An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) Previously Enrolled in Study A083-02 and in Patients With Charcot-Marie Tooth (CMT) Disease Types 1 and X Previously Enrolled in Study A083-03
Phase: PHASE2
Conditions: Facioscapulohumeral Muscular Dystrophy, Charcot-Marie-Tooth Disease
Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Official Title: An Open‐Label Extension Study to Evaluate the Long‐Term Effects of ACE‐083 in Patients 
with Facioscapulohumeral Muscular Dystrophy (FSHD) Previously Enrolled in Study A083‐02 and in 
Patients with Charcot‐Marie Tooth (CMT) Disease Types 1 and X Previously Enrolled in Study A083‐03 
NCT Number:  NCT03943290 
Document Dates: Original Protocol: 09‐Jan‐2019 
 

Clinical Study Protocol 
 
 
ACE-083 
Study A083-04 
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1. 
TITLE PAGE 
 
 
Protocol A083-04 
 
An Open-Label Extension Study to Evaluate the Long-Term Effects of 
ACE-083 in Patients with Facioscapulohumeral Muscular Dystrophy (FSHD) 
Previously Enrolled in Study A083-02 and in Patients with Charcot-Marie 
Tooth (CMT) Disease Types 1 and X Previously Enrolled in Study A083-03  
 
 
 
 
 
 
 
 
SPONSOR: 
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Tel: 617-649-9200 
Fax: 617-649-9988 
 
 
 
 
 
ORIGINAL PROTOCOL DATE: 
 
 
09 January 2019 
 
 
 
 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable Institutional Review Board (IRB)/Independent Ethics Committee (IEC).  Your acceptance of this document 
constitutes agreement that you will not disclose the information contained herein to others without written authorization from 
Acceleron Pharma Inc. 
 
 

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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Medical Monitor 
 
Acceleron Pharma Inc. 
128 Sidney Street  
Cambridge, MA 02139 
Office Tel: 
 
Mobile: 
 
Fax: 
 
 
Medpace Medical 
Monitor 
 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio  45227 
Office Tel: 
 
Mobile: 
 
Fax: 
 
 
Pharmacovigilance 
 
Acceleron Pharma Inc. 
128 Sidney Street  
Cambridge, MA 02139 
Office Tel: 
 
Fax: 
 
 
Medpace 
Pharmacovigilance 
Medpace Clinical Safety 
Medpace SAE Hotline-USA 
Tel: 866-336-0930  
or 800-730-5779 ext. 2999 
Fax: 866-336-5320 
medpace-safetynotification@medpace.com 
 
Medpace SAE Hotline-Europe 
Tel: 49 89 89 55 718 44 
Fax: 49 89 89 55 718 104 
medpace-safetynotification@medpace.com 
 
 

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................4 
LIST OF TABLES ...........................................................................................................................7 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................8 
4. 
PROTOCOL SYNOPSIS ...........................................................................................10 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background .................................................................................................................20 
5.2. 
Study Rationale ...........................................................................................................21 
6. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
7. 
STUDY DESIGN .......................................................................................................24 
7.1. 
Overview of Study Design ..........................................................................................24 
7.2. 
Justification for Dose Level ........................................................................................25 
7.3. 
Benefit/Risk Assessment ............................................................................................25 
8. 
STUDY POPULATION .............................................................................................26 
8.1. 
Inclusion Criteria ........................................................................................................26 
8.2. 
Exclusion Criteria .......................................................................................................26 
8.3. 
Screen Failures ............................................................................................................27 
9. 
DISCONTINUATION / WITHDRAWAL CRITERIA .............................................28 
9.1. 
Discontinuation of Study Treatment ...........................................................................28 
9.2. 
Withdrawal from the Study ........................................................................................28 
9.3. 
Lost to Follow Up .......................................................................................................29 
10. 
TREATMENT OF SUBJECTS ..................................................................................30 
10.1. 
Treatments Administered ............................................................................................30 
10.1.1. 
Individual Dose Modification Rules ...........................................................................31 
10.2. 
Safety Review Team ...................................................................................................31 
10.3. 
Concomitant Medications ...........................................................................................31 
10.4. 
Treatment Compliance ................................................................................................32 
10.5. 
Randomization and Blinding ......................................................................................32 
11. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................33 
11.1. 
Study Drug ..................................................................................................................33 

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11.2. 
Study Drug Packaging and Labeling ..........................................................................33 
11.3. 
Study Drug Storage .....................................................................................................33 
11.4. 
Study Drug Preparation ..............................................................................................33 
11.5. 
Study Drug Accountability .........................................................................................33 
11.6. 
Study Drug Handling and Disposal ............................................................................33 
12. 
STUDY PROCEDURES ............................................................................................34 
12.1. 
Written Informed Consent ..........................................................................................34 
12.2. 
Study Assessments......................................................................................................34 
12.3. 
Safety Assessments .....................................................................................................34 
12.4. 
Efficacy Assessments .................................................................................................34 
12.5. 
Pharmacokinetic and Pharmacodynamic Assessments ..............................................34 
13. 
SAFETY .....................................................................................................................35 
13.1. 
Definition of Adverse Events .....................................................................................35 
13.1.1. 
Adverse Event .............................................................................................................35 
13.1.1.1. 
Unexpected Adverse Events .......................................................................................35 
13.1.1.2. 
Events Not to Be Considered as Adverse Events .......................................................35 
13.1.1.3. 
Serious Adverse Event ................................................................................................35 
13.1.1.4. 
Events Not to Be Considered as Serious Adverse Events ..........................................36 
13.1.1.5. 
Suspected Unexpected Serious Adverse Reactions ....................................................36 
13.2. 
Severity .......................................................................................................................36 
13.3. 
Relationship to Study Drug ........................................................................................36 
13.4. 
Recording Adverse Events .........................................................................................37 
13.4.1. 
Documentation of Serious Adverse Events ................................................................37 
13.5. 
Reporting Adverse Events ..........................................................................................38 
13.6. 
Pregnancy ...................................................................................................................38 
13.7. 
Reporting Serious Adverse Events .............................................................................38 
13.7.1. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators ..........................................................39 
14. 
STATISTICS ..............................................................................................................40 
14.1. 
Analysis Populations ..................................................................................................40 
14.2. 
Statistical Analysis Considerations .............................................................................40 
14.2.1. 
Patient Demographics and Disposition .......................................................................40 
14.2.2. 
Drug Exposure ............................................................................................................40 

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14.2.3. 
Efficacy Data ..............................................................................................................40 
14.2.4. 
Pharmacodynamic Data ..............................................................................................42 
14.2.5. 
Safety Data ..................................................................................................................44 
14.2.6. 
Pharmacokinetic Data .................................................................................................44 
14.2.7. 
Anti-drug Antibody Data ............................................................................................44 
14.3. 
Determination of Sample Size ....................................................................................44 
14.4. 
Interim Analysis ..........................................................................................................45 
14.5. 
Deviation from Original Analysis Plan ......................................................................45 
15. 
ETHICS ......................................................................................................................46 
15.1. 
Institutional Review Board .........................................................................................46 
15.2. 
Ethical Conduct of the Study ......................................................................................46 
15.3. 
Subject Information and Consent ...............................................................................46 
15.4. 
Subject Data Protection ..............................................................................................46 
16. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES .............................47 
16.1. 
Study Monitoring ........................................................................................................47 
16.2. 
Audits and Inspections ................................................................................................47 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................48 
17.1. 
Data Quality Control and Quality Assurance .............................................................48 
17.1.1. 
Investigator Responsibility .........................................................................................48 
17.1.2. 
Protocol Modifications ...............................................................................................48 
18. 
CONFIDENTIALITY ................................................................................................49 
19. 
PUBLICATION POLICY ..........................................................................................50 
20. 
PROTOCOL AMENDMENTS ..................................................................................51 
21. 
DATA HANDLING AND RECORDKEEPING .......................................................52 
21.1. 
Case Report Form Completion ...................................................................................52 
21.2. 
Retention of Records ..................................................................................................52 
22. 
REFERENCES ...........................................................................................................53 
23. 
APPENDICES ............................................................................................................54 
APPENDIX 1.  SCHEDULE OF EVENTS ................................................................................55 
APPENDIX 2. CLINICAL SAFETY LABORATORY ASSESSMENTS ................................59 
APPENDIX 3. MEDICAL RESEARCH COUNCIL MANUAL MUSCLE TESTING 
GRADING SCALE ....................................................................................................60 
APPENDIX 4. PERFORMANCE OF THE UPPER LIMB .......................................................61 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms .............................................................................8 
Table 3: 
Part 1: Loading Phase; N=Up to 54; ACE-083 240 mg/muscle bilaterally 
q4w .............................................................................................................................12 
Table 4: 
Part 2: Maintenance Phase; N=Up to 150; ACE-083 240 mg/muscle 
bilaterally ....................................................................................................................13 
Table 5: 
Objectives and Endpoints ...........................................................................................23 
Table 6: 
Part 1: Loading Phase; N=Up to 54; ACE-083 240 mg/muscle bilaterally 
q4w .............................................................................................................................30 
Table 7: 
Part 2: Maintenance Phase; N=Up to 150; ACE-083 240 mg/muscle 
bilaterally ....................................................................................................................30 
Table 8: 
Schedule of Events for Part 1: Loading Phase ............................................................56 
Table 9: 
Schedule of Events for Maintenance Phase and Follow-up: q4w dosing arm ...........57 
Table 10: Schedule of Events for Maintenance Phase and Follow-up: q8w dosing arm ...........58 
Table 11: Clinical Safety Laboratory Assessments ....................................................................59 
 

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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 
ALS 
Amyotrophic lateral sclerosis 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BB 
Biceps brachii 
CK 
Creatine kinase 
CMAP 
Compound muscle action potential  
CMT 
Charcot-Marie-Tooth 
CMT-HI 
Charcot-Marie-Tooth health index 
CMTES2 
Charcot-Marie-Tooth examination score version 2 
CRF 
Case report form 
CRO 
Contract research organization 
CTX 
C-terminal collagen crosslinks  
DLT 
Dose limiting toxicity 
DUX4 
Double homeobox protein 4 
ECG 
Electrocardiogram 
EMG 
Electromyography 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FST 
Follistatin 
FSHD 
Facioscapulohumeral muscular dystrophy 
FSHD-HI 
Facioscapulohumeral muscular dystrophy-health index 
GCP 
Good clinical practice 
GDF8 
Growth and differentiation factor 8 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 

