Ambulation velocity (cm/s), Mean normalized velocity (Leg lengths/s), Number 
of steps, Cadence (steps/min.), Step time differential (ms), Step length differential 
(m), Cycle time differential (ms), Forward lean (deg.), Sway (m), Left step time 
(ms), Left Cycle Time (ms), Left Step Length (m), Left stride length (m), Left 
base width (m), Left single support (% gait cycle), Left initial double support (% 
gait cycle), Left terminal double support (% gait cycle), Left total double support 
(% gait cycle), Left swing (% gait cycle), Left stance (% gait cycle), Left step 
extremity ratio (ratio), Right step time (ms), Right Cycle Time (ms), Right Step 
Length (m), Right stride length (m), Right base width (m), Right single support 
(% gait cycle), Right initial double support (% gait cycle), Right terminal double 
support (% gait cycle), Right total double support (% gait cycle), Right swing (% 
gait cycle), Right stance (% gait cycle), Right step extremity ratio (ratio) 
 Initial measures:  Initial left hip flexion (deg.), initial left knee flexion (deg.), 
initial left ankle dorsiflexion (deg.), initial left clearance (cm), Initial right hip 
flexion (deg.), initial right knee flexion (deg.), initial right ankle dorsiflexion 
(deg.), initial right clearance (cm) 
 Peak measures: Peak left hip min (deg.), Peak left hip max (deg.), Peak left knee 
min (deg.), Peak left knee max (deg.), Peak left ankle dorsiflexion min (deg.), 
Peak left ankle dorsiflexion max (deg.), Peak left clearance max (cm.), Peak right 
hip min (deg.), Peak right hip max (deg.), Peak right knee min (deg.), Peak right 
knee max (deg.), Peak right ankle dorsiflexion min (deg.), Peak right ankle 
dorsiflexion max (deg.), Peak right clearance max (cm.) 
 Average measures: Average left hip min (deg.), Average left hip max (deg.), 
Average left knee min (deg.), Average left knee max (deg.), Average left ankle 
dorsiflexion min (deg.), Average left ankle dorsiflexion max (deg.), Average left 
clearance max (cm.), Average right hip min (deg.), Average right hip max (deg.), 
Average right knee min (deg.), Average right knee max (deg.), Average right 
ankle dorsiflexion min (deg.), Average right ankle dorsiflexion max (deg.), 
Average right clearance max (cm.) 
 100-meter timed test (patients receiving ACE-083 in the TA muscle during the Part 2 
open-label phase) 


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 Time to complete 100-meters (sec.) 
4.7.1.3.2. Upper Arm Functional Assessments 
 Performance of upper limb (PUL) – Middle level elbow dimension score 
 Sum of the 9 items for this particular dimension (Maximum = 34).  These include: 
“Hand(s) to Mouth”, “Hand(s) to table from lap”, “Move weight on table”, 
“Lifting light cans”, “Lifting heavy cans”, “Stacking light cans”, “Stacking heavy 
cans”, “Remove lid from container”, and “Tearing paper”. 
 Time to lift 5 light cans (sec.) 
 Time to stack 5 light cans (sec.) 
 Time to lift 5 heavy cans (sec.) 
 Time to stack 5 heavy cans (sec.) 
  Composite (or average) time to complete the following tasks:  lift 5 light cans, lift 
5 heavy cans, stack 5 light cans, and stack 5 heavy cans. 
a. Note that when deriving the average time to complete the selected tasks listed above, 
one or more of the times may be missing for a given patient at one or more time 
points.  If such a scenario occurs, the average of the “non-missing” times should then 
be determined.  For example, if the “Time to lift 5 light cans (sec.)” is missing for a 
patient at a particular time point (s), and the other 3 quantities are non-missing, then 
the average time to complete the selected tasks should be computed off of the 3 non-
missing quantities. 
 PUL high level/shoulder dimension (patients receiving ACE-083 in the BB muscle 
during the Part 2 open-label phase) 
 Shoulder domain score which represents the sum of the following 4 items that the 
patient is asked to do on the preferred side [either right or left side identified by 
patient to be done on the same side for all scheduled times]: 
a. 
Largest weight patient can use to perform shoulder abduction to shoulder 
height (elbow to shoulder level) 
b. 
Largest weight patient can use to perform shoulder abduction above 
shoulder height (elbow to eye level) 
c. 
Largest weight patient can use to perform shoulder flexion to shoulder 
height (elbow to shoulder level) 
d. 
Largest weight patient can use to perform shoulder flexion above shoulder 
height (elbow to eye level) 
Each of the 4 components above is scored depending on the highest weight performed where 
scores are: 0 = Unable; 1 = Able no weights; 2 = 200 g; 3 = 500 g; 4 = 1000 g.  The maximum 
score is 16. 
 
 


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4.7.1.4. 
Patient Reported Outcome Variables 
 Total Facioscapulohumeral Disease Health Index (FSHD-HI) score 
 The 14 subscale scores of the FSHD-HI survey 
 Shoulder and Arm Function, Mobility and Ambulation, Fatigue, Cognitive 
Function, Activity Limitation, Core Strength and Function, Gastrointestinal 
Function, Social Performance, Body Image, Hand and Finger Function, Social 
Satisfaction, Pain, Emotional Health, and Communication 
4.7.2. 
Analyses  
4.7.2.1. 
Part 1 
Unless otherwise specified, no imputations for missing data will be performed for Part 1 data. 
MRI and Muscle Strength Variables 
Unilateral Cohorts 
Individual MRI and strength data will be listed. 
For each MRI and strength variable, the raw data as well as the absolute and percent change from 
baseline in the treated TA or BB muscle, untreated TA or BB muscle, and the treated minus 
untreated TA or BB muscle will be summarized for each scheduled time point.   
Least square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced using an analysis of covariance (ANCOVA) for the 
following variables: TMV percent change from baseline 3 weeks post last dose, CCMV percent 
change from baseline 3 weeks post last dose, FF absolute change from baseline 3 weeks post last 
dose, percent change in elbow flexion MVIC 3 weeks post last dose (BB cohorts), and percent 
change in ankle dorsiflexion MVIC 3 weeks post last dose (TA cohorts).    
The ANCOVA model will contain the following covariates: 
 COHORT represents the dose level of ACE-083 administered to the muscle.  
 BASELINE represents the baseline value of the parameter of interest 
 BASELINE*COHORT represents the interaction of the baseline and cohort 
The analysis described above will be performed for the treated side as well as for the difference 
in treated and untreated sides and will be done separately for the TA and BB cohorts.   
For BB patients, the above analyses will be repeated using the patient’s “preferred” side used for 
the PUL test for patients.   
Additional analyses may be performed as appropriate. 
Bilateral Cohort 
For each MRI and strength parameter, descriptive statistics of the raw data as well as the 
absolute and percent change from baseline will be provided by side treated [left and right] as 
well as for the average of the left and right sides. 


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A one-sample t-test will be performed to estimate the effect of ACE-083 with corresponding 
90% and 95% confidence intervals for the following variables: TMV percent change from 
baseline 3 weeks post last dose, CCMV percent change from baseline 3 weeks post last dose, FF 
absolute change from baseline 3 weeks post last dose, and percent change in ankle dorsiflexion 
MVIC 3 weeks post last dose. 
The analysis described above will be performed using the data for the average absolute as well as 
the average percent change from baseline for the left and right sides.   
Motor Function Variables 
Individual motor function data will be listed. 
For motor function test variables (TA cohorts: cumulative distance at 6 minutes from the 
6-minute walk test, time to complete 10 meter walk/run test, 4-stair ascend time, 4-stair descend 
time, gait parameters; BB cohorts: PUL parameters)  the raw data as well as absolute and percent 
change from baseline will be provided.   
Least square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the percent change data at 3 weeks post last dose 
described above using an  ANCOVA with BASELINE, COHORT, and BASELINE* COHORT 
as covariates where: 
 BASELINE represents the baseline value of the parameter of interest 
 COHORT represents the dose level of ACE-083 administered to the muscle 
 BASELINE*COHORT represents the interaction of BASELINE and COHORT 
Additional analyses may be performed as appropriate. 
Patient reported outcome variables 
Individual FSHD-HI scored data (total score and each of the subscale scores) will be listed. 
Descriptive statistics of the raw data as well as for the absolute and percent change from baseline 
will be provided for the FSHD-HI total score as well as for each of the subscale scores. 
Least square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the absolute change data at 3 weeks post last dose 
described above using an ANCOVA with BASELINE, COHORT and BASELINE*COHORT as 
covariates where BASELINE, and COHORT are defined similarly as described above for other 
analyses. 
Additional analyses may be performed as appropriate. 
Gait 
Individual data will be listed. 
Descriptive statistics will be provided for each type of measurement recorded (i.e. “General 
measures”, “Initial measures”, “Peak measures”, and “Average measures”) by cohort and 
scheduled time. 


