A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy
Phase: PHASE2
Conditions: Facioscapulohumeral Muscular Dystrophy
Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

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 
 
 
09 January 2019 
Acceleron Pharma Inc. 
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. 
 
 

Clinical Study Protocol 
 
ACE-083 
Study A083-02 
Revision: 04 
 
 
09 January 2019 
Acceleron Pharma Inc. 
Page 2 of 64 
CONFIDENTIAL 
 
 
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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol 
 
ACE-083 
Study A083-02 
Revision: 04 
 
 
09 January 2019 
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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 
 
 

Clinical Study Protocol 
 
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Study A083-02 
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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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Study A083-02 
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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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Study A083-02 
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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 

Clinical Study Protocol 
 
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Study A083-02 
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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 

Clinical Study Protocol 
 
ACE-083 
Study A083-02 
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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 
reported SAE.  

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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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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 

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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

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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