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Abbreviation or Specialist Term Explanation 
IEC 
Independent ethics committee 
IGF-1 
Insulin-like growth factor-1  
IgG2 
Immunoglobulin G2 
IP 
Investigational product 
IRB 
Institutional review board 
MMT 
Manual muscle testing 
MRC 
Medical Research Council 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MVIC 
Maximum voluntary isometric contraction 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PUL 
Performance of the upper limb 
qXw 
Every X weeks  
QMT 
Quantitative muscle testing 
QoL 
Quality of life 
SAE 
Serious adverse event 
SD 
Standard deviation 
SRM 
Standardized response mean 
SRT 
Safety review team 
SUSAR 
Suspected unexpected serious adverse reaction 
TA 
Tibialis anterior 
TGF-β 
Transforming growth factor beta 
ULN 
Upper limit of normal 

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4. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Acceleron Pharma Inc., 128 Sidney Street, Cambridge, MA 02139 
Name of Investigational Product: ACE-083 
Name of Active Ingredient: ACE-083 is a recombinant fusion protein consisting of a modified 
form of human follistatin linked to a human IgG2 Fc domain. 
Title of Study: An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-083 
in Patients with Facioscapulohumeral Muscular Dystrophy (FSHD) Previously Enrolled in Study 
A083-02 and in Patients with Charcot-Marie Tooth (CMT) Disease Types 1 and X Previously 
Enrolled in Study A083-03 
Study Centers: Up to 30 centers 
Phase of Development: 2 
Objectives 
Primary: 
 To evaluate the long-term safety and pharmacodynamic (PD) effects of ACE-083 in 
patients with facioscapulohumeral muscular dystrophy (FSHD) previously enrolled in 
Study A083-02 and in patients with Charcot-Marie-Tooth (CMT) disease types 1 and X 
(CMT1 and CMTX) previously enrolled in Study A083-03. 
Secondary: 
 To evaluate the safety and PD effects of every 4 week (q4w) dosing in the loading phase, 
and of q4w and q8w dosing in the maintenance phase. 
 To evaluate changes in strength, motor function, and quality of life (patient-reported 
outcomes) during the maintenance and loading phases of treatment.  
 To evaluate the pharmacokinetics (PK) of ACE-083 when administered as a local muscle 
injection during the maintenance and loading phases of treatment. 
Exploratory: 
 To evaluate changes in biomarkers 
 To evaluate PK/PD relationships. 
Endpoints 
Primary: 
 Presence and nature of adverse events (AE), including injection site reactions and changes 
in clinical laboratory parameters  

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 Percent change from baseline in muscle volume of injected muscle by magnetic resonance 
imaging (MRI) 
Secondary: 
 Percent and absolute change from baseline in the intramuscular fat fraction of injected 
muscle by MRI 
 Percent change from baseline in strength measurements 
 Percent and absolute change from baseline in functional assessments: For tibialis anterior 
(TA) muscle: 10-meter walk/run, 6-minute walk test, 4-stair climb (subjects from A083-02 
only), and 100-meter timed test; for biceps brachii (BB) muscle: mid-level and high level 
performance of the upper limb (PUL) test 
 Absolute change from baseline in FSHD-health index (FSHD-HI, subjects from A083-02) 
or CMT health index (CMT-HI, subjects from A083-03) total score and subscale scores 
 PK parameters of ACE-083 serum concentrations over time 
Exploratory: 
 Percent and absolute change from baseline in biomarkers. 
 Percent and absolute change in PD parameters as a function of ACE-083 exposure 
Methodology 
Subjects who have signed the informed consent form (ICF) and meet the eligibility criteria will be 
enrolled into the study.  This is an open-label, multicenter, phase 2 extension study to evaluate the 
safety, tolerability, PK, PD, and efficacy of ACE-083 in subjects with FSHD previously enrolled 
in Study A083-02 and subjects with CMT1 and CMTX previously enrolled in Study A083-03.  
This study will be conducted in two Parts: Part 1, which is a loading phase of 6 months’ duration, 
and Part 2, the maintenance phase, which will last up to 24 months.  
 
 
 
 
 
 
 
 
 
 

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Study Design 
Figure 1: 
Schematic Diagram of Subject Enrollment and Disposition  
 
 
Table 3: 
Part 1: Loading Phase; N=Up to 54; ACE-083 240 mg/muscle bilaterally q4w  
Cohort 
Disease 
Muscle 
N 
1a 
FSHD 
Tibialis anterior (TA) 
Up to 18 
1b 
FSHD 
Biceps brachii (BB) 
Up to 18 
1c 
CMT 
Tibialis anterior (TA) 
Up to 18 
 
Part 1: 6-month, non-randomized, open-label, loading phase for subjects from A083-02 Part 
1 and A083-03 Part 1 
Part 1 will consist of 3 cohorts of up to 18 subjects each.  Subjects enrolled in Cohorts 1a and 1b 
will have completed Part 1 of Study A083-02; subjects enrolled in Cohort 1c will have completed 
Part 1 of Study A083-03.  In this loading phase, 240 mg/muscle ACE-083 will be administered 
bilaterally q4w for 6 doses (6 months) into either the TA muscle or the BB muscle, depending on 
the muscle injected in the previous study; subjects may not switch muscle cohort upon enrollment 
in this study.  Subjects will participate in a screening period of up to 4 weeks before receiving the 
first dose of ACE-083.  

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Table 4: 
Part 2: Maintenance Phase; N=Up to 150; ACE-083 240 mg/muscle bilaterally 
Cohort 
Disease 
Muscle 
Dose Interval 
N 
2a 
FSHD 
TA 
q4w 
Up to 23 
2b 
FSHD 
BB 
q4w 
Up to 23 
2c 
CMT 
TA 
q4w 
Up to 29 
3a 
FSHD 
TA 
q8w 
Up to 23 
3b 
FSHD 
BB 
q8w 
Up to 23 
3c 
CMT 
TA 
q8w 
Up to 29 
Part 2: 24-month randomized, open-label rollover maintenance phase for subjects from 
A083-02 Part 2, A083-03 Part 2, and A083-04 Part 1 
Subjects who complete Part 1 of this study (the loading phase), Part 2 of A083-02, or Part 2 of 
A083-03 will enroll directly into the Part 2 open-label maintenance phase of treatment with 
ACE-083.  These subjects will be randomized (1:1) to receive ACE-083, 240 mg/muscle 
bilaterally, either q4w or q8w. 
Number of Subjects (planned) 
Up to 54 subjects from Study A083-02 Part 1 and Study A083-03 Part 1will be enrolled in Part 1 
of the study.  A total of up to 150 subjects will be enrolled in Part 2 of the study; Part 2 will be 
comprised of up to 54 subjects from Part 1 of this study, up to 56 subjects from Part 2 of Study 
A083-02, and up to 40 subjects from Part 2 of Study A083-03. Total study enrollment will be up 
to 150 subjects. 
Diagnosis and Main Criteria for Eligibility 
Inclusion Criteria: 
1. Completion of treatment with study drug per protocol and completion of the end of 
treatment (ET) visit in Study A083-02 or Study A083-03 
2. 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 a 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 

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weeks following the last dose of ACE-083, even if they have undergone a vasectomy.  
Subjects must be counseled about contraception prior to the first dose of ACE-083 and 
every three months thereafter during the study. 
3. Ability to adhere to the study visit schedule/procedures and to understand and comply with 
protocol requirements 
4. 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. Co-morbidities, including symptomatic cardiopulmonary disease, significant orthopedic or 
neuropathic pain, or other conditions that, in the opinion of the investigator, would limit a 
subject’s ability to complete strength and/or functional assessments  
3. Type 1 or type 2 diabetes mellitus  
4. Thyroid disorder unless condition is stable with no change in treatment for at least 4 weeks 
before the first dose and no expected change for duration of study  
5. Renal impairment (serum creatinine ≥ 2 times the upper limit of normal [ULN]) 
6. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN 
7. 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 and for 
duration of study; single agent low dose aspirin [≤ 100 mg daily] is permitted) 
8. Severe deformity or ankle fixation that would sufficiently limit passive range of motion to 
affect functional assessments (TA subjects only) 
9. Major surgery within 4 weeks prior to Study Day 1 
10. Chronic pharmacologic doses of systemic corticosteroids (≥ 2 weeks) within 4 weeks 
before Study Day 1 and for duration of study; intra-articular/topical/inhaled/intranasal 
physiologic doses of systemic corticosteroids are permitted 
11. Androgens, growth hormone, insulin or oral hormone replacement therapy within 6 months 
before Study Day 1 and for duration of study; topical physiologic androgen replacement is 
permitted  
12. 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) 
13. Previous exposure to any other investigational agent (not including ACE-083) potentially 
affecting muscle volume, muscle strength, or muscle or nerve function, within 5 half-lives 
of last dose plus an additional 8-week washout period (or 12 weeks prior to Study Day 1 if 
half-life is unknown)  

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14. 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 
15. Any condition that would prevent the use of MRI or compromise the ability to obtain a 
clear and interpretable image of the treated muscles (e.g., knee/hip replacement metallic 
implants) 
16. Known active substance abuse, including alcohol 
17. History of sensitivity to protein pharmaceuticals 
18. Female that is pregnant or lactating/breast-feeding 
Investigational Product, Dosage, and Mode of Administration 
ACE-083 drug product is provided as a lyophilized powder contained in stoppered and sealed 
glass vials (64 mg/vial; nominal strength of each vial is 50 mg of ACE-083).  After reconstitution 
with 1.2 mL of sterile water for injection, 1.0 mL will deliver 50 mg ACE-083.  
Using electromyography (EMG) or ultrasound guidance, each dose of ACE-083 will be 
administered into the non-tendinous portion of the TA or BB as a series of 4 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 approximately 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. 
The maximum absolute dose and schedule is 240 mg/muscle (4.8 mL) administered bilaterally by 
injection into the left and right TA or BB muscles q4w for up to 30 months (30 doses).  
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.  At 
the discretion of the investigator, dosing may resume upon resolution of the AE to ≤ grade 1 or 
baseline and dose may be reduced.  Up to two dose reductions are permitted: from 240 mg/muscle 
to 200 mg/muscle and from 200 mg/muscle to 150 mg/muscle. Dose will not be reduced below 
150 mg/muscle.  Dose delay and/or modification may be considered and implemented unilaterally 
or bilaterally.  A maximum of 3 dose delays are allowed for subjects receiving q4w injections of 
ACE-083; only one dose delay is permitted for subjects in the q8w arm of Part 2 of the study. 
Duration of Treatment 
Study duration for a subject initially enrolled in Part 1 and then extended to Part 2 will be 
approximately 33 months, including a 1-month screening period, 6-month Part 1 loading phase, 
24-month Part 2 maintenance phase, and 2-month follow-up period.   