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For gait assessments that are reported in triplicates at a given visit for any patient and are 
assessed to be of good quality, the mean of these will be used for purposes of generating a single 
individual value for the patient at the scheduled visit which will then be summarized.   
In addition, “Stride Length” will be derived using the following formula: 
Stride Length (m) = {Mean of the triplicate measures of Left Step Length (m)} + {Mean 
of the triplicate measures of Right Step Length (m)} 
Additional analyses may be performed as appropriate. 
4.7.2.2. 
Part 2 
Primary Efficacy Analysis (Double-Blind Phase) 
MRI: Total Muscle Volume 
Individual total muscle volume data will be listed.  Descriptive statistics will be provided by 
treatment group and scheduled time for raw data and changes from baseline (absolute and 
percent change).  Absolute and percent changes from baseline will be provided for each side (left 
and right) as well as the average of the absolute change and average of the percent change for the 
left and right sides.  This will be done for the double-blind, placebo-controlled component as 
well as for the open-label component. 
For the double-blind component, the plot of mean (± SEM) for the average of left and right side 
percent change in total muscle volume from baseline by scheduled day and treatment group for 
each muscle group (BB and TA) during the double-blind period as well as during the open-label 
extension period will be provided. 
For the double-blind component, an ANCOVA model will be fitted in order to assess the effect 
of ACE-083 on the Day 190 average percent change from baseline in total muscle volume for the 
left and right sides.  Covariates to be included in the model are MUSCLE, TREATMENT, 
BASELINE, MRC-MMT GRADE CATEGORY, MUSCLE*TREATMENT, and 
BASELINE*MUSCLE where: 
 MUSCLE represents the muscle treated (BB or TA) 
 TREATMENT represents the treatment group (ACE-083 or placebo) 
 BASELINE represents the baseline total muscle volume (average of left and right 
sides) 
 MRC-MMT GRADE CATEGORY represents the randomization stratification factor 
(3 to 4- or 4- to 4+)  
 MUSCLE*TREATMENT represents the muscle-by-treatment interaction 
 BASELINE*MUSCLE represents the baseline-by-muscle interaction 
The effect of ACE-083 on the percent change in TMV from baseline of the injected TA or BB at 
Day 190 versus placebo will be estimated using the ANCOVA model described above and tested 
using a 0.1 significance level (2-sided) separately for TA and BB.  The least squares mean 
estimate along with the corresponding 90% confidence interval will be provided separately for 
TA and BB.  In addition, the 95% confidence interval will also be provided as well as a bar chart 


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of the least squares mean estimates (± SEM) for each of the treatment groups separately for TA 
and BB. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails. The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment (D43, 
D106, D190), MUSCLE*VISIT, TREATMENT*VISIT, and MUSCLE*TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  The seed to be used is specified in Section 
5.  The assumption of the missing data mechanism will be missing at random (MAR) unless the 
data suggest otherwise.  The missing data pattern (monotone or arbitrary) will also be evaluated 
and the regression method for imputing missing data will be utilized for each scheduled 
timepoint with missing data.  Covariates to be included when imputing missing data include:  
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, MUSCLE*TREATMENT, 
and TMV percent change data at scheduled timepoints prior to the timepoint at which TMV 
percent change is being imputed.   
The table below illustrates the covariates that should be used for imputing missing data: 
Data to be Imputed 
Covariates to use in Multiple Imputation Regression Model 
Baseline TMV 
MRC-MMT GRADE CATEGORY, MUSCLE, TREATMENT, 
MUSCLE*TREATMENT 
Day 43 Percent 
change in TMV from 
baseline 
MRC-MMT GRADE CATEGORY, MUSCLE, TREATMENT, 
MUSCLE*TREATMENT, BASELINE 
Day 106 Percent 
change in TMV from 
baseline 
MRC-MMT GRADE CATEGORY, MUSCLE, TREATMENT, 
MUSCLE*TREATMENT, BASELINE, Day 43 TMV percent change 
Day 190 Percent 
change in TMV from 
baseline 
MRC-MMT GRADE CATEGORY, MUSCLE, TREATMENT, 
MUSCLE*TREATMENT, BASELINE, Day 43 TMV percent change, 
Day 106 TMV percent change 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 
For BB patients, the above analyses will be repeated using the patient’s “preferred” side used for 
the PUL test for patients. 


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The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
MRI: Calculated Contractile Muscle Volume 
Individual calculated contractile muscle volume data will be listed.  Descriptive statistics will be 
provided by treatment group and scheduled time for raw data and changes from baseline 
(absolute and percent change).  Absolute and percent changes from baseline will be provided for 
each side (left and right) as well as the average of the left and right sides.  This will be done for 
the double-blind, placebo-controlled component as well as for the open-label component. 
For the double-blind component, the plot of mean (± SEM) for the average of left and right side 
percent change in calculated contractile muscle volume from baseline (average of left and right 
sides) by scheduled day and treatment group for each muscle group (BB and TA) during the 
double-blind period as well as during the open-label extension period. 
For the double-blind component, an ANCOVA model will be fitted in order to assess the effect 
of ACE-083 on the Day 190 average percent change from baseline in calculated contractile 
muscle volume for the left and right sides.  Covariates to be included in the model are: 
MUSCLE, TREATMENT, BASELINE, MRC-MMT GRADE CATEGORY, 
MUSCLE*TREATMENT, and BASELINE*MUSCLE where: 
 MUSCLE represents the muscle treated (BB or TA) 
 TREATMENT represents the treatment group (ACE-083 or placebo) 
 BASELINE represents the baseline calculated contractile muscle volume (average of 
left and right sides) 
 MRC-MMT GRADE CATEGORY represents the randomization stratification factor 
(3 to 4- or 4- to 4+)  
 MUSCLE*TREATMENT represents the muscle-by-treatment interaction 
 BASELINE*MUSCLE represents the baseline-by-muscle interaction 
The effect of ACE-083 on the Day 190 average percent change in calculated contractile muscle 
volume from baseline of the injected TA or BB versus placebo will be estimated using the 
ANCOVA model described above and tested using a 0.1 significance level (2-sided) separately 
for TA and BB.  The least square mean estimate along with the corresponding 90% confidence 
interval will be provided separately for TA and BB.  In addition, the 95% confidence interval 
will also be provided as well as a bar chart of the least squares mean estimates (± SEM) for each 
of the treatment groups separately for TA and BB. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment (D43, 
D106, D190), MUSCLE*VISIT, TREATMENT*VISIT, and MUSCLE*TREATMENT*VISIT.   


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For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  Imputations will be performed separately 
for BB and TA patients.  The seed to be used is specified in Section 6.  The assumption of the 
missing data mechanism will be missing at random (MAR) unless the data suggest otherwise.  
The missing data pattern (monotone or arbitrary) will also be evaluated and the regression 
method for imputing missing data will be utilized for each scheduled timepoint with missing 
data.  Covariates to be included when imputing missing data include:  MRC-MMT GRADE 
CATEGORY, TREATMENT, BASELINE, and CCMV percent change data at scheduled 
timepoints prior to the timepoint at which CCMV percent change is being imputed.   
The table below illustrates the covariates that should be used for imputing missing data: 
Data to be Imputed 
Covariates to use in Multiple Imputation Regression Model 
Baseline CCMV 
MRC-MMT GRADE CATEGORY, TREATMENT, 
MUSCLE*TREATMENT 
Day 43 Percent change 
in CCMV from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE 
Day 106 Percent change 
in CCMV from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Day 43 CCMV percent change 
Day 190 Percent change 
in CCMV from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Day 43 CCMV percent change, Day 106 CCMV percent change 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 
For BB patients, the above analyses will be repeated using the patient’s “preferred” side used for 
the PUL test for patients. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
MRI: Fat Fraction 
For fat fraction data, the absolute change from baseline (by side and average of left and right 
sides) of the injected TA or BB will be summarized for each scheduled time.  Such summaries 
will also be done for raw data and percent change from baseline. 
For the double-blind component, an ANCOVA model will be fitted in order to assess the effect 
of ACE-083 on the Day 190 absolute change in fat fraction from baseline data (average of left 
and right sides).  Covariates to be included in the model are MUSCLE, TREATMENT, 
MRC-MMT GRADE CATEGORY, BASELINE, BASELINE*MUSCLE and 
MUSCLE*TREATMENT where BASELINE represents the baseline fat fraction (average of left 


