Clinical trial NCT03124459
Conditions: Charcot-Marie-Tooth Disease
Keywords: CMT1 / CMTX
Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Start date: 2017-07-31; Completion date: 2020-03-11
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with Charcot-Marie-Tooth Disease Type 1 and Type X (CMT1 and CMTX), to be conducted in two parts. Part 1 is non-randomized, open-label, dose-escalation and Part 2 is randomized, double-blind, and placebo-controlled.

Detailed description:
Part 1 (non-randomized, open-label, dose-escalation)

Part 1 will consist of up to 3 cohorts of 6 patients each and will evaluate multiple ascending dose levels of ACE-083 administered bilaterally once every 3 weeks for up to 5 doses in the tibialis anterior (TA) muscle. Patients in each cohort will be enrolled in a 4-week screening period before beginning treatment.

Part 2 (randomized, double-blind, placebo-controlled) Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted by the Safety Review Team (SRT) to determine the recommended dose level (maximum 250 mg/muscle). A total of up to 40 new patients may be enrolled and randomized (1:1 randomization) to receive either ACE 083 (n=20) or placebo (n=20) bilaterally by injection into both TA muscles once every 3 weeks for up to 17 doses.

Study duration for Parts 1 and 2 for each patient will be approximately 24 weeks, including a 4-week screening period, a 12-week treatment period, and an 8-week follow-up period after the last dose.

Study duration for Part 2 will be 15 months, including 4-week screening, 6 months double blind placebo-controlled, 6 months open-label and 8 week follow-up.

Arms: arm 1: ACE-083 150 mg intramuscular (IM) (tibialis anterior muscle), once every 3 weeks for up to 5 doses. arm 2: ACE-083 200 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses. arm 3: ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 5 doses. arm 4: ACE-083 up to 250 mg IM (tibialis anterior muscle) or placebo, once every 3 weeks for up to 9 doses arm 5: ACE-083 up to 250 mg IM (tibialis anterior muscle), once every 3 weeks for up to 8 doses
Interventions: intervention 1: ACE-083 intervention 2: Placebo
Intervention descriptions: intervention 1: Part 1 - Recombinant fusion protein. Part 2 - Recombinant fusion protein or buffer solution. intervention 2: Recombinant fusion protein or buffer solution

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase 2 Randomized, Double‐Blind, Placebo‐Controlled Study of ACE‐083 in Patients with 
Charcot‐Marie‐Tooth Disease Types 1 and X 
NCT Number:  NCT03124459 
Document Dates: Protocol Amendment/Version 3: 09‐Jan‐2019 
 


Clinical Study Protocol 
 
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1. 
TITLE PAGE 
 
 
Protocol A083-03 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of 
ACE-083 in Patients with Charcot-Marie-Tooth Disease Types 1 and X 
 
 
 
 
 
 
 
 
 
 
SPONSOR:  
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Tel: 617-649-9200 
Fax: 617-649-9988 
 
 
 
 
 
ORIGINAL PROTOCOL DATE:   
 
27 October 2016 
 
AMENDMENT 01 DATE:  
 
 
 
 
01 March 2018 
 
AMENDMENT 02 DATE:  
 
 
 
 
23 October 2018 
 
AMENDMENT 03 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 
 
 
  
 
 
 
 
Pharmacovigilance 
 
 
  
 
 
 
 
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 ......................................................................................................23 
5.1. 
Background .................................................................................................................23 
5.2. 
Study Rationale ...........................................................................................................24 
6. 
OBJECTIVES AND ENDPOINTS ............................................................................25 
7. 
STUDY DESIGN .......................................................................................................27 
7.1. 
Overview of Study Design ..........................................................................................27 
7.2. 
Justification for Dose Level ........................................................................................28 
7.3. 
Benefit/Risk Assessment ............................................................................................28 
8. 
STUDY POPULATION .............................................................................................29 
8.1. 
Inclusion Criteria ........................................................................................................29 
8.2. 
Exclusion Criteria .......................................................................................................30 
8.3. 
Screen Failures ............................................................................................................31 
9. 
DISCONTINUATION/ WITHDRAWAL CRITERIA ..............................................32 
9.1. 
Discontinuation of Study Treatment ...........................................................................32 
9.2. 
Withdrawal from the Study ........................................................................................32 
9.3. 
Lost to Follow Up .......................................................................................................33 
10. 
TREATMENT OF PATIENTS ..................................................................................34 
10.1. 
Treatments Administered ............................................................................................34 
10.1.1. 
Individual Dose Modification Rules ...........................................................................34 
10.2. 
Safety Review Team ...................................................................................................35 
10.3. 
Concomitant Medications ...........................................................................................35 
10.4. 
Treatment Compliance ................................................................................................36 
10.5. 
Randomization and Blinding ......................................................................................36 
11. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
11.1. 
Study Drug ..................................................................................................................38 


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11.2. 
Study Drug Packaging and Labeling ..........................................................................38 
11.3. 
Study Drug Storage .....................................................................................................38 
11.4. 
Study Drug Preparation ..............................................................................................38 
11.5. 
Study Drug Accountability .........................................................................................38 
11.6. 
Study Drug Handling and Disposal ............................................................................38 
12. 
STUDY PROCEDURES ............................................................................................39 
12.1. 
Written Informed Consent ..........................................................................................39 
12.2. 
Study Assessments......................................................................................................39 
12.3. 
Safety Assessments .....................................................................................................39 
12.4. 
Efficacy Assessments .................................................................................................39 
12.5. 
Pharmacokinetic and Pharmacodynamic Assessments ..............................................39 
13. 
SAFETY .....................................................................................................................40 
13.1. 
Definition of Adverse Events .....................................................................................40 
13.1.1. 
Adverse Event .............................................................................................................40 
13.1.1.1. 
Unexpected Adverse Events .......................................................................................40 
13.1.1.2. 
Events Not to Be Considered as Adverse Events .......................................................40 
13.1.1.3. 
Serious Adverse Event ................................................................................................40 
13.1.1.4. 
Events Not to Be Considered as Serious Adverse Events ..........................................41 
13.1.1.5. 
Suspected Unexpected Serious Adverse Reactions ....................................................41 
13.2. 
Severity .......................................................................................................................41 
13.3. 
Relationship to Study Drug ........................................................................................41 
13.4. 
Recording Adverse Events .........................................................................................42 
13.4.1. 
Documentation of Serious Adverse Events ................................................................42 
13.5. 
Reporting Adverse Events ..........................................................................................43 
13.6. 
Pregnancy ...................................................................................................................43 
13.7. 
Reporting Serious Adverse Events .............................................................................43 
13.7.1. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators ..........................................................44 
14. 
STATISTICS ..............................................................................................................45 
14.1. 
Analysis Populations ..................................................................................................45 
14.2. 
Statistical Analysis Considerations .............................................................................45 
14.2.1. 
Patient Demographics and Disposition .......................................................................45 
14.2.2. 
Drug Exposure ............................................................................................................45 


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14.2.3. 
Efficacy Data ..............................................................................................................45 
14.2.4. 
Pharmacodynamic Data ..............................................................................................47 
14.2.4.1. 
Pooled Analyses ..........................................................................................................49 
14.2.5. 
Safety Data ..................................................................................................................49 
14.2.6. 
Pharmacokinetic Data .................................................................................................49 
14.2.7. 
Anti-drug Antibody Data ............................................................................................49 
14.3. 
Determination of Sample Size ....................................................................................49 
14.4. 
Interim Analysis ..........................................................................................................50 
14.5. 
Deviation from Original Analysis Plan ......................................................................50 
15. 
ETHICS ......................................................................................................................51 
15.1. 
Institutional Review Board .........................................................................................51 
15.2. 
Ethical Conduct of the Study ......................................................................................51 
15.3. 
Patient Information and Consent ................................................................................51 
15.4. 
Patient Data Protection ...............................................................................................51 
16. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES .............................52 
16.1. 
Study Monitoring ........................................................................................................52 
16.2. 
Audits and Inspections ................................................................................................52 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................53 
17.1. 
Data Quality Control and Quality Assurance .............................................................53 
17.1.1. 
Investigator Responsibility .........................................................................................53 
17.1.2. 
Protocol Modifications ...............................................................................................53 
18. 
CONFIDENTIALITY ................................................................................................54 
19. 
PUBLICATION POLICY ..........................................................................................55 
20. 
PROTOCOL AMENDMENTS ..................................................................................56 
21. 
DATA HANDLING AND RECORDKEEPING .......................................................57 
21.1. 
Case Report Form Completion ...................................................................................57 
21.2. 
Retention of Records ..................................................................................................57 
22. 
REFERENCES ...........................................................................................................58 
23. 
APPENDICES ............................................................................................................59 
APPENDIX 1.  SCHEDULE OF EVENTS ................................................................................60 
APPENDIX 2. CLINICAL SAFETY LABORATORY ASSESSMENTS ................................64 
APPENDIX 3.   CHARCOT-MARIE-TOOTH DISEASE CLASSIFICATION .......................65 


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APPENDIX 4. MEDICAL RESEARCH COUNCIL MANUAL MUSCLE TESTING 
GRADING SCALE ....................................................................................................66 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms .............................................................................8 
Table 3: 
Objectives and Endpoints ...........................................................................................25 
Table 4: 
Cohort Schedule for Study A083-03 ..........................................................................34 
Table 5: 
Schedule of Events for Part 1: Non-Randomized, Open-Label, Dose 
Escalation ....................................................................................................................60 
Table 6: 
Schedule of Events for Part 2: Randomized, Double-Blind, 
Placebo-Controlled with Open-Label Extension ........................................................62 
Table 7: 
Clinical Safety Laboratory Assessments ....................................................................64 
 
 
 


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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 
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 
ECG 
Electrocardiogram 
EMG 
Electromyography 
FDA 
Food and Drug Administration 
FST 
Follistatin 
GCP 
Good clinical practice 
GDF8 
Growth and differentiation factor 8 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent ethics committee 
IGF-1 
Insulin-like growth factor-1  
IgG2 
Immunoglobulin G2 
IM 
Intramuscular 
IP 
Investigational product 
IRB 
Institutional review board 


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Abbreviation or Specialist Term Explanation 
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 
QoL 
Quality of life 
RF 
Rectus femoris 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
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: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in 
Patients with Charcot-Marie-Tooth Disease Types 1 and X 
Study Centers: Approximately 20 centers 
Phase of Development: 2 
Objectives 
Part 1 
Primary: 
 To evaluate the safety and tolerability of ACE-083 in patients with 
Charcot-Marie-Tooth (CMT) disease types 1 and X (CMT1 and CMTX) 
Secondary: 
 To determine the recommended dose level of ACE-083 for Part 2 
 To evaluate change in muscle volume and intramuscular fat fraction of the injected 
muscle 
 To evaluate change in strength of the injected muscle 
 To estimate the systemic exposure of ACE-083 when administered as a local muscle 
injection 
 To evaluate changes in motor function related to the injected muscle  
 To evaluate changes in physician-reported and patient-reported outcome measures 
Exploratory: 
 To evaluate changes in gait parameters  
 To evaluate changes in biomarkers 
Part 2 
Primary: 


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 To determine whether treatment with ACE-083 vs placebo increases muscle volume of 
the injected muscle in patients with CMT1 and CMTX 
      Secondary: 
 To determine whether treatment with ACE-083 vs. placebo decreases intramuscular fat 
fraction of the injected muscle 
 To determine whether treatment with ACE-083 vs. placebo increases strength of the 
injected muscle 
 To determine whether treatment with ACE-083 vs. placebo improves motor function 
related to the injected muscle 
 To determine whether treatment with ACE-083 vs placebo improves physician-
reported and patient-reported outcome measures 
 To evaluate the safety and tolerability of ACE-083 
 To estimate the systemic exposure of ACE-083 when administered as a local muscle 
injection 
Exploratory: 
 To evaluate changes in biomarkers 
 To evaluate changes in tibialis anterior (TA) compound muscle action potential 
(CMAP) 
 To evaluate changes in gait, activity level, and fall parameters  
 To evaluate changes in motor function via the 100-meter timed test 
Endpoints 
Part 1 
Primary: 
 Presence and nature of adverse events (AE) including injection site reactions and 
changes in clinical laboratory parameters 
Secondary: 
 Percent change from baseline in muscle volume of injected muscle by magnetic 
resonance imaging (MRI) 
 Percent and absolute change from baseline in intramuscular fat fraction of injected 
muscle by MRI 
 Percent change from baseline in strength measurements by maximum voluntary 
isometric contraction of ankle dorsiflexion measured by quantitative muscle testing  
 Pharmacokinetic (PK) parameters for ACE-083 serum concentrations over time 


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 Percent change from baseline in functional assessments: 10-meter walk/run, 6-minute 
walk test, Berg balance scale 
 Percent and absolute change from baseline in CMT examination score version 2 
(CMTES2) and CMT-health index (CMT-HI)  
Exploratory: 
 Percent and absolute change from baseline in gait parameters 
 Percent and absolute change from baseline in biomarkers 
Part 2 
Primary: 
 Percent change from baseline in muscle volume of injected muscle by MRI 
      Secondary: 
 Percent and absolute change from baseline in intramuscular fat fraction of the injected 
muscle by MRI 
 Percent change from baseline in strength measurements by maximum voluntary 
isometric contraction of ankle dorsiflexion measured by quantitative muscle testing 
 Percent change from baseline in functional assessments: 10-meter walk/run, 6-minute 
walk test, Berg balance scale 
 Percent and absolute change from baseline in CMTES2 and CMT-HI  
 Presence and nature of AEs including injection site reactions and changes in clinical 
laboratory parameters 
 Pharmacokinetic parameters for ACE-083 serum concentrations over time   
Exploratory: 
 Percent and absolute change from baseline in biomarkers 
 Percent and absolute change from baseline in TA CMAP amplitude  
 Percent and absolute change from baseline in gait parameters  
 Activity level and falls (PamSysTM wearable device) 
 Percent change from baseline in the 100-meter timed test 
Methodology 
This is a multicenter, phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), 
efficacy, and PK of ACE-083 in patients with CMT1 and CMTX, to be conducted in two parts.  
Part 1 is non-randomized, open-label, dose-escalation and Part 2 is randomized, double-blind, and 


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placebo-controlled.  Patients who have signed the informed consent form (ICF) and meet the 
eligibility criteria will be enrolled into the study. 
Study Design 
Part 1: N=Up to 18 (non-randomized, open-label, dose-escalation) 
Cohort 
ACE-083 Dose  
per Musclea 
ACE-083 
n 
1 
150 mg  
6 
2 
TBD up to 200 mgb 
6 
3  
TBD up to 250 mgb 
6 
 
Part 2: N=Up to 40 (6-month, randomized, double-blind, placebo-controlled, with 6-month 
open-label extension) 
 
6-month placebo controlled 
6-month open-label extension 
ACE-083 Dose 
per Musclea 
ACE-083 
n 
Placebo 
n 
ACE-083 
n 
TBD up to 250 mgb 
20 
20 
40 
a Administered bilaterally by injection into the tibialis anterior muscle once every 3 weeks  
b Dose level to be based on recommendations from the Safety Review Team (SRT)  
Part 1 (non-randomized, open-label, dose-escalation) 
Part 1 will consist of up to 3 cohorts of 6 patients each and will evaluate multiple ascending dose 
levels of ACE-083 administered bilaterally once every 3 weeks for up to 5 doses in the tibialis 
anterior (TA) muscle.  Patients in each cohort will be enrolled in a 4-week screening period before 
beginning treatment.  
For Cohort 1, the dose level will be 150 mg/muscle administered bilaterally.   
For Cohort 2, the dose level will be based on review of safety data and recommendations made by 
the Safety Review Team (SRT).  The planned dose level for Cohort 2 is 200 mg/muscle 
administered bilaterally.  
For Cohort 3, the decision to enroll patients and the dose level will be based on recommendations 
of the SRT following review of safety and, as necessary, imaging data for prior cohorts.  The 
maximum possible dose level for Cohort is 250 mg/muscle administered bilaterally. 


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Part 2 (randomized, double-blind, placebo-controlled) 
Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted 
by the SRT to determine the recommended dose level (maximum 250 mg/muscle).  A total of up 
to 40 new patients may be enrolled and randomized (1:1 randomization) to receive either 
ACE-083 (n=20) or placebo (n=20) bilaterally by injection into both TA muscles.  Patients will 
receive blinded study drug once every 3 weeks for approximately 6 months (9 doses).   
Patients who complete the double-blind treatment period, will immediately roll over to open-label 
treatment with ACE-083, receiving the same dose of active drug, bilaterally in the TA muscle, 
once every 3 weeks for approximately 6-months (8 doses). In Part 2, the SRT will periodically 
review blinded safety data for each muscle treated.  
Number of Patients (planned) 
Up to 18 patients will be enrolled in Part 1 of the study (dose-escalation, non-randomized, 
open-label) and up to 40 patients (20 active, 20 placebo) will be enrolled in Part 2 (randomized, 
double-blind, placebo-controlled, with open-label extension) for a total of up to 58 patients.  Up to 
40 patients participating in the double-blind treatment period of Part 2 will participate in the open-
label extension all of which (including those on placebo during the double-blind treatment period) 
will receive the same dose of ACE-083 administered during the double-blind treatment period. 
Diagnosis and Main Criteria for Eligibility 
Inclusion Criteria: 
1. Age ≥ 18 years 
2. Diagnosis of CMT1 or CMTX confirmed by: 
a. Clinical presentation and electrodiagnostics  
b. Genetically-confirmed CMT1 or CMTX (Appendix 3) for the patient or first-degree  
relative   
3. Part 1:  
a. Six-minute walk distance (6MWD) of at least 150 meters (without a brace or 
walker) 
b. Independent ambulation for at least 10 meters, without a brace  
c. Left and right ankle plantar flexion MRC grade 4+ to 5, inclusive  
Part 2:  
a. 6MWD ≥ 150 and ≤ 500 meters  (without a brace or walker); a maximum of 20% 
of enrolled patients with 6MWD ≥ 450 meters will be included 
b. Left and right ankle plantar flexion MRC grade 4- to 5, inclusive 


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4. Left and right ankle dorsiflexion Medical Research Council (MRC) manual muscle testing 
(MMT) grade 3 to 4+, inclusive (Appendix 4).  No more than 12 of the 40 enrolled 
subjects may have a grade of 3 or 3+ on one or both sides. 
5. Females of childbearing potential (defined as sexually mature women who have not 
undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal 
≥ 24 consecutive months) must have negative urine pregnancy test prior to enrollment and 
use highly effective birth control methods (abstinence, oral contraceptives, barrier method 
with spermicide, or surgical sterilization) during study participation and for 8 weeks 
following the last dose of ACE-083.  Hormonal birth control use must be stable for at least 
14 days prior to Day 1.  Males must agree to use a condom during any sexual contact with 
females of childbearing potential while participating in the study and for 8 weeks 
following the last dose of ACE-083, even if he has undergone a successful vasectomy.  
Patients must be counseled concerning measures to be used to prevent pregnancy prior to 
the first dose of ACE-083. 
6. Ability to adhere to the study visit schedule/procedures, and to understand and comply 
with protocol requirements 
7. Signed written informed consent 
Exclusion Criteria: 
1. Current/active malignancy (e.g., remission less than 5 years’ duration), with the exception 
of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 
squamous cell carcinomas of the skin  
2. Symptomatic cardiopulmonary disease, significant functional impairment, significant 
orthopedic or neuropathic pain, or other co-morbidities that in the opinion of the 
investigator would limit a patient’s ability to complete strength and/or functional 
assessments on study 
3. 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 assessment of dorsiflexion strength  
9. Major surgery within 4 weeks prior to Study Day 1 


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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 investigational agent 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. Any previous or current exposure to ACE-083 
15. 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 
16. Any condition that would prevent MRI scanning or compromise the ability to obtain a 
clear and interpretable scan of the lower leg, as applicable (e.g., knee/hip replacement  
metallic implants) 
17. Known active substance abuse, including alcohol 
18. History of sensitivity to protein pharmaceuticals 
19. Female that is 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.  After reconstitution with 1.2 mL of sterile water, the ACE-083 drug product solution 
for injection has a concentration of 50 mg/mL.  The nominal strength of each vial is 50 mg of 
ACE-083.  
Using electromyography (EMG) or ultrasound guidance, each dose of ACE-083 will be 
administered into the non-tendinous portion of the TA as a series of up to 4 equal-volume 
injections.  The use of EMG or ultrasound guidance will ensure that viable muscle is present at the 
injection site.  If the degree of atrophy or fibro-fatty infiltration poses administration challenges, 
injections of ACE-083 should be distributed 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 for both Parts 1 and 2 is 250 mg/muscle administered 
bilaterally by injection into the left and right TA muscles every 3 weeks for up to 5 doses (actual 
dose levels to be based on recommendations of the SRT). 