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For subjects who enrolled directly into Part 2 of this study from Part 2 of Studies A083-02 and 
A083-03, the duration of the study will be approximately 26 months, including a 24-month 
maintenance phase and a 2-month follow-up period. 
If a subject has a positive anti-drug antibody (ADA) result at the last visit, the subject will be 
asked to return for additional ADA testing approximately every 3 months until a negative result is 
obtained or the titer is no longer increasing. 
Safety Assessment 
Safety Review Team: 
An SRT, comprised at minimum of a principal investigator, medical monitor, and an independent 
neuromuscular specialist, will meet periodically (approximately every 3 months for the first six 
months, and every six months thereafter) to review safety for each cohort.  The reviews will 
include all collected safety data and will begin when at least 10 subjects have received at least 3 
doses of ACE-083 in this study. The SRT will review safety data, including AEs, laboratory 
results, and vital signs, to assess overall safety.  The SRT may request review of additional data 
including PD and efficacy measurements. 
Based on review of relevant data, the SRT will make one or more of the following 
recommendations: 
 Continue ACE-083 administration at the current dose  
 Reduce the dose for all subjects within a cohort, or for the study as a whole 
 Discontinue one or more cohorts, or the study as a whole 
Any changes in the dose level or schedule (e.g., continued treatment with q4w or q8w) in this 
study will be determined following review of study data and recommendations from the SRT. 
Further details on the role of the SRT 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, physical examination findings   
Pharmacokinetics: ACE-083 serum concentrations 
Pharmacodynamics:  
Muscle assessments: Muscle volume and intramuscular fat fraction of TA or BB by MRI 
Biomarkers: including, but not limited to, serum C-terminal collagen crosslinks (CTX) 
Efficacy:  
Muscle strength: Quantitative muscle testing using maximum voluntary isometric contraction 
(MVIC) by hand-held dynamometry and manual muscle testing (MRC grade) of elbow flexion, 
ankle dorsiflexion, plantar flexion, and/or knee extension 
Motor function tests: TA muscle function by 10-meter walk/run, 6-minute walk test, 4-stair climb 
(subjects from A083-02 only), 100-meter timed test; BB muscle function by PUL test 

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Patient-reported health-related quality of life (QoL): FSHD-HI (for FSHD patients) or CMT-HI 
(for CMT patients) total score and subscale scores 
Statistical Methods: 
Sample Size Calculation:  
There was no formal sample size calculation for Part 1 or Part 2 of this study.   
The sample size for Part 1 is determined by how many subjects from Part 1 of Studies A083-02 
and A083-03 decide to participate in this study.  Similarly, the sample size for Part 2 is based upon 
how many subjects from Part 2 of Studies A083-02 and A083-03 and Part 1 of this study 
participate in Part 2 of this study. 
Non-inferiority of the q8w or q4w maintenance dose regimen during the first 6 months of the 
maintenance phase for the percent change in total muscle volume relative to the start of the 
maintenance phase (or equivalently the end of the loading phase – either from Part 2 of phase 2 
studies A083-02 and A083-03 or from Part 1 of this study) will be analyzed.  Based upon data 
from Parts 1 of Studies A083-02 and A083-03, it is assumed that the standard deviation is 
approximately 9.  A non-inferiority margin of -5 and a 0.05 significance level is used.  If 75 
subjects per maintenance regimen participate and the observed mean percent change in total 
muscle volume at the first 6 months of the maintenance regimen from the start of the maintenance 
regimen is -2, the probability to conclude that the effect of any single maintenance regimen (q8w 
or q4w) is non-inferior is approximately 89%.  If 65 subjects per maintenance regimen participate 
and the observed mean percent change is -2, the probability to conclude that the effect of any 
single maintenance regimen (q8w or q4w) is non-inferior is approximately 85%.  If 57 subjects 
per maintenance regimen participate, the probability is approximately 80%. 
Statistical Analysis:  
Additional detail concerning the planned statistical analyses outlined below are included in 
Section 14. STATISTICS and will be described further in a separate statistical analysis plan 
(SAP). 
Part 1 
Safety: Unless otherwise specified, safety data will be summarized, by cohort and overall, using 
descriptive statistics; individual safety data will be listed.  AEs will be coded using the current 
version of the Medical Dictionary for Regulatory Activities and incidence of treatment-emergent 
AEs will be presented by system organ class and preferred term.  AE incidence rates will be 
described by cohort with and without regard to causality.  The frequency of occurrence of overall 
toxicity, categorized by toxicity grades (NCI-CTCAE, current version), will be summarized.  
Change from baseline in clinical laboratory parameters, ECG, 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. 
Pharmacodynamics: Individual PD data (e.g., total muscle volume, contractile muscle volume, 
intramuscular fat fraction, and biomarker data) will be listed.  For individual PD data that are 
measured bilaterally (e.g., MRI), the average of the left and right side assessments will also be 
listed and summarized.  Descriptive statistics (raw data and change from baseline [percent and 

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absolute change]) will be provided by cohort and scheduled time where baseline is defined to be 
the last non-missing assessment done prior to first dose.   
For total muscle volume, contractile muscle volume, and intramuscular fat fraction, a mixed model 
will be fitted to the data and the least squares estimate of the mean difference in the percent 
change from baseline at 6 months post first dose under the q4w regimen of ACE-083 versus 
placebo will be determined for each cohort with the corresponding 90% confidence interval, where 
placebo refers to data from the double-blind component of Part 2 of either study A083-02 or 
A083-03.  This will be compared with the findings from Part 2 of studies A083-02 and A083-03 
for the mean difference in the percent change from baseline under the q3w regimen vs placebo. 
For biomarker data (e.g. CTX), raw data and changes from baseline (percent and absolute change) 
will be summarized by cohort and scheduled time. 
Efficacy: Individual efficacy data will be listed.  For muscle strength, both quantitative muscle 
testing (QMT) and manual muscle testing (MMT) will be measured for the left and right sides and 
average of the two sides will be calculated.  QMT is based on maximum voluntary isometric 
contraction (MVIC) using a hand-held dynamometer, and the MMT is based on Medical Research 
Council (MRC) grade.  The MMT-MRC grades will be converted to decimal scores in the 
following way: 5 = 5.0, 5- = 4.67, 4+ = 4.33, 4 = 4.0, 4- = 3.67, 3+ = 3.33, 3 = 3.0, 3- = 2.67, 
2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 1=1.0.   
For the MVIC values and the decimal MMT-MRC scores for each side treated as well as the 
average from the left and right sides, CMT-HI total score and selected subscale scores, FSHD-HI 
subscale scores, FSHD-HI total score, and motor function test assessments, raw data and changes 
from baseline (percent and absolute change) for the injected muscles will be summarized for each 
scheduled time using descriptive statistics.  For each efficacy parameter, a mixed model will be 
fitted and least-square mean estimates of the effect of ACE-083 and the corresponding 90% 
confidence intervals will be provided for the percent and/or absolute change from baseline 
(depending on the parameter).     
Pharmacokinetics: Individual listings of serum ACE-083 concentrations, actual blood sampling 
times, and PK parameters, including graphs of concentration versus time, will be prepared.  PK 
parameters of ACE-083 will be determined using the standard non-compartmental method.  
Descriptive statistics of PK parameters will be summarized by treatment group. 
Part 2 
Pharmacodynamics: Individual PD data will be listed.  Descriptive statistics will be provided by 
cohort and scheduled time for raw data and changes from the start of the maintenance phase (or 
equivalently the end of the loading phase). 
The primary PD variable will be the difference in mean percent change in total muscle volume 
(average of left and right side) at the first 6 months of the maintenance phase (Day 169, q4w or 
q8w) from the total muscle volume (average of left and right sides) at the start of the maintenance 
phase (or equivalently the end of the loading phase).  A mixed model will be fitted to the data and 
a non-inferiority analysis will be performed using a non-inferiority margin of -5.  
Secondary MRI PD variables include the difference in mean percent change for contractile muscle 
volume (average of left and right side) as well as intramuscular fat fraction (average of left and 

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right side) at the end of the first 6 months of the maintenance phase (Day 169, q4w or q8w) from 
the start of the maintenance phase (or equivalently the end of the loading phase).  Secondary PD 
variables also include the difference in mean percent and/or absolute (raw) change from the start 
of the maintenance phase for biomarker variables such as CTX at the end of the first 6 months of 
the maintenance phase (Day 169, q4w or q8w). 
For each secondary MRI PD variable, a mixed model will be fitted to the data and least square 
estimates of the mean difference and corresponding 90% confidence interval will be provided for 
each maintenance dose regimen.  For biomarker data, a mixed model will be fitted and least square 
estimates of the mean percent and/or absolute change from baseline for the first 6 months of the 
maintenance phase along with the corresponding 90% confidence interval will be provided for 
each maintenance dose regimen. 
Least square estimates of the mean percent or absolute change from baseline for other scheduled 
times during the maintenance phase along with the corresponding 90% confidence interval may be 
provided as appropriate.   
Safety: Same as in Part 1  
Efficacy: Individual efficacy data will be listed.  Descriptive statistics will be provided by cohort, 
treatment regimen and scheduled time for raw data and changes from baseline.  For assessments 
that are performed on the left and right sides, such as MVIC and decimal MMT-MRC scores, 
descriptive statistics will be provided for each side as well as the average of the left and right 
sides.   
For each muscle strength and motor function efficacy parameter, a mixed model will be fitted and 
least-square estimates of the mean percent change from maintenance phase baseline (Day 1) for 
the first 6 months of the maintenance phase along with the corresponding 90% confidence interval 
will be provided for each treatment regimen for MVIC of ankle dorsiflexion, plantar flexion, and 
knee extension (TA patient data, average of left and right sides), MVIC of elbow flexion (BB 
patient data, average of left and right sides) decimal MMT-MRC scores (average of left and right 
sides), and each motor function test.  For each patient reported health-related quality of life 
parameter (FSHD-HI total score and selected subscale scores [for FSHD subjects] and CMT-HI 
total score and selected subscale scores [for CMT subjects]), a mixed model will be fitted and least 
square estimates of the mean absolute change from baseline for the first 6 months of the 
maintenance phase along with the corresponding 90% confidence interval will be provided for 
each treatment regimen for FSHD-HI total score and selected subscale scores [FSHD subject data] 
as well as for CMT-HI total score and selected subscale scores [CMT subject data].   
Least square estimates of the mean percent or absolute change from baseline for other scheduled 
times during the maintenance phase along with the corresponding 90% confidence interval may be 
provided as appropriate.   
Pharmacokinetics: Same as in Part 1  
Anti-drug antibody data (Parts 1 and 2): Individual ADA data will be listed.  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 analyses will be performed on the potential 
effect of ADA on ACE-083 PK exposure if ADA tests are 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.  FST 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  FST 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.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, which 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 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.  When administered by injection into muscle, ACE-083 remains primarily within 
the injected muscle, resulting in an increase in mass and strength of the targeted muscle while 
minimizing systemic distribution and off-target effects.  
As described in the ACE-083 Investigator’s Brochure (IB), a number of nonclinical 
pharmacology studies have defined the ligand-binding properties of ACE-083 and assessed 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 is a result 
of increased fiber hypertrophy and not hyperplasia.  This ACE-083-induced muscle hypertrophy 
translates 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, 
representative of a degenerative muscle disorder, as well as the SOD1 mouse model of human 
amyotrophic lateral sclerosis (ALS), representative of a neurogenic disorder.  ACE-083 
treatment in both mouse models resulted in significant increases in the mass and peak strength 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 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.6  
Forty-two subjects have received ACE-083 at doses of 50 to 200 mg administered as single or 
multiple injections into either the right rectus femoris or right TA muscle.  ACE-083 was 
generally safe and well tolerated in this study with no serious adverse events or grade ≥ 3 AEs 
reported.  A significant dose-dependent change in volume of the injected muscle was noted in the 
subjects treated with ACE-083.6 