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and right sides) and each of the other covariates are defined similarly as what was done for the 
primary efficacy analysis.  
The effect of ACE-083 on the Day 190 absolute change of fat fraction from baseline (average of 
left and right sides) of the injected TA or BB versus placebo will be estimated using the 
ANCOVA model described above and tested using a 0.1 significance level (2-sided) separately 
for TA and BB.  The least-square mean estimate along with the corresponding 90% confidence 
interval will be provided.  In addition, the 95% confidence interval will also be provided 
separately for TA and BB. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment (D43, 
D106, D190), MUSCLE*VISIT, TREATMENT*VISIT, and MUSCLE*TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  The seed to be used is specified in 
Section 6.  The assumption of the missing data mechanism will be missing at random (MAR) 
unless the data suggest otherwise.  The missing data pattern (monotone or arbitrary) will also be 
evaluated and the regression method for imputing missing data will be utilized for each 
scheduled timepoint with missing data.  Covariates to be included when imputing missing data 
include:  MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, and FF absolute 
change data at scheduled timepoints prior to the timepoint at which FF absolute change is being 
imputed.   
The table below illustrates the covariates that should be used for imputing missing data: 
Data to be Imputed 
Covariates to use in Multiple Imputation Regression Model 
Baseline FF 
MRC-MMT GRADE CATEGORY, TREATMENT,  
Day 43 Absolute change 
in FF from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE 
Day 106 Absolute change 
in FF from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Day 43 FF absolute change 
Day 190 Absolute change 
in FF from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Day 43 FF absolute change, Day 106 FF absolute change 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 


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For BB patients, the above analyses will be repeated using the patient’s “preferred” side used for 
the PUL test for patients. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
MRI: Calculated Intramuscular Fat 
For calculated intramuscular fat data (volume and mass), the average percent change from 
baseline (left and right sides) of the injected TA or BB will be summarized for each scheduled 
time.  Such summaries will also be done for raw data and change from baseline. 
For the double-blind component, an ANCOVA model will be fitted in order to assess the effect 
of ACE-083 on the Day 190 average percent change in intramuscular fat from baseline (left and 
right sides).  Covariates to be included in the model are MUSCLE, TREATMENT, MRC-MMT 
GRADE CATEGORY, BASELINE, BASELINE*MUSCLE, and MUSCLE*TREATMENT 
where BASELINE represents the baseline calculated intramuscular fat value and each of the 
other covariates are defined similarly as what was done for the primary analysis.  
The effect of ACE-083 on the Day 190 average percent change of calculated intramuscular fat 
from baseline (left and right sides) of the injected TA or BB versus placebo will be estimated 
using the ANCOVA model described above and tested using a 0.1 significance level (2-sided) 
separately for TA and BB.  The least-square mean estimate along with the corresponding 90% 
confidence interval will be provided.  In addition, the 95% confidence interval will also be 
provided separately for TA and BB. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment (D43, 
D106, D190), MUSCLE*VISIT, TREATMENT*VISIT, and MUSCLE*TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Imputations will be performed separately for the BB and TA patients.  Twenty 
imputations will be performed.  The seed to be used is specified in Section 6.  The assumption of 
the missing data mechanism will be missing at random (MAR) unless the data suggest otherwise.  
The missing data pattern (monotone or arbitrary) will also be evaluated and the regression 
method for imputing missing data will be utilized for each scheduled timepoint with missing 
data.  Covariates to be included when imputing missing data include:  MRC-MMT GRADE 
CATEGORY, TREATMENT, BASELINE, and CIMF (volume or mass) percent change data at 
scheduled timepoints prior to the timepoint at which CIMF (volume or mass) percent change is 
being imputed.   
The table below illustrates the covariates that should be used for imputing missing data: 


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Data to be Imputed 
Covariates to use in Multiple Imputation Regression Model 
Baseline CIMF 
MRC-MMT GRADE CATEGORY, TREATMENT 
Day 43 Percent change in 
CIMF from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE 
Day 106 Percent change 
in CIMF from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Day 43 CIMF percent change 
Day 190 Percent change 
in CIMF from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Day 43 CIMF percent change, Day 106 CIMF percent change 
Note:  The above is to be applied for volume (CIMFV) as well as mass (CIMFM). 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
Muscle Strength (MVIC) 
Descriptive statistics will be provided by treatment group and scheduled time for raw data and 
changes from baseline (absolute and percent change).  Absolute and percent changes from 
baseline will be provided for each side (left and right) as well as the average of the absolute 
change and average of the percent change for the left and right sides.  This will be done for the 
double-blind placebo-controlled component as well as for the open-label component. 
 A plot of the mean (± SEM) of the average percent change from baseline (left and right sides) 
by scheduled day and treatment group will also be provided. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the average Day 
190 percent change in elbow flexion MVIC (left and right sides for patients receiving study drug 
in the biceps brachii muscle) from baseline data (average of left and right sides).  Covariates to 
be included in the model are TREATMENT, BASELINE, and MRC-MMT GRADE 
CATEGORY, where BASELINE refers to the baseline MVIC (average of left and right sides) 
and each of the other covariates are defined similarly as what was done for the primary efficacy 
analysis.   
A similar ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 
190 average percent change in ankle dorsiflexion MVIC (left and right sides for patients 
receiving study drug in the tibialis anterior muscle) from baseline data (average of left and right 
sides).  Covariates will be the same set as described above for the elbow flexion MVIC analysis. 
The effect of ACE-083 on the Day 190 average percent change in the MVIC from baseline of the 
injected TA or BB versus placebo will be estimated using the ANCOVA models described above 


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and tested using a 0.1 significance level (2-sided) separately for TA and BB.  For TA and BB 
groups, the least squares mean estimate along with the corresponding 90% confidence interval 
will be provided.  In addition, the 95% confidence interval will also be provided. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  The seed to be used is specified in 
Section 6 .  The assumption of the missing data mechanism will be missing at random (MAR) 
unless the data suggest otherwise.  The missing data pattern (monotone or arbitrary) will also be 
evaluated and the regression method for imputing missing data will be utilized for each 
scheduled timepoint with missing data.  Covariates to be included when imputing missing data 
include:  MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, and MVIC percent 
change data at scheduled timepoints prior to the timepoint at which MVIC percent change is 
being imputed.   
The table below illustrates the covariates that should be used for imputing missing data for 
selected timepoints: 
Data to be Imputed Covariates to use in Multiple Imputation Regression Model 
Baseline MVIC 
MRC-MMT GRADE CATEGORY, TREATMENT 
Day 22 Percent 
change in MVIC 
from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE 
Day 43 Percent 
change in MVIC 
from baseline 
MRC-MMT GRADE CATEGORY, MUSCLE, TREATMENT, 
MUSCLE*TREATMENT, BASELINE, Day 22 MVIC percent change 
Day 190 Percent 
change in MVIC 
from baseline 
MRC-MMT GRADE CATEGORY, MUSCLE, TREATMENT, 
MUSCLE*TREATMENT, BASELINE, Days 22, 43, 64, 85, 106, and 
148 MVIC percent change from baseline 
Note: The above is to be applied for elbow flexion MVIC (BB treated patients) and ankle 
dorsiflexion (TA treated patients). 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 


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For BB patients, the above analyses will be repeated using the patient’s “preferred” side used for 
the PUL test for patients. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
MRC-MMT Decimal Score 
Descriptive statistics will be provided for raw and average percent change from baseline (left and 
right sides) for the MRC-MMT decimal score where MRC-MMT decimal score represents the 
conversion of the MRC-MMT grade to the decimal version as follows:  5 = 5.0, 5- = 4.67, 4+ = 
4.33,  4 = 4.0, 4- = 3.67, 3+ = 3.33, 3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 
1 = 1.0.  The average percent change from baseline (left and right sides) is derived by computing 
the percent change from baseline separately for the left and right sides and then taking the 
average. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
average percent change in MRC-MMT score (for ankle dorsiflexion {TA patients} or for elbow 
flexion {BB patients}) versus placebo will be estimated using the following covariates:  
TREATMENT and BASELINE MRC-MMT DECIMAL SCORE, where TREATMENT is 
defined similarly as what was done for the primary analysis.     
No imputations for missing data will be performed. 
In addition, a summary table will be provided that will summarize the number and percentage of 
patients by treatment group for each side (left and right side) as well as the weaker of the two 
sides that 
 Improved at least one grade at Day 190 compared to the baseline grade 
 No change in MRC-MMT grade at Day 190 compared to the baseline grade 
 Decreased at least one grade at Day 190 compared to the baseline grade 
An improvement of at least one grade means that the patient moved from one grade to any  
higher grade on the range of possible values for the MRC-MMT grade (e.g. from a 4- to a 4).   
A decrease of at least one grade means that the patient moved from one grade to any lower grade 
on the range of possible values for the MRC-MMT grade (e.g. from a 4 to a 4-).   
Additional analyses may be performed as appropriate. 
Motor Function (Lower Leg): 10-Meter Walk/Run Test (TA Muscle Group) 
Individual data will be listed. 
Descriptive statistics of raw data as well as absolute and percent change from baseline will be 
provided by cohort (for Part 1) and treatment group (for Part 2) for each scheduled time.  A plot 
of mean ± SEM will also be provided for the percent change from baseline for each treatment 
group. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
percent change in the time to complete the 10-meter walk/run test from baseline data.  Covariates 
to be included in the model are TREATMENT, HEIGHT, MRC-MMT GRADE CATEGORY, 
and BASELINE where BASELINE represents the baseline time to complete the 10 meter 