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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 may be reduced to the previously tolerated dose (i.e. from 240 to 200 mg or from 200 
to 150 mg).  Dose will not be reduced to below 100 mg (Part 1) or 150 mg (Part 2).  
Duration of Treatment 
Study duration for a patient enrolled in Part 1 will be approximately 24 weeks, including a 4-week 
screening period, a 12-week treatment period, and an 8-week follow-up period after the last dose. 
Study duration for a patient enrolled in Part 2 will be approximately 15 months, including a 
4-week screening period, a 12-month treatment period (6-month double-blind, placebo controlled 
and a 6-month open-label extension), and an 8-week follow-up period after the last dose.  If a 
patient has a positive anti-drug antibody (ADA) result at the last visit, the patient will be asked to 
return for additional ADA testing approximately every 3 months, until a negative result is obtained 
or the result is considered to be stabilized. 
Reference Therapy, Dosage, and Mode of Administration 
The placebo (control agent) to be used in Part 2 of this study will be sterile normal saline (0.9% 
sodium chloride for injection).  Sterile normal saline will be supplied by the investigational site’s 
pharmacist.  The manufacturer’s directions for saline storage and handling are to be followed, as 
are standard clinical practices for ensuring sterility.  Saline-filled syringes will be prepared by 
unblinded study personnel and provided to blinded study personnel for administration. 
Placebo will be administered using EMG or ultrasound guidance into the non-tendinous portion of 
the TA as a series of up to 4 equal-volume injections.  If the degree of atrophy or fibro-fatty 
infiltration poses administration challenges, injections of placebo 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. 
Safety Assessment: 
Dose-Limiting Toxicity (DLT) Definition:  
 A serious adverse event (SAE), possibly or probably related to study drug 
OR 
 An adverse event (AE), injection site reaction, laboratory parameter abnormality, or 
vital sign abnormality, possibly or probably related to study drug, and either grade ≥ 3 
(National Cancer Institute-Common Terminology Criteria for Adverse Events 
[NCI-CTCAE], current version) or grade ≥ 2 and considered clinically significant. 
Part 1 Dose Escalation Stopping Rules (under SRT review):  


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Dosing at current levels will continue unless the following condition occurs: 
 ≥ 2 DLTs of the same character in a cohort 
Safety Review Team: 
An SRT, comprised at minimum of a principal investigator, medical monitor, and an independent 
neuromuscular specialist, will meet to review safety and, as needed, imaging data, for each cohort.  
The review will include all collected safety data (and, as necessary, imaging data) when at least 4 
patients in a cohort have completed at least their Day 22 visit.  For both parts of the study, the 
SRT safety data will include, but not be limited to, AEs, laboratory results (including hematology, 
chemistry, and urinalysis) and vital signs data to assess for DLTs and overall safety.  The SRT 
may request review of additional data collected in currently enrolled patients. 
Based on review of relevant data, the SRT will make one or more of the following 
recommendations: 
 Continue enrollment of remaining patients in the current cohort at the current dose 
level 
 Open next cohort in Part 1 or open Part 2 of the study at a recommended dose (higher 
or lower dose level) 
 Discontinue one or more cohorts in Part 1, or the study as a whole 
SRT recommendations for dose escalation in Part 1 will be based in part upon the dose escalation 
stopping rules.  If a stopping rule is met, a lower intermediate dose may be recommended or the 
previous dose level will be considered the maximally tolerated dose (MTD).  The SRT may also 
recommend no further enrollment in the presence of AEs that do not meet dose stopping rules if 
the nature of these AEs is deemed a significant risk to patients in a given cohort.  
For Part 2, the SRT will periodically review blinded preliminary safety data. Further details on the 
role of the SRT during Part 2 are included in the SRT Guidelines.  
Assessments for Evaluation: 
Safety: AEs, injection site reactions, concomitant medications, clinical laboratory tests (including 
hematology, chemistry, and ADA), urinalysis, vital signs, physical examination findings   
Pharmacokinetics: ACE-083 serum concentrations 
Pharmacodynamics:  
Muscle assessments: Muscle volume and intramuscular fat fraction of TA by MRI; CMAP of TA 
Biomarkers: including but not limited to: insulin-like growth factor-1 (IGF-1), serum C-terminal 
collagen crosslinks (CTX) 
Efficacy:  
Muscle strength: Muscle strength (maximum voluntary isometric contraction [MVIC]) of ankle 
dorsiflexion measured by quantitative muscle testing (by handheld dynamometer) 


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Motor function tests: 10-meter walk/run, 6-minute walk test, 100-meter timed test (Part 2 open 
label), gait, activity and fall parameters, Berg balance scale 
Physician-reported functional rating scale: CMTES2 
Patient-reported health-related quality of life (QoL): CMT-HI 
Statistical Methods: 
Sample Size Calculation:  
Part 1 
There is no formal sample size calculation for Part 1.  Six patients in each cohort will provide 
sufficient data to evaluate safety and to make a preliminary assessment of changes in muscle 
volume and muscle strength. 
Part 2   
The sample size calculation for Part 2 is based upon the expected percent change from baseline in 
total muscle volume of the injected TA 3 weeks after the last dose.  A 10% difference between 
ACE-083-treated and placebo groups in the percent change in total muscle volume from baseline 
is considered to be clinically meaningful.  The standard deviation (SD) is estimated to be 
approximately 10% for each group based on preliminary MRI data for the ACE-083-treated side 
of the TA muscle from Part 1 of the Phase 2 study in FSHD patients.  
Assuming a 2-sided type 1 error rate of 0.10, a 10% difference in percent change from baseline 
between the ACE-083-treated and placebo groups in total muscle volume, a SD of 10% for each 
group, and a 1:1 randomization, 90% power is achieved with a total sample size of n=36 patients 
(18 active, 18 placebo), based on a standard t-test.   
In addition, this sample size provides 90% power to detect a 10% difference in 6MWD, based on 
an assumed estimated SD of 10% (based off of available data from Part 1 of the Phase 2 study in 
FSHD patients as well as available data from Part 1 of this study) and a 2-sided type 1 error rate of 
0.1. 
In order to account for dropouts (up to 10%), 40 patients will be randomized to study treatment 
(20 active, 20 placebo) to ensure that at least 18 patients per treatment group complete the double-
blind treatment period. 
Analysis Populations: 
Full Analysis Set: Part 1: All patients enrolled in the study and who have received at least one 
dose of study drug; Part 2: All patients randomized in the study 
Safety Population: All patients enrolled/randomized in the study who have received at least one 
dose of study drug (including placebo) 
Per Protocol Set: All patients enrolled/randomized in the study, who have received at least one 
dose of study drug (including placebo) with no CSR-reportable protocol violations and at least one 
post-baseline MRI evaluation 


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Pharmacokinetic Population: All patients who have received at least one dose of study drug and 
have sufficient PK samples collected and assayed for PK analysis 
Statistical Analysis:  
Details regarding the final data analysis will be described in a separate statistical analysis plan. 
Part 1  
Safety: Unless otherwise specified, safety data will be summarized using descriptive statistics and 
individual safety data will be listed.  AEs will be coded using the Medical Dictionary for 
Regulatory Activities.  Incidence of treatment-emergent AEs will be presented by system organ 
class and preferred term.  AE incidence rates will be described by cohort 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 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.      
Efficacy: Individual efficacy data will be listed.  For muscle strength (as assessed by handheld 
dynamometer), the MVIC will be derived for each side and the average MVIC [from the left and 
right sides] will be determined for each individual patient and scheduled time.  For the MVIC 
value for each side treated as well as the average from the left and right sides, CMTES2 score, 
CMT-HI total score and selected subscale scores, and motor function test assessments, raw data 
and changes from baseline (percent and absolute change) for the injected muscle will be 
summarized for each scheduled time using descriptive statistics.  For each efficacy variable, a 
repeated measures analysis of covariance (ANCOVA) model will be fitted and least squares 
estimates of the effect of ACE-083 and the corresponding 90% confidence intervals will be 
provided for the percent change from baseline.  For muscle strength parameters, the change from 
the screening to baseline value will serve as the control for each cohort and will be summarized 
together with post-baseline data.   
Pharmacokinetic: Listings of individual patient serum ACE-083 concentrations, actual blood 
sampling times, and PK parameters including graphs of concentration versus time will be prepared 
by dose level.  PK parameters of ACE-083 will be determined using the standard 
non-compartmental method.  Descriptive statistics of PK parameters will be summarized by 
treatment group. 
Pharmacodynamic: Individual pharmacodynamic data (e.g., muscle volume, intramuscular fat 
fraction, and biomarker data) will be listed.  For individual pharmacodynamic data that are 
measured on the left and right side (e.g., MRI), the average of the left and right side assessments 
will also be listed and summarized.  This will also be done for Part 2.  Descriptive statistics (raw 
data and change from baseline [percent and absolute change]) will be provided by treatment group 
and scheduled time.  For muscle volume and intramuscular fat fraction, estimates of the effect of 
ACE-083 and corresponding 90% confidence intervals 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 treatment group and scheduled time. 
 


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Part 2 
Pharmacodynamic: Individual pharmacodynamic parameter data will be listed. 
The primary pharmacodynamic parameter will be the percent change in total muscle volume 
(average of left and right side) 3 weeks after the last dose of the double-blind treatment period 
(Day 190) from the corresponding baseline.  A mixed model will be used to assess the treatment 
effect (ACE-083 vs. placebo) using a 2-sided 0.10 significance level.  If data from the end of 
treatment visit are missing, the last observation will be carried forward.  Additional techniques for 
handling missing data will also be evaluated as sensitivity analyses to the last observation carried 
forward approach.   
Least squares estimates of the effect of ACE-083 and the corresponding 90% confidence interval 
will be produced.  Descriptive statistics for the percent change in total muscle volume from 
baseline will be provided for each treated side as well as the average of the left and right side by 
treatment for each scheduled time.   
For secondary pharmacodynamic parameters, descriptive statistics will be provided by treatment 
and scheduled time.  In addition, a mixed  model will be used to assess the treatment effect using a 
2-sided 0.10 significance level for the following secondary pharmacodynamic variables: percent 
change from baseline for the average of the left and right side at 3 weeks after the last dose of the 
double-blind treatment period (Day 190) for muscle volume and intramuscular fat fraction as well 
as derived variables such as contractile muscle fraction and contractile muscle volume.  Least 
squares estimates of the effect of ACE-083 and corresponding 90% confidence interval will be 
provided. 
For biomarker data (e.g., IGF-1 and CTX) as well as TA CMAP amplitude, raw data and changes 
from baseline (percent and absolute change) will be summarized by treatment group and 
scheduled time.   
Safety: Same as in Part 1  
Efficacy: Individual efficacy data will be listed.  For muscle strength, the MVIC value will be 
derived for each side and the average MVIC value [from the left and right sides] will be 
determined for each individual patient and scheduled time.  For the MVIC value for each side 
treated as well as the average from the left and right sides, CMTES2 score, CMT-HI total score 
and selected subscale scores, and motor function test assessments, raw data and the absolute and 
percent change from baseline will be summarized by treatment for each scheduled time using 
descriptive statistics.  In addition, a mixed model will be used to assess the treatment effect 
(ACE-083 vs. placebo) using a 2-sided 0.10 significance level for the percent change from 
baseline.  Least squares estimates of the treatment effect and corresponding 90% confidence 
intervals will be provided.   
Pharmacokinetic: Same as in Part 1  
Anti-drug antibody data (Parts 1 and 2): 
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 


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performed on the potential effect of ADA on ACE-083 PK exposure if ADA tests are determined 
to be positive. 
Part 1 and Part 2 Pooled Analysis: If applicable, similar analyses will be performed for pooled Part 
1 and 2 data for patients at the same dose level.  Pooling by the estimated local dose of ACE-083 
in the injected muscle (i.e., mg ACE-083/g muscle) may also be performed. 


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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 in body tissues.2  Growth 
and differentiation factor 8 (GDF8), also known as myostatin, is a powerful negative regulator of 
skeletal muscle development and growth.3  Inhibition of the modulating effects of both activin 
and myostatin on skeletal muscle growth has been identified as a promising therapeutic approach 
for degenerative diseases of skeletal muscle.4  Unlike myostatin, in which the expression and site 
of action is primarily restricted to skeletal muscle, activin is produced in many different tissues 
and mediates a wide range of biologic processes in animals and humans, throughout all stages of 
development.5  The challenge for therapeutic intervention in muscle diseases, therefore, has been 
in the selective inhibition of activin/myostatin activity only in the target tissue (i.e., skeletal 
muscle) in order to prevent or minimize undesirable off-target effects due to broad systemic 
inhibition of activin.  ACE-083 has been engineered and developed as a locally-active ligand trap 
of activin and myostatin in addition to other ligands.  The properties of ACE-083 are such that, 
when administered by IM injection, the drug remains primarily within the injected muscle(s) to 
increase mass and strength of the particular muscle(s).  
As described in the ACE-083 Investigator’s Brochure (IB), a number of nonclinical 
pharmacology studies have been conducted with ACE-083 to define the ligand-binding 
properties of the molecule and assess its anabolic effects on skeletal muscle in normal animals 
and in a mouse model of muscle disease.  Preclinical studies in normal mice and rats have 
demonstrated increased muscle mass as a result of increased fiber hypertrophy and not 
hyperplasia.  This ACE-083-induced muscle hypertrophy has also been shown to translate to 
functional improvement in muscle strength in normal mice.  ACE-083 has also been evaluated in 
a well-established mouse model of human Duchenne muscular dystrophy as representative of a 
degenerative muscle disorder 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 a degenerative skeletal muscle disease. 
In addition, Study A083-01, a Phase 1, double-bind, placebo-controlled, dose-ranging study 
designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of local 
muscle injections of ACE-083 in healthy postmenopausal women has been completed.  
Forty -two subjects have received ACE-083 at dose levels of 50 to 200 mg administered as single 
or multiple injections into either the right rectus femoris or right tibialis anterior muscle.  
ACE-083 was generally safe and well tolerated in this study with no serious adverse events or 
grade ≥ 3 AEs reported.  A significant dose-dependent change in volume of the injected muscle 
has been seen in the treated versus placebo group.  


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5.2. 
Study Rationale 
Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth (CMT) 
disease, is the most common form of hereditary neuropathy with a prevalence of 1 in 2500 
individuals or about 125,000 people.6  A specific mutation in one of several myelin genes results 
in defects in myelin structure, maintenance, and formation.  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 are the second most common form of CMT and account for 
approximately 10 to 15 percent of cases.7 
Patients with CMT typically present with both motor and sensory nerve manifestations, distal leg 
weakness, foot deformities (pes cavus, hammer toes), and sensory deficits.  Involvement of the 
hands may also follow as the patient progresses.  Weakness in the lower leg manifests as “foot 
drop” and patients have difficulty lifting their toes during ambulation.  As this weakness 
progresses, patients begin to lose mobility and are at increased risk for falls and injury.   
To date, treatment of CMT has been restricted to symptomatic interventions.  Although some 
clinical and pharmacological trials have been performed, the results have not been encouraging.8 
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 has been shown to successfully treat deformities of the foot as well 
as foot drop but it is a more invasive option and not always an appropriate intervention in every 
case.  In some patients, exercise is the recommended therapy but it is still uncertain whether 
exercise should be considered safe for the general CMT population and, if so, how the frequency, 
timing, and type of exercise should be selected for each patient.9 
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.  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 muscle 
that is contributing to functional limitations.  In CMT patients with lower limb weakness and 
atrophy of the TA, an increase in TA muscle volume has the potential to increase strength and 
function associated with ankle dorsiflexion, which could improve a patient’s mobility and 
ultimately their quality of life. 
 


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6. 
OBJECTIVES AND ENDPOINTS 
Table 3: 
Objectives and Endpoints  
Part 1 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability of 
ACE-083 in patients with CMT1 and 
CMTX 
 
Presence and nature of AEs including 
injection site reactions and changes in 
clinical laboratory parameters 
Secondary 
 
To determine the recommended dose level 
of ACE-083 for Part 2 
 
Recommendation from SRT 
 
To evaluate change in muscle volume and 
intramuscular fat fraction of the injected 
muscle 
 
Percent change from baseline in muscle 
volume of injected muscle  
 
Percent and absolute change from baseline in 
intramuscular fat fraction of injected muscle  
 
To evaluate change in strength of the 
injected muscle 
 
Percent change from baseline in strength 
measurements by maximum voluntary 
isometric contraction of ankle dorsiflexion 
measured by quantitative muscle testing  
 
To estimate the systemic exposure of 
ACE-083 when administered as a local 
muscle injection 
 
PK parameters for ACE-083 serum 
concentrations over time 
 
To evaluate changes in motor function 
related to the injected muscle 
 
Percent change from baseline in functional 
assessments 
 
To evaluate changes in physician-reported 
and patient-reported outcome measures 
 
Percent and absolute change from baseline in 
CMTES2 and CMT-HI 
Exploratory 
 
To evaluate changes in gait parameters 
 
 
To evaluate changes in biomarkers 
 
 
Percent and absolute change from baseline in 
gait parameters 
 
Percent and absolute change from baseline in 
biomarkers 
 
 
 


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Part 2 
Objectives 
Endpoints 
Primary 
 
To determine whether treatment with 
ACE-083 vs placebo increases muscle 
volume of the injected muscle in patients 
with CMT1 and CMTX 
 
Percent change from baseline in muscle 
volume of injected muscle by MRI 
Secondary 
 
To determine whether treatment with 
ACE-083 vs placebo decreases 
intramuscular fat fraction of the injected 
muscle 
 
Percent and absolute change from baseline 
in intramuscular fat fraction of the injected 
muscle by MRI 
 
To determine whether treatment with 
ACE-083 vs placebo increases strength of 
the injected muscle 
 
Percent change from baseline in strength 
measurements by maximum voluntary 
isometric contraction of ankle dorsiflexion 
measured by quantitative muscle testing  
 
To determine whether treatment with 
ACE-083 vs placebo improves motor 
function related to the injected muscle 
 
Percent change from baseline in functional 
assessments 
 
To determine whether treatment with 
ACE-083 vs placebo improves physician-
reported and patient-reported outcome 
measures 
 
Percent and absolute change from baseline 
in CMTES2 and CMT-HI 
 
To evaluate the safety and tolerability of 
ACE-083 
 
Presence and nature of AEs including 
injection site reactions and changes in 
clinical laboratory parameters 
 
To estimate the systemic exposure of 
ACE-083 when administered as a local 
muscle injection 
 
PK parameters for ACE-083 serum 
concentrations over time 
Exploratory 
 
To evaluate changes in biomarkers 
 
Percent and absolute change from baseline 
in biomarkers 
 
To evaluate changes in TA compound 
muscle action potential (CMAP) 
 
Percent and absolute change from baseline 
in TA CMAP amplitude 
 
To evaluate changes in gait, activity level 
and fall parameters  
 
To evaluate changes in motor function via 
the 100-meter timed test 
 
Percent and absolute change from baseline 
in gait parameters 
 
Activity level and falls (PamSysTM wearable 
device)  
 
Percent change from baseline in the 100-
meter timed test 


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7. 
STUDY DESIGN 
7.1. 
Overview of Study Design 
Study A083-03 is a multicenter, Phase 2 study to evaluate the safety, tolerability, 
pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with 
CMT1 and CMTX, to be conducted in two parts.  Part 1 is non-randomized, open-label, and 
dose-escalation; Part 2 is randomized, double-blind, and placebo-controlled.  Patients who have 
signed the informed consent form (ICF) and meet the eligibility criteria will be enrolled into the 
study.   
Duration of Treatment  
Study duration for a patient enrolled in Part 1 will be approximately 24 weeks, including a 
4-week screening period, a 12-week treatment period, and an 8-week follow-up period after the 
last dose.  Study duration for a patient enrolled in Part 2 will be approximately 15 months, 
including a 4-week screening period, a 12-month treatment period (6-month double-blind, 
placebo controlled and a 6-month open-label extension), and an 8-week follow-up period after 
the last dose.  
If a patient has a positive anti-drug antibody (ADA) result after the last visit, the patient will be 
asked to return for additional ADA testing approximately every 3 months, until a negative result 
is obtained or the result is considered to be stabilized.  
Part 1 (non-randomized, open-label, dose-escalation) 
Part 1 will consist of up to 3 cohorts of 6 patients each and will evaluate multiple ascending dose 
levels of ACE-083 administered bilaterally once every 3 weeks for up to 5 doses in the tibialis 
anterior (TA) muscle.  Patients in each cohort will be enrolled in a 4-week screening period 
before beginning treatment.  
For Cohort 1, the dose level will be 150 mg/muscle administered bilaterally.   
For Cohort 2, the dose level will be based on review of safety data and recommendations made 
by the Safety Review Team (SRT).  The planned dose level for Cohort 2 is 200 mg/muscle 
administered bilaterally.  
For Cohort 3, the decision to enroll patients and the dose level will be based on 
recommendations of the SRT following review of safety and, as necessary, imaging data for 
prior cohorts.  The maximum possible dose level for Cohort is 250 mg/muscle administered 
bilaterally. 
The SRT will provide recommendations to the sponsor regarding the conduct of the current or 
subsequent cohorts in the study (e.g., dose level) as described in Section 7.2 below. 
Part 2 (randomized, double-blind, placebo-controlled) 
Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted 
by the SRT to determine the recommended dose level (maximum 250 mg/muscle).  A total of up 
to 40 new patients may be enrolled and randomized (1:1 randomization) to receive either 


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ACE-083 (n=20) or placebo (n=20) bilaterally by injection into both TA muscles. Patients will 
receive blinded study drug once every 3 weeks for approximately 6 months (9 doses).  
Patients who complete the double-blind treatment period will immediately roll over to open-label 
treatment of ACE-083, receiving the same dose of active drug, bilaterally in the TA muscle, once 
every 3 weeks for approximately 6 months (8 doses).  In Part 2, the SRT will periodically review 
blinded safety data for each muscle treated.  
7.2. 
Justification for Dose Level 
ACE-083 was administered into either the rectus femoris (RF) or TA muscle of healthy 
post-menopausal women in the Phase 1 Study A083-01 at absolute dose levels per muscle of up 
to 200 mg (RF) or 150 mg (TA) as either a single dose or repeated dose every 3 weeks.  The 
estimated ACE-083 (mg/g muscle) within the muscle was calculated using the dose administered 
to each patient and the size of each patient’s RF muscle as measured by baseline MRI.  The 
highest dose of ACE-083 evaluated (200 mg x 2 doses for RF; 150 mg x 2 doses for TA) 
produced a mean increase from baseline in muscle volume of 14.5% and 8.9% for RF and TA, 
respectively, at 3 weeks following the last dose.  These dose levels were considered safe and 
generally well tolerated.  
A starting dose level of 150 mg/muscle is considered appropriate and safe based on the Phase 1 
clinical trial results.  This starting dose level will protect patient safety and also ensure that the 
initial exposures achieved within the muscle have the potential to impact efficacy endpoints. All 
subsequent dose levels (higher or lower) will be determined following review of study data and 
recommendations from the SRT. A maximum absolute dose level of 250 mg/muscle following 
dose escalation has been chosen based 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 
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening: 
Inclusion Criteria: 
1. Age ≥ 18 years 
2. Diagnosis of CMT1 or CMTX confirmed by:  
a. Clinical presentation and electrodiagnostics 
b. Genetically confirmed CMT1 or CMTX (Appendix 3) for the patient or 
first-degree relative 
3. Part 1: 
a. Six-minute walk distance (6MWD) of at least 150 meters (without a brace or 
walker) 
b. Independent ambulation for at least 10 meters, without a brace 
c. Left and right ankle plantar flexion MRC grade 4+ to 5, inclusive 
Part 2:  
a. 6MWD ≥ 150 and ≤ 500 meters (without a brace or walker); a maximum of 20% 
of enrolled patients with 6MWD ≥ 450 meters will be included 
b. Left and right ankle plantar flexion MRC grade 4- to 5, inclusive 
4. Left and right ankle dorsiflexion Medical Research Council (MRC) manual muscle 
testing (MMT) grade 3 to 4+ inclusive (Appendix 4).  No more than 12 of the 40 subjects 
may have a grade of 3 or 3+ on one or both sides. 
5. Females of childbearing potential (defined as sexually mature women who have not 
undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal 
≥ 24 consecutive months) must have negative urine pregnancy test prior to enrollment 
and use highly effective birth control methods (abstinence, oral contraceptives, barrier 
method with spermicide, or surgical sterilization) during study participation and for 8 
weeks following the last dose of ACE-083.  Hormonal birth control use must be stable for 
at least 14 days prior to Day 1.  Males must agree to use a condom during any sexual 
contact with females of childbearing potential while participating in the study and for 8 
weeks following the last dose of ACE-083, even if he has undergone a successful 
vasectomy.  Patients must be counseled concerning measures to be used to prevent 
pregnancy prior to the first dose of ACE-083. 
6. Ability to adhere to the study visit schedule/procedures, and to understand and comply 
with protocol requirements 
7. Signed written informed consent 


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8.2. 
Exclusion Criteria 
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:  
1. Current active malignancy (e.g., remission less than 5 years duration), with the exception 
of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 
squamous cell carcinomas of the skin  
2. Symptomatic cardiopulmonary disease, significant functional impairment, significant 
orthopedic or neuropathic pain, or other co-morbidities that in the opinion of the 
investigator would limit a patient’s ability to complete strength and/or functional 
assessments on study 
3. 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; low dose aspirin [≤ 100 mg daily] is permitted) 
8. Severe deformity or ankle fixation that would sufficiently limit passive range of motion 
to affect assessment of dorsiflexion strength.  
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 investigational agent 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. Any previous or current exposure to ACE-083 
15. 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 


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16. Any condition that would prevent MRI scanning or compromise the ability to obtain a 
clear and interpretable scan of the lower leg, as applicable (e.g., knee/hip replacement  
metallic implants) 
17. Known active substance abuse, including alcohol 
18. History of sensitivity to protein pharmaceuticals 
19. Female that is lactating/breast-feeding 
8.3. 
Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 additional times.  The interval between rescreenings should be at least 4 
weeks after the end of the 4-week screening period (i.e., the earliest re-consent may occur is 8 
weeks after the prior consent was signed).  Each time a rescreening is performed, the individual 
must sign a new ICF and will be assigned a new identification number.  If a test is repeated 
within the screening window, the patient does not need to sign a new ICF. 