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5.2. 
Study Rationale 
ACE-083 is intended for the treatment of focal myopathies that affect specific skeletal muscles 
and/or muscle groups (e.g., facioscapulohumeral muscular dystrophy [FSHD], Charcot Marie 
Tooth [CMT] disease, and sporadic inclusion body myositis [sIBM]).  The initial clinical 
indications being pursued are FSHD and CMT disease, as specific features of these diseases lend 
themselves favorably to treatment with ACE-083. The ongoing Phase 2 studies (Study A083-02 
and Study A083-03) in subjects with FSHD and CMT, respectively, have been designed to assess 
safety and tolerability of ACE-083, as well as to determine if local injection of ACE-083 results 
in clinically meaningful effects on specific skeletal muscles that could result in improved clinical 
function. This study is an extension of A083-02 and A083-03 with the primary goal of 
establishing long-term safety and tolerability of ACE-083.   
This extension study will also assess the efficacy of ACE-083 in the treatment of FSHD and 
CMT by examining muscle volume, muscle strength, and motor function parameters, as well as 
patient- and physician-reported disease burden and quality of life measures.  Part 2 of this study 
will evaluate the long-term safety, tolerability, and efficacy of ACE-083, as well as assess 
different dosing regimens in the maintenance phase to determine if dosing less frequently (q8w 
versus q4w) is sufficient to maintain increases in total muscle volume that are produced with an 
initial 6-month loading phase of q3w and/or q4w.  Less frequent dosing may improve patient 
convenience and compliance. 
FSHD is one of the most common muscular dystrophies and has an autosomal dominant 
inheritance pattern in most patients.7,8 FSHD is characterized by complex genetic mechanisms 
relating to the double homeobox protein 4 gene (DUX4).  DUX4 is normally repressed in 
somatic cells through epigenetic mechanisms but 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 
associated with DNA hypomethylation and chromatin structural changes.  FSHD2 is also 
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.  The types are 
phenotypically indistinguishable.9  Laboratory and muscle biopsy findings are often non-specific 
and therefore are not required for diagnosis; diagnosis of the most common variants of FSHD, as 
well as other rare atypical variants of the disease, is by genetic testing.  
Patients with FSHD typically present in their second decade of life and live a normal lifespan.  
The disease is clinically characterized by slowly progressive focal and asymmetric areas of 
muscle weakness, typically involving facial, scapular, upper arm, lower leg, and abdominal 
muscles.  Weakness of the tibialis anterior (TA), a commonly affected lower extremity muscle in 
FSHD patients, often results in impaired dorsiflexion and foot drop, which can lead to gait 
instability and falls requiring the use of assistive devices.  The biceps brachii (BB) muscle, 
located in the upper arm, is another muscle that is often affected in FSHD and whose loss of 
function is detrimental to patient movement and quality of life.  
Another indication being pursued for ACE-083 is the treatment of hereditary motor sensory 
neuropathy (HMSN), more commonly known as Charcot-Marie-Tooth (CMT) disease.  CMT is 
the most common form of hereditary peripheral neuropathy, with a worldwide prevalence of 1 in 
2500 individuals; it affects approximately 125,000 people in the US.10  A specific mutation in 

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one of several myelin genes results in defects in myelin formation, structure, and maintenance in 
patient with CMT type 1.  Duplication of the PMP22 gene causes CMT1A, the most common 
type of CMT, accounting for approximately 40 percent of cases.  X-linked forms of CMT 
(CMTX) account for approximately 10 to 15 percent of cases11. 
Patients with CMT typically present with both motor and sensory nerve symptoms, including 
distal leg weakness, foot deformities (pes cavus, hammer toes), and sensory deficits.  
Involvement of the hands may also follow as the disease progresses.  Weakness in the lower leg 
manifests as foot drop, and patients have difficulty lifting their toes while walking.  As this 
weakness progresses, patients lose mobility and are at increased risk for falls and injury.   
There is a high unmet medical need for drug therapy options in both CMT and FSHD.  Although 
some clinical and pharmacological trials have been performed in both patient populations, the 
results have not been encouraging, and there is currently no approved therapy available for either 
condition.9,12  To date, treatment for both FSHD and CMT has been restricted to symptomatic 
interventions.  Patients will commonly wear braces and/or use assistive devices such as canes 
and walkers to preserve mobility, but each of these orthopedic interventions is associated with 
practical as well as social limitations.  Surgery can successfully treat some, but not all, foot 
deformities (in CMT) and foot drop (in CMT and FSHD), but surgical intervention is not 
appropriate for every case.  Exercise is recommended for some patients; however, the safety of 
exercise, as well as the appropriate regimen of exercise, must be established for each individual 
patient.13 
In our Phase 1 study, local injection of ACE-083 into the tibialis anterior (TA) of healthy 
volunteers led to a dose-dependent increase in TA muscle volume.  In Phase 2 Studies A083-02 
and A083-03, subjects received 150 to 240 mg/muscle, unilaterally or bilaterally q3w for 3 
months (5 doses, Part 1) or 240 mg/muscle bilaterally for 12 months (17 doses, Part 2).  
Preliminary data for Part 1 of the study indicated that the study drug was well tolerated and 
produced significant muscle volume increases that were maintained for up to 8 weeks following 
the last dose.   
Because CMT disease selectively impacts muscles in the lower leg innervated by longer nerve 
fibers, including the TA, a locally acting agent such as ACE-083 can be can be used to 
selectively target atrophied muscles that are contributing to functional limitations.  In CMT and 
FSHD patients with lower limb weakness and atrophy of the TA, or in FSHD patients with 
affected BB muscles, an ACE-083-mediated increase in muscle volume has the potential to 
increase strength and function associated with ankle dorsiflexion or elbow flexion, respectively. 
This could improve a patient’s mobility, activities of daily living, and ultimately their quality of 
life.  This study will evaluate the longer-term safety, tolerability, efficacy, and pharmacokinetics 
of ACE-083 for up to 30 months. 

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6. 
OBJECTIVES AND ENDPOINTS 
Table 5: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the long-term safety and 
pharmacodynamic (PD) effects of ACE-
083 in patients with facioscapulohumeral 
muscular dystrophy (FSHD) previously 
enrolled in study A083-02 and in patients 
with Charcot Marie Tooth (CMT) disease 
types 1 and X (CMT1 and CMTX) 
previously enrolled in study A083-03. 
 
 
Presence and nature of adverse events (AE) 
including injection site reactions and 
changes in clinical laboratory parameters  
 
Percent change from baseline in muscle 
volume of injected muscle by magnetic 
resonance imaging (MRI) 
 
Secondary 
 
To evaluate safety and PD effects of every 
4 week (q4w) dosing in the loading phase, 
and of q4w and q8w dosing in the 
maintenance phase. 
 
Percent and absolute change from baseline in 
the intramuscular fat fraction of injected 
muscle by MRI 
 
Percent change from baseline in strength 
measurements 
 
Percent and absolute change from baseline in 
functional assessments: For tibialis anterior 
(TA) muscle: 10-meter walk/run, 6-minute 
walk test, 4-stair climb (subjects from A083-
02 only), and 100-meter timed test; for 
biceps brachii (BB) muscle, mid-level and 
high level performance of the upper limb 
(PUL) test 
 
Absolute change from baseline in FSHD-
health index (FSHD-HI, subjects from 
A083-02) or CMT health index (CMT-HI, 
subjects from A083-03) total score and 
subscale scores 
 
PK parameters for ACE-083 serum 
concentrations over time 
 
To evaluate changes in strength, motor 
function, and quality of life (patient-
reported outcomes) during the 
maintenance and loading phases of 
treatment.  
 
To evaluate the PK of ACE-083 when 
administered as a local muscle injection 
during the maintenance and loading 
phases of treatment. 
 
To evaluate safety and PD effects of every 
4 week (q4w) dosing in the loading phase, 
and of q4w and q8w dosing in the 
maintenance phase. 
 
 
Exploratory 
 
To evaluate changes in biomarkers 
 
To evaluate ACE-083 PK/PD 
relationships. 
 
 
 
Percent and absolute change from baseline in 
biomarkers 
 
Percent and absolute change in PD 
parameters as a function of ACE-083 
exposure. 
 