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walk/run test, HEIGHT is the height of the patient in centimeters, and each of the other 
covariates are defined similarly as what was done for the primary efficacy analysis.  
The effect of ACE-083 on the Day 190 percent change in the time to complete the 10-meter 
walk/run test from versus placebo will be estimated using the ANCOVA model described above 
and tested using a 0.1 significance level (2-sided).  The least-squares mean estimate along with 
the corresponding 90% confidence interval will be provided.  In addition, the 95% confidence 
interval will also be provided as well as a bar chart of the least squares mean estimates (± SEM) 
for each of the treatment groups. 
An ANCOVA model will also be fitted in order to assess the effect of ACE-083 on the Day 190 
absolute change in the time to complete the 10-meter walk/run test from baseline data.  
Covariates to be included in the model are TREATMENT, HEIGHT, MRC-MMT GRADE 
CATEGORY, and BASELINE where BASELINE represents the baseline time to complete the 
10 meter walk/run test, HEIGHT is the height of the patient in centimeters, and each of the other 
covariates are defined similarly as what was done for the primary efficacy analysis.  
The effect of ACE-083 on the Day 190 absolute change in the time to complete the 10-meter 
walk/run test from versus placebo will be estimated using the ANCOVA model described above 
and tested using a 0.1 significance level (2-sided).  The least-squares mean estimate along with 
the corresponding 90% confidence interval will be provided.  In addition, the 95% confidence 
interval will also be provided as well as a bar chart of the least squares mean estimates (± SEM) 
for each of the treatment groups. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  The seed to be used is specified in 
Section 6.  The assumption of the missing data mechanism will be missing at random (MAR) 
unless the data suggest otherwise.  The missing data pattern (monotone or arbitrary) will also be 
evaluated and the regression method for imputing missing data will be utilized for each 
scheduled timepoint with missing data.  Covariates to be included when imputing missing data 
include:  MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT, BASELINE, and 
10mW/R percent change data at scheduled timepoints prior to the timepoint at which 10mW/R 
percent change is being imputed.   
The table below illustrates the covariates that should be used for imputing missing data for 
selected timepoints: 
 
 


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Data to be imputed 
Covariates to use in multiple imputation regression model 
Baseline time to complete 
10mW/R 
MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT 
Day 22 percent change in 
time to complete 10mW/R 
from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT, 
BASELINE 
Day 43 percent change in 
time to complete 10mW/R 
from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT, 
BASELINE, Day 22 10mW/R percent change 
Day 190 Percent change in 
time to complete 10mW/R 
from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT, 
BASELINE, Days 22, 43, 64, 85, 106, 148, and 169 10mW/R 
percent change from baseline 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 
The above multiple imputation will also be done for missing absolute changes from baseline 
similarly to what is outlined above for the missing percent changes from baseline. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
Motor Function (Lower Leg): 6-Minute Walk Test (TA Muscle Group) 
Individual data will be listed. 
Descriptive statistics of raw data as well as changes from baseline (absolute and percent change) 
will be provided by cohort (for Part 1) and by treatment group (for Part 2) by scheduled time 
separately for cumulative distance recorded at 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 
minutes, and 6 minutes.  A plot of mean ± SEM for the cumulative distance recorded at 6 
minutes will also be provided for the percent change from baseline for each treatment group. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
percent change in the cumulative distance recorded at 6 minutes from baseline data paying 
particular attention to the appropriate choice of covariance structure.  Covariates to be included 
in the model are TREATMENT, HEIGHT, MRC-MMT GRADE CATEGORY, and BASELINE 
where BASELINE represents the baseline distance walked in 6 minutes, HEIGHT represents the 
patient’s height in centimeters, and each of the other covariates are defined the same as what was 
done for the primary efficacy analysis.  
The effect of ACE-083 on the Day 190 percent change in the cumulative distance recorded at 6 
minutes from baseline versus placebo will be estimated using the ANCOVA model described 


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above and tested using a 0.1 significance level (2-sided).  The least-squares mean estimate along 
with the corresponding 90% confidence interval will be provided.  In addition, the 95% 
confidence interval will also be provided as well as a bar chart of the least squares mean 
estimates (± SEM) for each of the treatment groups. 
An ANCOVA model will be also be fitted in order to assess the effect of ACE-083 on the Day 
190 absolute change in the cumulative distance recorded at 6 minutes from baseline data.  
Covariates to be included in the model are TREATMENT, HEIGHT, MRC-MMT GRADE 
CATEGORY, and BASELINE where BASELINE represents the baseline distance walked in 6 
minutes, HEIGHT represents the height of the patient in centimeters, and each of the other 
covariates are defined the same as what was done for the primary efficacy analysis. 
The effect of ACE-083 on the Day 190 absolute change in the cumulative distance recorded at 6 
minutes from baseline versus placebo will be estimated using the ANCOVA model described 
above and tested using a 0.1 significance level (2-sided).  The least-squares mean estimate along 
with the corresponding 90% confidence interval will be provided.  In addition, the 95% 
confidence interval will also be provided as well as a bar chart of the least squares mean 
estimates (± SEM) for each of the treatment groups. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  The seed to be used is specified in 
Section 6.  The assumption of the missing data mechanism will be missing at random (MAR) 
unless the data suggest otherwise.  The missing data pattern (monotone or arbitrary) will also be 
evaluated and the regression method for imputing missing data will be utilized for each 
scheduled timepoint with missing data.  Covariates to be included when imputing missing data 
include: MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT, BASELINE, and 
6MWD percent change data at scheduled timepoints prior to the timepoint at which 10mW/R 
percent change is being imputed.   
The table below illustrates the covariates that should be used for imputing missing data for 
selected timepoints: 
 
 


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Data to be imputed 
Covariates to use in multiple imputation regression model 
Baseline 6MWD 
MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT 
Day 22 percent change 
in 6MWD from 
baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT, 
BASELINE 
Day 43 percent change 
in 6MWD from 
baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT, 
BASELINE, Day 22 6MWD percent change 
Day 190 Percent 
change in 6MWD from 
baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, HEIGHT, 
BASELINE, Days 22, 43, 64, 85, 106, 148, and 169 6MWD percent 
change from baseline 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data. 
The above multiple imputation will also be done for missing absolute changes from baseline 
similarly to what is outlined above for the missing percent changes from baseline.  The analyses 
where multiple imputations are performed are considered to be primary. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
In addition, the ANCOVA analyses described above for the 6MWD will be repeated for the 
cumulative distance walked at 2 minutes.  This analysis is considered exploratory and it is not 
planned to impute missing data.  Additional analyses may be performed as appropriate. 
Motor Function (Lower Leg): 4-Stair Climb (TA Muscle Group) 
Individual data will be listed. 
Descriptive statistics of raw data as well as absolute and percent changes from baseline will be 
provided by cohort (for Part 1) and by treatment group (for Part 2) for time to ascend as well as 
time to descend data. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
percent change in the time to ascend 4-stairs from baseline data.  Covariates to be included in the 
model are TREATMENT, MRC-MMT GRADE CATEGORY, and BASELINE where 
BASELINE represents the baseline time to ascend 4-stairs, and each of the other covariates are 
defined the same as what was done for the primary efficacy analysis.  
The effect of ACE-083 on the Day 190 percent change in the time to ascend 4-stairs from 
baseline versus placebo will be estimated using the ANCOVA model described above and tested 
using a 0.1 significance level (2-sided).  The least-squares mean estimate along with the 
corresponding 90% confidence interval will be provided.  In addition, the 95% confidence 


