A Randomized, Double-Blind, Placebo-Controlled, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple-Doses of AOC 1001 Administered Intravenously to Adult Myotonic Dystrophy Type 1 (DM1) Patients
Phase: PHASE1
Conditions: DM1, Myotonic Dystrophy 1, Myotonic Dystrophy, Myotonic Dystrophy Type 1 (DM1), Dystrophy Myotonic, Myotonic Disorders, Steinert Disease, Myotonic Muscular Dystrophy
Sponsor: Avidity Biosciences, Inc.



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PROTOCOL SIGNATURE  
I hereby acknowledge that I have read and agree to conduct the study as described in the 
clinical protocol titled below: 
 
Protocol Number: AOC 1001-CS1 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 1/2 Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of Single and Multiple-Doses of AOC 1001 Administered Intravenously to 
Adult Myotonic Dystrophy Type 1 (DM1) Patients  
Study Name: 
MARINATM 
Protocol Version:  Version 5.0 
Date:  
21 October 2022 
 
I agree to comply with the International Council on Harmonization Tripartite Guideline on Good 
Clinical Practice (ICHE6(R2)), and in accordance with the ethical principles that originated from 
the Declaration of Helsinki, and applicable national and/or regional regulations/guidelines. I 
agree to conduct this trial according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines. 
 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• me (including, if applicable, my spouse [or legal partner] and dependent children) 
• my sub-investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) at the start of the study and for up to one year after the study is 
completed, if there are changes that affect my financial disclosure status. 
 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Avidity Biosciences.  
 
 
 
 
 
 
 
 
 
 
Investigator’s Signature 
 
 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS....................................................................................................................... 3 
LIST OF TABLES ................................................................................................................................ 8 
LIST OF FIGURES .............................................................................................................................. 8 
STUDY GLOSSARY ............................................................................................................................ 9 
1. 
PROTOCOL SUMMARY ............................................................................................... 13 
1.1. 
Protocol Synopsis ....................................................................................................... 13 
1.2. 
Study Design and Treatment Schema........................................................................ 17 
1.3. 
Schedule of Assessments – Part A ............................................................................. 20 
1.4. 
Schedule of Assessments – Part B ............................................................................. 24 
2. 
BACKGROUND AND RATIONALE ................................................................................ 30 
2.1. 
Disease Overview ....................................................................................................... 30 
2.2. 
AOC 1001 Background ............................................................................................... 32 
2.3. 
Therapeutic Rationale................................................................................................ 32 
2.4. 
AOC 1001 Preclinical Experience ............................................................................... 33 
2.5. 
AOC 1001 Clinical Experience .................................................................................... 33 
2.6. 
Rationale for Study Design ........................................................................................ 33 
2.7. 
Dose Rationale ........................................................................................................... 34 
2.7.1. 
Starting Dose in Part A ............................................................................................... 34 
2.7.2. 
Dose Escalation and Maximal Dose ........................................................................... 35 
2.8. 
Benefit-Risk Assessment ............................................................................................ 36 
2.8.1. 
Benefit Assessment ................................................................................................... 36 
2.8.2. 
Risk Evaluation ........................................................................................................... 36 
2.8.3. 
Risks and Mitigation Due to the COVID-19 Pandemic ............................................... 39 
2.8.4. 
Overall Assessment of Benefit: Risk .......................................................................... 40 
3. 
OBJECTIVES AND ENDPOINTS .................................................................................... 41 
4. 
INVESTIGATIONAL PLAN ............................................................................................ 43 
4.1. 
Study Design .............................................................................................................. 43 
4.1.1. 
Part A ......................................................................................................................... 43 
4.1.2. 
Part B.......................................................................................................................... 44 
4.2. 
Safety Oversight ......................................................................................................... 44 
 
 
 
 