 

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7. 
STUDY DESIGN 
7.1. 
Overview of Study Design 
This is an open-label, multicenter, phase 2 extension study to evaluate the safety, tolerability, 
PD, efficacy, and PK of ACE-083 in patients with FSHD previously enrolled in Study A083-02 
and patients with CMT1 and CMTX previously enrolled in Study A083-03.  This study will be 
conducted in two Parts: Part 1, consisting of a loading phase of 6 months, and Part 2, consisting 
of a maintenance phase of 24 months.  Subjects who enroll in this study without interruption of 
treatment following the previous study will enroll directly into Part 2 of this study.   
Part 1 is a non-randomized, open-label, loading phase in which subjects will receive bilateral 
injections of 240 mg/muscle ACE-083 every 4 weeks.  Part 1 will include subjects previously 
treated in Part 1 of Studies A083-02 and A083-03 after a washout period of at least 3 months. 
Upon completion of this 6-month loading phase, these subjects will then rollover into Part 2 of 
this study, which is the maintenance phase.   
Subjects who complete Part 2 of study A083-02 or A083-03 will enroll directly into Part 2 of this 
study without interruption.  The end-of-treatment visit in the previous study will coincide with 
the Day 1 visit of this study.  Part 2 is an open-label maintenance phase study in which subjects 
will be randomized to receive bilateral injections of 240 mg/muscle ACE-083 either every 4 
weeks or every 8 weeks.  A schematic diagram of subject enrollment and disposition is shown in 
Figure 1. 
Duration of Treatment  
For subjects enrolled in Part 1 and Part 2 of this study, study duration will be approximately 33 
months, including a screening period of up to 1 month, the 6-month Part 1 loading phase, the 
Part 2 maintenance phase of 24 months, and a 2-month follow-up period.   
For subjects who enroll directly into Part 2 of this study from Part 2 of Study A083-02 or 
A083-03, study duration will be approximately 26 months, including a maintenance phase of 24 
months and a 2-month follow-up period.  These subjects will sign the Informed Consent Form 
(ICF) for this study at the end-of-treatment visit for Study A083-02 or Study A083-03 (i.e., Day 
1 of this study). 
If a subject has a positive anti-drug antibody (ADA) result at the last scheduled follow-up visit, 
the subject may be asked to return for additional ADA testing approximately every 3 months, 
until a negative result is obtained or the titer is no longer increasing. 
Part 1 (non-randomized, open-label, loading phase with subjects from A083-02 Part 1 and 
A083-03 part 1) 
Part 1 will consist of 3 cohorts of up to 18 subjects each.  In this loading phase, 240 mg/muscle 
ACE-083 will be administered bilaterally q4w for 6 doses (6 months) into either the TA muscle 
or BB muscle, depending on the muscle injected in the previous study; subjects may not switch 
muscle cohort upon enrollment in this study.  Subjects in each cohort will be enrolled in a 
screening period of up to 4 weeks before beginning treatment.  
Subjects enrolled in Cohorts 1a and 1b will have completed the 3-month, dose escalation, non-
randomized, open-label Part 1 of Study A083-02.  As part of that study, these subjects will have 

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previously received injections of up to 240 mg/muscle ACE-083, either unilaterally or 
bilaterally, q3w for up to 5 doses.  
Subjects enrolled in Cohort 1c, will have completed the 3-month, dose escalation, non-
randomized, open-label Part 1 of Study A083-03.  These subjects will have previously received 
up to 240 mg/muscle ACE-083 bilaterally by injection into the TA every q3w for up to 5 doses.  
Part 2 (randomized, open-label rollover maintenance phase, with subjects from Part 1 
A083-04 and A083-02 part 2 and A083-03 part 2) 
Part 2 will consist of 6 additional cohorts.  Cohorts 2a, 2b, and 2c will receive 240 mg/muscle 
ACE-083 q4w, and Cohorts 3a, 3b, and 3c will receive 240 mg/muscle ACE-083 q8w.  Cohorts 
are separated and randomized based upon disease (FSHD or CMT) and target muscle (BB or 
TA). 
Subjects who complete Part 1 (loading phase), will immediately rollover into Part 2 (open-label 
maintenance phase) treatment with ACE-083.  The subjects will be randomized into treatment 
groups to receive 240 mg/muscle ACE-083 bilaterally either q4w or q8w. 
Subjects who completed Part 2 of Study A083-02 or Part 2 of Study A083-03 will directly enter 
into Part 2 (open-label maintenance phase) of this study and will be randomized to receive 
240 mg/muscle either q4w or q8w.  The first study visit of this study will coincide with the 
end-of-treatment visit of the previous study (either A083-02 or A083-03).   
7.2. 
Justification for Dose Level 
A starting dose of 150 mg/muscle was used in the dose escalation cohorts in Part 1 of Phase 2 
Study A083-02 and Part 1 of Phase 2 Study A083-03, with a maximum dose in these studies of 
240 mg/muscle unilaterally or bilaterally q3w for 3 months (5 doses).  All doses were well-
tolerated, including bilateral cohorts.  The most common TEAEs in all cohorts were grade 1 
injection site reactions, and there were no treatment-related SAEs. Injections of 150 to 
240 mg/muscle ACE-083 produced significant, dose-dependent muscle volume increases that 
were maintained for up to 8 weeks following the last dose.   
Based upon these safety and efficacy data, the dose of 240 mg/muscle bilaterally was chosen for 
Part 2 of the A083-02 and A083-03 studies as well as for this extension study.  This study will 
evaluate if long-term, maintenance phase dosing of 240 mg/muscle q8w and/or q4w can maintain 
total muscle volume increases and functional improvements reached at the conclusion of the 
loading phase (q3w or q4w for 6 months).  Any changes in the dose level or schedule in this 
study will be determined following review of study data and recommendations from the SRT. A 
maximum absolute dose level of 240 mg/muscle has been chosen based in part on administration 
feasibility and volume constraints.  
7.3. 
Benefit/Risk Assessment 
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 
Subjects are eligible to be included in the study only if they meet all of the following criteria at 
screening: 
Inclusion Criteria: 
1. Completion of treatment with study drug per protocol and completion of the end of 
treatment (ET) visit in Study A083-02 or Study A083-03.   
2. 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 they have undergone a vasectomy.  
Subjects must be counseled about contraception prior to the first dose of ACE-083 and 
every three months thereafter during the study. 
3. Ability to adhere to the study visit schedule/procedures and to understand and comply 
with protocol requirements 
4. Signed written informed consent 
8.2. 
Exclusion Criteria 
Subjects 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. Co-morbidities, including symptomatic cardiopulmonary disease, significant orthopedic 
or neuropathic pain, or other conditions that, in the opinion of the investigator, would 
limit a subject’s ability to complete strength and/or functional assessments  
3. Type 1 or type 2 diabetes mellitus  
4. Thyroid disorder unless condition is stable with no change in treatment for at least 4 
weeks before the first dose and no expected change for duration of study  
5. Renal impairment (serum creatinine ≥ 2 times the upper limit of normal [ULN]) 
6. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN 
7. 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 and for 
duration of study; single agent low dose aspirin [≤ 100 mg daily] is permitted) 

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8. Severe deformity or ankle fixation that would sufficiently limit passive range of motion 
to affect functional assessments (TA patients only) 
9. Major surgery within 4 weeks prior to Study Day 1 
10. Chronic pharmacologic doses of systemic corticosteroids (≥ 2 weeks) within 4 weeks 
before Study Day 1 and for duration of study; intra-articular/topical/inhaled/intranasal 
physiologic doses of systemic corticosteroids are permitted 
11. Androgens, growth hormone, insulin or oral hormone replacement therapy within 6 
months before Study Day 1 and for duration of study; topical physiologic androgen 
replacement is permitted  
12. 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) 
13. Previous exposure to any other investigational agent (not including ACE-083) potentially 
affecting muscle volume, muscle strength, or muscle or nerve function within 5 half-lives 
of last dose plus an additional 8-week washout period (or 12 weeks prior to Study Day 1 
if half-life is unknown)  
14. 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  
15. Any condition that would prevent MRI scanning or compromise the ability to obtain a 
clear and interpretable scan of the treated muscles (e.g., knee/hip replacement metallic 
implants) 
16. Known active substance abuse, including alcohol 
17. History of sensitivity to protein pharmaceuticals 
18. Female that is pregnant or 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 re-screenings 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 a rescreening is performed, the individual 
must sign a new ICF.  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 reasons for treatment discontinuation / study withdrawal must be recorded in the patient’s 
case report form (CRF).  The investigator must notify the sponsor and medical monitor when a 
patient has been withdrawn from the study.  
All patients who are withdrawn from the study prior to the end of treatment (EOT) visit should 
complete the tests and evaluations (excluding the MRI if it has been done within 4 weeks of 
study withdrawal) scheduled for the EOT visit (Day 673) at the time of 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:  
 Study terminated by sponsor1 
 Patient’s request  
 Screen failure  
 Patient’s unwillingness or inability to comply with the protocol 
 Death 
 Lost to follow-up  
 Adverse event 
                                                 
1 The sponsor may terminate this study 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 subject 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 SUBJECTS 
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 target muscle (TA or BB) as a series of up to 
4 equal-volume injections.  The use of EMG or ultrasound guidance will help to 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 approximately 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 IP Handling Guide. 
For Part 1 of this study, the dose and schedule will be 240 mg/muscle administered bilaterally by 
injection into the TA or BB muscles every 4 weeks for up to 6 doses.  
For Part 2, ACE-083 will be administered q4w for up to 24 months (24 doses) or q8w for up to 
24 months (12 doses).  Subjects who complete the Phase 1 loading phase treatment period will 
immediately be randomized into the 24-month maintenance phase. The planned dose schemes 
for Parts 1 and 2 are shown in Table 6 and Table 7. 
Table 6: Part 1: Loading Phase; N=Up to 54; ACE-083 240 mg/muscle bilaterally q4w 
Cohort 
Disease 
Muscle 
N 
1a 
FSHD 
Tibialis anterior (TA) 
Up to 18 
1b 
FSHD 
Biceps brachii (BB) 
Up to 18 
1c 
CMT 
Tibialis anterior (TA) 
Up to 18 
 
Table 7: Part 2: Maintenance Phase; N=Up to 150; ACE-083 240 mg/muscle bilaterally 
Cohort 
Disease 
Muscle 
Dose Interval 
N 
2a 
FSHD 
TA 
q4w 
Up to 23 
2b 
FSHD 
BB 
q4w 
Up to 23 
2c 
CMT 
TA 
q4w 
Up to 29 
3a 
FSHD 
TA 
q8w 
Up to 23 
3b 
FSHD 
BB 
q8w 
Up to 23 
3c 
CMT 
TA 
q8w 
Up to 29 

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10.1.1. 
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.  At 
the discretion of the investigator, dosing may resume upon resolution of the AE to ≤ grade 1 or 
baseline and dose may be reduced.  Dose delay and/or modification may be considered and 
implemented unilaterally or bilaterally.  Up to two dose reductions are permitted: from 
240 mg/muscle to 200 mg/muscle and from 200 mg/muscle to 150 mg/muscle.  Dose will not be 
reduced below 150 mg/muscle.  A maximum of 3 dose delays are allowed for subjects receiving 
q4w injections of ACE-083; only one dose delay is permitted for subjects in the q8w arm of Part 
2 of the study. 
10.2. 
 Safety Review Team  
An SRT, comprised at minimum of a principal investigator, medical monitor, and an independent 
neuromuscular specialist, will meet periodically (approximately every 3 months for the first six 
months, every six months thereafter) to review safety for each cohort.  The reviews will include 
all collected safety data and will begin when at least 10 subjects have received at least 3 doses of 
ACE-083. The SRT will review safety data, including AEs, laboratory results, and vital signs, to 
assess overall safety.  The SRT may request review of additional data including PD and efficacy 
measurements. 
Based on review of relevant data, the SRT will make one or more of the following 
recommendations: 
 Continue ACE-083 administration at the current dose 
 Reduce the dose for all subjects within a cohort, or for the study as a whole 
 Discontinue one or more cohorts, or the study as a whole 
Any changes in the dose level or schedule (e.g., continued treatment with q4w or q8w) in this 
study will be determined following review of study data and recommendations from the SRT.  
Further details on the role of the SRT are included in the SRT Guidelines. 
10.3. 
Concomitant Medications 
During screening and throughout the study, subjects may take stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol.  These medications include: 
single agent low dose aspirin (≤ 100 mg daily), intra-articular/topical/inhaled/intranasal 
physiologic doses of corticosteroids, and topical physiologic androgen replacement.  Any change 
in medications potentially affecting muscle strength or function (e.g., creatinine, CoQ10, or 
systemic beta adrenergic agonist) is not allowed.  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.  The investigator may consult the medical monitor regarding what constitutes a 
stable dose or a 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.   