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interval will also be provided as well as a bar chart of the least squares mean estimates (± SEM) 
for each of the treatment groups.   
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
percent change in the time to descend 4-stairs from baseline data.  An unstructured covariance 
structure will be used to model the within-patient covariance across visits.  Other covariance 
structures will be considered if the unstructured covariance fails.  Covariates to be included in 
the model are TREATMENT, MRC-MMT GRADE CATEGORY, and BASELINE where 
BASELINE represents the baseline time to descend 4-stairs, and each of the other covariates are 
defined the same as what was done for the primary efficacy analysis.  
The effect of ACE-083 on the Day 190 percent change in the time to descend 4-stairs from 
baseline versus placebo will be estimated using the ANCOVA model described above and tested 
using a 0.1 significance level (2-sided).  The least-squares mean estimate along with the 
corresponding 90% confidence interval will be provided.  In addition, the 95% confidence 
interval will also be provided as well as a bar chart of the least squares mean estimates (± SEM) 
for each of the treatment groups. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analyses described above.  The covariates to be included consist of all of the 
covariates described above for the ANCOVA with the addition of the following additional 
covariates:  VISIT where VISIT represents the scheduled visit day post first dose of MRI 
assessment and TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  The seed to be used is specified in 
Section 6 .  The assumption of the missing data mechanism will be missing at random (MAR) 
unless the data suggest otherwise.  The missing data pattern (monotone or arbitrary) will also be 
evaluated and the regression method for imputing missing data will be utilized for each 
scheduled timepoint with missing data.  Covariates to be included when imputing missing data 
include: MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, and 4-stair ascend (or 
descend) time percent change data at scheduled timepoints prior to the timepoint at which 4-stair 
ascend (or descend) time percent change is being imputed.   
The table below illustrates the covariates that should be used for imputing missing data for 
selected timepoints: 
 
 


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Data to be Imputed 
Covariates to use in Multiple Imputation Regression Model 
Baseline time to ascend (or 
descend) 4 stairs 
MRC-MMT GRADE CATEGORY, TREATMENT 
Day 22 percent change in 
time to ascend (or descend) 4 
stairs from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, 
BASELINE 
Day 43 percent change in 
time to ascend (or descend) 4 
stairs from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, 
BASELINE, Day 22 4-stair climb ascend (or descend) time 
percent change 
Day 190 Percent change in 
time to ascend (or descend) 4 
stairs from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT,  
BASELINE, Days 22, 43, 64, 85, 106, 148, and 169 4-stair 
climb ascend (or descend) time percent change from baseline 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
Motor Function (Upper Arm):  Performance of Upper Limb (PUL) [Middle Level Elbow 
Dimension] – (BB Muscle Group) 
Individual data will be listed. 
Descriptive statistics will be provided by treatment group for those receiving study drug in the 
biceps brachii muscle for the following components from the mid-level PUL: 
 Composite (or average) of time to complete the four timed tasks from the mid-level PUL 
 Time to lift 5 light cans 
 Time to stack 5 light cans 
 Time to lift 5 heavy cans 
 Time to stack 5 heavy cans 
 Mid-level elbow dimension total score 
For the composite (or average) of times to complete the four timed tasks from the mid-level 
PUL, an ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
percent change from baseline data.  Covariates to be included in the model are TREATMENT, 
MRC-MMT GRADE CATEGORY, and BASELINE where BASELINE represents the baseline 


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PUL composite time and each of the other covariates are defined the same as what was done for 
the primary analysis.  
The effect of ACE-083 on the Day 190 percent change in the mid-level PUL composite time 
from baseline versus placebo will be estimated using the ANCOVA model described above and 
tested using a 0.1 significance level (2-sided).  The least-squares mean estimate along with the 
corresponding 90% confidence interval will be provided.  In addition, the 95% confidence 
interval will also be provided as well as a bar chart of the least squares mean estimates (± SEM) 
for each of the treatment groups. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  The seed to be used is specified in 
Section 6.  The assumption of the missing data mechanism will be missing at random (MAR) 
unless the data suggest otherwise.  The missing data pattern (monotone or arbitrary) will also be 
evaluated and the regression method for imputing missing data will be utilized for each 
scheduled timepoint with missing data.  Covariates to be included when imputing missing data 
include:  MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, and PUL percent 
change data at scheduled timepoints prior to the timepoint at which PUL percent change is being 
imputed.   
The table below illustrates the covariates that should be used for imputing missing data for 
selected timepoints: 
Data to be imputed 
Covariates to use in multiple imputation regression model 
Baseline PUL 
MRC-MMT GRADE CATEGORY, TREATMENT 
Day 22 percent change 
in PUL from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE 
Day 43 percent change 
in PUL from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Day 22 PUL percent change 
Day 190 Percent change 
in PUL from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Days 22, 43, 64, 85, 106, 148, and 169 PUL percent change from 
baseline 
Note: PUL means either the composite (mean) time to perform the 4 timed activities or the PUL 
mid-level dimension score. 


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Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 
The analyses described above will also be performed for the mid-level PUL dimension score. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
Motor function (upper arm): Performance of upper limb (PUL) [Upper level 
dimension] – (BB muscle group) 
Individual data will be listed. 
The number and percentage of subjects of weight used to perform each of the four components 
of the PUL upper level dimension (shoulder domain) will be presented by treatment group and 
scheduled time.  The four components are: 
 Shoulder abduction to shoulder height (elbow to shoulder level) 
 Shoulder abduction above shoulder height (elbow to eye level) 
 Shoulder flexion to shoulder height (elbow to shoulder level) 
 Shoulder flexion above shoulder height (elbow to eye level) 
Descriptive statistics will be provided by scheduled time for the raw PUL shoulder domain score 
(average PUL shoulder domain score of left and right sides) and changes from baseline (absolute 
and percent change) by treatment group sequence in the open-label phase of Part 2. 
Additional analyses may be performed as appropriate. 
Patient Reported Outcomes: Facioscapulohumeral Disease Health Index (FSHD-HI) 
Survey 
Individual FSHD-HI scored data (total score and each of the subscale scores) will be listed. 
Descriptive statistics of the raw data as well as for the absolute and percent change from baseline 
will be provided for the FSHD-HI total score as well as for each of the subscale scores. 
Least square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the Day 190 absolute change data described above 
using an ANCOVA with MUSCLE, BASELINE, TREATMENT MRC-MMT GRADE 
CATEGORY, and MUSCLE*TREATMENT  as covariates where MUSCLE, BASELINE, 
TREATMENT, and MRC-MMT GRADE CATEGORY are defined similarly as described above 
for other analyses.  In addition, a bar chart of the least squares mean estimates (± SEM) by 
muscle for each of the treatment groups will be provided for the following FSHD-HI parameters:  
FSHD-HI total score, FSHD-HI Arm/Shoulder function (BB only), FSHD-HI Mobility (TA 
only), and FSHD-HI Activity limitation. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 


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model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose assessment, 
MUSCLE*VISIT, TREATMENT*VISIT, and MUSCLE*TREATMENT*VISIT.   
For both the ANCOVA and MMRM analyses, multiple imputations will be performed for 
missing data.  Twenty imputations will be performed.  Imputations will be performed separately 
for the BB and TA patients.  The seed to be used is specified in Section 6.  The assumption of the 
missing data mechanism will be missing at random (MAR) unless the data suggest otherwise.  
The missing data pattern (monotone or arbitrary) will also be evaluated and the regression 
method for imputing missing data will be utilized for each scheduled timepoint with missing 
data.  Covariates to be included when imputing missing data include:  MRC-MMT GRADE 
CATEGORY, TREATMENT, BASELINE and FSHD-HI absolute change data at scheduled 
timepoints prior to the timepoint at which FSHD-HI absolute change is being imputed.   
The table below illustrates the covariates that should be used for imputing missing data: 
Data to be imputed 
Covariates to use in multiple imputation regression model 
Baseline FSHD-HI 
MRC-MMT GRADE CATEGORY, TREATMENT 
Day 22 absolute 
change from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE 
Day 43 absolute 
change from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Day 22 FSHD-HI absolute change 
Day 190 absolute 
change from baseline 
MRC-MMT GRADE CATEGORY, TREATMENT, BASELINE, 
Days 22, 43, 64, 85, 106, and 148 FSHD-HI absolute change 
Analysis findings will be presented for Day 190 percent change data where missing data is not 
imputed (observed data) as well as for Day 190 percent change data where multiple imputations 
are performed for missing data to assess the impact of the missing data on the observed study 
data.  The analyses where multiple imputations are performed are considered to be primary. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
Gait 
Individual data will be listed. 
Descriptive statistics will be provided for each type of measurement recorded (e.g., “General 
measures”, “Initial measures”, “Peak measures”, and “Average measures”) by treatment group 
and scheduled time. 