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9. 
DISCONTINUATION/ WITHDRAWAL CRITERIA  
The 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 visit should complete 
the tests and evaluations (excluding the MRI if it has been done within 4 weeks of study 
withdrawal) scheduled for the end of treatment visit (Day 106/ET for Part 1, Day 358/ET for Part 
2) at the time of 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 or a dose level after consultation with the investigator and the SRT at any 
time for safety or administrative reasons.  The sponsor will terminate the study if the occurrence of SAEs or other 
findings suggests unacceptable risk to the health of the patients. 


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


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10. 
TREATMENT OF PATIENTS 
10.1. 
Treatments Administered 
Using electromyography (EMG) or ultrasound guidance, each dose of study drug will be 
administered into the non-tendinous portion of the TA as a series of up to 4 equal-volume 
injections.  The use of EMG or ultrasound guidance will ensure that viable muscle is present at 
the injection site.  If the degree of atrophy or fibro-fatty infiltration poses administration 
challenges, injections of ACE-083 should be distributed approximately 2 cm apart into viable 
muscle.  Injection site locations as well as measures to avoid adjacent nerves, blood vessels, and 
prevent intravascular injection are outlined in the IP Handling Guide. 
The maximum absolute dose level and schedule, based on SRT review, is 250 mg/muscle 
administered bilaterally by injection into the left and right TA muscles every 3 weeks for up to 5 
doses in Part 1 and up to 17 doses in Part 2. 
For Part 2, ACE-083 or placebo (normal saline) will be administered blinded study drug every 3 
weeks for approximately 6 months (9 doses). Patients who complete the double-blind treatment 
period will immediately roll over to open-label treatment with ACE-083, receiving the same dose 
of active drug, bilaterally in the TA muscle once every 3 weeks for approximately 6 months (8 
doses).  
The planned dose scheme for Part 1 and 2 is shown in Table 4.  
Table 4: 
Cohort Schedule for Study A083-03 
Part 1: N=Up to 18 (non-randomized, open-label, dose-escalation) 
Cohort 
ACE-083 Dose per 
Musclea 
ACE-083 
n 
1 
150 mg  
6 
2 
TBD up to 200 mgb 
6 
3  
TBD up to 250 mgb 
6 
Part 2: N= Up to 40 (6-month, randomized, double-blind, placebo-controlled, with 6-month 
open-label extension) 
 
6-month double-blind, placebo 
controlled 
6-month open-label extension  
ACE-083 Dose 
per Musclea 
ACE-083 
n 
Placebo 
n 
ACE-083 
n 
TBD up to 250 mgb 
20 
20 
40 
 
a Administered bilaterally by injection into the tibialis anterior muscle once every 3 weeks  
b Dose level to be based on recommendations from the SRT  
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 


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baseline and may be reduced to the previously tolerated dose (i.e. from 240 to 200 mg or from 
200 to 150 mg).  Dose will not be reduced to below 100 mg (Part 1) or 150 mg (Part 2). If dosing 
does not resume within 6 weeks of the last dose given, the patient will be discontinued from 
treatment.  
10.2. 
Safety Review Team  
Dose-Limiting Toxicity (DLT) Definition:  
 An SAE, possibly or probably related to study drug 
OR 
 An AE, injection site reaction, laboratory parameter abnormality, or vital sign 
abnormality, possibly or probably related to study drug, and either Grade ≥ 3 
(NCI-CTCAE, current version) or Grade ≥ 2 and considered clinically significant 
Part 1 Dose Escalation Stopping Rules (under SRT review):  
Dosing at current levels will continue unless the following condition occurs: 
 ≥ 2 DLTs of the same character in a cohort 
Safety Review Team: 
An SRT, comprised at minimum of a principal investigator, medical monitor, and an independent 
neuromuscular specialist, will meet to review safety and, as needed, imaging data, for each 
cohort.  The review will include all collected safety data (and, as necessary imaging data) when 
at least 4 patients in a cohort have completed at least their Day 22 visit.  For both parts of the 
study, the SRT safety data will include, but not be limited to, AEs, laboratory results (including 
hematology, chemistry, and urinalysis) and vital signs data to assess for DLTs and overall safety.  
The SRT may request review of additional data collected in currently enrolled patients. 
Based on review of relevant data, the SRT will make one or more of the following 
recommendations: 
 Continue enrollment of remaining patients in the current cohort at the current dose 
level 
 Open next cohort in Part 1 or open Part 2 of the study at a recommended dose (higher 
or lower dose level) 
 Discontinue one or more cohorts in Part 1, or the study as a whole 
SRT recommendations for dose escalation in Part 1 will be based in part upon the dose escalation 
stopping rules.  If a stopping rule is met, a lower intermediate dose may be recommended or the 
previous dose level will be considered the MTD.  The SRT may also recommend no further 
enrollment in the presence of AEs that do not meet dose stopping rules if the nature of these AEs 
is deemed a significant risk to patients in a given cohort.   
For Part 2, the SRT will review blinded preliminary safety data. Further details on the role of the 
SRT during Part 2 are included in the SRT Guidelines.  
10.3. 
Concomitant Medications 
During screening and throughout the study, patients may take stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol.  These medications include: 


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single agent low dose aspirin (≤ 100 mg daily), intra-articular/topical/inhaled/intranasal 
physiologic doses of systemic 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.   
Patients are not permitted to take the following: anticoagulation / platelet modifying therapies, 
systemic corticosteroids, androgens, growth hormone, insulin, or 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.  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, dose escalation phase that does not require randomization. 
Part 2: Patients who have signed the informed consent and meet all eligibility criteria will be 
stratified by CMT disease type (CMT1 or CMTX) and then randomized to receive ACE-083 
(at a dose level determined by Part 1) or placebo.  The randomization scheme will be computer 
generated and will be prepared by a statistical group designated by the sponsor.  
If a patient discontinues the study for reasons other than a safety issue related to ACE-083 and 
the patient had not completed visit Day 43, the patient may be replaced.  The replacement patient 
will receive the same treatment as the patient replaced.  Both the replacement and originally 
allocated patient numbers will be unique numbers. 
Among study personnel, only the pharmacist or his/her designee who prepares the study drug 
(ACE-083 or placebo), an unblinded clinical monitor designated by the sponsor, and the 
analytical laboratory will be unblinded to the patient treatment assignments.  All other study 
personnel (including but not limited to investigators, study coordinators, nursing staff, and 
clinical monitors) and all patients will remain blinded to the study treatment assignments.  The 
sponsor and the sponsor’s representatives will also remain blinded to the study treatment 
assignments.  
In the event of a medical emergency for an individual patient in which knowledge of the study 
drug is critical to the patient’s medical management, the investigator may break the blind for that 
patient.  However, prior to breaking the blind, every effort must be made by the investigator to 
first discuss the need to break the blind with the medical monitor.  Further, it must be determined 


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by the investigator that breaking the treatment blind is necessary information for the medical 
management of that patient.  If the blind is broken prior to Day 190, the patient must be 
withdrawn from the study and complete the tests and evaluations scheduled for the end of 
treatment visit (Day 358/ET) and will be expected to return to the clinic to complete the 
remaining follow-up visit assessments. 


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


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12. 
STUDY PROCEDURES 
12.1. 
Written Informed Consent 
Patients will be required to sign an independent ethics committee (IEC)/institutional review 
board (IRB)-approved ICF prior to any study-related procedures, including screening 
evaluations. 
12.2. 
Study Assessments 
For each patient, all study procedures should be conducted according to the Schedule of Events 
(Appendix 1) and following the study-specific recommendations included in the Study Manual.   
12.3. 
Safety Assessments 
Safety assessment include monitoring of adverse events, injection site reactions, concomitant 
medications, clinical laboratory assessments (including ADA), vital signs, and physical 
examination findings.  
Specifically for ADA, if a patient has a positive ADA result at the last visit, the patient will be 
asked to return for additional ADA testing approximately every three months, until a negative 
result is obtained or the result is considered to be stabilized. 
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) of ankle 
dorsiflexion measured by quantitative muscle testing (by handheld dynamometer) 
Motor function tests: 10-meter walk/run, 6-minute walk test, 100-meter timed test (Part 2 open-
label), gait, activity and fall parameters, Berg balance scale 
Physician-reported functional rating scale: CMTES2 
Patient-reported health-related QoL: CMT-HI 
12.5. 
Pharmacokinetic and Pharmacodynamic Assessments 
Pharmacokinetic assessments: ACE-083 serum concentrations (PK samples for patients taking 
concomitant medications may be analyzed for changes in cytochrome P450 enzymes.) 
Pharmacodynamic assessments 
Muscle assessments: Muscle volume and intramuscular fat fraction of TA by MRI; CMAP of TA 
Biomarkers: including but not limited to: insulin-like growth factor-1 (IGF-1), 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 in a clinical investigational study in 
which a patient is administered a study drug (i.e., on or after the Dose 1 Day 1 dose), which does 
not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the study drug whether or not it is considered 
related to the study drug.  
Abnormal laboratory and other abnormal investigational findings (e.g., physical exam, ECG) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to treatment discontinuation, or are otherwise considered clinically relevant by the investigator.  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.  In the case of a fatality, the cause of death 
is considered as the AE, and the death is considered as its outcome. 
13.1.1.1. Unexpected Adverse Events 
An unexpected AE is an AE that is not described in nature or severity in the IB under the  
Reference Safety Information. 
13.1.1.2. Events Not to Be Considered as Adverse Events 
Pre-existing medical conditions/signs/symptoms present before the screening period that do not 
worsen in severity or frequency during the study are defined as baseline medical conditions, and 
are not to be considered AEs. 
13.1.1.3. Serious Adverse Event  
An SAE is any AE (on or after the Dose 1 Day 1 dose), occurring at any dose, regardless of 
causality, that: 
 Results in death 
 Is life-threatening: life-threatening means that the patient was at immediate risk of 
death from the reaction as it occurred (i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form) 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
however, a hospitalization for an elective procedure will not be considered a SAE  
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event: an important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered 
an SAE when, based upon appropriate medical judgment, it may jeopardize the 


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patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions for SAEs.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.  
13.1.1.4. Events Not to Be Considered as Serious Adverse Events 
Elective hospitalizations to administer or to simplify study treatment or perform procedures are 
not considered SAEs.  Unexpected complications and/or prolongation of elective hospitalization 
should be recorded as AEs.  
13.1.1.5. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and the investigator identifies as related to the investigational product or procedure. 
Acceleron follows procedures for the expedited reporting of SUSARs consistent with global 
regulations and associated guidances.    
13.2. 
Severity 
Investigators must evaluate the severity/intensity of AEs according to the CTCAE 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. 
Patients will be evaluated and questioned generally for AEs during the course of the study,.  The 
investigator must report in detail all adverse signs and symptoms which are either volunteered by 
patients or observed during or following the course of investigational product administration on 
the appropriate CRF page.  All clearly related signs, symptoms, and abnormal diagnostic 
procedure results should be recorded as a single diagnosis.  All untoward medical occurrences 
arising after signing of the ICF until a patient is dosed on 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 
141/End of Study visit (Part 1) or Day 393/End of Study visit (Part 2) are to be reported and 
documented on the AE CRF.  
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the AE CRF.  Any clinically relevant changes in laboratory assessments, or other 
clinical findings as described in Section 13.1 , are considered AEs and must be recorded on the 
AE CRF. AEs are to be followed for resolution as described in in Section 13.5.  
It is important that each AE report include a description of the event, duration (onset and 
resolution dates), severity, relationship with ACE-083, any other potential causal factors, any 
treatment given, or other action taken (including dose delay or discontinuation of study drug) and 
outcome.  In addition, SAEs should be identified and the appropriate seriousness criteria 
documented.  AEs categorized as SAEs must also be documented using an SAE Report Form as 
described in Section 13.4.1.  
Specific guidance can be found in the CRF Completion Guidelines provided by the sponsor or 
designee. 
13.4.1. 
Documentation of Serious Adverse Events 
All SAEs that occur after the first study drug administration on Dose 1 Day 1 until Day 141/End 
of Study visit (Part 1) or Day 393/End of Study visit (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 


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information on a new SAE Report Form.  In all instances, the investigator should follow up with 
patients until the outcome of the SAE is known. 
13.5. 
Reporting Adverse Events 
As described in Section 13.4 , all AEs must be recorded in the CRF up until the last follow-up 
visit.  All patients who received at least one dose of study drug, whether they completed the 
treatment period or not, should complete the end of treatment procedures.       
All AEs will be followed until clinical database lock (or resolution if it occurs before database 
lock).  All SAEs will undergo active follow-up until the event(s) have returned to baseline status, 
have stabilized, or until the investigator and sponsor have agreed that follow-up is no longer 
necessary.  Follow-up data for SAEs obtained after clinical database lock will be incorporated 
into the study drug safety database.  If a patient experiences an SAE that is considered to be 
related to study treatment at any time after the study, it must be reported to the sponsor. 
13.6. 
Pregnancy 
Female patients who are of childbearing potential at the time of consent or who become of 
childbearing potential during study participation must agree to use a highly effective method of 
birth control for the duration of the study and for 8 weeks after the last dose of ACE-083.  
Male patients and their partners must be using a highly effective method of birth control for the 
duration of the study and for 8 weeks after last dose of ACE-083.  
All pregnancies occurring during the study and up to 8 weeks after the last dose of ACE-083 
must be reported immediately to the investigator.  The investigator must report all pregnancies to 
the sponsor within 24 hours of notification.  A pregnant female participant must discontinue 
study drug immediately.  Monitoring of the patient should continue until conclusion of the 
pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the investigator should notify 
Medpace Clinical Safety.  At the completion of the pregnancy, the investigator will document the 
outcome of the pregnancy.  If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the investigator should follow the procedures for reporting an 
SAE.  
13.7. 
Reporting Serious Adverse Events 
If an SAE occurs during the reporting period, the investigator must immediately (i.e., within a 
maximum 24 hours after becoming aware of the event) inform the 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 
This section outlines the planned statistical analyses.  Additional details will be described in a 
separate statistical analysis plan (SAP). 
14.1. 
Analysis Populations 
Full Analysis Set:  Part 1: All patients enrolled in the study and have received at least one dose 
of study drug; Part 2: All patients randomized in the study 
Safety Population: All patients enrolled/randomized in the study who have received at least one 
dose of study drug (including placebo) 
Per Protocol Set: All patients enrolled/randomized in the study, who have received at least one 
dose of study drug (including placebo) with no CSR-reportable protocol violations and at least 
one post-baseline MRI evaluation 
Pharmacokinetic Population: All patients who have received at least one dose of study drug and 
have sufficient PK samples collected and assayed for PK analysis 
14.2. 
Statistical Analysis Considerations 
14.2.1. 
Patient Demographics and Disposition  
Individual patient demographic data will be listed by patient.   
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be provided for 
continuous demographic variables (age, weight, height, and BMI) and frequency counts will be 
tabulated for categorical demographic variables (sex, race, ethnicity) by treatment and overall for 
each study part (Part 1 and Part 2).  Age will be calculated based on birth date and informed 
consent date.  
Individual patient disposition data will be listed by patient.   
Frequency counts will be tabulated for disposition data and will consist of the number of patients 
completing the study (Yes / No) along with frequency counts of primary reason for 
discontinuation (provided there is at least one patient who discontinued).  Summaries will be 
provided by treatment and overall for each study part (Part 1 and Part 2). 
14.2.2. 
Drug Exposure 
Individual study drug administration data will be listed by patient.  Descriptive statistics of study 
drug exposure will be presented. 
14.2.3. 
Efficacy Data 
Part 1 
Individual efficacy data will be listed.  For muscle strength (as assessed by handheld 
dynamometer), the MVIC value will be derived for each side and the average maximum peak 
force value [from the left and right sides] will be determined for each individual patient and 
scheduled time.  For the MVIC value for each side treated as well as the average from the left 
and right sides, CMTES2 score, CMT-HI total score and selected subscale scores, and motor 


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function test assessments, raw and changes from baseline (percent and absolute change) for the 
injected muscle will be summarized for each scheduled time using descriptive statistics.   For 
each efficacy variable, a repeated-measures ANCOVA 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 change from baseline.  For muscle strength parameters, the change from 
the screening to baseline value will serve as the control for each cohort and will be summarized 
together with post-baseline data. Baseline is defined as the last non-missing value prior to 
dosing.  Theoretically, this should be the Day 1 predose value.  Other strength measurements will 
be summarized and reported similarly.  Additional analyses may be performed as appropriate. 
Analyses described above concerning selected motor function test assessments related to gait 
will be considered as exploratory. 
Part 2 
Individual efficacy data will be listed. For muscle strength, the MVIC value and decimal MMT-
MRC score will be derived for each side and the average [from the left and right sides] will be 
determined for each individual patient and scheduled time.   
Double-blind, placebo-controlled phase 
For the MVIC value and decimal MMT-MRC score for each side treated as well as the average 
from the left and right sides, CMTES2 score, CMT-HI total score and selected subscale scores, 
and motor function test assessments, raw data and changes from baseline (percent and absolute 
change) from baseline will be summarized by treatment for each scheduled time using 
descriptive statistics.  In addition, a mixed model will be fitted to assess the treatment effect 
(ACE-083 vs. placebo) using a 2-sided 0.10 significance level for the percent change from 
baseline.  Least squares estimates of the treatment effect and corresponding 90% confidence 
intervals will be provided.  In addition, least squares estimates of the treatment effect and 
corresponding 90% confidence intervals will be provided for patients having dorsiflexion MMT-
MRC grade of 4- to 4+ on both sides.   
Additional analyses may be performed as appropriate. 
Open-label extension 
For the MVIC value and decimal MMT-MRC score for each side treated as well as the average 
from the left and right sides, CMTES2 score, CMT-HI total score and selected subscale scores, 
and motor function test assessments, raw data and changes (percent and absolute change) from 
the start of the open-label extension (Day 190) will be summarized by treatment for each 
scheduled time using descriptive statistics.   
Additional analyses may be performed as appropriate. 
Open-label extension vs. double-blind placebo-controlled phase 
For the MVIC value [average from the left and right sides] decimal MMT-MRC score [average 
from the left and right sides], CMTES2 score, CMT-HI total score and selected subscale scores, 
and motor function test assessments, the effect of ACE-083 administered during the open-label 
extension compared to the treatment administered in the double-blind placebo-controlled phase 
will be examined for those receiving ACE-083 during the double-blind phase and separately for 
those receiving placebo during the double-blind phase by comparing the absolute and/or percent 


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changes [depending on the parameter] observed between Day 190 and pre-first treatment 
baseline (1st 6 months) and Day 358 versus Day 190 (2nd 6 months) using a mixed model.  Least 
squares estimates of this effect and 95% confidence intervals will be provided.  In addition, least 
squares estimates of this effect and corresponding 95% confidence intervals will be provided for 
patients having dorsiflexion MRC-MMT grade of 4- to 4+ on both sides. 
Additional analyses may be performed as appropriate. 
 
14.2.4. 
Pharmacodynamic Data 
Part 1 
Individual pharmacodynamic data will be listed.  For individual pharmacodynamic data that is 
measured on the left and right side (i.e., MRI), the average of the left and right side assessments 
will also be listed and summarized.   
Descriptive statistics (change from baseline [percent and absolute change]) will be provided by 
treatment group and scheduled time.  In addition, for muscle volume and intramuscular fat 
fraction, a repeated measures ANCOVA will be fitted to the percent change from baseline data 
and estimates of the effect of ACE-083 at 3 weeks post last dose and corresponding 90% 
confidence intervals will be provided.  
Additional analyses may be performed as appropriate. 
Part 2 
Individual pharmacodynamic data will be listed.  For individual pharmacodynamic data that is 
measured on the right and left side (i.e., MRI), the average of the left and right side assessments 
will also be listed and summarized.   
Double-blind, placebo-controlled phase 
Descriptive statistics for raw data and changes from baseline (percent and/or absolute change) 
will be provided for each pharmacodynamic parameter by treatment group for each scheduled 
time.  For pharmacodynamic parameters that are measured on the right and left side (i.e., MRI), 
the descriptive statistics will include summaries for each side and the average of the right and left 
sides. 
The primary pharmacodynamic parameter will be the percent change in total muscle volume 
(average of left and right side) 3 weeks after the last dose of the double-blind treatment period 
(Day 190) from the corresponding baseline.  A mixed model will be used to assess the treatment 
effect (ACE-083 vs. placebo) using a 2-sided, 0.10 significance level.  If data from the end of 
treatment visit are missing, the last observation will be carried forward.  Additional techniques 
for handling missing data will also be evaluated as sensitivity analyses to the last observation 
carried forward approach.  Least squares estimates of the effect of ACE-083 and the 
corresponding 90% confidence interval will be produced.  In addition, least squares estimates of 
the treatment effect and corresponding 90% confidence intervals will be provided for patients 
having dorsiflexion MRC-MMT grade of 4- to 4+ on both sides. 
For each secondary pharmacodynamic parameter, a mixed model will also be used to assess the 
treatment effect using a 2-sided 0.10 significance level for the following secondary 


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pharmacodynamic variables:  percent change from baseline for the average of the left and right 
side at 3 weeks after the last dose of the double-blind treatment period (Day 190) for 
intramuscular fat fraction as well as derived variables such as contractile muscle fraction and 
contractile muscle volume.   Least squares estimates of the effect of ACE-083 and corresponding 
90% confidence interval will be provided.  In addition, least squares estimates of the treatment 
effect and corresponding 90% confidence intervals will be provided for patients having 
dorsiflexion MRC-MMT grade of 4- to 4+ on both sides. 
For biomarker data (e.g., IGF-1 and CTX) and TA CMAP amplitude, raw data and changes from 
baseline (percent and absolute change) will be summarized by treatment group and scheduled 
time.  Such analyses will be considered exploratory. 
Additional analyses may be performed as appropriate.   
Open-label extension 
Descriptive statistics for the percent change from baseline will be provided for each 
pharmacodynamic variable by treatment group for each scheduled time.  For pharmacodynamic 
variables that are measured on the right and left side (i.e., MRI), the descriptive statistics will 
include summaries for each side and the average of the right and left sides. 
For each pharmacodynamic variable, raw data and changes (percent and/or absolute change) 
from the start of the open-label extension (Day 190) will be summarized by treatment for each 
scheduled time using descriptive statistics. 
Additional analyses may be performed as appropriate.   
Open-label extension vs. double-blind placebo-controlled phase 
For each of the following pharmacodynamic variables, a mixed model will be used to assess the 
effect ACE-083 administered during the open-label extension [Day 358 vs. Day 190 (2nd 6 
months)] compared to the effect of the treatment administered in the double-blind 
placebo-controlled phase [Day 190 vs. pre-first treatment baseline (1st 6 months)] separately for 
those receiving placebo during the double-blind phase as well as for those receiving ACE-083 
during the double-blind phase: 
 Percent change in total muscle volume (average of right and left sides) during the open-
label extension vs. double-blind phase 
  Percent change in intramuscular fat fraction (average of right and left sides) during the 
open-label extension vs. double-blind phase 
 Percent change in contractile muscle fraction (average of right and left sides) during the 
open-label extension vs. double-blind phase 
 Percent change in contractile muscle volume (average of right and left sides) during the 
open-label extension vs. double-blind phase 
Least squares estimates of this effect and 95% confidence intervals will be provided.  In addition, 
point estimates of this effect and corresponding 95% confidence intervals will be provided for 
patients having dorsiflexion MRC-MMT grade of 4- to 4+ on both sides. 
Additional analyses may be performed as appropriate.   