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Subjects are not permitted to take the following: anticoagulation/platelet modifying therapies, 
systemic corticosteroids, systemic androgens, growth hormone, insulin, or estrogen ± 
progesterone hormone replacement therapy.  Additionally, patients must be withdrawn from 
study treatment if at any time during their participation they receive other investigational 
compound(s) or start any new experimental or approved therapies related to the treatment of 
CMT or FSHD.  This withdrawal excludes standard of care procedures and participation in 
observational research. 
10.4. 
Treatment Compliance 
Each dose of study drug will be administered via injections 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 extension study enrolling subjects from Study A083-02 part 1 and 
Study A083-03 part 1 and does not require randomization. 
Part 2: Subjects who have signed the informed consent and meet all eligibility criteria will be 
grouped by disease (FSHD or CMT) and target muscle (for FSHD; BB or TA) and then 
randomized to receive 240 mg/muscle bilateral ACE-083 either q4w or q8w.  The randomization 
scheme will be computer-generated and will be prepared by a statistical group designated by the 
sponsor.  
Because this study is an open-label extension of Studies A083-02 and A083-03, no blinding is 
necessary.  Subjects will retain the unique identifying number assigned to them in the previous 
study. 

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11. 
STUDY DRUG MATERIALS AND MANAGEMENT 
11.1. 
Study Drug 
Study drug is ACE-083.  ACE-083 is a recombinant fusion protein consisting of a modified form 
of human follistatin linked to a human IgG2 Fc domain.   
11.2. 
Study Drug Packaging and Labeling 
ACE-083 drug product is provided as a lyophilized powder contained in stoppered and sealed 
glass vials (64 mg/vial; nominal strength of each vial is 50 mg of ACE-083).  After 
reconstitution with 1.2 mL of sterile water for injection, 1.0 mL will deliver 50 mg ACE-083. 
11.3. 
Study Drug Storage 
ACE-083 should be stored as a lyophilized powder at °C until use.   
11.4. 
Study Drug Preparation 
Please refer to the IP Handling Guideline, provided separately, for detailed study drug handling, 
administration, and storage instructions.   
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 (subject-by-subject 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 management 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 
Subjects will be required to sign an independent ethics committee (IEC)/institutional review 
board (IRB)-approved ICF prior to the conduct of any study-related procedures, including 
screening evaluations. 
12.2. 
Study Assessments 
For each subject, 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 assessment include monitoring of adverse events, injection site reactions, concomitant 
medications, clinical laboratory assessments (including ADA), vital signs, and physical 
examination findings.  
If a subject has a positive ADA result at the last visit, the subject will be asked to return for 
additional ADA testing approximately every three months, until a negative result is obtained or 
the titer is no longer increasing. 
Please refer to Appendix 2 for the Clinical Laboratory Assessments that will be performed 
during this study. 
12.4. 
Efficacy Assessments 
Muscle strength: Muscle strength (maximum voluntary isometric contraction) measured by 
quantitative muscle testing (by handheld dynamometer) and manual muscle testing (MRC 
grade).  For subjects who receive BB treatment, elbow flexion will be assessed.  In TA-treated 
subjects, ankle dorsiflexion, plantar flexion, and knee extension will be assessed. 
Motor function tests: 10-meter walk/run, 6-minute walk test, 4-stair climb (subjects from 
A083-02 only), 100-meter timed test, and PUL  
Patient-reported health-related quality of life (QoL): FSHD-HI (FSHD patients) or CMT-HI (for 
CMT patients) total score and subscale scores 
12.5. 
Pharmacokinetic and Pharmacodynamic Assessments 
Pharmacokinetic assessments: ACE-083 serum concentrations (PK samples for subjects taking 
concomitant medications may be analyzed for changes in cytochrome P450 activity). 
Pharmacodynamic assessments 
Muscle assessments: Muscle volume and the intramuscular fat fraction of TA or BB muscles by 
MRI 
Biomarkers: including but not limited to: 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 AE is any untoward medical occurrence during the treatment period that 
occurs in a subject who has received a treatment in this protocol.  An AE does not necessarily 
have a causal relationship with treatment and can be any unfavorable and unintended sign, 
symptom, or disease (including an abnormal laboratory finding) temporally associated with the 
use of 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 (after the first dose in this protocol), 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 in a child of a subject that was exposed to study 
drug prior to conception or during pregnancy 
 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 guidance.    
13.2. 
Severity 
Investigators must evaluate the severity/intensity of AEs according to the CTCAE current 
version, 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 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. 
Subjects 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 
subjects 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 Dose 1 Day 1 are to be documented on 
the medical history CRF.  All AEs occurring on or after the Dose 1 Day 1 dose through Day 
701/End of Study visit 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 until resolution as described in Section 13.5.  
It is important that each AE report include a description of the event, duration (onset and 
resolution dates), severity, relationship to 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 in Part 1 until the End of Study visit 
in 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 13.5.  When new significant information is 
obtained as well as when the outcome of an event is known, the investigator should record the 
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. 

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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 subjects 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 subject 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 subjects 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 
subjects 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.  Subjects must be counseled 
about effective contraception at the beginning of this study and every three months thereafter 
until the EOS Visit.  
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 subject must discontinue study drug 
immediately.  Monitoring of the subject 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 contract research organization 
(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 IRB that approved the study. 
In accordance with 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 both serious and 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 subjects enrolled in the study who have received at least one dose 
of study drug; Part 2: All subjects randomized in the study 
Safety Population: All subjects enrolled/randomized in the study who have received at least one 
dose of study drug  
Per Protocol Set: All subjects enrolled/randomized in the study, who have received at least one 
dose of study drug with no CSR-reportable protocol violations and at least one post-baseline 
MRI evaluation 
Pharmacokinetic Population: All subjects 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 
This section and sections that follow outline planned statistical analyses and describe sample size 
considerations.  Further details will be provided in a separate statistical analysis plan. 
14.2.1. 
Patient Demographics and Disposition  
Individual demographic data will be listed by subject.   
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 (sex, race, ethnicity) by cohort/treatment 
regimen and overall for each study part (Part 1 and Part 2).  Age will be calculated based on birth 
date and informed consent date.  
Individual disposition data will be listed by subject.   
Frequency counts will be tabulated for disposition data and will consist of the number of subjects 
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 cohort as well as by treatment regimen and overall for each study part (Part 1 and 
Part 2). 
14.2.2. 
Drug Exposure 
Study drug administration data will be listed by subject.  Descriptive statistics of study drug 
exposure will be presented. 
14.2.3. 
Efficacy Data 
The primary analysis population for efficacy data will be the Per Protocol Set.  The secondary 
analysis population will be the Full Analysis Set. 
Efficacy parameters consist of the following: 

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 Muscle strength: Quantitative muscle testing (maximum voluntary isometric contraction 
[MVIC] by hand-held dynamometer) and manual muscle testing (MRC grade) of elbow 
flexion, ankle dorsiflexion, plantar flexion, and/or knee extension 
 Motor function tests: TA muscle function by 10-meter walk/run, 6-minute walk test, 
4-stair climb (subjects from A083-02 only), 100-meter timed test; BB muscle function by 
PUL test 
 Patient-reported health-related quality of life (QoL): FSHD-HI (for FSHD patients) or 
CMT-HI (for CMT patients) total score and subscale scores 
Part 1 
Individual efficacy data will be listed.  For muscle strength (as assessed by hand-held 
dynamometer [MVIC] and MMT assessment), the MVIC value as well as the decimal MMT-
MRC score will be derived for each side and the average of the two sides will be determined for 
each individual and scheduled time.  Decimal MMT-MRC scores will be derived from MMT-
MRC grades in the following way:  5 = 5.0, 5- = 4.67, 4+ = 4.33, 4 = 4.0, 4- = 3.67, 3+ = 3.33, 
3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 1=1.0.   
For the MVIC value for each side treated as well as the average of the left and right sides, 
decimal MMT-MRC score for each side treated as well as the average of the left and right sides, 
CMT-HI total score and selected subscale scores (CMT patients), FSHD-HI total score and 
subscale scores (FSHD patients) and motor function test assessments, raw data and changes from 
baseline (percent and absolute change) will be summarized for each scheduled time using 
descriptive statistics.  For each muscle strength, motor function test, and selected patient-
reported health-related quality of life parameters, a mixed model will be fitted and least squares 
estimates of the effect of ACE-083 and the corresponding 90% confidence interval will be 
provided for the percent and/or absolute change from baseline (depending on the parameter).  
Baseline is defined as the last non-missing value prior to first dose of study medication.  
Theoretically, this should be the Day 1 pre-dose value.  Additional analyses may be performed as 
appropriate. 
Part 2 
Individual efficacy data will be listed.  Descriptive statistics will be provided by cohort and 
scheduled time for raw data and changes from baseline.  Unless otherwise specified, baseline is 
defined to be the last non-missing value prior to first dose of the maintenance phase.  For 
assessments that are performed on the left and right sides, such as MVIC and decimal 
MMT-MRC scores (as described for Part 1 above), descriptive statistics will be provided for 
each side as well as the average of the left and right sides. 
For each muscle strength and motor function test parameters, a mixed model will be fitted and 
least squares estimates of the mean percent change from baseline to the first 6 months of the 
maintenance phase (Day 169) along with the corresponding 90% confidence interval will be 
provided for each treatment regimen for MVIC of ankle dorsiflexion (TA subject data – average 
of left and right sides), MVIC of elbow flexion (BB subject data – average of left and right 
sides), decimal MMT-MRC scores (including plantar flexion and knee extension, as appropriate; 
average of left and right sides), and each motor function test.  For each patient reported health-
related quality of life parameter (FSHD-HI total score and selected subscale scores [for FSHD 
subjects] and CMT-HI total score and selected subscale scores [for CMT subjects], a mixed 