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For gait assessments that are reported in triplicates at a given visit for any patient and are 
assessed to be of good quality, the mean of these will be used for purposes of generating a single 
individual value for the patient at the scheduled visit which will then be summarized.   
In addition, “Stride Length” will be derived using the following formula: 
Stride Length (m) = {Mean of the triplicate measures of Left Step Length (m)} + {Mean of the 
triplicate measures of Right Step Length (m)} 
Additional analyses may be performed as appropriate. 
No imputations will be performed for missing gait data. 
4.7.2.3. 
Part 2 Open-Label Extension 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
Descriptive statistics will be provided for raw data and changes (percent and absolute change) 
from the start of the open-label extension (Day 190) will be provided by treatment sequence for 
each scheduled time.  The treatment sequence refers to the treatment sequence from double-blind 
to open label (i.e. ACE-083  ACE-083 or Placebo  ACE-083).  For MRI and strength data, 
such summaries will be provided by scheduled time for each side treated as well as the average 
of the left and right sides.   
Additional analyses may be performed as appropriate. 
Open-Label Extension vs. Double-Blind Placebo-Controlled Phase 
Selected MRI, and FSHD-HI Total Score and FSHD-HI Activity Limitation Subscale Score 
For total muscle volume, calculated contractile muscle volume, fat fraction, FSHD-HI total 
score, and FSHD-HI activity limitation subscale score, descriptive statistics will be provided for 
the Placebo  ACE-083 treatment sequence for the difference in percent (or absolute) change 
observed between Day 190 and pre-first treatment baseline (1st 6 months) and the percent (or 
absolute) change observed between Day 358 and the open-label treatment baseline (2nd 6 
months). 
In addition, the effect of ACE-083 administered during the open-label extension compared to the 
treatment administered in the double-blind placebo-controlled phase will be examined for those 
receiving ACE-083 during the double-blind phase and separately for those receiving placebo 
during the double-blind phase by comparing the percent (or absolute) change observed between 
Day 190 and pre-first treatment baseline (1st 6 months) and Day 358 versus the  open-label 
treatment baseline (2nd 6 months) using an ANCOVA model for each individual data parameter.   
Covariates to be included into the model are MUSCLE, SEQUENCE, MRC-MMT GRADE 
CATEGORY, BASELINE, and MUSCLE*SEQUENCE where: 
 MUSCLE refers to the muscle treated (i.e. BB or TA) 
 SEQUENCE refers to the treatment sequence from double-blind to open-label (ACE-083 
 ACE-083 or Placebo  ACE-083) 


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 MRC-MMT GRADE CATEGORY refers to the randomization stratification factor from 
the double-blind phase 
 BASELINE refers to baseline from the double-blind phase 
 MUSCLE*SEQUENCE refers to the muscle-by-sequence interaction 
Least squares estimates of the SEQUENCE*MUSCLE effect and the corresponding 90% 
confidence interval will be provided and will be tested using a 0.1 significance level (2-sided).  
In addition, the least squares estimates for each sequence along with the corresponding 90% 
confidence interval will be provided separately for each muscle and will be tested using a 0.1 
significance level (2-sided).  
Multiple imputations will be performed for missing data.  Twenty imputations will be performed. 
The seed to be used is specified in Section 6.  The assumption of the missing data mechanism 
will be missing at random (MAR) unless the data suggest otherwise.  The missing data pattern 
(monotone or arbitrary) will also be evaluated and the regression method for imputing missing 
data will be utilized for each scheduled timepoint with missing data.  Covariates to be included 
when imputing missing data include: MRC-MMT GRADE CATEGORY, MUSCLE, 
SEQUENCE, BASELINE, MUSCLE*SEQUENCE, and percent (or absolute change) of the 
analysis variable at scheduled timepoints prior to the timepoint at which the analysis variable 
percent (or absolute) change is being imputed. 
Analysis findings will be presented where missing data is not imputed (observed data) as well as 
for the case where multiple imputations are performed for missing data to assess the impact of 
the missing data on the observed study data.  The analyses where multiple imputations are 
performed are considered to be primary. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
Selected Motor Function, FSHD-HI Arm/Shoulder Function Subscale Score, MVIC, 
MRC-MMT Score, FSHD-HI Mobility and Ambulation Subscale Score 
For mid-level PUL composite time (BB patients only), 6MWD (TA patients only), time to 
complete the 10mW/R (TA patients only), 4-stair climb ascend time (TA patients only), 4-stair 
descend time (TA patients only), FSHD-HI arm/shoulder function subscale score (BB patients 
only), FSHD-HI mobility and ambulation subscale score (TA patients only), MVIC (elbow 
flexion – BB patients), MVIC (ankle dorsiflexion – TA patients), MRC-MMT score (elbow 
flexion – BB patients), MRC-MMT score (ankle dorsiflexion – TA patients), descriptive 
statistics will be provided for the Placebo  ACE-083 treatment sequence for the difference in 
percent (or absolute) change observed between Day 190 and pre-first treatment baseline (1st 6 
months) and the percent (or absolute) change observed between Day 358 and the open-label 
treatment baseline (2nd 6 months). 
In addition, the effect of ACE-083 administered during the open-label extension compared to the 
treatment administered in the double-blind placebo-controlled phase will be examined for those 
receiving ACE-083 during the double-blind phase and separately for those receiving placebo 
during the double-blind phase by comparing the percent (or absolute) change observed between 


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Day 190 and pre-first treatment baseline (1st 6 months) and Day 358 versus open-label treatment 
baseline (2nd 6 months) using an ANCOVA model for each individual data parameter.   
Covariates to be included into the model are SEQUENCE, MRC-MMT GRADE CATEGORY, 
HEIGHT (only for 6MWD and 10mW/R) and BASELINE where: 
 SEQUENCE refers to the treatment sequence from double-blind to open-label (ACE-083 
 ACE-083 or Placebo  ACE-083) 
 MRC-MMT GRADE CATEGORY refers to the randomization stratification factor from 
the double-blind phase 
 BASELINE refers to baseline from the double-blind phase 
 HEIGHT refers to the patient’s height (cm) 
Least squares estimates for each sequence and 90% confidence intervals will be provided and 
will be tested using a 0.1 significance level (2-sided).   
Multiple imputations will be performed for missing data.  Twenty imputations will be performed.  
The seed to be used is specified in Section 6.  The assumption of the missing data mechanism 
will be missing at random (MAR) unless the data suggest otherwise.  The missing data pattern 
(monotone or arbitrary) will also be evaluated and the regression method for imputing missing 
data will be utilized for each scheduled timepoint with missing data.  Covariates to be included 
when imputing missing data include: MRC-MMT GRADE CATEGORY, SEQUENCE, 
BASELINE, HEIGHT (only for 6MWD and 10mW/R) and percent (or absolute change) of the 
analysis variable at scheduled timepoints prior to the timepoint at which the analysis variable 
percent (or absolute) change is being imputed. 
Analysis findings will be presented where missing data is not imputed (observed data) as well as 
for the case where multiple imputations are performed for missing data to assess the impact of 
the missing data on the observed study data.  The analyses where multiple imputations are 
performed are considered to be primary. 
The Per Protocol Set will be used for the primary analysis.  The analyses described above will 
also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
4.7.2.4. 
Subgroup Analyses (Part 2 Only) 
Subgroups consist of the following: 
 D4Z4 fragment size (< 23 kb; ≥ 23 kb) 
 Dose per Calculated Contractile Muscle Mass (mg/g) 
o BB: (<2 .9; ≥ 2.9); TA: (< 3.5; ≥ 3.5) 
 Exercise Program: (Some; None) 
 Baseline FSHD-HI Total Score: 
o BB: (< median; ≥ median); TA: (< median; ≥ median) 


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Note that the median will be the median of the average of the FSHD-HI total score for the 
assessments performed at Screening Days -28 and -7 and Day 1 and will be determined 
separately for BB and TA patients. 
 Baseline Fat Fraction (%) 
o BB: (< median; ≥ median); TA: (< median; ≥ median) 
Note that the median will be determined separately for BB and TA patients. 
 Knee Extension MRC-MMT Grade {weaker of two sides – TA patients only} 
o (2- to 4-; 4 to 5) 
 Elbow Flexion MRC-MMT Grade {weaker of two sides – BB patients only} 
o (3 to 4-; 4 to 4+) 
 Ankle Dorsiflexion MRC-MMT Grade {weaker of two sides – TA patients only} 
o (3 to 4-; 4 to 4+) 
Subgroup analyses will be performed for the following parameters: 
 Day 190 average percent change in total muscle volume from baseline 
 Day 190 average percent change in calculated contractile muscle volume from 
baseline 
 Day 190 average absolute change in fat fraction from baseline 
 Day 190 average percent change in fat fraction from baseline 
 Day 190 average percent change in elbow flexion MVIC from baseline 
o To be done for all subgroups above with the exception of “Knee Extension 
MRC-MMT Grade” and “Ankle Dorsiflexion MRC-MMT Grade” subgroups 
 Day 190 average percent change in ankle dorsiflexion MVIC from baseline 
o To be done for all subgroups above with the exception of “Elbow Flexion 
MRC-MMT Grade” 
 Day 190 percent change in 6MWD from baseline 
o To be done for all subgroups above with the exception of “Elbow Flexion 
MRC-MMT Grade” 
  Day 190 percent change in time to complete 10mW/R from baseline 
o To be done for all subgroups above with the exception of “Elbow Flexion 
MRC-MMT Grade” 
 Day 190 percent change in PUL composite time from baseline 
o To be done for all subgroups above with the exception of “Knee Extension 
MRC-MMT Grade” and “Ankle Dorsiflexion MRC-MMT Grade” subgroups 
 Day 190 absolute change in FSHD-HI total score from baseline 