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14.2.4.1. Pooled Analyses 
If applicable, similar analyses will be performed for pooled Part 1 and 2 data for patients at the 
same dose level.  Pooling by the estimated local dose of ACE-083 in the injected muscle 
(i.e., mg ACE-083/g muscle) may also be performed.  Details of these analyses will be included 
in the SAP. 
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 Medical Dictionary for 
Regulatory Activities.  Incidence of treatment-emergent AEs will be presented by system organ 
class and preferred term.  AE incidence rates will be described by cohort 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 patient 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 
The results of ADA testing for ACE-083 versus time as well as results following further 
characterization of positive ADA samples will also be presented.  Exploratory analysis will be 
performed on the potential effect of ADA on ACE-083 PK exposure if ADA tests are determined 
to be positive. 
14.3. 
Determination of Sample Size 
There is no formal sample size calculation for Part 1.  Six patients in each cohort will provide 
sufficient data to evaluate safety and preliminary efficacy data. 
The sample size calculation for Part 2 is based upon the expected percent change from baseline 
in total muscle volume of the injected TA 3 weeks after the last dose.  A 10% difference between 
ACE-083-treated and placebo groups in the percent change in total muscle volume from baseline 
is considered to be clinically meaningful.  The SD is estimated to be approximately 10% for each 
group based on preliminary MRI data for the ACE-083 treated side of the TA muscle from Part 1 
of the Phase 2 study in FSHD patients.  Assuming a 2-sided type 1 error rate of 0.10, a 10% 
difference in percent change from baseline between the ACE-083-treated and placebo groups in 
total muscle volume, a standard deviation of 10% for each group, and a 1:1 randomization, 90% 
power is achieved with a total sample size of n=36 patients (18 active, 18 placebo), based on a 
standard t-test. 


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In addition, this sample size provides 90% power to detect a 10% difference in 6MWD, based on 
an assumed estimated SD of 10% (based off of available data from Part 1 of the Phase 2 study in 
FSHD patients as well as data from Part 1 of this study, 3-weeks post last dose) and a 2-sided 
type 1 error rate of 0.10. 
In order to account for dropouts (up to 10%), 40 patients will be randomized to study treatment 
(20 active, 20 placebo) to ensure that at least 18 patients per treatment group complete the 
double-blind treatment period. 
14.4. 
Interim Analysis 
For Part 1, periodic reviews of the available safety and tolerability will be done to assist dose 
escalation decisions.  For Part 2, no interim analyses are planned. 
14.5. 
Deviation from Original Analysis Plan 
A formal statistical analysis plan for the analysis and presentation of data from this study will be 
prepared before the database lock.  Deviations from the statistical analyses outlined in this 
protocol will be indicated in this plan; any further modifications will be noted in the final clinical 
study report. 


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


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


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


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


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


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


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


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22. 
REFERENCES 
1. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev 2000;14:627-44. 
2. Welt C, Sidis Y, Keutmann H, Schneyer A. Activins, inhibins, and follistatins: from 
endocrinology to signaling. A paradigm for the new millennium. Exp Biol Med (Maywood) 
2002;227:724-52. 
3. Lee SJ, Lee YS, Zimmers TA, et al. Regulation of muscle mass by follistatin and activins. 
Mol Endocrinol 2010;24:1998-2008. 
4. Tsuchida K, Nakatani M, Hitachi K, et al. Activin signaling as an emerging target for 
therapeutic interventions. Cell Commun Signal 2009;7:15. 
5. Xia Y, Schneyer AL. The biology of activin: recent advances in structure, regulation and 
function. J Endocrinol 2009;202:1-12. 
6. National Institute of Neurological Disorders and Stroke. Charcot-Marie-Tooth Disease Fact 
Sheet. Last updated January 14, 2016. (Accessed at 
http://www.ninds.nih.gov/disorders/charcot_marie_tooth/detail_charcot_marie_tooth.htm.) 
7. 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. 
8. 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. 
9. 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. 
10. Hoyle JC, Isfort MC, Roggenbuck J, Arnold WD. The genetics of Charcot-Marie-Tooth 
disease: current trends and future implications for diagnosis and management. Appl Clin Genet 
2015;8:235-43. 
11. Daniels L, Worthingham C. Muscle testing : techniques of manual examination. 5th ed. 
Philadelphia: Saunders; 1986. 
12. 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 
 


Clinical Study Protocol 
 
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APPENDIX 1.  
SCHEDULE OF EVENTS 
Table 5: 
Schedule of Events for Part 1: Non-Randomized, Open-Label, Dose Escalation 
 
 
Screening 
Period 
Treatment Period 
Follow-Up Period 
Day -28 to 
Day -7 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Day 
106/ET2 
(±3d) 
Day 141 
(±3d) 
Day 11 
Day 8 
(±1d) 
Day 221 
(±3d) 
Day 431 
(±3d) 
Day 641 
(±3d) 
Day 851 
(±3d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Urine pregnancy test3 
 
X 
 
X 
X 
X 
X 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
MRT assessment (MRC)15 
X 
 
 
 
 
 
 
 
 
Genetic testing17 
X 
 
 
 
 
 
 
 
 
Physical examination4 
X 
X 
 
X 
 
X 
 
X 
 
Injection site examination5 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology7 
X 
X 
 
X 
X 
X 
X 
X 
 
Chemistry7 
X 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis7 
X 
X 
 
 
X 
X 
 
X 
 
Biomarkers7 
X 
X 
 
X 
X 
X 
 
X 
X 
Anti-drug antibody 
 
X 
X 
X 
X 
X 
X 
X 
X8 
Serum PK9 
 
0, 1, 2, 4, 6 h 
X 
X 
X 
X 
0, 1, 2, 4, 6 h 
X 
X 
ECG (12 lead) 
 
X 
 
 
 
 
 
 
 
Bilateral MRI10 
 
X 
 
 
X 
 
 
X 
X 
Timed function tests11 
X 
X 
 
X 
X 
X 
X 
X 
X 
Balance and gait tests12 
X 
X 
 
 
X 
 
 
X 
X 
Strength test13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMTES214 
X 
X 
 
 
X 
 
 
X 
X 
CMT-HI14 
X 
 
 
 
X 
 
 
X 
X 
Monitoring of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration16 
 
X 
 
X 
X 
X 
X 
 
 


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1   Study procedures must be done prior to administration of study drug.  Reference the Study Manual for the order of study procedures. Laboratory samples and functional/strength 
assessments may be collected up to 24 hours prior to administration of study drug.  All visit-day windows should be considered relative to the date of the previous dose of 
ACE-083. Actual visit days (e.g., day 1, day 8, day 22) may be different than planned due to windows on visits and potential dosing delays. Time of study drug administration is the 
time of the first injection.  
2   Patients who discontinue prior to the Day 106/ET visit should complete the Day 106/ET visit at the time of discontinuation and return for the remaining follow-up period visit.  
If an MRI has been completed within 4 weeks of discontinuation, it does not need to be repeated as part of the Day 106/ET visit procedures.  
3 Pregnancy test for women of childbearing potential to be performed and negative result confirmed before dosing.  
4   Full physical examination (skin, head, eyes, ears, nose, throat and neck, lymph nodes, cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neurological), at 
screening and Day 106/ET; limited physical examination (skin, cardiovascular, respiratory, musculoskeletal, and neurological assessments) for Days 1, 22, 64.  
5   Injection site examination including but not limited to evaluating erythema, pain, bruising, bleeding, and other signs of discomfort or skin reaction to be completed at least 30 
minutes after injection. 
6 Vital signs (weight, heart rate, systolic and diastolic blood pressure) must be taken prior to administration of study drug on dosing days.  Height is collected only at screening. 
7 Including but not limited to: insulin-like growth factor-1 (IGF-1), serum C-terminal collagen crosslinks (CTX) 
8    If a patient has a positive ADA result at Day 141, the patient will be asked to return to the clinical site for additional follow-up approximately every 3 months until a negative or 
stable result is obtained. 
9    PK samples on dosing day have a ±15 minute window for post-dose sample collection, based on time of first injection.  Pre-dose samples may be collected up to 4 hours prior to 
dosing.  
10  MRI assessments should be completed within 5 days prior to the scheduled dose administration, with the exception of the Day 1 MRI which may be completed within 14 days 
prior to Day 1 visit. MRI assessments during the follow-up period (Day 106/ET and Day 141) have a ± 5 day window.    
11 10-meter walk/run, 6-minute walk.  Tests may be performed within 3 days prior to Day 1 visit.   
12 Gait parameters, Berg balance scale.  Tests may be performed within 3 days prior to Day 1 visit.   
13 Maximum voluntary isometric contraction testing will be conducted using a handheld dynamometer.  Both sides will be tested (right and left). 
14 CMTES2 to be assessed by investigator; CMT-HI to be completed by patient 
15 Includes knee extension, ankle dorsiflexion, and ankle plantarflexion  
16 Study drug administration should occur within 21 days (± 3 days) of the previous dose.  
17 To be performed at screening if patient has not already had testing performed previously.  
 
 
 
 
 


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Table 6: 
Schedule of Events for Part 2: Randomized, Double-Blind, Placebo-Controlled with Open-Label Extension  
 
 
Screening 
Double-Blind, Placebo-Controlled 
Open-Label 
ET2 
EOS23 
Dose(s)  
-- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 12, 13, 14 
15 
16 
17 
-- 
-- 
Planned Day(s)  
-28 to -7 
11 
8 
(±1d) 
221 
(±1d) 
431 
(±3d) 
641 
(±3d) 
851 
(±3d) 
1061 
(±3d
) 
1271 
(±3d) 
1481 
(±3d) 
1691 
(±3d) 
1901 
(±3d) 
(211, 232, 
253, 274)1 
(±3d) 
2951 
(±3d) 
3161 
(±3d) 
3371 
(±3d) 
358 
(±3d) 
393 
(±3d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test3 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMT assessment (MRC)4 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
Genetic testing5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination6 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Limited physical 
examination7 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Injection site examination8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology10 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Chemistry10 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Urinalysis10 
X 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Biomarkers11 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
Anti-drug antibody 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X12 
Serum PK13 
 
0, 1, 2, 
4, 6 h 
X 
 
 
 
0, 1, 2, 
4, 6 h 
 
 
 
 
X 
 
X 
 
 
X 
X 
ECG (12 lead) 
X 
4 h14 
 
 
 
 
4 h14 
 
 
 
 
 
 
 
 
 
 
 
Bilateral MRI15 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Timed function tests16 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
Balance and gait tests17  
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Strength tests18 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
CMTES219 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
CMT-HI19 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
CMAP of tibialis anterior  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 


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Revision: 03 
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Acceleron Pharma Inc. 
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Screening 
Double-Blind, Placebo-Controlled 
Open-Label 
ET2 
EOS23 
Dose(s)  
-- 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 12, 13, 14 
15 
16 
17 
-- 
-- 
Planned Day(s)  
-28 to -7 
11 
8 
(±1d) 
221 
(±1d) 
431 
(±3d) 
641 
(±3d) 
851 
(±3d) 
1061 
(±3d
) 
1271 
(±3d) 
1481 
(±3d) 
1691 
(±3d) 
1901 
(±3d) 
(211, 232, 
253, 274)1 
(±3d) 
2951 
(±3d) 
3161 
(±3d) 
3371 
(±3d) 
358 
(±3d) 
393 
(±3d) 
Monitoring of concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monitoring of adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization20 
X 
Distribution of PAMSysTM 
Device21 
X 
Study drug administration22 
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.  Laboratory samples and functional/strength assessments may be collected up to 24 hours 
prior to administration of study drug.  All visit-day windows should be considered relative to the date of the previous dose of ACE-083. Actual visit days (e.g., Day 1, Day 8, Day 22) may be different than planned due to 
windows on visits and potential dosing delays.  Time of study drug administration is the time of the first injection.  
2 Patients who discontinue prior to the Day 358/ET visit should complete the Day 358/ET visit at the time of discontinuation and return for the remaining follow-up period visit.  If an MRI has been completed within 4 weeks 
of discontinuation, it does not need to be repeated as part of the Day 358/ET visit procedures. 
3 Pregnancy test for women of childbearing potential to be performed and negative result confirmed before dosing. 
4 Includes knee extension, ankle dorsiflexion, and ankle plantarflexion.  
5 To be performed at screening if patient has not already had testing performed previously. 
6 Full physical examination includes skin, head, eyes, ears, nose, throat and neck, lymph nodes, cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neurological 
7 Limited physical examination includes skin, cardiovascular, respiratory, musculoskeletal and neurological assessments 
8 Injection site examination including but not limited to evaluating erythema, pain, bruising, bleeding, and other signs of discomfort or skin reaction to be completed at least 30 minutes after injection. 
9 Vital signs (weight, heart rate, systolic and diastolic blood pressure) must be taken prior to administration of study drug on dosing days.  Height is collected only at screening. 
10 Tests defined in Appendix 2, Table 7. 
11 Including but not limited to: insulin-like growth factor-1 (IGF-1) and serum C-terminal collagen crosslinks (CTX) 
12 If a patient has a positive ADA result at Day 393/EOS, the patient will be asked to return to the clinical site for additional follow-up approximately every 3 months until a negative or stable result is obtained. 
13 PK samples on a dosing day have a ±15 minute window for post-dose sample collection, based on the time of the first injection.  Pre-dose samples may be collected up to 4 hours prior to dosing. 
14 ECG is to be conducted ±1 hour of the 4h PK sample.  
15 MRI assessments should be completed within 5 days prior to the scheduled dose administration, with the exception of the Day 1 MRI which may be completed within 14 days prior to Day 1 visit. MRI assessments during 
the follow-up period (Day 358/ET and Day 393/EOS) have a ± 5 day window.    
16 10-meter walk/run, 6-minute walk, 100-meter timed test (Part 2, open-label only; starting at the Dose 10 visit and continuing through to the EOS visit at all timepoints noted).  Tests may be performed within 3 days prior to 
Day 1 visit. 
17 Gait parameters, Berg balance scale.  Tests may be performed within 3 days prior to Day 1 visit.   
18 Maximum voluntary isometric contraction testing will be conducted using a handheld dynamometer.  Both sides will be tested (right and left). 
19 CMTES2 to be assessed by investigator; CMT-HI to be completed by patient 
20 Randomization should occur within 24 hours prior to Day 1 dose.  
21 PamSysTM device is a physical activity monitoring system that will be worn by the patient for the duration of the study.  
22 Study drug administration should occur within 21 days (± 3 days) of the previous dose.  
23 If subjects enroll directly into a separate extension study and will receive additional treatment with ACE-083, they do not need to complete the EOS visit.  For these subjects, their final Study Visit in this protocol will be 
the ET visit. 


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APPENDIX 2. CLINICAL SAFETY LABORATORY ASSESSMENTS 
Table 7: 
Clinical Safety Laboratory Assessments 
Type of Assessment 
Details 
Hematology 
Hemoglobin, hematocrit, platelet count, red blood cell count, white blood cell 
(WBC) count, and WBC differential 
Chemistry 
AST, ALT, lactate dehydrogenase (LDH) and isoenzymes 1-5, gamma-glutamyl 
transpeptidase (GGT), blood urea nitrogen (BUN), creatinine, creatine kinase 
(CK), myoglobin, aldolase, sodium, potassium, glucose, albumin, total bilirubin    
Urinalysis 
Dipstick analysis (pH, specific gravity, protein, myoglobin, glucose, ketones, 
blood, leukocyte esterase, and nitrite) 
 


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APPENDIX 3.  
CHARCOT-MARIE-TOOTH DISEASE CLASSIFICATION 
Classification and Genetics of CMT Disease10 


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APPENDIX 4. 
MEDICAL RESEARCH COUNCIL MANUAL MUSCLE 
TESTING GRADING SCALE  
Grading Scale for Manual Muscle Testing (MMT)11,12  
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 
 

SAP_001.pdf: 
Official Title: A Phase 2 Randomized, Double‐Blind, Placebo‐Controlled Study of ACE‐083 in Patients with 
Charcot‐Marie‐Tooth Disease Types 1 and X 
NCT Number:  NCT03124459 
Document Dates: SAP version 3, 13‐Feb‐2020 


Confidential and Proprietary 
1 
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Statistical Analysis Plan 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study 
of ACE-083 in Patients with Charcot-Marie-Tooth Disease Types 
1 and X 
Sponsor: 
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Tel: +1 617-649-9200 
Fax: +1 617-576-0479 
Investigational Product: 
ACE-083 
Protocol Number: 
A083-03 
EudraCT Number: 
N/A 
Version Number: 
3.0 
Date: 
13 February 2020 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, especially unpublished data, is the property of 
Acceleron Pharma Inc. (or under its control), and therefore provided to you in confidence for 
review by you and/or your staff. It is understood that this information will not be disclosed to 
others without written authorization from Acceleron.




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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................5 
2. 
STUDY OBJECTIVES ................................................................................................5 
2.1. 
Primary Objective .........................................................................................................5 
2.2. 
Secondary Objectives ...................................................................................................5 
2.3. 
Exploratory Objectives .................................................................................................6 
3. 
OVERALL STUDY DESIGN ......................................................................................7 
3.1. 
Part 1 .............................................................................................................................7 
3.2. 
Part 2 .............................................................................................................................7 
4. 
STATISTICAL METHODS .........................................................................................9 
4.1. 
General Method ............................................................................................................9 
4.1.1. 
Sample Size Determination ..........................................................................................9 
4.1.2. 
Computing Environment ..............................................................................................9 
4.1.3. 
Treatment Description ..................................................................................................9 
4.1.4. 
Definitions of Baseline ...............................................................................................10 
4.1.5. 
Data Handling Conventions ........................................................................................11 
4.2. 
Analysis Population ....................................................................................................12 
4.3. 
Subject Disposition .....................................................................................................13 
4.4. 
Demographic and Baseline Characteristics ................................................................14 
4.4.1. 
Demographics .............................................................................................................14 
4.4.2. 
Baseline Characteristics ..............................................................................................14 
4.5. 
Prior and Concomitant Medications/Therapy .............................................................16 
4.6. 
Study Drug Exposure ..................................................................................................17 
4.6.1. 
Extent of Exposure .....................................................................................................17 
4.7. 
Efficacy Data ..............................................................................................................17 
4.7.1. 
Variables .....................................................................................................................17 
4.7.1.1. 
Muscle Strength ..........................................................................................................17 
4.7.1.2. 
Motor Function ...........................................................................................................18 
4.7.1.3. 
Patient Reported Outcome Variables..........................................................................20 
4.7.1.4. 
Physician Reported Outcome Variables .....................................................................20 
4.7.2. 
Analyses ......................................................................................................................20 
4.7.2.1. 
Part 1 ...........................................................................................................................20 


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4.7.2.2. 
Part 2 ...........................................................................................................................22 
4.7.2.3. 
Other Analyses ............................................................................................................36 
4.8. 
Pharmacodynamic Data ..............................................................................................36 
4.8.1. 
Variables .....................................................................................................................36 
4.8.1.1. 
MRI .............................................................................................................................36 
4.8.1.2. 
Biomarkers ..................................................................................................................37 
4.8.1.3. 
CMAP of TA ..............................................................................................................37 
4.8.2. 
Analyses ......................................................................................................................37 
4.8.2.1. 
Part 1 ...........................................................................................................................37 
4.8.2.2. 
Part 2 ...........................................................................................................................38 
4.9. 
Subgroup Analyses .....................................................................................................43 
4.10. 
Safety Data ..................................................................................................................45 
4.10.1. 
Adverse Events ...........................................................................................................45 
4.10.2. 
Clinical Laboratory Evaluations .................................................................................47 
4.10.3. 
Anti-Drug Antibodies .................................................................................................47 
4.10.4. 
Other Safety Data .......................................................................................................48 
4.11. 
Missing Data Handling ...............................................................................................48 
4.11.1. 
Efficacy and Pharmacodynamic Data .........................................................................48 
4.11.2. 
Safety Data ..................................................................................................................48 
4.11.2.1. 
Missing Dates for Adverse Event ...............................................................................48 
4.12. 
Pharmacokinetic Data .................................................................................................49 
5. 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE 
PROTOCOL ...............................................................................................................50 
6. 
PROGRAMMING SPECIFICATIONS .....................................................................51 
7. 
APPENDICES ............................................................................................................53 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................54 
 