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model will be fitted and least squares estimates of the mean absolute change from baseline to the 
first 6 months of the maintenance phase along with the corresponding 90% confidence interval 
will be provided for each treatment regimen for FSHD-HI total score and selected subscale 
scores [FSHD subject data] as well as for CMT-HI total score and selected subscale scores 
[CMT subject data].   
Least squares estimates of the mean percent or absolute change from baseline for each treatment 
regimen at other scheduled times during the maintenance phase along with the corresponding 
90% confidence interval may be provided as appropriate. 
Additional analyses may be performed as appropriate. 
14.2.4. 
Pharmacodynamic Data 
The primary analysis population for pharmacodynamic data will be the Per Protocol Set.  The 
secondary analysis population will be the Full Analysis Set. 
Pharmacodynamic parameters consist of the following: 
 Muscle assessments: Muscle volume and intramuscular fat fraction of TA or BB by MRI 
 Biomarkers: including, but not limited to, serum C-terminal collagen crosslinks (CTX) 
Part 1 
Individual pharmacodynamic data (e.g., total muscle volume, contractile muscle volume, 
intramuscular fat fraction, and biomarker data) will be listed.  For individual pharmacodynamic 
data that are measured on the left and right side, the average of the left and right side assessments 
will also be listed and summarized.  Descriptive statistics (raw data and change from baseline 
[percent and absolute change]) will be provided by cohort and scheduled time where baseline is 
defined to be the last non-missing assessment done prior to first dose.   
For the percent change in total muscle volume at 6-months from baseline, a mixed model will be 
fitted using the data from Part 1 as well as the data from the double-blind component of Part 2 of 
studies A083-02 and A083-03 and the loading dose treatment effect will be assessed.  Baseline is 
defined to be the last non-missing value prior to first dose of study medication.  The least squares 
mean difference for each loading dose regimen (q4w and q3w) vs. placebo and corresponding 
90% confidence interval will be provided where placebo subjects come from the double-blind 
component of Part 2 of A083-02 and A083-03.  This will also be provided by cohort.  If data 
from the 6-month (Day 169) visit are missing, the missing data mechanism will be investigated 
and an appropriate method for handling the missing data will be applied.  Sensitivity analyses 
will also be performed.   
For contractile muscle volume and intramuscular fat fraction, similar analyses as described 
above for total muscle volume will be provided.  For biomarker data (e.g., IGF-1 and CTX), raw 
data and changes from baseline (percent and absolute change) will be summarized by cohort and 
scheduled time. 
Additional analyses may be performed as appropriate. 
 
 

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Part 2 
Individual pharmacodynamic parameter data will be listed.  Descriptive statistics will be 
provided by cohort, treatment regimen and scheduled time for raw data and changes from 
baseline. 
The primary pharmacodynamic variable will be the difference in mean percent change in total 
muscle volume (average of left and right side) for the first 6 months of the maintenance phase 
(Day 169) from the total muscle volume (average of left and right sides) at the start of the 
maintenance phase (or equivalently the end of the loading phase).  An mixed model will be fitted 
to the data and a non-inferiority analysis will be performed using a non-inferiority margin of -5.  
The non-inferiority analysis will be done for each maintenance dose regimen (q4w and q8w).  
The lower bound of the one-sided 95% confidence interval will be used to assess non-inferiority.  
If data from the 6-month (Day 169) visit are missing, the missing data mechanism will be 
investigated and an appropriate method for handling the missing data will be applied.  Sensitivity 
analyses will also be performed.  In addition, using the same mixed model, the percent change in 
total muscle volume for the first 6 months of the maintenance phase (Day 169) from the start of 
the maintenance phase (or equivalently the end of the loading phase) will be compared between 
the two dosing regimens (q8w vs q4w).   
Secondary MRI pharmacodynamic variables include the difference in mean percent change for 
contractile muscle volume (average of left and right sides) as well intramuscular fat fraction 
(average of left and right sides) at the end of the first 6 months of the maintenance phase (Day 
169, q4w or q8w) from the start of the maintenance phase (or equivalently the end of the loading 
phase).  Secondary pharmacodynamic variables also include the percent and/or absolute (raw) 
change in biomarker variables such as CTX at the end of the first 6 months of the maintenance 
phase (Day 169).  For each secondary MRI pharmacodynamic variable, an mixed model will be 
fitted to the data and least square estimates of the mean difference and corresponding 90% 
confidence interval will be provided for each maintenance dose regimen.  If data from the 
6-month (Day 169) visit are missing, the missing data mechanism will be investigated and an 
appropriate method for handling the missing data will be applied.  Sensitivity analyses will also 
be performed.   
For biomarker data, a mixed model will be fitted and least-square estimates of the mean percent 
and/or absolute change from baseline for the first 6 months of the maintenance phase along with 
the corresponding 90% confidence interval will be provided for each maintenance dose regimen.  
If data from the 6-month (Day 169) visit are missing, the missing data mechanism will be 
investigated and an appropriate method for handling the missing data will be applied.  Sensitivity 
analyses will also be performed. 
Least square estimates of the mean percent or absolute change from the start of the maintenance 
phase (or equivalently the end of the loading phase) for other scheduled times during the 
maintenance phase along with the corresponding 90% confidence interval may be provided as 
appropriate.   
Additional analyses may be performed as appropriate.     

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14.2.5. 
Safety Data 
Unless otherwise specified, safety data will be summarized using descriptive statistics and 
individual safety data will be listed.  AEs will be coded using the current version of the Medical 
Dictionary for Regulatory Activities, and incidence of treatment-emergent AEs will be presented 
by system organ class and preferred term.  AE incidence rates will be described by cohort with 
and without regard to causality.  The frequency of occurrence of overall toxicity, categorized by 
toxicity grades (NCI-CTCAE, current version) will be summarized.  Change from baseline in 
clinical laboratory parameters, ECG, 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.   
14.2.6. 
Pharmacokinetic Data 
Individual serum ACE-083 concentrations will be listed and summarized by treatment group. 
Listings will also include dosing times and actual sampling times relative to dosing. Individual 
and mean concentration data versus time will also be presented graphically.  PK parameters of 
ACE-083 will be determined using the standard non-compartmental method.  Individual PK 
parameters will be listed and will be summarized by treatment group. 
14.2.7. 
Anti-drug Antibody Data 
Individual ADA data will be listed.  The results of ADA testing for ACE-083 over 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. 
14.3. 
Determination of Sample Size 
There was no formal sample size calculation for Part 1 or Part 2 of this study.   
The sample size for Part 1 is determined by how many subjects from Part 1 of Studies A083-02 
and A083-03 decide to participate in this study.  Similarly, the sample size for Part 2 is based 
upon how many subjects from Part 2 of Studies A083-02 and A083-03 and Part 1 of this study 
participate in Part 2 of this study. 
Non-inferiority of the q8w or q4w maintenance dose regimen during the first 6 months of the 
maintenance phase for the percent change in total muscle volume relative to the start of the 
maintenance phase (or equivalently the end of the loading phase – either from Part 2 of phase 2 
studies A083-02 and A083-03 or from Part 1 of this study) will be analyzed. 
Based on data from Parts 1 of Studies A083-02 and A083-03, it is assumed that the standard 
deviation is approximately 9.  A non-inferiority margin of -5 and a 0.05 significance level is 
used.  If 75 subjects per maintenance regimen participate and the observed mean percent change 
in total muscle volume at the first 6 months of the maintenance regimen from the start of the 
maintenance regimen is -2, the probability to conclude that the effect of any single maintenance 
regimen (q8w or q4w) is non-inferior is approximately 89%.  If 65 subjects per maintenance 
regimen participate and the observed mean percent change is -2, the probability to conclude that 
the effect of any single maintenance regimen (q8w or q4w) is non-inferior is approximately 85%.  
If 57 subjects per maintenance regimen participate, the probability is approximately 80%. 

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14.4. 
Interim Analysis 
Periodic reviews of the available safety and tolerability will be planned and reported to the SRT 
in accordance with the SRT charter.  During the course of Part 2, an interim analysis may be 
performed when some or all subjects have completed 6 months post start of the maintenance 
phase in order to assess adequacy of dosing regimens in this study and to plan for future studies 
with ACE-083.  Details will be described in the Statistical Analysis Plan. 
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. 
Subject Information and Consent  
Informed written consent is required from each subject 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 subjects.  It is the responsibility of the investigator to obtain consent and 
to provide the subject with a copy of the signed and dated ICF.  Confirmation of a subject’s 
informed consent must also be documented in the subject’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. 
Subject Data Protection  
Prior to any testing under this protocol, including screening tests and evaluations, subjects must 
authorize the release and use of protected health information, as required by local law.  
The subject 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/IRB, 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 subject 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 subject’s confidentiality will 
be maintained and will not be made publicly available.  The subject’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/IRB 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/IRB, as appropriate. 
 

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21. 
DATA HANDLING AND RECORDKEEPING 
21.1. 
Case Report Form Completion 
CRFs will be completed for each enrolled subject.  It is the investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data reported in the subject’s CRF.  Source 
documentation supporting the CRF data should indicate the subject’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 subjects 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. Glasser CE, Gartner MR, Wilson D, Miller B, Sherman ML, Attie KM. Locally acting ACE-
083 increases muscle volume in healthy volunteers. Muscle Nerve 2018;57:921-6. 
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. 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. 
9. 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. 
10. Barreto LC, Oliveira FS, Nunes PS, et al. Epidemiologic Study of Charcot-Marie-Tooth 
Disease: A Systematic Review. Neuroepidemiology 2016;46:157-65. 
11. Fridman V, Bundy B, Reilly MM, et al. CMT subtypes and disease burden in patients 
enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional 
analysis. J Neurol Neurosurg Psychiatry 2015;86:873-8. 
12. Pareyson D, Schenone A, Fabrizi GM, et al. A multicenter, randomized, double-blind, 
placebo-controlled trial of long-term ascorbic acid treatment in Charcot-Marie-Tooth disease 
type 1A (CMT-TRIAAL): the study protocol [EudraCT no.: 2006-000032-27]. Pharmacol Res 
2006;54:436-41. 
13. Sman AD, Hackett D, Fiatarone Singh M, Fornusek C, Menezes MP, Burns J. Systematic 
review of exercise for Charcot-Marie-Tooth disease. J Peripher Nerv Syst 2015;20:347-62. 
14. Daniels L, Worthingham C. Muscle testing : techniques of manual examination. 5th ed. 
Philadelphia: Saunders; 1986. 
15. Medical Research Council. Aids to the Investigation of Peripheral Nerve Injuries. London, 
England: Her Majesty's Stationary Office; 1976. 
 