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 Day 190 absolute change in FSHD-HI mobility and ambulation subscale score from 
baseline 
o To be done only for the “Knee Extension MRC-MMT Grade” and “Ankle 
Dorsiflexion MRC-MMT Grade” subgroups 
 Day 190 absolute change in FSHD-HI activity limitation subscale score from baseline 
o To be done only for the “Knee Extension MRC-MMT Grade”, “Elbow Flexion 
MRC-MMT Grade”, and “Ankle Dorsiflexion MRC-MMT Grade” subgroups. 
Subgroup analyses will be performed using similar ANCOVA models described in previous 
sections for each subgroup category provided that the sample size is at least 4 within each 
muscle.  Because of the reduced sample size within each subgroup category, it is not planned to 
include MRC-MMT GRADE CATEGORY into such models.  For each subgroup category, the 
treatment effect will be estimated and tested using a 0.1 (two-sided) significance level with the 
corresponding 90% confidence interval separately for TA and BB.  Bar charts of the least 
squares mean estimates (± SEM) for each of the treatment groups will be provided for the 
individual muscle.   
For purposes of this study, findings of subgroup analyses are considered to yield hypothesis 
generating statements for future study.  It is not planned to control the overall type-1 error.   
Additional analyses may be performed as appropriate. 
Multiple imputations will be performed for missing data using the same approach outlined in 
Section 4.7.2.2 or the parameter of interest. 
4.7.2.5. 
Other Analyses  
The number and percentage of patients belonging to each of the following criteria will be 
summarized by treatment group: 
 Day 190 percent change in TMV from baseline ≥ 10%  
 Day 190 percent change in 6MWD from baseline ≥ 10% 
 Day 190 absolute change in 6MWD from baseline ≥ 30 m 
 Day 190 percent change in time to complete 10mW/R from baseline ≥ 10% 
 Day 190 absolute change in time to complete 10mW/R from baseline ≥ 0.5 sec. 
 Day 190 percent change in 4-stair ascend time from baseline ≥10% 
 Day 190 percent change in PUL composite (mean) time to perform 4 timed activities 
from baseline ≥ 10% 
 Day 190 absolute change in FSHD-HI total score from baseline ≤ -8 
 Day 190 absolute change in FSHD-HI arm/shoulder sub-score from baseline ≤ -8 
(BB patients only) 
 Day 190 absolute change in FSHD-HI mobility sub-score from baseline ≤ -8 (TA 
patients only) 
 Day 190 absolute change in FSHD-HI activity limitation sub-score from baseline ≤ -8 


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For each criterion listed above, Fisher’s exact test will be used to compare the proportions of 
patients belonging to the individual criterion between the two treatment groups using a 0.1 
significance level. 
4.8. 
Pharmacodynamic Data 
4.8.1. 
Variables 
Pharmacodynamic data consists of the following selected laboratory data (e.g. CTX and 
hemoglobin). 
4.8.2. 
Analyses 
4.8.2.1. 
Part 1 
Individual pharmacodynamic data will be listed.   
For each pharmacodynamic variable, raw data and changes from baseline will be summarized by 
dose cohort and scheduled time.  Such summaries may be accompanied by a plot of 
mean ± SEM.  No imputations for missing data will be performed. 
Additional analyses may be performed as appropriate. 
4.8.2.2. 
Part 2 
Double-Blind Period 
Individual pharmacodynamic data will be listed.   
For each pharmacodynamic variable, raw data and changes from baseline will be summarized by 
treatment group and scheduled time.  Such summaries may be accompanied by a plot of 
mean ± SEM.  No imputations for missing data will be performed. 
Additional analyses may be performed as appropriate. 
Open-Label Period 
Individual pharmacodynamic data will be listed.   
For each pharmacodynamic variable, raw data and changes from baseline will be summarized by 
treatment sequence and scheduled time.  Pooled summaries across treatment sequences will also 
be provided.  Such summaries may be accompanied by a plot of mean ± SEM. 
No imputations for missing data will be performed. 
Additional analyses may be performed as appropriate. 
4.9. 
Safety Data 
4.9.1. 
Adverse Events 
Adverse events (AEs) will be coded using MedDRA Version 19.1.   
All AEs will be listed and will include but not necessarily be limited to the following: verbatim 
term, MedDRA preferred term, treatment group, severity, relationship to study medication, 


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action taken with respect to study medication, and whether or not the AE is treatment-emergent 
although not necessarily in that order.   
Treatment-emergent AEs (TEAEs) are defined those AEs that start or worsen in intensity on or 
after the first study drug administration up to the end of the follow-up period (Day 141 [Part 1] / 
Day 393 [Part 2]).  AEs classified as TEAEs will be summarized.  Planned summaries include 
the following (for each muscle group unless otherwise specified): 
 Overall summary of TEAEs by treatment group 
 Summary of TEAEs by MedDRA System Organ Class and Preferred Term for each 
treatment group – Number of Patients 
 Summary of TEAEs by MedDRA System Organ Class and Preferred Term for each 
treatment group – Number of Events 
 Summary of TEAEs by MedDRA Preferred Term for each treatment group – Number 
of Patients 
 Summary of TEAEs by MedDRA Preferred Term for each treatment group– Number 
of Events 
 Summary of CTCAE Grade 3 or Higher TEAEs by MedDRA System Organ Class 
and Preferred Term for each treatment group – Number of Patients 
 Summary of CTCAE Grade 3 or Higher TEAEs by MedDRA System Organ Class 
and Preferred Term for each treatment group – Number of Events 
 Summmary of CTCAE Grade 3 or Higher TEAEs by MedDRA Preferred Term for 
each treatment group – Number of Patients 
 Summmary of CTCAE Grade 3 or Higher TEAEs by MedDRA Preferred Term for 
each treatment group – Number of Events 
 Summary of TEAEs possibly or probably related to study drug by MedDRA System 
Organ Class and Preferred Term for each treatment group – Number of Patients 
 Summary of TEAEs possibly or probably related to study drug by MedDRA System 
Organ Class and Preferred Term for each treatment group– Number of Events 
 Summary of TEAEs possibly or probably related to study drug by MedDRA 
Preferred Term for each treatment group – Number of Patients 
 Summary of TEAEs possibly or probably related to study drug by MedDRA 
Preferred Term for each treatment group– Number of Events 
 Summary of TEAEs by MedDRA Preferred Term by CTCAE Grade and Relationship 
to Drug for each treatment group – Number of Patients 
 Summary of TEAEs by MedDRA Preferred Term by CTCAE Grade and Relationship 
to Drug for each treatment group – Number of Events 
 Summary of Serious Adverse Events – Number of Patients 
 
 


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4.9.2. 
Clinical Laboratory Evaluations  
The following table lists the planned clinical laboratory assessments: 
 
In addition to the tests listed below, a urine pregnancy test is performed on all females of 
childbearing potential according to scheduled times listed in the protocol. 
Descriptive statistics of raw data and change from baseline data will be provided by treatment 
group for each scheduled time.   
Plots of individual patient data will be provided by treatment group and scheduled time for 
continuous laboratory data.  Plots of mean ± SEM will be provided for raw data and change from 
baseline data for the following selected laboratory data: hemoglobin, glucose, aldolase, blood 
urea nitrogen (BUN), creatinine kinase (CK), creatinine, and myoglobin. 
Shift tables describing out-of-range shifts from baseline (in frequency counts) will be created for 
post-dose time points. 
Additional analyses may be performed as appropriate. 
Vital Signs 
Vital sign parameters consist of weight, heart rate, systolic and diastolic blood pressure.   
Descriptive statistics will be provided for raw data and absolute change from baseline by 
scheduled time for each treatment group.  Post-dose recheck values will not be used for 
calculation of descriptive statistics. 
With the exception of weight, plots of individual patient data will be provided by treatment 
group and scheduled time.  Plots of mean ± SEM will be provided for raw data and change from 
baseline data. 
Additional analyses may be performed as appropriate. 
Electrocardiogram 
Twelve-lead electrocardiogram (ECG) parameters consist of the following:  (heart rate, PR, 
QRS, QT, and QTc (Bazett correction).   
Descriptive statistics will be provided for raw data and absolute change from baseline by 
scheduled time for each treatment group.  Post-dose recheck values will not be used for 
calculation of descriptive statistics.   
Additional analyses may be performed as appropriate. 