LIST OF TABLES 
Table 1:  
Planned Doses to be Administered for Part 1 ...............................................................7 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical techniques to be used to analyze data for study protocol A083-03.  The purpose of 
the SAP is to ensure the credibility of the study findings by pre-specifying the statistical 
approaches to the analysis of study data prior to database lock. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
Part 1 
 To evaluate the safety and tolerability of ACE-083 in patients with 
Charcot-Marie-Tooth (CMT) disease types 1 and X (CMT1 and CMTX) 
Part 2 
 To determine whether treatment with ACE-083 vs. placebo increases total muscle 
volume of the injected muscle in patients with CMT1 and CMTX 
2.2. 
Secondary Objectives 
Part 1 
 To determine the recommended dose level(s) of ACE-083 for Part 2 
 To evaluate changes in muscle volume and intramuscular fat fraction of the injected 
muscle 
 To evaluate changes in strength of the injected muscle 
 To estimate the systemic exposure of ACE-083 when administered as a local muscle 
injection 
 To evaluate changes in motor function related to the injected muscle 
 To evaluate changes in physician-reported and patient-reported outcome measures 
Part 2 
 To determine whether treatment with ACE-083 vs. placebo decreases intramuscular 
fat fraction of the injected muscle 
 To determine whether treatment with ACE-083 vs. placebo increases strength of the 
injected muscle 
 To determine whether treatment with ACE-083 vs. placebo improves motor function 
related to the injected muscle 
 To determine whether treatment with ACE-083 vs. placebo improves physician-
reported and patient-reported outcome measures 
 To evaluate safety and tolerability of ACE-083 


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 To estimate the systemic exposure of ACE-083 when administered as a local muscle 
injection 
2.3. 
Exploratory Objectives  
Part 1 
 To evaluate changes in gait parameters 
 To evaluate changes in biomarkers 
Part 2 
 To evaluate changes in biomarkers 
 To evaluate changes in tibialis anterior (TA) compound muscle action potential 
(CMAP) 
 To evaluate changes in gait, activity level, and fall parameters 
 To evaluate changes in motor function via the 100-meter timed test 
 
 


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3. 
OVERALL STUDY DESIGN 
This study is a two-part multicenter, phase 2 study to evaluate the safety, tolerability, 
pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with 
CMT1 and CMTX.  Part 1 is non-randomized, open-label, dose-escalation and Part 2 is 
randomized, double blind, placebo-controlled with an open-label extension.   
Patients who participate in Part 1 are not eligible to participate in Part 2. 
The total study duration for individual patients in Part 1 will be approximately 6 months, which 
includes a 1-month screening period, a 3-month treatment period, and a 2-month follow-up 
period after the last dose.  The total study duration for individual patients in Part 2 will be 
approximately 15 months, which includes a 1-month screening period, a 12-month treatment 
period (6-month double-blind, placebo-controlled followed by a 6-month open-label extension), 
and a 2-month follow-up period after the last dose. 
3.1. 
Part 1 
Part 1 will consist of up to 3 cohorts of patients and will evaluate multiple ascending dose levels 
of ACE-083 in the tibialis anterior (TA).  Patients in each cohort will be enrolled in a 1-month 
screening period before beginning treatment. 
Table 1 below outlines the planned doses to be administered. 
Table 1:  
Planned Doses to be Administered for Part 1 
Cohort 
Dosing 
Days 
Muscle 
Planned 
Dose 
Level 
Type of 
Administration 
ACE-083 
n 
1 
1, 22, 43, 64, 
and 85 
Tibialis 
Anterior 
150 mg 
Bilateral 
6 
2 
1, 22, 43, 64, 
and 85 
Tibialis 
Anterior 
200 mg 
Bilateral 
6 
3 
1, 22, 43, 64, 
and 85 
Tibialis 
Anterior 
240 mg 
Bilateral 
6 
Total Number of Patients (Planned) 
18 
Periodic reviews of selected blinded safety and imaging data will be reviewed by the Safety 
Review Team (SRT) in accordance with the SRT Guidelines.  
3.2. 
Part 2 
Prior to the initiation of Part 2, a review of the safety and efficacy data from Part 1 will be done 
in order to determine the recommended dose level.  Up to 40 patients will be enrolled and 
randomized (1:1 ratio) to receive either ACE-083 (n=20) or placebo (n=20) bilaterally.  Patients 
will receive study drug once every three weeks for approximately 6 months (9 doses).  If a 
patient discontinues the study for reasons other than a safety issue related to investigational study 
drug and the patient had not completed the Day 43 visit, the patient may be replaced.  The 
replacement patient will receive the same treatment as the patient replaced. 


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Patients who complete the double-blind treatment period will immediately roll over to open-label 
treatment with ACE-083.  All patients will receive ACE-083 administered at the same dose as in 
the double-blind period.  They will receive bilateral injections, once every three weeks for 
approximately 6 months (8 doses).  In Part 2, the SRT will periodically review the blinded safety 
data. 
A stratified randomization schedule will be prepared under the direction of the Sponsor with the 
stratification factor of “CMT disease type” (values are CMT1 and CMTX).  Because Part 2 is 
multicenter, an Interactive Response Technology (IRT) system will be used to randomize 
patients sequentially across clinical sites.   
Similar to Part 1, periodic reviews of selected blinded safety and imaging data will be reviewed.  
Further details concerning the frequency and timing of SRT reviews of Part 2 data are described 
in the SRT Guidelines. 
 
 


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4. 
STATISTICAL METHODS 
4.1. 
General Method 
4.1.1. 
Sample Size Determination 
There was no formal sample size calculation for Part 1.  Six patients in each cohort will provide 
sufficient data to evaluate safety and a preliminary assessment of changes in muscle volume and 
muscle strength.   
The sample size calculation for Part 2 is based upon the percent change from baseline in total 
muscle volume of the injected TA muscle 3 weeks after the last dose.  A 10% difference between 
ACE-083-treated and placebo groups in the percent change in total muscle volume from baseline 
is considered to be clinically meaningful.  The standard deviation (SD) is assumed to be 
approximately 10% for each group, based on preliminary MRI data for the ACE-083-treated side 
from the initial TA cohort in Part 1 of the Phase 2 study in FSHD patients. 
Assuming a 2-sided type I error rate of 0.10, a 10% difference in percent change from baseline 
between ACE-083-treated and placebo groups in total muscle volume, a standard deviation of 
10% for each group, and a 1:1 randomization, 90% power is achieved with a total sample size of 
36 (18 active, 18 placebo), based on a standard t-test. 
In addition, this sample size also provides 90% power to detect a 10% difference in 6-minute 
walk test distance, based on a similar estimated SD of 10% (based off of available data from Part 
1 of the Phase 2 study in FSHD patients as well as data from Part 1 of this study, 3-weeks post 
last dose) and a 2-sided type 1 error rate of 0.10. 
In order to account for dropouts (up to 10%), 40 patients will be randomized to study treatment 
for each muscle (20 active, 20 placebo) to ensure that at least 18 patients per treatment group 
complete the double-blind treatment period. 
4.1.2. 
Computing Environment 
The analysis of clinical data from both Parts 1 and 2 will be performed under the direction of the 
Acceleron Pharma Biostatistics Department, using SAS® (version 9.4 or higher) and R. 
4.1.3. 
Treatment Description  
Treatment descriptions as well as abbreviations used in tables, listings, and figures are described 
below: 
Part 1 
Unless otherwise stated, tables and figures will be presented as shown below: 
Part 1 – Tibialis Anterior 
ACE-083 150 mg ACE-083 200 mg ACE-083 240 mg Overall 
Listings will contain only the treatment groups shown with no “Overall” group. 
 
 


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Part 2 
Unless otherwise stated, tables and figures will be presented using one or more of the following 
as shown below, depending on what is being summarized/analyzed. 
Part 2 – Double-blind period 
Placebo ACE-083 Overall 
Part 2 – Open-label period –by treatment group sequence 
ACE-083ACE-083 PlaceboACE-083 
Part 2 – Open-label period – Pooled across treatment group sequence 
ACE-083 
Listings will contain the treatment groups shown above however, there will be no “Overall” 
group. 
4.1.4. 
Definitions of Baseline 
Part 1 and Part 2 (Double-blind Phase) 
Baseline is defined to be the last non-missing assessment prior to the first dose of study drug 
administration.  Theoretically, this could be either the Screening assessment or the Day 1 
assessment depending on the parameter.   
The first dose date will serve as the reference from which the non-missing pre-treatment values 
would be identified. For patients that are randomized (applicable to patients participating in 
Part 2) but do not receive any study drug administration, the date of randomization will be the 
baseline reference.    
 
 


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Part 2 (Open-label Extension) 
For assessments performed in the open-label extension the baseline is defined to be the Day 190 
assessment.   
4.1.5. 
Data Handling Conventions 
Unless otherwise stated or indicated: 
 Individual data for all patients will be presented in data listings, sorted by “Study 
Part” (Part 1 or Part 2), “Treatment Group”, and “Patient Number”; 
 For any parameter analyzed, only observations from visits and/or time points planned 
in the protocol will be used in descriptive statistics.  An exception to this rule is for a 
baseline assessment.  Should an unscheduled assessment be taken after the scheduled 
baseline assessment but before the first dose of study medication, then the 
unscheduled assessment may be used as the baseline; 
 For variables where the Day 1 assessment is defined as the baseline, should an 
individual patient have a Day 1 assessment after having received their first dose, then 
an unscheduled assessment may be used as the baseline, provided that the 
unscheduled assessment was done prior to first dose. 
 Should a patient be assigned to the wrong CMT-type stratum (e.g. a CMT1 patient 
assigned to the CMTX stratum or a CMTX patient assigned to the CMT1 stratum), 
the patient’s true CMT-type (CMT1 or CMTX) will be used in statistical models 
where CMT-type is used as a covariate. 
 With the exception of what is described in the preceding bullet, unscheduled 
assessments will not be collectively summarized in summary tables or figures; 
however, these data will appear in individual patient listings. 
 For adverse events where the assessment of “Relationship to study drug” is missing, it 
will be assumed that the adverse event is “Probably Related” to study drug. 
 For selected pharmacodynamic and efficacy data, tests of statistical hypotheses and 
estimation using the end-of-treatment visit or the Day 190 visit (Part 2 double-blind 
component), multiple imputation for missing data will be performed.  Additional 
techniques for handling missing data may also be considered and evaluated.   
 If a patient has a Day 190 assessment performed after having received the Day 190 
dose (first dose in the open-label phase), then the Day 190 assessment for that patient 
will be included in statistical analyses of Day 190 data only if the difference between 
the Day 190 assessment and the Day 190 dose date is less than or equal to 7 days. 
 Descriptive statistics for quantitative parameters will be provided using number of 
observations (N), mean, standard deviation (SD), standard error of the mean (SEM), 
median, minimum and maximum; 
 Should it be necessary to convert duration in days to duration in months, the duration 
in days will be divided by 30.417 (365/12) to calculate duration in months. 


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 Descriptive statistics for qualitative parameters will be provided using frequencies 
(N) and percentages (%). 
 If the result of a continuous variable contains nonnumeric values (e.g. ‘<X’ or ‘>X’), 
the imputed values used for the descriptive statistics will be determined by 
considering the following rules: 
 If the value is ‘<X’, the value used will be X/2; 
 If the value is ‘>X’, the value used will be X. 
 Concerning the determination of absolute and percent change from baseline for data 
such as MRI and muscle strength where assessments are reported separately for the 
left and right sides and the average absolute and/or percent change from baseline is 
needed, the absolute and/or percent change is determined for the left and right sides 
separately and then averaged.  The “average” represents the “average” absolute (or 
percent) change from baseline for the left and right sides.  For MRI and muscle 
strength data, should a patient have an MRI and/or strength assessment on one side 
(i.e. right side) but not the other side at an individual time point, the value for the 
average absolute (or percent) change from baseline for that patient and time point will 
be the absolute (or percent) change from the side from which the MRI and/or strength 
assessment was obtained. 
4.2. 
Analysis Population 
The analysis populations include the following: 
 Full Analysis Set: Part 1 – All patients enrolled in the study receiving at least one 
dose of ACE-083. Part 2 – All patients randomized who have received at least one 
dose of study drug (includes placebo); 
 Safety Set: All patients enrolled/randomized in the study who have received at least 
one dose of study drug (includes placebo); 
 Per Protocol Set: All patients enrolled/randomized in the study who have received at 
least one dose of study drug (includes placebo) with no data or study procedural 
related issues that would otherwise impact the interpretability of the efficacy and/or 
pharmacodynamic data. 
Such issues include but are not necessarily limited to: 
 Patients who discontinue the study prior to the Dose 3 Day 43 visit; these patients 
may have been replaced per protocol 
 Patients whose Day 1 MRI or Day 190 MRI was done 7 or more days following 
study drug administration 
 Patients who did not receive the full study drug administration planned per 
protocol at all injection sites on any or both sides (right or left) for 2 or more 
consecutive visits for reasons other than dose reductions for the safety of the 
patient or feasibility concern (i.e., the site intended to administer the full dose but 
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 Patients whose Screening cumulative distance walked at 6 minutes is greater than 
500 meters or less than 150 meters. 
A review of the patient data will be performed and a list of patients to be excluded from the Per 
Protocol Set along with the reason for exclusion will be completed before the data is locked and 
unblinded. 
Statistical analyses of efficacy and pharmacodynamics data will be performed on the Per 
Protocol Set (primary analysis population) and the Full Analysis Set (secondary analysis 
population).  Analyses of safety data will be performed on the Safety Set.  Should the statistical 
analysis populations be identical (e.g., Full Analysis Set = Per Protocol Set), statistical analyses 
will not be duplicated or repeated.   
4.3. 
Subject Disposition 
Individual patient disposition data will be listed. 
Frequency counts will be tabulated for disposition data and will include the following: 
 Number of patients enrolled [Part 1 only], 
 Number of patients randomized [Part 2 only], 
 Number (%) of patients completing the study [Part 1 only], 
 Number (%) of patients completing the double-blind treatment period [Part 2 only] 
 A patient is said to have completed the double-blind treatment period if the 
patient completed up to and including the Day 190 visit. 
 Number (%) of patients entered into the open-label period [Part 2 only] 
 Number (%) of patients completing the open-label treatment period [Part 2 only] 
 A patient is said to have completed the open-label treatment period if the patient 
completed up to and including the Day 337 visit. 
 Number (%) of patients that rollover to the extension study, A083-04 
 Patients that rollover to the extension study consist only of patients participating 
in Part 2 of this study who complete both the double-blind treatment period AND 
the open-label treatment period who will not have the Day 393/EOS visit.  These 
patients’ final study visit will be the Day 358/ET visit. 
 Number (%) of patients that do not rollover to the extension study A083-04 
 Patients that do not rollover to the extension study will have both the Day 358/ET 
and Day 393/EOS visits completed. 
 Number (%) of patients discontinuing from the study prior to completing both the 
double-blind period and the open label period [Part 2 only] 
 Number (%) of patients that discontinued during the double-blind period  
 Number (%) of patients that discontinued during the open-label period  


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 Number (%) of patients for primary reason for discontinuation will also be 
provided [provided there is at least one patient who discontinued]. 
Summaries will be provided by treatment and overall for each study part (Part 1 and Part 2). 
4.4. 
Demographic and Baseline Characteristics 
4.4.1. 
Demographics 
Individual demographic data will be listed. 
Descriptive statistics (N, mean, SD, median, minimum and maximum) will be provided for 
continuous demographic variables (age, weight, height, and BMI) and frequency counts will be 
tabulated for categorical demographic variables (gender, race, ethnicity) by treatment and overall 
for each study part (Part 1 and Part 2).  Age will be calculated based on birth date and informed 
consent date. 
4.4.2. 
Baseline Characteristics 
Baseline characteristics of the patient population consist of selected items from the CMT disease 
history, MRI, MRC-MMT, and functional test data.  Such data includes the following: 
 Age at onset of symptoms (years) 
 Age at diagnosis (years) 
 Duration since onset of symptoms (years) 
 Duration since onset of symptoms = Age (years) – Age at onset of symptoms 
(years) 
 Duration since diagnosis (years) 
 Duration since diagnosis = Age (years) – Age at diagnosis (years) 
 Total muscle volume (mm3) 
 See Section 4.8.1 for definition. 
 Total muscle mass (g) 
 See Section 4.8.1 for definition. 
 Calculated contractile muscle volume (mm3) 
 See Section 4.8.1 for definition. 
 Calculated contractile muscle mass (g) 
 See Section 4.8.1 for definition. 
 Fat fraction (%) 
 6-minute walk distance (m) 
 Time to complete 10 meter walk/run (s) 


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 Number and percent of patients belonging to specified CMT Type (i.e., CMT1, 
CMTX) 
 Number and percent of CMT1 patients belonging to specified CMT1 subtype/gene 
mutation (e.g., CMT1A, CMT1B) 
 Number and percent of CMTX patients belonging to specified CMTX subtype/gene 
mutation (e.g., CMTX1) 
 Number and percent of patients belonging to specific forms of CMT (e.g., 
demyelinating, axonal, mixed) 
 Number and percent of patients with first degree relatives with CMT 
 Number and percent of patients who have fallen to the ground in the past 6 months 
 Number and percent of patients who have had past history of fractures 
 Number and percent of patients who have had past surgery for CMT 
 Number and percent of patients who wears any lower limb orthotics/braces 
 Number and percent of patients who uses assistive devices 
 Number and percent of patients who have a regular (at least once a week) exercise 
program 
 For those who have a regular exercise program, the type (aerobic, resistance 
training, or both) and frequency of exercise program (1-2, 3-4, or 5+ times per 
week) will also be summarized. 
 Number and percent of patients who have known nerve conduction velocity 
 For those who have a known nerve conduction velocity, the category (< 38 m/s, 
≥ 38) will also be summarized. 
  Number and percent of patients with MRC-MMT grades belonging to the following 
categories:  [3 to 4-], [4 to 4+], [5- to 5] 
 Summaries will be provided for each side (left and right) separately for ankle 
dorsiflexion, knee extension, and plantar flexion. 
 MRC-MMT grades will also be summarized (frequency with percent) by the weakest 
grade (left or right) for ankle dorsiflexion, knee extension, and plantar flexion. 
 MRC-MMT SCORE which represents the conversion of the MRC-MMT grade to the 
decimal version as follows: 5 = 5.0, 5- = 4.67, 4+ = 4.33, 4 = 4.0, 4- = 3.67, 
3+ = 3.33, 3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 1 = 1.0. 
 This will be determined for each side (left and right) and then averaged.  The 
average will be presented in the summary table.  This will be done for ankle 
dorsiflexion. 
 Dose of ACE-083 expressed as (mg/g calculated total muscle mass) 
 Dose of ACE-083 expressed as (mg/g calculated contractile muscle mass) 


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 CMTES2 Score 
 See Section 4.7.1.4 for details on how this score is derived. 
 Berg Balance Scale total score 
 See Section 4.7.1.4 for details on how this score is derived. 
The table below outlines how to derive the dose of ACE-083 expressed as either mg/g total 
muscle, or mg/g contractile muscle: 
 
Dose of ACE-083 Expressed as 
mg/g Calculated Total Muscle Mass 
mg/g Calculated Contractile Muscle Mass 
Bilateral  
Cohorts 
Step 1: For each side (right and left), compute 
the following: Dose injected (mg) /(Baseline 
CCMV {mm3}* [1.06/1000] + Baseline 
CIMFV {mm3}* [0.9/1000]) 
Step 2: Compute average of the Dose of 
ACE-083 expressed as mg/g total muscle for 
each side using the information obtained from 
Step 1. 
Step 1: For each side (right and left), 
compute the following: Dose injected (mg) 
/(Baseline CCMV {mm3}* [1.06/1000]) 
Step 2: Compute average of the Dose of 
ACE-083 expressed as mg/g contractile 
muscle for each side using the information 
obtained from Step 1. 
CCMV = Calculated contractile muscle volume; CIMFV = Calculated intramuscular fat volume 
This data will be summarized using appropriate descriptive statistics.   
4.5. 
Prior and Concomitant Medications/Therapy 
Prior and concomitant medications recorded during the study will be listed.  These will be coded 
with the WHO Drug Dictionary (Version 201603 DDE). 
Medications will be assigned as prior or concomitant based on the following rules: 
 If both the start and stop date exist and are before the first dose date of study drug, the 
medication will be classified as a prior medication. 
 If the start date is on or after the first dose date of study drug, the medication will be 
classified as a concomitant medication. 
 If the start date is before the first dose date of study drug and the stop date is after the 
first dose date of study drug or the medication is ongoing, the medication will be 
classified as prior and concomitant. 
 If the start date is missing and the stop date is before the first dose of study drug, the 
medication will be classified as prior. 
 If the start date is missing and the stop date is after the first dose of study drug or the 
medication is ongoing, the medication will be classified as concomitant. 
 If the start and stop dates are missing, the medication will be classified as 
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4.6. 
Study Drug Exposure 
4.6.1. 
Extent of Exposure 
A listing of individual patient dosing data will be provided. 
Study drug exposure will be summarized descriptively by cohort (Part 1) and by treatment group 
for each muscle (Part 2) for the safety population.  Such summaries will include the total number 
of treatment doses, the number and percentage of patients with dose delay and reduction.  If no 
patients experience dose delay and reduction, then no such summaries will be provided. 
The total number of doses will be summarized by presenting the number and percentage of 
patients in each category.  Categories refer to the total number of treatment doses.  For Part 1, the 
possible values of the total number of treatment doses are:  “1”, “2”, “3”, “4”, and “5”.  For Part 
2 (double-blind period), the possible values of the total number of treatment doses over the 
course of the double-blind treatment period is: “1”, “2”, “3”, “4”, “5”, “6”, “7”, “8”, or “9”.  For 
Part 2 (open-label extension), the possible values of the total number of treatment doses over the 
course of the open-label extension is: “1”, “2”, “3”, “4”, “5”, “6”, “7”, or “8”. 
The total study drug exposure in weeks will also be summarized and will be derived according to 
the following formula: Exposure (weeks) = [(Last dose date – First dose date) +21] / 7. 
For Part 1, summaries of the total study drug exposure in weeks will be provided by cohort using 
descriptive statistics.  The summary table will include a pooled summary across cohorts within 
each muscle treated. 
For Part 2, summaries of the total study drug exposure in weeks will be provided by treatment 
group for each muscle treated.  This will be done for the double-blind and open-label periods. 
4.7. 
Efficacy Data 
4.7.1. 
Variables 
4.7.1.1. 
Muscle Strength 
Muscle strength variables consist of the following: 
 Maximum (of 3 measurements) right ankle dorsiflexion MVIC  
o MVIC = maximum force (from 3 measurements) from the hand-held 
dynamometer 
 Maximum (of 3 measurements) left ankle dorsiflexion MVIC  
  (Part 2 only):  MRC-MMT SCORE which represents the conversion of the MRC-MMT 
grade to the decimal version as follows:  5 = 5.0, 5- = 4.67, 4+ = 4.33, 4 = 4.0, 4- = 3.67, 
3+ = 3.33, 3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 1=1.0 
For each of the muscle strength variables listed above, the absolute and percent change from 
baseline will be determined for each side (left, right) at each time point.  In addition, the absolute 
and percent change from baseline will be determined for the average of the left and right sides at 
each time point. 