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23. 
APPENDICES 

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APPENDIX 1.  
SCHEDULE OF EVENTS 
 

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Table 8: 
Schedule of Events for Part 1: Loading Phase 
* The L before the Dose in this table denotes that these doses occur in the Loading Phase. 
1 Study procedures must be done prior to administration of study drug.  Reference the Study Manual for the order of study procedures.  All visit-day windows should be considered relative to the date of 
the previous dose of ACE-083.  Actual visit days (e.g. Day 29, Day 57) may be different than planned due to windows on visits and dosing delays. 
2 Full physical examination during the screening period; limited physical examination for Days 1, 85.  
3 Vital signs (weight, heart rate, systolic and diastolic blood pressure) must be taken prior to administration of study drug on dosing days 
4 MRI should be completed within 5 days prior to scheduled dose administration, with the exception of the Day 1 MRI, which may be completed within 14 days prior to the Day 1 visit.  If performed on 
the same day as study drug administration, the subject should receive the MRI first. 
5 These function tests may be performed within 3 days prior to Day 1 visit. 
6 PK samples on dosing day have a ±15 minute window with the exception of the 24 h time point, which has a ± 2 window.  Pre-dose samples may be collected up to 4 h prior to dosing. 
7 ECG to be conducted ±1 hour of the 4h PK sample 
   
Screening 
Part 1: Loading Phase* 
Dose 
- 
L1 
L2 
L3 
L4 
L5 
L6 
Planned Day 
-28 to -1 
1 
 
29 
± 3d 
57 
± 3d 
85 
± 3d 
113 
± 3d 
141 
± 3d 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
X 
 
X 
 
Medical History 
X 
 
 
 
 
 
 
MMT assessment (MRC) 
X 
X 
 
 
X 
 
 
Full Physical examination2 
X 
 
 
 
 
 
 
Limited Physical examination2 
 
X 
 
 
X 
 
 
Injection site examination 
 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
 
Chemistry 
X 
X 
 
X 
 
X 
 
Urinalysis 
 
X 
 
X 
 
X 
 
Biomarkers 
 
X 
 
 
X 
 
 
Anti-drug antibody 
X 
X 
 
X 
 
X 
 
Serum PK6 
 
0,1, 2, 4, 24 h 
 
 
0,1, 2, 4, 24 h 
X 
X 
ECG (12 lead)7 
X 
X 
 
 
X 
 
 
Bilateral MRI4 
 
X 
 
 
X 
 
 
10MWR, 6MWT, 100mTT (all TA subjects); 4-stair 
climb (FSHD TA subjects); PUL (FSHD BB subjects)5 
X 
X 
 
 
X 
 
 
QMT assessment (MVIC by hand-held dynamometer)  
X 
X 
 
 
X 
 
 
FSHD-HI or CMT-HI 
X 
X 
 
 
X 
 
 
Monitoring of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Monitoring of adverse events 
X 
X 
X 
X 
X 
X 
X 
Study drug administration1 
 
X 
X 
X 
X 
X 
X 

Clinical Study Protocol 
 
ACE-083 
Study A083-04 
Revision: 00 
 
 
09 January 2019 
Acceleron Pharma Inc. 
Page 57 of 61 
CONFIDENTIAL 
Table 9: Schedule of Events for Maintenance Phase and Follow-up: q4w dosing arm 
  
Part 2: Maintenance Phase   
Follow-up Visits 
Planned Day(s) 
1 
± 3d 
29 
± 3d 
57 
± 3d 
85 
± d 
113 
± 3d 
141 
± 3d 
 169 
± 3d 
197-309 
± 3d 
337 
± 3d 
365-477 
± 3d 
505 
± 3d 
533-645 
± 3d 
ET 
673 
± 5d 
EOS 
701 
± 5d 
Dose number (q4w) 
1 
2 
3 
4 
5 
6 
7 
8-12 
13 
14-18 
19 
20-24 
Study Drug Administration1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
Urine pregnancy test 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
MMT assessment (MRC) 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
X 
Limited physical examination2 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
 
X 
Injection site examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
 
Chemistry 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
 
Urinalysis 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
 
Biomarkers 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Anti-drug antibody 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
X 
ECG (12 lead) 
X 
  
  
  
 X 
  
X 
  
X 
  
X 
  
X 
 
Bilateral MRI 4 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
 
10MWR, 6MWT, 100mTT (all TA 
subjects); 4-stair climb (FSHD TA 
subjects); PUL (FSHD BB subjects) 5 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
X 
QMT assessment (MVIC by hand-held 
dynamometer) 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
X 
CMT-HI/FSHD-HI 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Study procedures must be done prior to administration of study drug.  Reference the Study Manual for the order of study procedures. For subjects who enroll in A083-04 without treatment interruption, the Day 1 Dose 1 
(D1D1) visit may coincide with the ET visit of the base study (either A083-032 or A083-03).  For these subjects without treatment interruption, the D1D1 procedures shaded in grey may be conducted as part of the ET visit 
for Study A083-02 or A083-03 and may not need to be repeated for study A083-04. 
Visit schedule: All visit-day windows should be considered relative to the date of the previous dose of ACE-083.  Actual visit days (e.g. Day 29, Day 57, Day 85) may be different than planned due to windows on visits and 
potential dosing delays. 
2 Limited physical examination (skin, cardiovascular, respiratory, musculoskeletal, and neurological assessments) only.  
3 Vital signs (weight, heart rate, systolic and diastolic blood pressure) must be taken prior to administration of study drug on dosing days 
4 MRI assessments should be completed within 5 days prior to scheduled dose administration, with the exception of the Day 1 MRI, which may be completed within 14 days prior to the Day 1 visit.  If performed on the same 
day as study drug administration, the subject should receive the MRI first.  MRI assessments during the follow-up period have a ± 5-day window. 
5 These function tests may be performed within 3 days prior to Day 1 visit. 
 
 

Clinical Study Protocol 
 
ACE-083 
Study A083-04 
Revision: 00 
 
 
09 January 2019 
Acceleron Pharma Inc. 
Page 58 of 61 
CONFIDENTIAL 
Table 10: 
Schedule of Events for Maintenance Phase and Follow-up: q8w dosing arm 
 
Part 2: Maintenance Phase  
Follow-up 
Visits 
Planned Day(s) 
1 
57 
± 5d 
113 
± 5d 
169 
± 5d 
225 
± 5d 
281 
± 5d 
337 
± 5d 
393 
± 5d 
449 
± 5d 
505 
± 5d 
561 
± 5d 
617 
± 5d 
ET 
673 
± 5d 
EOS 
701 
± 5d 
Dose number (q8w) 
1 
2 
3 
4  
5 
6 
7 
8 
9 
10 
11 
12 
Study Drug Administration1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
Urine pregnancy test 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
MMT assessment (MRC) 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
X 
Limited physical examination2 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
X 
Injection site examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
 
Chemistry 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
 
Urinalysis 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
 
Biomarkers 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Anti-drug antibody 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
X 
ECG (12 lead) 
X 
  
 X 
X 
  
  
X 
  
  
X 
  
  
X 
 
Bilateral MRI 4 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
 
10MWR, 6MWT, 100mTT (all TA 
subjects); 4-stair climb (FSHD TA subjects); 
PUL (FSHD BB subjects)5 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
X 
QMT assessment (MVIC by hand-held 
dynamometer) 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
X 
CMT-HI/FSHD-HI 
X 
  
X 
X 
  
  
X 
  
  
X 
  
  
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1Study procedures must be done prior to administration of study drug.  Reference the Study Manual for the order of study procedures. For subjects who enroll in A083-04 without treatment 
interruption, the Day 1 Dose 1 (D1D1) visit may coincide with the ET visit of the base study (either A083-032 or A083-03).  For these subjects without treatment interruption, the D1D1 procedures 
shaded in grey may be conducted as part of the ET visit for Study A083-02 or A083-03 and may not need to be repeated for study A083-04. 
Visit schedule: All visit-day windows should be considered relative to the date of the previous dose of ACE-083.  Actual visit days (e.g. Day 29, Day 57, Day 113) may be different than planned due 
to windows on visits and potential dosing delays. 
2 Limited physical examination (skin, cardiovascular, respiratory, musculoskeletal, and neurological assessments) only.  
3 Vital signs (weight, heart rate, systolic and diastolic blood pressure) must be taken prior to administration of study drug on dosing days 
4 MRI assessments should be completed within 5 days prior to scheduled dose administration, with the exception of the Day 1 MRI, which may be completed within 14 days prior to the Day 1 visit.  If 
performed on the same day as study drug administration, the subject should receive the MRI first. MRI assessments during the follow-up period have a ± 5-day window. 
5 These function tests may be performed within 3 days prior to Day 1 visit. 

Clinical Study Protocol 
 
ACE-083 
Study A083-04 
Revision: 00 
 
 
09 January 2019 
Acceleron Pharma Inc. 
Page 59 of 61 
CONFIDENTIAL 
APPENDIX 2. CLINICAL SAFETY LABORATORY ASSESSMENTS 
Table 11: 
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    
Urinalysis 
Dipstick analysis (pH, specific gravity, protein, myoglobin, glucose, ketones, 
blood, leukocyte esterase, and nitrite) 
 

Clinical Study Protocol 
 
ACE-083 
Study A083-04 
Revision: 00 
 
 
09 January 2019 
Acceleron Pharma Inc. 
Page 60 of 61 
CONFIDENTIAL 
APPENDIX 3. 
MEDICAL RESEARCH COUNCIL MANUAL MUSCLE 
TESTING GRADING SCALE  
Grading Scale for Manual Muscle Testing (MMT)14,15  
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 resist 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 
 
For subjects who receive BB treatment, elbow flexion will be tested.  In TA-treated subjects, 
dorsiflexion, plantar flexion, and knee extension measurements will be taken. 
 
 

Clinical Study Protocol 
 
ACE-083 
Study A083-04 
Revision: 00 
 
 
09 January 2019 
Acceleron Pharma Inc. 
Page 61 of 61 
CONFIDENTIAL 
APPENDIX 4. 
PERFORMANCE OF THE UPPER LIMB