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4.9.3. 
Anti-Drug Antibodies 
Individual anti-drug antibody (ADA) data will be listed. 
The frequency and percentage of ADA responses will be summarized by treatment group and 
scheduled time. 
The frequency and percentage of all patients testing positive for ADA at any point during the 
study (i.e. ADA prevalence) will be summarized by treatment group.  This will include 
summaries of the prevalence ADA confirmed as “Anti-ACE-083” or “Anti-FST315”.  In 
addition, for ACE-083 ADA, a summary of the prevalence of ACE-083 ADA and titer summary 
(median, minimum, and maximum value) will be provided by scheduled visit and antibody 
follow-up visit (as applicable). 
The ACE-083 ADA incidence is defined as the sum of both “treatment-induced” and 
“treatment-boosted” ACE-083 ADA positive subjects as a proportion of patients with at least one 
sample taken post study drug administration that is appropriate for ADA testing.  Treatment 
induced ACE-083 ADA is defined as ACE-083 ADA developing de novo following study drug 
administration at any time following the first study drug administration in a patient without 
pre-existing ACE-083 ADA.  Treatment boosted ACE-083 ADA is defined as a pre-existing 
ACE-083 ADA that was boosted to a higher level following study drug administration.  
ACE-083 ADA incidence will be summarized by treatment group. 
Additional analyses may be performed as appropriate. 
4.9.4. 
Other Safety Data 
Not applicable.  
4.10. 
Pharmacokinetic Data 
Pharmacokinetic data will be summarized under the direction of the Acceleron Clinical 
Pharmacologist and summaries will be outlined in a separate analysis plan. 


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5. 
MODIFICATIONS FROM THE STATISTICAL SECTION OF 
THE PROTOCOL 
The following modifications from the statistical section of the protocol have been implemented 
in the statistical analysis plan: 
 For statistical analyses where confidence intervals for the least-squares mean are 
provided, the 95% confidence interval will be provided in addition to the 90% 
confidence interval.   
 The “Safety Population” is now called the “Safety Set”. 
 For muscle strength, “Peak force value” is now called “MVIC”. 
 For motor function data (lower leg and upper arm functional assessments), strength 
(QMT by handheld device), gait, and FSHD-HI data whose pre-treatment assessments 
are performed up to three times prior to the first dose, the baseline is defined as the 
average of the non-missing values.    
 The “Per Protocol Set” is defined as all patients enrolled/randomized in the study who 
have received at least one dose of study drug (includes placebo) with no major 
protocol violations. 
 The last observation carried forward approach is not being performed in the statistical 
analyses.  Standard multiple imputation will be performed to assess the impact of 
missing data on the observed data. 


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6. 
PROGRAMMING SPECIFICATIONS 
Seed to Use for Multiple Imputations of Missing Data 
The seed to be used for multiple imputations of MRI data is 1111. 
The seed to be used for multiple imputations of FSHD-HI data is 2222. 
The seed to be used for multiple imputations of TA functional data is 3333. 
The seed to be used for multiple imputations of PUL data is 4444. 
The seed to be used for multiple imputations of elbow flexion MVIC data is 5555. 
The seed to be used for multiple imputations of ankle dorsiflexion MVIC data is 6666. 
Representation of Scheduled Times in Listings 
Because data for this study comes from multiple sources, such information will be standardized 
in the listings.  The standardization is outlined below: 
Lab (MRL), FSHD-HI, 
eCRF (long) 
eCRF (short) 
MRI 
Mapping for Tables and 
Listings 
Plots 
Screening Day -28 
SCN 
 
S1D-28 
-28 
Screening Day -7 
SCN2 
 
S2D-7 
-7 
Cycle 1 Day 1 
C1D1 
DAY 1 
C1D1 
1 
Cycle 1 Day 2 
C1D2 
 
C1D2 
2 
Cycle 1 Day 8 
C1D8 
 
C1D8 
8 
Cycle 2 Day 22 
C2D22 
 
C2D22 
22 
Cycle 3 Day 43 
C3D43 
DAY 43 
C3D43 
43 
Cycle 4 Day 64 
C4D64 
 
C4D64 
64 
Cycle 5 Day 85 
C5D85 
 
C5D85 
85 
Cycle 5 Day 86 
C5D86 
 
C5D86 
86 
Follow-Up Day 106/ETa ET 
DAY 106 F1D106_ET 
106 
Cycle 6 Day 106b 
C6D106 
DAY 106 C6D106 
106 
Cycle 7 Day 127b 
C7D127 
 
C7D127 
127 
Follow-Up Day 141a 
FUP 
DAY 141 F2D141 
141 
Cycle 8 Day 148b 
C8D148 
 
C8D148 
148 


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Lab (MRL), FSHD-HI, 
eCRF (long) 
eCRF (short) 
MRI 
Mapping for Tables and 
Listings 
Plots 
Cycle 9 Day 169b 
C9D169 
 
C9D169 
169 
Cycle 10 Day 190b 
C10D190 
DAY 190 C10D190 
190 
Cycle 11 Day 211b 
C11D211 
 
C11D211 
211 
Cycle 12 Day 232b 
C12D232 
 
C12D232 
232 
Cycle 13 Day 253b 
C13D253 
 
C13D253 
253 
Cycle 14 Day 274b 
C14D274 
 
C14D274 
274 
Cycle 15 Day 295b 
C15D295 
DAY 295 C15D295 
295 
Cycle 16 Day 316b 
C16D316 
 
C16D316 
316 
Cycle 17 Day 337b 
C17D337 
 
C17D337 
337 
Day 358/ETb 
ET 
DAY 358 F1D358_ET 
358 
Follow-Up Day 393b 
FUP 
DAY 393 F2D393 
393 
a Applies to Part 1; b Applies to Part 2 
 
Partial Date of Birth Entries 
In the event that a patient does not have a complete date of birth present in the clinical database, 
the date of birth will be interpolated as follows: 
 If the date of birth contains the month and year of birth but no value of day (i.e. day is 
missing or has value “UNK”), the value of day will be imputed to the 1st for purposes 
of any calculations that involve the complete birthdate of the patient (i.e. age). 
 If the date of birth only contains the year but no value of month and day (i.e. 
“UNK-UNK-yyyy”), the birthdate will be imputed to “01-Jan-yyyy” where “yyyy” 
refers to the year that is reported for that patient for purposes of any calculations that 
involve the complete birthdate of the patient (i.e. age). 
Partial AE Start Dates 
The following rules will be utilized for partial AE start dates: 
 If the year is unknown, the date will not be imputed and will be assigned a missing 
value. 
 If the month is unknown, then: 
 If the year matches the first dose date for the patient with the partial AE start date, 
then the month and day of the first dose date will be imputed. 


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 Otherwise, the month will be imputed to January. 
 If the day is unknown, then: 
 If the month and year match the first dose date, then the day of the first dose date 
will be imputed. 
 Otherwise, the day will be imputed to ‘01’. 
Classification of Aes as Teaes 
In general, the start of reporting of adverse events for an individual patient starts after receiving 
the first dose of study drug.  However: 
 If both the AE start and stop date exist and are before the first dose date of study 
drug, the AE will be classified as a pre-treatment AE and not considered treatment 
emergent. 
 If the AE start date is on or after the first dose date of study drug, the AE will be 
considered a TEAE. 
 If the AE start date is before the first dose date of study drug and the AE stop date is 
after the first dose of study drug and the AE worsened in intensity, the AE will be 
considered a TEAE. 
 If the AE start date is missing and the stop date is before the first dose of study drug, 
the AE will be not be considered a TEAE. 
 If the AE start date is missing and the stop date is after the first dose of study drug, 
the AE will be considered a TEAE. 
 If the AE start and stop dates are missing, the AE will be considered a TEAE. 
Unilateral vs. Bilateral (Part 1) 
In Part 1 of this study, patients may be treated unilaterally (meaning that the patient receives 
his/her dose either on the left TA or BB muscle or the right TA or BB muscle) or bilaterally 
(meaning that the patient receives his/her dose on both the right and left sides). 
For patients receiving ACE-083 unilaterally, the side treated will vary from patient to patient 
within a cohort.  To properly identify the side treated, the dataset(s) that identify the dose 
administrations for the individual patient will be used. 
Patients that Discontinue Early 
For patients that discontinue early, end-of-treatment and follow-up assessments will be 
completed and analyzed as such.     


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7. 
APPENDICES  


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APPENDIX 1. SCHEDULE OF EVENTS 
Part 1  
 
 
 
 


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Part 2 
 
 


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