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4.7.1.2. 
Motor Function  
10-Meter Walk/Run Test 
 Time to complete 10-meter walk/run (seconds) 
6-Minute Walk Test 
 Cumulative distance traveled at 1 minute (meters) 
 Cumulative distance traveled at 2 minutes (meters) 
 Cumulative distance traveled at 3 minutes (meters) 
 Cumulative distance traveled at 4 minutes (meters) 
 Cumulative distance traveled at 5 minutes (meters) 
 Cumulative distance traveled at 6 minutes (meters) 
100-meter timed test (Part 2 open-label period only) 
 Time to complete 100-meters (sec.) 
Gait assessments 
 General measures: Stride time (sec.), Stride length A (m), Stride length B (% height), 
Stride velocity A (m/s), Stride velocity B (height/s), Cadence (steps/min), Step length 
left (m), Step length right (m) 
 Gait cycle phase measures:  Swing left (%), Swing right (%), Stance left (%), Stance 
right (%), Double support initial right (%), Double support terminal left (%), Double 
support total (%) 
 Gait assessment range of motion: Knee ROM left (deg.), Knee ROM right (deg.), Hip 
ROM left (deg.), Hip ROM right (deg.), Ankle ROM left (deg.), Ankle ROM right 
(deg.), Peak hip flexion angle in swing left (deg.), Peak hip flexion angle in swing 
right (deg.), Peak knee flexion angle in swing left (deg.), Peak knee flexion angle in 
swing right (deg.), Peak ankle flexion angle in swing left (deg.), Peak ankle flexion 
angle in swing right (deg.) 
 Gait assessment foot drop: Mid-swing foot angle left (deg.), Mid-swing foot angle 
right (deg.) 
For gait assessments reported on the left and right sides, the absolute and percent change from 
baseline will be determined for each side and then averaged.  Should a patient have a gait 
assessment reported for one side (i.e. right side) but not the other side at an individual time point, 
the value for the average absolute (or percent) change from baseline for that patient and time 
point will be the absolute (or percent) change from the side from which the gait assessment was 
obtained. 
Berg Balance Scale 
 Total score from the 14 items on the instrument.   


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 The 14 items on the instrument are:  Sitting to standing, Standing unsupported, 
Sitting with back unsupported but feet supported on floor or on a stool, Standing 
to sitting, Transfers, Standing unsupported with eyes closed, Standing 
unsupported with feet together, Reaching forward with outstretched arm while 
standing, Pick up object from the floor from a standing position, Turning to look 
behind over left and right shoulders while standing, Turn 360 degrees, Placing 
alternate foot on step or stool while standing unsupported, Standing unsupported 
one foot in front, and Standing on one leg.   
 Each item score ranges from 0 to 4.  The total score ranges from 0 to 56. 
Falls (Part 2 double-blind and open-label) 
 Number of falls reported by patients wearing the PAMSys™ device 
 From Week 1 to Week 12 (3 months) [inclusive] 
 From Week 13 (3 months) up to Week 24 (6 months) [inclusive] 
 From Week 1 to Week 24 (6 months) [inclusive] 
 From Week 25 to Week 36 [inclusive] 
 From Week 37 to Week 40 [inclusive] 
 From Week 25 (6 months) to Week 48 (12 months) [inclusive] 
 From Week 1 up to Week 48 (12 months) [inclusive] 
 Number of patients who fell at least once 
 From Week 1 to Week 12 (3 months) [inclusive] 
 From Week 13 (3 months) up to Week 24 (6 months) [inclusive] 
 From Week 1 to Week 24 (6 months) [inclusive] 
 From Week 25 to Week 36 [inclusive] 
 From Week 37 to Week 40 [inclusive] 
 From Week 25 (6 months) to Week 48 (12 months) [inclusive] 
 From Week 1 up to Week 48 (12 months) [inclusive] 
 Risk of recurrent falls from Week 1 up to Week 24 (6 months) 
 Risk of recurrent falls from Week 1 up to Week 48 (12 months) 
Activity Level (Part 2 double-blind and open-label) 
Activity level is defined as the average number of steps per day as measured by the PAMSys™ 
device over the patient’s study participation, adjusted for overall compliance in using the device 
to record such activity. 


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4.7.1.3. 
Patient Reported Outcome Variables 
Charcot-Marie-Tooth Health Index (CMT-HI) 
 CMT-HI total score 
 The 18 subscale scores of the CMT-HI 
 Mobility, Foot and ankle strength, Balance, Activities, Hand and finger function, 
Shoulder and arm function, Numbness, Pain, Fatigue, Sleep and daytime 
sleepiness, Emotions, Social Performance, Cognition, Heartburn, Constipation, 
Hearing, Breathing, and Ability to swallow 
4.7.1.4. 
Physician Reported Outcome Variables 
Charcot-Marie-Tooth Examination Score – Version 2 (CMTES2) 
 This is the sum of the following items from the CMT neuropathy score instrument 
(Murphy et al., 2011): Sensory symptoms, Motor symptoms (legs), Motor symptoms 
(arms), Pinprick Sensibility, Vibration, Strength (legs), and Strength (arms) 
 Each individual item is assessed using a rating from 0 to 4 inclusive.  The range 
of CMTES2 scores is from 0 to 28 inclusive. 
4.7.2. 
Analyses  
4.7.2.1. 
Part 1 
Unless otherwise specified, no imputations for missing data will be performed for Part 1 data. 
Muscle Strength [Maximum voluntary isometric contraction {MVIC}] 
Individual MVIC data will be listed. 
Descriptive statistics of the raw data as well as the absolute and percent change from baseline 
will be provided by side treated [left and right].  The average absolute and average percent 
change from baseline for the left and right sides will also be provided. 
Least squares mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the average percent change data (left and right sides) at 
3-weeks post last dose [theoretically the Day 106 assessment] described above using an  analysis 
of covariance (ANCOVA) with  BASELINE, COHORT, BASELINE*COHORT, and CMT-
TYPE as covariates where: 
 COHORT represents the dose level of ACE-083 administered to the muscle 
 BASELINE represents the baseline value (average for the left and right sides) 
 BASELINE*COHORT represents the interaction of the baseline and cohort 
 CMT-TYPE refers to the type of patient (e.g. CMT1 or CMTX) 
Additional analyses may be performed as appropriate. 


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Motor Function Variables 
Individual motor function data will be listed. 
For motor function test variables (e.g. cumulative distance at 6 minutes from the 6-minute walk 
test, time to complete 10-meter walk/run test, gait parameters, Berg Balance Scale), descriptive 
statistics of the raw data as well as absolute and percent change from baseline will be provided.   
With the exception of gait parameters, cumulative distances at 1 to 5 minutes inclusive, and the 
Berg Balance Scale, least squares mean estimates of the effect of ACE-083 and corresponding 
90% and 95% confidence intervals will be produced for the percent change data (as well as 
absolute change data for 6MWD) at 3 weeks post last dose [theoretically the Day 106/End-of-
Treatment assessment] described above using an ANCOVA with BASELINE, COHORT, 
BASELINE*COHORT, and CMT-TYPE as covariates where BASELINE refers to the baseline 
motor function value and the other covariates are defined similarly as for the strength variables 
above. 
Additional analyses may be performed as appropriate. 
Patient Reported Outcome Variables 
Individual CMT-HI data will be listed. 
For CMT-HI total score and subscale scores, descriptive statistics of the raw data as well as 
absolute change from baseline will be provided. 
Least square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the absolute change data at 3 weeks post last dose 
[theoretically the Day 106/End-of-Treatment assessment] described above using an ANCOVA 
with BASELINE, COHORT, BASELINE*COHORT, and CMT-TYPE as covariates where 
BASELINE refers to the baseline patient reported outcome variable (i.e. CMT-HI total score or 
CMT-HI subscale score) and the other covariates are defined similarly as for the strength 
variables above. 
Additional analyses may be performed as appropriate. 
Physician Reported Outcome Variables 
Individual data from the CMTES2 will be listed. 
For CMTES2, descriptive statistics of the raw data as well as the absolute and percent change 
from baseline will be provided. 
Least square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the absolute change data at 3 weeks post last dose 
[theoretically the Day 106/End-of-Treatment assessment] described above using an ANCOVA 
with BASELINE, COHORT, BASELINE*COHORT, and CMT-TYPE as covariates where 
BASELINE represents the baseline CMTES2 and the other covariates are defined similarly as 
for the strength variables above. 
Additional analyses may be performed as appropriate. 


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4.7.2.2. 
Part 2 
4.7.2.2.1. Double-Blind Period 
Muscle Strength (MVIC) 
Individual MVIC data will be listed. 
Descriptive statistics of the raw data as well as the absolute and percent change from baseline 
will be provided by side treated [left and right].  The average absolute and average percent 
change from baseline for the left and right sides will also be provided. 
A plot of the mean (± SEM) of the average percent change from baseline for the left and right 
sides by scheduled day and treatment group will also be provided. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the average 
percent change from baseline for the left and right side at Day 190 with the following covariates:  
TREATMENT, MRC-MMT DECIMAL SCORE, BASELINE, CMT-TYPE where: 
 TREATMENT represents the treatment group (ACE-083 or placebo) 
 MRC-MMT DECIMAL SCORE represents the conversion of the screening MRC-
MMT grade to the decimal version as follows:  5 = 5.0, 5- = 4.67, 4+ = 4.33,  4 = 4.0, 
4- = 3.67, 3+ = 3.33, 3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 
1=1.0 
 This quantity will be the average from the left and right sides and will be 
computed for each individual patient. 
 BASELINE represents the baseline MVIC (average of left and right sides) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
The effect of ACE-083 versus placebo will be estimated using the ANCOVA model described 
above and tested using a 0.1 significance level (2-sided).  The least-square mean estimate along 
with the corresponding 90% confidence interval will be provided.  In addition, the 95% 
confidence interval will also be provided.  A bar chart of the least squares mean ± SEM of the 
percent change from baseline will be provided. 
If the Day 190 MVIC assessment has no missing data, then the above ANCOVA model will be 
used for analysis.  If missing data is present, a standard multiple imputation with the above 
ANCOVA model will be used for analysis as described in Section 4.11.1.  
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails to converge.  The covariates to be included consist of all of 
the covariates described above for the ANCOVA with the addition of the following additional 
covariates:  VISIT where VISIT represents the scheduled visit day post first dose of MRI 
assessment and TREATMENT*VISIT. 


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Similar to what was described for the ANCOVA analysis above, if missing data is present, a 
standard multiple imputation with the above MMRM model will be used for analysis as 
described in Section 4.11.1 . 
The findings from the ANCOVA model described above will be considered primary. 
Additional analyses may be performed as appropriate. 
MRC-MMT Decimal Score 
Descriptive statistics will be provided for raw and percent change from baseline for the 
MRC-MMT decimal score for ankle dorsiflexion for each side where the MRC-MMT decimal 
score represents the conversion of the MRC-MMT grade to the decimal version as follows: 
5 = 5.0, 5- = 4.67, 4+ = 4.33,  4 = 4.0, 4- = 3.67, 3+ = 3.33, 3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 
2- = 1.67, 1+ = 1.33, 1=1.0.  The average percent change from baseline for the left and right 
sides will also be provided. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the average Day 
190 absolute change in the MRC-MMT decimal score for ankle dorsiflexion with placebo.  The 
ANCOVA model will contain the following covariates:  TREATMENT, BASELINE 
MRC-MMT DECIMAL SCORE, and CMT-TYPE where BASELINE MRC-MMT DECIMAL 
SCORE represents the MRC-MMT decimal score for ankle dorsiflexion (average of right and 
left sides) and the other covariates are defined similarly as described for MVIC.  A bar chart of 
the least squares mean ± SEM of the percent change from baseline will be provided. 
No imputations will be performed for missing data. 
Additional analyses may be performed as appropriate. 
10-Meter Walk/Run Test 
Individual data will be listed. 
Descriptive statistics of raw data as well as absolute and percent change from baseline will be 
provided by treatment group for each scheduled time.  A plot of mean ± SEM will also be 
provided for the percent change from baseline for each treatment group. 
An ANCOVA model will also be fitted in order to assess the effect of ACE-083 on the Day 190 
percent change in the time to complete the 10-meter walk/run test from baseline data.  Covariates 
to be included in the model are TREATMENT, HEIGHT, CMT-TYPE and BASELINE where 
BASELINE represents the baseline time to complete the 10-meter walk/run, HEIGHT represents 
the height of the patient in centimeters, and each of the other covariates are defined similarly as 
what was described for MVIC. 
The effect of ACE-083 on the Day 190 percent change in the time to complete the 10-meter 
walk/run test from baseline versus placebo will be estimated using the ANCOVA model 
described above and tested using a 0.1 significance level (2-sided).  The least-square mean 
estimate along with the corresponding 90% confidence interval will be provided.  In addition, the 
95% confidence interval will also be provided as well as a bar chart of the least squares mean 
estimates (± SEM) for each of the treatment groups. 


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If the Day 190 10-meter walk/run test has no missing data, then the above ANCOVA model will 
be used for analysis.  If missing data is present, a standard multiple imputation with the above 
ANCOVA model will be used for analysis as described in Section 4.11.1  
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT. 
Similar to what was described for the ANCOVA analysis above, if missing data is present, a 
standard multiple imputation with the above MMRM model will be used for analysis as 
described in Section 4.11.1. 
The findings from the ANCOVA model described above will be considered primary.  
The analyses described above will also be done for the absolute change from baseline.  
The analyses described above will also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
6-Minute Walk Test 
Individual data will be listed. 
Descriptive statistics of raw data as well as changes from baseline (absolute and percent change) 
will be provided by treatment group by scheduled time separately for cumulative distance 
recorded at 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, and 6 minutes.  A plot of mean 
± SEM for the cumulative distance recorded at 6 minutes will also be provided for the percent 
change from baseline for each treatment group. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
percent change in the cumulative distance recorded at 6 minutes.  Covariates to be included in 
the model are TREATMENT, HEIGHT, CMT-TYPE, and BASELINE where HEIGHT refers to 
the height of the patient (cm) and BASELINE represents the baseline distance walked in 6 
minutes and each of the other covariates are defined the same as what was described for MVIC.  
The effect of ACE-083 on the Day 190 percent change in the cumulative distance recorded at 6 
minutes from baseline versus placebo will be estimated using the ANCOVA model described 
above and tested using a 0.1 significance level (2-sided).  The least-square mean estimate along 
with the corresponding 90% confidence interval will be provided.  In addition, the 95% 
confidence interval will also be provided as well as a bar chart of the least squares mean 
estimates (± SEM) for each of the treatment groups. 
An ANCOVA model will also be fitted in order to assess the effect of ACE-083 on the Day 190 
absolute change in the cumulative distance recorded at 6 minutes from baseline data.  Covariates 
to be included in the model are TREATMENT, HEIGHT, CMT-TYPE, and BASELINE where 
HEIGHT refers to the height of the patient (cm) and BASELINE represents the baseline distance 


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walked in 6 minutes and each of the other covariates are defined the same as what was described 
for MVIC. 
The effect of ACE-083 on the Day 190 absolute change in the cumulative distance recorded at 6 
minutes from baseline versus placebo will be estimated using the ANCOVA model described 
above and tested using a 0.1 significance level (2-sided).  The least-square mean estimate along 
with the corresponding 90% confidence interval will be provided.  In addition, the 95% 
confidence interval will also be provided as well as a bar chart of the least squares mean 
estimates (± SEM) for each of the treatment groups. 
If the Day 190 cumulative distance recorded at 6 minutes has no missing data, then the 
ANCOVA models described above will be used for analysis.  If missing data is present, a 
standard multiple imputation with the above ANCOVA models will be used for analysis as 
described in Section 4.11.1. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analyses described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT. 
Similar to what was described for the ANCOVA analyses above, if missing data is present, a 
standard multiple imputation with the above MMRM model will be used for analysis as 
described in Section 4.11.1. 
The findings from the ANCOVA model described above will be considered primary. 
The analyses described above will also be done for the absolute change from baseline. 
The analyses described above will also be repeated for the Full Analysis Set. 
Additional analyses may be performed as appropriate. 
Berg Balance Scale 
Individual data will be listed. 
Descriptive statistics of raw data as well as changes from baseline (absolute and percent change) 
will be provided by treatment group and scheduled time. 
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
absolute change in the Berg Balance Score from baseline.  Covariates to be included are 
TREATMENT, CMT-TYPE, and BASELINE where BASELINE refers to the baseline Berg 
Balance Score and the other covariates are defined similarly as for MVIC. 
The effect of ACE-083 on the Day 190 absolute change in the Berg Balance Scale versus 
placebo will be estimated using the ANCOVA model described above and tested using a 
0.1 significance level (2-sided).  The least-square mean estimate along with the corresponding 
90% confidence interval will be provided.  In addition, the 95% confidence interval will also be 
provided as well as a bar chart of the least squares means estimates (± SEM) for each of the 
treatment groups. 


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If the Day 190 Berg balance assessment has no missing data, then the above ANCOVA model 
will be used for analysis.  If missing data is present, a standard multiple imputation with the 
above ANCOVA model will be used for analysis as described in Section 4.11.1. 
The statistical analyses described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
Additional analyses may be performed as appropriate. 
Falls 
Individual data on the number and type of falls recorded in 4-week time intervals along with 
details on the timing and classification of the individual falls recorded, type of assistance, and 
information related to input (whether the fall was recorded by device detection or recorded by 
the individual patient) will be provided in a listing. 
The number of falls, as well as the number of patients who fell at least once occurring from 
Week 1 to Week 24 (6 months) will be summarized by treatment group.  Summaries will be 
provided for the additional subintervals between Weeks 1 and 24 as outlined in Section 4.7.1.2.  
A record of “Near-fall” will not be counted as a “Fall”. 
The hazard ratio of recurring falls between ACE-083 and placebo between Weeks 1 and 24 will 
be estimated using the Andersen-Gill recurrent events model with the following covariates:  
TREATMENT, CMT-TYPE, and ankle dorsiflexion MRC-MMT decimal score where the 
covariates are defined similarly as what was described for MVIC.  The point estimate, p-value 
and 90% confidence interval for the hazard ratio for TREATMENT will be provided. 
Additional methods for the statistical analysis of the recurring event of falls may be considered 
and performed as appropriate (e.g. negative binomial regression with similar covariates as listed 
for the Andersen-Gill recurrent events model described above). 
No imputations will be performed for missing data. 
The statistical analyses described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
Additional analyses may be performed as appropriate. 
CMT-HI 
Individual CMT-HI scored data (total score and each of the subscale scores) will be listed. 
Descriptive statistics for the total CMT-HI score as well as for each subscale score will be 
provided by treatment group and scheduled time for raw data and absolute change from baseline.  
A line graph of the mean ± SEM will also be provided for the absolute change from baseline by 
treatment for each scheduled time. 
Least square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the Day 190 absolute change data described above 
using an ANCOVA model with BASELINE, CMT-TYPE, and TREATMENT as covariates 


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where BASELINE, CMT-TYPE, and TREATMENT are defined similarly as described above 
for other analyses. 
Similar analyses will be done for each of the individual subscale scores. 
In addition, a bar chart of the Day 190 least squares mean absolute change estimates (± SEM) 
will be provided for the following CMT-HI parameters:  CMT-HI total score, CMT-HI mobility, 
CMT-HI activities, CMT-HI pain, and CMT-HI balance. 
If the Day 190 CMT-HI has no missing data, then the above ANCOVA model will be used for 
analysis.  If missing data is present, a standard multiple imputation with the above ANCOVA 
model will be used for analysis as described in Section 4.11.1. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analyses described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT.  
Similar to what was described for the ANCOVA analysis above, if missing data is present, a 
standard multiple imputation with the above MMRM model will be used for analysis as 
described in Section 4.11.1. 
The findings from the ANCOVA model described above will be considered primary. 
Additional analyses may be performed as appropriate. 
CMTES2 
Individual data will be listed. 
Descriptive statistics for the CMTES2 score will be provided by treatment group for raw data 
and changes from baseline (absolute and percent change).  In addition, a line graph of the mean ± 
SEM will also be provided for the absolute change from baseline by treatment for each 
scheduled time. 
Least square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the Day 190 absolute change data described above 
using an ANCOVA model with CMT-TYPE, BASELINE, and TREATMENT as covariates 
where BASELINE refers to the baseline CMTES2 score and CMT-TYPE and TREATMENT are 
defined similarly as described above for other analyses.  In addition, a bar chart of the least 
squares mean estimates (± SEM) for each treatment group will be provided. 
If the Day 190 CMTES2 assessment has no missing data, then the above ANCOVA model will 
be used for analysis.  If missing data is present, a standard multiple imputation with the above 
ANCOVA model will be used for analysis as described in Section 4.11.1. 
The statistical analyses described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 


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Additional analyses may be performed as appropriate. 
Gait 
Individual data will be listed. 
Descriptive statistics of the raw data and change from baseline (percent and absolute change) 
will be provided for each type of measurement recorded (i.e. “General measures”, “Gait cycle 
phase measures”, “Gait assessment range of motion”, and “Gait assessment foot drop”) by cohort 
and scheduled time (for Part 1) and by treatment group and scheduled time (for Part 2).  
Descriptive statistics for the average absolute and average percent change from baseline for the 
left and right sides will also be provided. 
Lease square mean estimates of the effect of ACE-083 and corresponding 90% and 95% 
confidence intervals will be produced for the Day 190 average absolute change from baseline for 
the left and right sides for the mid-swing foot angle using an ANCOVA model with CMT-TYPE, 
BASELINE, and TREATMENT as covariates where BASELINE refers to the baseline average 
mid-swing foot angle for the left and right sides and CMT-TYPE and TREATMENT are defined 
similarly as described above for other analyses.  In addition, a bar chart of the least squares mean 
estimates (± SEM) for each treatment group will be provided. 
The statistical analysis described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses will also be repeated for the Full Analysis Set. 
No imputations will be performed for missing data. 
Additional analyses may be performed as appropriate. 
Activity Level 
Individual data will be listed. 
Exploratory analyses may be performed as appropriate. 
No imputations will be performed for missing data. 
4.7.2.2.2. Open-Label Extension 
Muscle Strength (MVIC) 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
Descriptive statistics will be provided for raw data and changes (percent and absolute change) 
from the start of the open-label extension (Day 190) will be provided by treatment for each 
scheduled time for each side treated as well as the average from the left and right sides. 
Additional analyses may be performed as appropriate. 
MRC-MMT Decimal Score 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 


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Descriptive statistics will be provided for raw data and changes (percent and absolute change) 
from the start of the open-label extension (Day 190) will be provided by treatment for each 
scheduled time for each side treated as well as the average from the left and right sides. 
Additional analyses may be performed as appropriate. 
10-Meter Walk/Run Test 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
For the time to complete the 10-meter walk/run, descriptive statistics will be provided for raw 
data and changes (percent and absolute change) from the start of the open-label extension 
(Day 190) will be provided by treatment for each scheduled time. 
Additional analyses may be performed as appropriate. 
6-Minute Walk Test 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
For the cumulative distance recorded at 6 minutes, descriptive statistics will be provided for raw 
data and changes (percent and absolute change) from the start of the open-label extension 
(Day 190) will be provided by treatment for each scheduled time. 
Additional analyses may be performed as appropriate. 
Berg Balance 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
Descriptive statistics will be provided for raw data and changes (absolute and percent change) 
from the start of the open-label extension (Day 190) will be provided by treatment for each 
scheduled time. 
Additional analyses may be performed as appropriate. 
Falls 
Individual data on the number and type of falls recorded in 4-week time intervals along with 
details on the timing and classification of the individual falls recorded, per day, type of 
assistance, and information related to input (whether the fall was recorded by device detection or 
recorded by the individual patient) will be provided in a listing.  This data will be included with 
the data collected in the double-blind placebo-controlled phase. 
The number of falls as well as the number of patients who fell at least once occurring from Week 
25 up to Week 48 inclusive will be summarized by treatment, including separate summaries for 
subintervals as outlined in Section 4.7.1.2.  A record of “Near-fall” will not be counted as a 
“Fall”. 
Additional analyses may be performed as appropriate. 