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4.2.1. 
Safety Review Committee (SRC) ................................................................................ 44 
4.2.2. 
Independent Data Monitoring Committee (IDMC) ................................................... 45 
4.3. 
Cohort Safety Management Rules ............................................................................. 45 
5. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ................................................... 47 
5.1. 
Inclusion and Exclusion Criteria ................................................................................. 47 
5.1.1. 
Inclusion Criteria ........................................................................................................ 47 
5.1.2. 
Exclusion Criteria ....................................................................................................... 47 
5.2. 
Screen Failures ........................................................................................................... 49 
5.3. 
Discontinuation of Study Drug ................................................................................... 49 
5.4. 
Declining of Study Procedure .................................................................................... 50 
5.5. 
Participant Discontinuation/Withdrawal from the Study ......................................... 50 
5.6. 
Lost to Follow Up ....................................................................................................... 51 
6. 
STUDY INTERVENTIONS AND OTHER REQUIREMENTS .............................................. 52 
6.1. 
Study Drug Description, Administration, and Storage .............................................. 52 
6.1.1. 
Packaging and Labeling .............................................................................................. 53 
6.1.2. 
Study Drug Accountability ......................................................................................... 53 
6.2. 
Randomization and Blinding ...................................................................................... 53 
6.2.1. 
Unblinding .................................................................................................................. 53 
6.3. 
Dosing ........................................................................................................................ 53 
6.3.1. 
Part A: Single Dose ..................................................................................................... 53 
6.3.2. 
Part B: MAD ............................................................................................................... 54 
6.3.3. 
Dose Modification...................................................................................................... 54 
6.3.4. 
Treatment Compliance and Documentation ............................................................. 54 
6.3.5. 
Continued Access to Study Intervention after the End of the Study ........................ 54 
6.4. 
Contraception Requirements .................................................................................... 54 
6.5. 
Disallowed Therapy ................................................................................................... 56 
6.6. 
Lifestyle Considerations ............................................................................................. 56 
6.6.1. 
Spirometry ................................................................................................................. 57 
7. 
STUDY ASSESSMENTS ................................................................................................ 58 
7.1. 
General Assessments ................................................................................................. 58 
7.1.1. 
Medications ............................................................................................................... 58 
 
 
 
 

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7.1.2. 
Demographics ............................................................................................................ 58 
7.1.3. 
Medical History and Disease History ......................................................................... 58 
7.1.4. 
Physical Examinations ................................................................................................ 59 
7.1.5. 
ECG ............................................................................................................................. 59 
7.1.6. 
Vital Signs, Height, and Weight ................................................................................. 60 
7.1.7. 
Echocardiogram ......................................................................................................... 60 
7.1.8. 
MRI ............................................................................................................................. 60 
7.1.9. 
Telehealth Visits ......................................................................................................... 61 
7.1.10. 
Considerations Relating to COVID-19 Pandemic ....................................................... 61 
7.2. 
Assessments by Clinicians .......................................................................................... 61 
7.2.1. 
Muscular Impairment Rating Scale (MIRS) ................................................................ 61 
7.2.2. 
Clinical Global Impression of Severity and Change (CGIS, CGIC) ............................... 62 
7.3. 
Assessments by Participants ...................................................................................... 62 
7.3.1. 
Patient Reported Outcome Measures (PRO) and Scales ........................................... 62 
7.3.2. 
DM1 Neuromuscular Severity Measure (DM1-NSM) ................................................ 62 
7.3.3. 
DM1-NSM Patient Global Impression of Severity and Change (DM1-NSM-
PGIS, DM1-NSM-PGIC) ............................................................................................... 63 
7.3.4. 
Fatigue and Daytime Sleepiness Scale (FDSS) ........................................................... 63 
7.3.5. 
DM1 Activity and Participation Scale for Clinical Use (DM1-Activ) ........................... 63 
7.3.6. 
EuroQol 5 Dimension 5 Level Quality of Life Scale (EQ-5D-5L) ................................. 63 
7.3.7. 
Myotonic Dystrophy Health Index (MDHI) ................................................................ 63 
7.3.8. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................... 63 
7.4. 
Efficacy Assessments – Measures of Function and Strength .................................... 63 
7.4.1. 
Manual Muscle Testing (MMT) .................................................................................. 64 
7.4.2. 
Quantitative Myometry Testing (QMT) ..................................................................... 65 
7.4.3. 
Pinch Strength by dynamometer ............................................................................... 65 
7.4.4. 
10-Meter Walk/Run Test (10MWRT) ......................................................................... 65 
7.4.5. 
Timed Up and Go (TUG) ............................................................................................. 65 
7.4.6. 
Timed 4 Stair Climb and Timed 4 Stair Descend ........................................................ 65 
7.4.7. 
9-Hole Peg Test (9HPT) .............................................................................................. 66 
7.4.8. 
Myotonia Video Recording (vHOT) ............................................................................ 66 
 