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CMT-HI 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
For the total CMT-HI and subgroup scores, descriptive statistics will be provided for raw data 
and absolute change from the start of the open-label extension (Day 190) will be provided by 
treatment for each scheduled time. 
Additional analyses may be performed as appropriate. 
CMTES2 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
For the CMTES2 score, descriptive statistics will be provided for raw data and absolute change 
from the start of the open-label extension (Day 190) will be provided by treatment for each 
scheduled time. 
Additional analyses may be performed as appropriate. 
Gait 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
For each type of measurement recorded (i.e. “General measures”, “Gait cycle phase measures”, 
“Gait assessment range of motion”, and “Gait assessment foot drop”), descriptive statistics will 
be provided for raw data as well as absolute and percent changes from the start of the open-label 
extension (Day 190) will be provided by treatment for each scheduled time.  Descriptive 
statistics of the average absolute and average percent change from baseline for the left and right 
sides will also be provided. 
Additional analyses may be performed as appropriate. 
Activity Level 
Individual data will be listed. 
Exploratory analyses may be performed as appropriate. 
No imputations will be performed for missing data. 
4.7.2.2.3. Open-Label vs. Double-Blind Placebo-Controlled Period 
MVIC  
The effect of ACE-083 administered during the open-label extension compared to the treatment 
administered in the double-blind placebo-controlled phase will be examined for those receiving 
ACE-083 during the double-blind phase and separately for those receiving placebo during the 
double-blind phase by comparing the average absolute and/or percent changes [depending on the 
parameter] observed between Day 190 and pre-first treatment baseline (1st 6 months) and Day 
358 versus Day 190 (2nd 6 months) using an ANCOVA model. 


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Possible covariates to be included into the model are SEQUENCE, MRC-MMT SCORE, 
CMT-TYPE and BASELINE where: 
 SEQUENCE represents the treatment sequence from double blind to open-label 
(ACE-083  ACE-083 or Placebo  ACE-083) 
 MRC-MMT SCORE represents the conversion of the screening MRC-MMT grade to 
the decimal version as follows:  5 = 5.0, 5- = 4.67, 4+ = 4.33,  4 = 4.0, 4- = 3.67, 
3+ = 3.33, 3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 1=1.0 
 CMT TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
 BASELINE represents the baseline value from the double-blind phase 
Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided.   
If the Day 358 and/or Day 190 assessments have no missing data, then the above ANCOVA 
model will be used for analysis.  If missing data is present, a standard multiple imputation with 
the above ANCOVA model will be used for analysis as described in Section 4.11.1.  
In addition, a line graph of the mean ± SEM of the percent change from baseline will be 
provided by sequence for each scheduled time. 
Additional analyses may be performed as appropriate. 
MRC-MMT Decimal Score 
The effect of ACE-083 administered during the open-label extension compared to the treatment 
administered in the double-blind placebo-controlled phase will be examined for those receiving 
ACE-083 during the double-blind phase and separately for those receiving placebo during the 
double-blind phase by comparing the average absolute change [depending on the parameter] 
observed between Day 190 and pre-first treatment baseline (1st 6 months) and Day 358 versus 
Day 190 (2nd 6 months) using an ANCOVA model. 
Possible covariates to be included into the model are SEQUENCE, MRC-MMT SCORE, 
CMT-TYPE and BASELINE where: 
 SEQUENCE represents the treatment sequence from double blind to open-label 
(ACE-083  ACE-083 or Placebo  ACE-083 
 MRC-MMT SCORE represents the conversion of the screening MRC-MMT grade to 
the decimal version as follows:  5 = 5.0, 5- = 4.67, 4+ = 4.33,  4 = 4.0, 4- = 3.67, 
3+ = 3.33, 3 = 3.0, 3- = 2.67, 2+ = 2.33, 2 = 2.0, 2- = 1.67, 1+ = 1.33, 1=1.0 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
 BASELINE represents the baseline value from the double-blind phase 
Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided.   


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10-Meter Walk/Run Test 
The effect of ACE-083 administered during the open-label extension compared to the treatment 
administered in the double-blind placebo-controlled phase will be examined for those receiving 
ACE-083 during the double-blind phase and separately for those receiving placebo during the 
double-blind phase by comparing the absolute and/or percent changes observed between Day 
190 and pre-first treatment baseline (1st 6 months) and Day 358 versus Day 190 (2nd 6 months) 
using an ANCOVA model. 
Covariates to be included into the model are SEQUENCE, HEIGHT, CMT-TYPE, and 
BASELINE where: 
 SEQUENCE represents the treatment sequence from double blind to open-label 
(ACE-083  ACE-083 or Placebo  ACE-083) 
 HEIGHT represents the height of the patient (cm) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
 BASELINE represents the baseline value of the parameter of interest from the 
double-blind phase 
Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided.   
If the Day 358 and/or Day 190 assessments have no missing data, then the above ANCOVA 
model will be used for analysis.  If missing data is present, a standard multiple imputation with 
the above ANCOVA model will be used for analysis as described in Section 4.11.1. 
In addition, a line graph of the mean ± SEM of the percent change from baseline will be 
provided by sequence for each scheduled time. 
Additional analyses may be performed as appropriate. 
6-Minute Walk Test 
The effect of ACE-083 administered during the open-label extension compared to the treatment 
administered in the double-blind placebo-controlled phase will be examined for those receiving 
ACE-083 during the double-blind phase and separately for those receiving placebo during the 
double-blind phase by comparing the absolute and/or percent changes observed between Day 
190 and pre-first treatment baseline (1st 6 months) and Day 358 versus Day 190 (2nd 6 months) 
using an ANCOVA model. 
Covariates to be included into the model are SEQUENCE, HEIGHT, CMT-TYPE, and 
BASELINE where: 
 SEQUENCE represents the treatment sequence from double blind to open-label 
(ACE-083  ACE-083 or Placebo  ACE-083) 
 HEIGHT represents the height of the patient (cm) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
 BASELINE represents the baseline value of the parameter of interest from the 
double-blind phase 


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Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided. 
If the Day 358 and/or Day 190 assessments have no missing data, then the above ANCOVA 
model will be used for analysis.  If missing data is present, a standard multiple imputation with 
the above ANCOVA model will be used for analysis as described in Section 4.11.1. 
In addition, a line graph of the mean ± SEM of the percent change from baseline will be 
provided by sequence for each scheduled time. 
Additional analyses may be performed as appropriate 
Berg Balance Scale 
The effect of ACE-083 administered during the open-label extension compared to the treatment 
administered in the double-blind placebo-controlled phase will be examined for those receiving 
ACE-083 during the double-blind phase and separately for those receiving placebo during the 
double-blind phase by comparing the absolute changes observed between Day 190 and pre-first 
treatment baseline (1st 6 months) and Day 358 versus Day 190 (2nd 6 months) using an 
ANCOVA model. 
Covariates to be included into the model are SEQUENCE, CMT-TYPE, and BASELINE where: 

SEQUENCE represents the treatment sequence from double blind to open-label
(ACE-083  ACE-083 or Placebo  ACE-083)

CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX)

BASELINE represents the baseline value of the parameter of interest from the
double-blind phase
Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided. 
If the Day 358 and/or Day 190 assessments have no missing data, then the above ANCOVA 
model will be used for analysis.  If missing data is present, a standard multiple imputation with 
the above ANCOVA model will be used for analysis as described in Section 4.11.1. 
The statistical analysis described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
In addition, a line graph of the mean ± SEM of the absolute change from baseline will be 
provided by sequence for each scheduled time. 
Additional analyses may be performed as appropriate 
Falls 
The hazard ratio of recurring falls between ACE-083 and placebo during the entire 12 months 
(excluding the screening interval) will be estimated using the Andersen-Gill recurrent events 
model with the following covariates:  SEQUENCE, CMT-TYPE, PERIOD,  and ankle 
dorsiflexion MRC-MMT decimal score where SEQUENCE refers to the treatment sequence 
from double-blind to open-label (ACE-083  ACE-083 or Placebo  ACE-083), and PERIOD 


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refers to the period of time of observation ( “Double-blind”, “Open-label”).  The “Double-Blind” 
period covers Weeks 1 to 24 and the “Open-label” period covers Weeks 25 to 48.  The point 
estimate, p-value and 90% confidence interval for the hazard ratio for SEQUENCE will be 
provided. 
Additional methods for the statistical analysis of the recurring event of falls may be considered 
and performed as appropriate (e.g. negative binomial regression with similar covariates as listed 
for the Andersen-Gill recurrent events model described above). 
No multiple imputations will be performed for missing data. 
The statistical analyses described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
Additional analyses may be performed as appropriate. 
CMT-HI 
For the total CMT-HI and subgroup scores, the effect of ACE-083 administered during the open-
label extension compared to the treatment administered in the double-blind placebo-controlled 
phase will be examined for those receiving ACE-083 during the double-blind phase and 
separately for those receiving placebo during the double-blind phase by comparing the absolute 
change observed between Day 190 and pre-first treatment baseline (1st 6 months) and Day 358 
versus Day 190 (2nd 6 months) using an ANCOVA model. 
Covariates to be included into the model are SEQUENCE, CMT-TYPE, and BASELINE where: 
 SEQUENCE represents the treatment sequence from double blind to open-label 
(ACE-083  ACE-083 or Placebo  ACE-083) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
 BASELINE represents the baseline value of the parameter of interest from the 
double-blind phase 
Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided. 
If the Day 358 and/or Day 190 assessments have no missing data, then the above ANCOVA 
model will be used for analysis.  If missing data is present, a standard multiple imputation with 
the above ANCOVA model will be used for analysis as described in Section 4.11.1. 
The statistical analysis described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
In addition, a line graph of the mean ± SEM of the absolute change from baseline will be 
provided by sequence for each scheduled time. 
Additional analyses may be performed as appropriate. 


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CMTES2 
For the CMTES2 score, the effect of ACE-083 administered during the open-label extension 
compared to the treatment administered in the double-blind placebo-controlled phase will be 
examined for those receiving ACE-083 during the double-blind phase and separately for those 
receiving placebo during the double-blind phase by comparing the absolute change observed 
between Day 190 and pre-first treatment baseline (1st 6 months) and Day 358 versus Day 190 
(2nd 6 months) using an ANCOVA model. 
Covariates to be included into the model are SEQUENCE, CMT-TYPE, and BASELINE where: 
 SEQUENCE represents the treatment sequence from double-blind to open-label 
(ACE-083 | ACE-083 or Placebo | ACE-083) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
 BASELINE represents the baseline value of the parameter of interest from the 
double-blind phase 
Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided. 
If the Day 358 and/or Day 190 assessments have no missing data, then the above ANCOVA 
model will be used for analysis.  If missing data is present, a standard multiple imputation with 
the above ANCOVA model will be used for analysis as described in Section 4.11.1. 
The statistical analysis described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
In addition, a line graph of the mean ± SEM of the absolute change from baseline will be 
provided by sequence for each scheduled time. 
Additional analyses may be performed as appropriate. 
Gait 
For each type of measurement recorded (i.e. “General measures”, “Gait cycle phase measures”, 
“Gait assessment range of motion”, and “Gait assessment foot drop”), the effect of ACE-083 
administered during the open-label extension compared to the treatment administered in the 
double-blind placebo-controlled phase will be examined for those receiving ACE-083 during the 
double-blind phase and separately for those receiving placebo during the double-blind phase by 
comparing the absolute change observed between Day 190 and pre-first treatment baseline (1st 6 
months) and Day 358 versus Day 190 (2nd 6 months) by descriptive statistics.  This will also be 
done for the average absolute change from baseline for assessments performed on the left and 
right sides. 
The effect of ACE-083 on the average absolute change for mid-swing foot angle administered 
during the open-label extension compared to the treatment administered in the double-blind 
placebo-controlled phase will be examined for those receiving ACE-083 during the double-blind 
phase by comparing the average absolute change observed between Day 190 and pre-first 
treatment baseline (1st 6 months) and Day 358 versus Day 190 (2nd 6 months) using an 
ANCOVA model. 


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Covariates to be included into the model are SEQUENCE, CMT-TYPE, and BASELINE where 
baseline represents the baseline from the double-blind phase and SEQUENCE and CMT-TYPE 
are defined similarly as for MVIC. 
Lease squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided. 
A line graph of the mean ± SEM will be provided by sequence for each scheduled time for the 
average absolute change for mid-swing foot angle. 
Additional analyses may be performed as appropriate. 
Activity Level 
Exploratory analyses may be performed as appropriate. 
4.7.2.3. 
Other Analyses  
The number and percentage of patients belonging to each of the following criteria will be 
summarized by treatment group: 
 Day 190 percent change in TMV from baseline ≥ 10%  
 Day 190 percent change in 6MWD from baseline ≥ 10% 
 Day 190 absolute change in 6MWD from baseline ≥ 30 m 
 Day 190 percent change in time to complete 10mW/R from baseline ≤ -10% 
 Day 190 absolute change in time to complete 10mW/R from baseline ≤ -0.5 sec. 
 Day 190 absolute change in CMT-HI total score from baseline ≤ -8 
 Day 190 absolute change in CMT-HI mobility subscale score from baseline ≤ -8  
 Day 190 absolute change in CMT-HI activities subscale score from baseline ≤ -8 
 Day 190 absolute change in ankle dorsiflexion MRC-MMT decimal score ≥ 0.16 
 Percent change in number of falls during Weeks 13 to 24 from the number of falls 
during Weeks 1 to 12 ≤ -20% 
For each criterion listed above, Fisher’s exact test will be used to compare the proportions of 
patients belonging to the individual criterion between the two treatment groups using a 
0.1 significance level. 
4.8. 
Pharmacodynamic Data 
4.8.1. 
Variables 
4.8.1.1. 
MRI 
MRI variables consist of the following: 


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Variable 
Unit 
Formula for derivation or SAS variable name/expression from SDTM FA 
Total muscle volume 
(TMV) 
mm3 
TMV = Contractile muscle tissue volume (SAS variable FASTRESN in SDTM FA 
where FATESTCD = “MVOL”) + Intramuscular fat volume (SAS variable 
FASTRESN in SDTM FA where FATESTCD=”IFATVOL”) 
Intramuscular fat 
volume (IMFV) 
mm3 
SAS variable FASTRESN in SDTM FA where FATESTCD=”IFATVOL” 
Contractile muscle 
volume (CMV) 
mm3 
SAS variable FASTRESN in SDTM FA where FATESTCD=”MVOL” 
Fat fraction (FF) 
% 
SAS variable FASTRESN in SDTM FA where FATESTCD=”FATF” 
Contractile muscle 
fraction (CMF) 
% 
CMF = 100 – FF 
Calculated contractile 
muscle volume 
(CCMV) 
mm3 
CCMV = TMV * CMF/100 
Calculated 
intramuscular fat 
volume (CIMFV) 
mm3 
CIMFV = TMV * FF/100 
Contractile muscle 
mass (CMM) 
g 
CMM = CMV * 1.06/1000 
Intramuscular fat mass 
(IMFM) 
g 
IMFM = IMFV * 0.9/1000 
Total muscle mass 
(TMM) 
g 
TMM = CMM + IMFM 
Calculated contractile 
muscle mass (CCMM) 
g 
CCMM = CCMV * 1.06/1000 
Calculated 
intramuscular fat mass 
(CIMFM) 
g 
CIMFM = CIMFV * 0.9/1000 
Calculated total muscle 
mass (CTMM) 
g 
CTMM = CCMM + CIMFM 
4.8.1.2. 
Biomarkers 
Biomarker data include but are not necessarily limited to the following selected laboratory data: 
CTX and hemoglobin. 
4.8.1.3. 
CMAP of TA 
This is an exploratory variable that is collected for Part 2 patients. 
4.8.2. 
Analyses 
4.8.2.1. 
Part 1 
MRI 
Individual MRI data will be listed. 


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For each MRI variable, the raw data as well as the absolute and percent change from baseline 
will be summarized by cohort for each scheduled time and side treated [left and right].  The 
average absolute and percent change [from left and right sides] will also be provided. 
For total muscle volume, calculated contractile muscle volume, fat fraction, and calculated 
intramuscular fat, least squares estimates of the effect of ACE-083 and corresponding 90% and 
95% confidence intervals will be produced for the average percent change data at Day 106 [from 
left and right sides] (absolute change for fat fraction at Day 106) using an ANCOVA with 
BASELINE, COHORT, and BASELINE*COHORT as variables where: 
 COHORT represents the dose level of ACE-083 administered to the muscle 
 BASELINE represents the baseline value of the parameter of interest 
 BASELINE*COHORT represents the interaction of baseline and cohort 
Graphical summaries of the mean ± SEM will be provided for each cohort and scheduled time. 
Additional analyses may be performed as appropriate. 
Biomarker Data 
Individual biomarker data will be listed. 
Biomarker data will be summarized by cohort and scheduled time for raw data and changes from 
baseline (absolute and/or percent).  Graphical displays will also be provided (e.g. plot of mean ± 
SEM). 
4.8.2.2. 
Part 2 
4.8.2.2.1. Double-Blind Period 
MRI: Total Muscle Volume (TMV) 
Individual total muscle volume data will be listed. 
Descriptive statistics will be provided by treatment group and scheduled time for raw data and 
changes from baseline (absolute and percent change) for each side [left and right].  The average 
absolute change and average of the percent change for the left and right sides will also be 
provided. 
The primary pharmacodynamic analysis will consist of an ANCOVA in order to assess the effect 
of ACE-083 on the Day 190 average percent change from baseline for the left and right sides.  
Covariates to be included into the model are TREATMENT, BASELINE, and CMT-TYPE 
where: 
 TREATMENT represents the treatment group (ACE-083 or placebo) 
 BASELINE represents the baseline total muscle volume (average of left and right 
sides) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
The effect of ACE-083 versus placebo will be estimated using the ANCOVA model described 
above and tested using a 0.1 significance level (2-sided).  The least-square mean estimate along 


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with the corresponding 90% confidence interval will be provided.  In addition, the 95% 
confidence interval will also be provided. 
If the Day 190 TMV has no missing data, then the above ANCOVA model will be used for 
analysis.  If missing data is present, a standard multiple imputation with the above ANCOVA 
model will be used for analysis as described in Section 4.11.1. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT. 
Similar to what was described for the ANCOVA analysis above, if missing data is present, a 
standard multiple imputation with the above MMRM model will be used for analysis as 
described in Section 4.11.1. 
The statistical analyses described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
In addition, a line graph of the mean ± SEM of the percent change from baseline will be 
provided by treatment for each scheduled time. 
Additional analyses may be performed as appropriate. 
MRI: Calculated Contractile Muscle Volume (CCMV), Fat Fraction (FF), and Calculated 
Intramuscular Fat (CIMV) 
Individual data will be listed. 
Descriptive statistics will be provided by treatment group and scheduled time for raw data and 
changes from baseline (absolute and percent change) for each side [left and right].  The average 
absolute and average of the percent change for the left and right sides will also be provided.    
An ANCOVA model will be fitted in order to assess the effect of ACE-083 on the Day 190 
average of left and right side percent change (absolute change for FF) from baseline.  Covariates 
to be included in the model are TREATMENT, BASELINE, and CMT-TYPE where: 
 TREATMENT represents the treatment group (ACE-083 or placebo) 
 BASELINE represents the baseline parameter of interest (average of left and right 
sides) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
For each of the selected MRI parameters, the effect of ACE-083 on the Day 190 average percent 
change (absolute change for FF) from baseline will be estimated using the ANCOVA model 
described above and tested using a 0.1 significance level (2-sided).  The least-square mean 
estimate along with the corresponding 90% confidence interval will be provided.  In addition, the 


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95% confidence interval will also be provided as well as a bar chart of the least squares mean 
estimates (± SEM) for each of the treatment groups. 
If the Day 190 selected MRI parameter has no missing data, then the above ANCOVA model 
will be used for analysis.  If missing data is present, a standard multiple imputation with the 
above ANCOVA model will be used for analysis as described in Section 4.11.1. 
A mixed model repeated measures (MMRM) analysis will be performed to assess the sensitivity 
to the ANCOVA analysis described above.  An unstructured covariance structure will be used to 
model the within-patient covariance across visits.  Other covariance structures will be considered 
if the unstructured covariance fails.  The covariates to be included consist of all of the covariates 
described above for the ANCOVA with the addition of the following additional covariates:  
VISIT where VISIT represents the scheduled visit day post first dose of MRI assessment and 
TREATMENT*VISIT. 
Similar to what was described for the ANCOVA analysis above, if missing data is present, a 
standard multiple imputation with the above MMRM model will be used for analysis as 
described in Section 4.11.1. 
The statistical analyses described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
In addition, a line graph of the mean ± SEM of the percent change from baseline will be 
provided by treatment for each scheduled time.  For fat fraction, the line graph to be generated 
will consist of the mean ± SEM of the absolute change from baseline by treatment for each 
scheduled time. 
Additional analyses may be performed as appropriate. 
MRI: Other Parameters 
Individual data will be listed.  The listing of such data will be collated with the other MRI data. 
Descriptive statistics will be provided for raw data and changes (percent and absolute change) 
from baseline by treatment for each scheduled time for each side treated [left and right].  The 
average absolute change and average of the percent change for the left and right sides will also 
be provided. 
Additional analyses may be performed as appropriate. 
Biomarker Data 
Individual biomarker data will be listed. 
Biomarker data will be summarized by treatment group and scheduled time for raw data and 
changes from baseline (absolute and/or percent).  Graphical displays will also be provided 
(e.g. plot of mean ± SEM). 
CMAP for TA 
Individual CMAP for TA data will be listed. 


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CMAP data will be summarized by treatment group and scheduled time for raw data and changes 
from baseline (absolute and/or percent). 
Additional analyses may be performed as appropriate. 
4.8.2.2.2. Open-Label Extension 
MRI: TMV 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
Descriptive statistics will be provided for raw data and changes (percent and absolute change) 
from the start of the open-label extension (Day 190) will be provided by treatment for each 
scheduled time and side treated as well as the average absolute change and average percent 
change from baseline for the left and right sides. 
Additional analyses may be performed as appropriate. 
MRI: CCMV, FF, and CIMF 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
Descriptive statistics will be provided for raw data and changes (percent and absolute change) 
from the start of the open-label extension (Day 190) will be provided by treatment for each 
scheduled time and side treated as well as the average absolute change and average percent 
change from baseline for the left and right sides. 
Additional analyses may be performed as appropriate. 
MRI: Other Parameters 
Individual data will be listed.  The listing of such data will be collated with the data collected in 
the double-blind, placebo-controlled phase. 
Descriptive statistics will be provided for raw data and changes (percent and absolute change) 
from the start of the open-label extension (Day 190) will be provided by treatment for each 
scheduled time and side treated as well as the average absolute change and average percent 
change from baseline for the left and right sides. 
Additional analyses may be performed as appropriate. 
Biomarker Data 
Individual biomarker data will be listed and will be collated with data from the double-blind 
period.   
Descriptive statistics of raw data and changes from baseline will be summarized by treatment 
sequence and scheduled time.  Pooled summaries across treatment sequences will also be 
provided.  Such summaries may be accompanied by a plot of mean ± SEM. 
Additional analyses may be performed as appropriate. 


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4.8.2.2.3. Open-Label vs. Double-Blind Placebo-Controlled Period 
MRI: TMV 
The effect of ACE-083 administered during the open-label extension compared to the treatment 
administered in the double-blind placebo-controlled phase will be examined for those receiving 
ACE-083 during the double-blind phase and separately for those receiving placebo during the 
double-blind phase by comparing the average percent change (left and right side) observed 
between Day 190 and pre-first treatment baseline (1st 6 months) and Day 358 versus Day 190 
(2nd 6 months) using an ANCOVA model. 
Covariates to be included into the model are SEQUENCE, CMT-TYPE, and BASELINE where: 
 SEQUENCE represents the treatment sequence from double blind to open-label 
(ACE-083  ACE-083 or Placebo  ACE-083) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
 BASELINE represents the baseline TMV from the double-blind period 
Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided.   
If the Day 358 and/or Day 190 assessments have no missing data, then the above ANCOVA 
model will be used for analysis.  If missing data is present, a standard multiple imputation with 
the above ANCOVA model will be used for analysis as described in Section 4.11.1. 
The statistical analysis described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
In addition, a line graph of the mean ± SEM of the percent change from baseline will be 
provided by sequence for each scheduled time. 
Additional analyses may be performed as appropriate. 
MRI: CCMV, FF, and CIMF 
The effect of ACE-083 administered during the open-label extension compared to the treatment 
administered in the double-blind placebo-controlled phase will be examined for those receiving 
ACE-083 during the double-blind phase and separately for those receiving placebo during the 
double-blind phase by comparing the average percent change (left and right side) observed 
between Day 190 and pre-first treatment baseline (1st 6 months) and Day 358 versus Day 190 
(2nd 6 months) using an ANCOVA model. 
Covariates to be included into the model are SEQUENCE, CMT-TYPE, and BASELINE where: 
 SEQUENCE represents the treatment sequence from double blind to open-label 
(ACE-083  ACE-083 or Placebo  ACE-083) 
 CMT-TYPE refers to the type of CMT (e.g. CMT1 or CMTX) 
 BASELINE represents the baseline TMV from the double-blind period 


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Least squares estimates of the SEQUENCE effect and 90% confidence intervals will be 
provided.   
If the Day 358 and/or Day 190 assessments have no missing data, then the above ANCOVA 
model will be used for analysis.  If missing data is present, a standard multiple imputation with 
the above ANCOVA model will be used for analysis as described in Section 4.11.1. 
The statistical analysis described above will be done on the Per Protocol Set and will be 
considered primary.  The analyses described above will also be repeated for the Full Analysis 
Set. 
In addition, a line graph of the mean ± SEM of the percent change from baseline will be 
provided by treatment sequence for each scheduled time.  For fat fraction, the line graph to be 
generated will consist of the mean ± SEM of the absolute change from baseline by treatment 
sequence for each scheduled time. 
Additional analyses may be performed as appropriate. 
MRI: Other Parameters 
Descriptive statistics will be provided by sequence where sequence represents the treatment 
sequence from double-blind to open-label (ACE-083  ACE-083 or Placebo  ACE-083) for 
the comparison of the percent change observed between Day 190 and pre-first treatment baseline 
(1st 6 months) and Day 358 versus Day 190 (2nd 6 months). 
Additional analyses may be performed as appropriate. 
4.9. 
Subgroup Analyses 
Subgroup analyses will be performed for selected efficacy and pharmacodynamics data from the 
double-blind period of Part 2.   
Subgroups consist of the following: 
 Ankle Dorsiflexion MRC-MMT Grade {weaker of two sides at Screening}: (3 to 
4-; 4 to 4+) 
 Ankle Dorsiflexion Screening MRC-MMT Grade of 4- to 4+ on both left and right 
sides 
 Plantar Flexion MRC-MMT Grade {weaker of two sides at Screening}: (4- to 4+; 
5- to 5) 
 Knee Extension MRC-MMT Grade {weaker of two sides at Screening}: (3+ to 4+; 
5- to 5) 
 MRC-MMT Grade {weaker of two sides at Screening} for plantar flexion and knee 
extension 
 Levels are “Both 5- to 5” and “Not both 5- to 5”.   
 “Both 5- to 5” means that the MRC-MMT grade {weaker of two sides} for both 
plantar flexion and knee extension must both be between 5- and 5. 


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 “Not both 5- to 5+” means that the MRC-MMT grade {weaker of two sides} for 
any or both plantar flexion and knee extension should not both be between 5- and 
5+.  For example, a patient with plantar flexion MRC-MMT grade {weaker of 
two sides} of a 5- and knee extension MRC-MMT grade {weaker of two sides} of 
4 would be classified as “Not both 5- to 5+”. 
 Baseline Fat Fraction (%): (< median; ≥ median) 
 CMT type: (CMT1, CMTX) 
 CMT gene mutation: (CMT1A, not CMT1A) 
 Usage of Braces (Yes; No) 
 This information is contained in the individual patient’s CMT disease history 
 Dose per Calculated Contractile Muscle Mass (mg/g): (< median; ≥ median) 
 Exercise Program: (resistance; no resistance) 
 The “resistance” subgroup includes patients who responded “Yes” to the question 
“Does the patient have a regular (at least once a week) exercise program?” and 
reported “Resistance training” as a type of exercise program. 
 The “no resistance” subgroup includes patients who responded “Yes” to the 
question “Does the patient have a regular (at least once a week) exercise 
program?” and did not report “Resistance training” as a type of exercise program. 
 Baseline CMT-HI Total Score: (< median; ≥ median) 
 Activity level (steps/d):  (< median; ≥ median) 
 This is defined as the average number of steps per day as measured by the 
PAMSys™ device over the patient’s study participation in the Part 2 double-blind 
period, adjusted for overall compliance in using the device to record such activity. 
 ADA (ADA +; ADA-) 
 ADA+ means that the patient had positive ADA for ACE-083 at least once during 
the double-blind period of Part 2 
 ADA- means that the patient did not have positive ADA for ACE-083 at least 
once during the double-blind period of Part 2 
Subgroup analyses will be performed for the following parameters: 
 Day 190 average percent change in total muscle volume from baseline 
 Day 190 average percent change in calculated contractile muscle volume from 
baseline 
 Day 190 average absolute change in fat fraction from baseline 
 Day 190 average percent change in fat fraction from baseline 
 Day 190 average percent change in ankle dorsiflexion MVIC from baseline 


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 Day 190 average absolute change in ankle dorsiflexion MMT-MRC decimal score 
from baseline 
 Day 190 percent change in 6MWD from baseline 
 Day 190 percent change in time to complete 10mW/R from baseline 
 Day 190 absolute change in CMT-HI total score from baseline 
 Day 190 absolute change in CMT-HI foot/ankle strength subscale score from baseline 
 Day 190 absolute change in CMT-HI balance subscale score from baseline 
 Day 190 absolute change in CMT-HI fatigue subscale score from baseline 
 Day 190 absolute change in CMT-HI mobility subscale score from baseline 
 Day 190 absolute change in CMT-HI activities subscale score from baseline 
 Fall risk reduction during double-blind period 
Subgroup analyses will be performed using similar ANCOVA models described in previous 
sections for each subgroup category provided that the sample size is at least 4.  Because of the 
reduced sample size within each subgroup category, it is not planned to include CMT-TYPE into 
such models.  For each subgroup category, the treatment effect will be estimated and tested using 
a 0.1 (two-sided) significance level with the corresponding 90% confidence interval.  Bar charts 
of the least squares mean estimates (± SEM) for each of the treatment groups will be provided.   
For purposes of this study, findings of subgroup analyses are considered to yield hypothesis 
generating statements for future study.  It is not planned to control the overall type-1 error.   
Additional analyses may be performed as appropriate. 
Data from multiple imputations described in Section 4.7.2.2.1 will be used. 
4.10. 
Safety Data 
4.10.1. 
Adverse Events 
Adverse events (AEs) will be coded using MedDRA Version 19.1.   
All AEs will be listed and will include but not necessarily be limited to the following: verbatim 
term, MedDRA preferred term, treatment group, severity, relationship to study medication, 
action taken with respect to study medication, and whether or not the AE is treatment-emergent 
although not necessarily in that order.   
Treatment-emergent AEs (TEAEs) are defined those AEs that start or worsen in intensity on or 
after the first study drug administration up to the end of the follow-up period (Day 141 [Part 1] / 
Day 393 [Part 2]).  AEs classified as TEAEs will be summarized.  Planned summaries include 
the following (for each muscle group unless otherwise specified): 
 Overall summary of TEAEs by treatment group 
 Summary of TEAEs by MedDRA System Organ Class and Preferred Term for each 
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 Summary of TEAEs by MedDRA System Organ Class and Preferred Term for each 
treatment group – Number of Events 
 Summary of TEAEs by MedDRA Preferred Term for each treatment group – Number 
of Patients 
 Summary of TEAEs by MedDRA Preferred Term for each treatment group– Number 
of Events 
 Summary of CTCAE Grade 3 or Higher TEAEs by MedDRA System Organ Class 
and Preferred Term for each treatment group – Number of Patients 
 Summary of CTCAE Grade 3 or Higher TEAEs by MedDRA System Organ Class 
and Preferred Term for each treatment group – Number of Events 
 Summary of CTCAE Grade 3 or Higher TEAEs by MedDRA Preferred Term for 
each treatment group – Number of Patients 
 Summary of CTCAE Grade 3 or Higher TEAEs by MedDRA Preferred Term for 
each treatment group – Number of Events 
 Summary of TEAEs possibly or probably related to study drug by MedDRA System 
Organ Class and Preferred Term for each treatment group – Number of Patients 
 Summary of TEAEs possibly or probably related to study drug by MedDRA System 
Organ Class and Preferred Term for each treatment group– Number of Events 
 Summary of TEAEs possibly or probably related to study drug by MedDRA 
Preferred Term for each treatment group – Number of Patients 
 Summary of TEAEs possibly or probably related to study drug by MedDRA 
Preferred Term for each treatment group– Number of Events 
 Summary of TEAEs by MedDRA Preferred Term by CTCAE Grade and Relationship 
to Drug for each treatment group – Number of Patients 
 Summary of TEAEs by MedDRA Preferred Term by CTCAE Grade and Relationship 
to Drug for each treatment group – Number of Events 
 Summary of Serious Adverse Events – Number of Patients 
 
 


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4.10.2. 
Clinical Laboratory Evaluations  
Individual clinical laboratory data will be listed. 
The following table lists the planned clinical laboratory assessments: 
Type of Assessment 
Details 
Hematology 
Hemoglobin, hematocrit, platelet count, red blood cell count, white 
blood cell (WBC) count, and WBC differential 
Chemistry 
AST, ALT, lactate dehydrogenase (LDH) and isoenzymes 1-5, 
gamma-glutamyl transpeptidase (GGT), blood urea nitrogen (BUN), 
creatinine, creatine kinase (CK), myoglobin, aldolase, sodium, 
potassium, glucose, albumin, total bilirubin 
Urine 
Urinalysis by dipstick analysis (pH, specific gravity, protein, 
myoglobin, glucose, ketones, blood, leukocyte esterase, and nitrite) 
In addition to the tests listed below, a urine pregnancy test is performed on all females of 
childbearing potential according to scheduled times listed in the protocol. 
Descriptive statistics of raw data and change from baseline data will be provided by treatment 
group for each scheduled time.   
Plots of mean ± SEM will be provided for raw data and change from baseline data for the 
following selected laboratory data: hemoglobin, glucose, aldolase, blood urea nitrogen (BUN), 
creatinine kinase (CK), creatinine, and myoglobin. 
Additional analyses may be performed as appropriate. 
Vital Signs 
Individual vital sign data will be listed. 
Vital sign parameters consist of weight, heart rate, systolic and diastolic blood pressure.   
Descriptive statistics will be provided for raw data and absolute change from baseline by 
scheduled time for each treatment group.  Post-dose recheck values will not be used for 
calculation of descriptive statistics. 
Additional analyses may be performed as appropriate. 
Electrocardiogram 
Individual twelve-lead electrocardiogram (ECG) data will be listed and consists of the following: 
heart rate, PR, QRS, QT, and QTcB (Bazett correction).   
Descriptive statistics will be provided for raw data and absolute change from baseline by 
scheduled time for each treatment group.  Post-dose recheck values will not be used for 
calculation of descriptive statistics.   
Additional analyses may be performed as appropriate. 
4.10.3. 
Anti-Drug Antibodies 
Individual anti-drug antibody (ADA) data will be listed. 


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The frequency and percentage of ADA responses will be summarized by treatment group and 
scheduled time. 
The frequency and percentage of all patients testing positive for ADA at any point during the 
study (i.e. ADA prevalence) will be summarized by treatment group.  This will include 
summaries of the prevalence ADA confirmed as “Anti-ACE-083” or “Anti-FST315”.  In 
addition, for ACE-083 ADA, a summary of the prevalence of ACE-083 ADA and titer summary 
(median, minimum, and maximum value) will be provided by scheduled visit and antibody 
follow-up visit (as applicable). 
Additional analyses may be performed as appropriate. 
4.10.4. 
Other Safety Data 
Not applicable.  
4.11. 
Missing Data Handling 
4.11.1. 
Efficacy and Pharmacodynamic Data 
Statistical analyses of selected efficacy and pharmacodynamics data will make use of standard 
multiple imputation (MI).  For missing data points, the monotonic or fully conditional 
specification (FCS) regression is used to fill in the missing data points depending on the missing 
data pattern (monotone or arbitrary) in the order of time points using values calculated at the 
previous time points.  This analysis involves the following steps: 
1. The missing data are filled “m” times (e.g. m = 20) in order to generate “m” complete 
datasets using the monotonic or FCS regression model. 
2. Each of the “m” complete datasets are analyzed using the analysis methods specified in 
Section 4.7.2.2 or Section 4.8.2.2  
3. The results from the “m” complete datasets are combined for the inference. 
The above assumes that any missing data are Missing At Random (MAR).  The seeds to be used 
to perform the multiple imputations are listed in Section 6. 
4.11.2. 
Safety Data 
As a general principle, no imputation of missing data will be done unless otherwise specified.  
Exceptions are the start and stop dates of AEs with rules listed below.  The imputed dates will be 
used to determine whether an AE is/is not treatment emergent.  Listings of the AEs will present 
the actual partial dates; imputed dates will not be shown. 
4.11.2.1. Missing Dates for Adverse Event 
Imputing partial AE start dates: 
a. If the year is unknown, the date will not be imputed and will be assigned a missing 
value. 
b. If the month is unknown, then: 


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1. If the year matches the first dose date, then impute the month and day of the first 
dose date. 
2. Otherwise, assign January. 
c. If the day is unknown, then: 
3. If the month and year match the first AE stop month and year and AE stop day is 
not missing, then impute the start day as the stop day. 
4. Otherwise impute start day using the last day of the start month. 
Imputing partial AE stop dates: 
a. If the year is unknown, the date will not be imputed and will be assigned a missing 
value. 
b. If the month is unknown, then assign December or date of last participation in the 
study, whichever is earlier. 
c. If the day is unknown, then assign the last day of the month. 
4.12. 
Pharmacokinetic Data 
Pharmacokinetic data will be summarized under the direction of the Acceleron Clinical 
Pharmacologist and summaries will be outlined in a separate analysis plan. 


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5. 
MODIFICATIONS FROM THE STATISTICAL SECTION OF 
THE PROTOCOL 
The following modifications from the statistical section of the protocol have been implemented 
in the statistical analysis plan: 
 For statistical analyses where confidence intervals for the least-squares mean are 
provided, the 95% confidence interval will be provided in addition to the 90% 
confidence interval.   
 The “Safety Population” is now called the “Safety Set”. 
 The “Per Protocol Set” definition was redefined to be what is listed in this document.. 
 The last observation carried forward approach is not being performed in the statistical 
analyses.  Standard multiple imputation will be performed to assess the impact of 
missing data on the observed data. 
 For statistical analyses of data to compare the effects of ACE-083 administered in the 
open-label extension versus the treatment received in the double-blind period of Part 
2, the 90% confidence interval will be provided in place of the 95% confidence 
interval. 


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6. 
PROGRAMMING SPECIFICATIONS 
Seed to Use for Multiple Imputations of Missing Data 
The seed to be used for multiple imputations of ankle dorsiflexion MVIC data is 1111. 
The seed to be used for multiple imputations of functional data is 2222. 
The seed to be used for multiple imputations of Berg balance data is 3333. 
The seed to be used for multiple imputations of CMT-HI data is 4444. 
The seed to be used for multiple imputations of CMTES2 data is 5555. 
The seed to be used for multiple imputations of MRI data is 6666. 
Representation of Scheduled Times in Listings 
Because data for this study comes from multiple sources, such information will be standardized 
in the listings.   
The standardization is outlined below: 
Lab (MRL), CMT-HI, 
eCRF (long) 
eCRF (short) 
MRI 
Mapping for Tables and 
Listings 
Plots 
Screening Day -28 to Day -7 
SCN 
 
S1D-28 
-28 
Dose 1 Day 1 
DOSE1D1 
DAY 1 
D1D1 
1 
Dose 1 Day 2 
DOSE1D2 
 
D1D2 
2 
Dose 1 Day 8 
DOSE1D8 
 
D1D8 
8 
Dose 2 Day 22 
DOSE2D22 
 
D2D22 
22 
Dose 3 Day 43 
DOSE3D43 
DAY 43 
D3D43 
43 
Dose 4 Day 64 
DOSE4D64 
 
D4D64 
64 
Dose 5 Day 85 
DOSE5D85 
 
D5D85 
85 
Follow-Up Day 106/ETa 
ET 
DAY 106 
F1D106_ET 
106 
Dose 6 Day 106b 
DOSE6D106 
DAY 106 
D6D106 
106 
Dose 7 Day 127b 
DOSE7D127 
 
D7D127 
127 
Follow-Up Day 141a 
FUP 
DAY 141 
F2D141 
141 
Dose 8 Day 148b 
DOSE8D148 
 
D8D148 
148 
Dose 9 Day 169b 
DOSE9D169 
 
D9D169 
169 
Dose 10 Day 190b 
DOSE10D190 
DAY 190 
D10D190 
190 
Dose 11 Day 211b 
DOSE11D211 
 
D11D211 
211 
Dose 12 Day 232b 
DOSE12D232 
 
D12D232 
232 
Dose 13 Day 253b 
DOSE13D253 
 
D13D253 
253 
Dose 14 Day 274b 
DOSE14D274 
 
D14D274 
274 


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Lab (MRL), CMT-HI, 
eCRF (long) 
eCRF (short) 
MRI 
Mapping for Tables and 
Listings 
Plots 
Dose 15 Day 295b 
DOSE15D295 
DAY 295 
D15D295 
295 
Dose 16 Day 316b 
DOSE16D316 
 
D16D316 
316 
Dose 17 Day 337b 
DOSE17D337 
 
D17D337 
337 
Day 358/ETb 
ET 
DAY 358 
F1D358_ET 
358 
Follow-Up Day 393b 
FUP 
DAY 393 
F2D393 
393 
a Applies to Part 1; b Applies to Part 2 
Partial Date of Birth Entries 
In the event that a patient does not have a complete date of birth present in the clinical database, 
the date of birth will be interpolated as follows: 
 If the date of birth contains the month and year of birth but no value of day (i.e. day is 
missing or has value “UNK”), the value of day will be imputed to the 1st for purposes 
of any calculations that involve the complete birthdate of the patient (i.e. age). 
 If the date of birth only contains the year but no value of month and day (i.e. 
“UNK-UNK-yyyy”), the birthdate will be imputed to “01-Jan-yyyy” where “yyyy” 
refers to the year that is reported for that patient for purposes of any calculations that 
involve the complete birthdate of the patient (i.e. age). 
Classification of AEs as TEAEs 
In general, the start of reporting of adverse events for an individual patient starts after receiving 
the first dose of study drug.  However: 
 If both the AE start and stop date exist and are before the first dose date of study 
drug, the AE will be classified as a pre-treatment AE and not considered treatment 
emergent. 
 If the AE start date is on or after the first dose date of study drug, the AE will be 
considered a TEAE. 
 If the AE start date is before the first dose date of study drug and the AE stop date is 
after the first dose of study drug and the AE worsened in intensity, the AE will be 
considered a TEAE. 
 If the AE start date is missing and the stop date is before the first dose of study drug, 
the AE will be not be considered a TEAE. 
 If the AE start date is missing and the stop date is after the first dose of study drug, 
the AE will be considered a TEAE. 
 If the AE start and stop dates are missing, the AE will be considered a TEAE. 
Patients that Discontinue Early 
For patients that discontinue early, end-of-treatment and follow-up assessments will be 
completed and analyzed as such.     


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7. 
APPENDICES  


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APPENDIX 1. SCHEDULE OF EVENTS 
Part 1  
 
 
 
 
 


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Part 2