 
 
 

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7.4.9. 
Spirometry ................................................................................................................. 66 
7.5. 
Muscle Needle Biopsy for Pharmacokinetic, Pharmacodynamic and 
Spliceopathy Evaluations ........................................................................................... 66 
7.6. 
Pharmacokinetic and Immunogenicity Evaluations .................................................. 66 
7.7. 
DMPK Gene Analysis .................................................................................................. 67 
7.8. 
Clinical Laboratory Tests ............................................................................................ 67 
7.8.1. 
Guidance for Clinically Relevant Abnormal Labs ....................................................... 67 
7.8.2. 
Pregnancy Test ........................................................................................................... 67 
7.8.3. 
Laboratory Analyte List .............................................................................................. 68 
8.
SAFETY DATA AND ADVERSE EVENT COLLECTION AND REPORTING ........................ 71 
8.1. 
Definition of Adverse Events (AE) .............................................................................. 71 
8.2. 
Definition of Serious Adverse Events (SAE) ............................................................... 72 
8.3. 
Serious Adverse Reaction and Suspected Unexpected Serious Adverse 
Reactions.................................................................................................................... 73 
8.4. 
Reporting Procedures for Adverse Events (AE and SAE) ........................................... 73 
8.4.1. 
Assessment of Severity .............................................................................................. 73 
8.4.2. 
Assessment of Causality ............................................................................................ 74 
8.4.3. 
Action Taken with Study Drug ................................................................................... 75 
8.4.4. 
Treatment Given for Adverse Event .......................................................................... 75 
8.4.5. 
Outcome of Adverse Events ...................................................................................... 75 
8.5. 
Follow up of Adverse Events...................................................................................... 75 
8.6. 
Reporting Procedures for Serious Adverse Events .................................................... 76 
8.7. 
COVID-19 Specific Guidance ...................................................................................... 76 
8.8. 
Pregnancy and Lactation Reporting........................................................................... 77 
8.9. 
Guidance for Infusion-Related Reactions (IRR) ......................................................... 77 
8.9.1. 
Categorization of Infusion-Related Reaction ............................................................. 78 
8.9.2. 
Management of Infusion-Related Reactions ............................................................. 78 
8.10. 
Guidance for Hypersensitivity Reactions ................................................................... 79 
8.10.1. 
Evaluation and Reporting of Hypersensitivity Reactions .......................................... 79 
8.11. 
Guidance for Adverse Events with Cutaneous Involvement ..................................... 80 
8.12. 
Guidance for Liver Function Test Abnormality .......................................................... 80 
8.12.1. 
Monitoring Rule ......................................................................................................... 80 
 
 
 
 

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8.12.2. 
Criteria for Withholding or Stopping Study Drug ...................................................... 81 
8.12.3. 
Additional Assessments in Participants Who Experience Elevated 
Transaminases ........................................................................................................... 82 
8.13. 
Guidance Relating to Iron Homeostasis .................................................................... 83 
8.13.1. 
Monitoring Rule ......................................................................................................... 83 
8.13.2. 
Dosing Pause Rule ...................................................................................................... 84 
9. 
STATISTICAL CONSIDERATIONS ................................................................................. 85 
9.1. 
Statistical Analysis Plan .............................................................................................. 85 
9.2. 
General Considerations ............................................................................................. 85 
9.3. 
Sample Size Determination ....................................................................................... 85 
9.4. 
Analysis Sets ............................................................................................................... 86 
9.5. 
Interim Analysis (IA) ................................................................................................... 86 
9.6. 
Safety Evaluations ...................................................................................................... 87 
9.7. 
Pharmacokinetic and Immunogenicity Evaluations .................................................. 87 
9.8. 
Pharmacodynamic Evaluations .................................................................................. 87 
9.9. 
Efficacy Evaluations ................................................................................................... 88 
10. 
REGULATORY, LEGAL, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ........... 89 
10.1. 
Obligations to Regulatory Authorities and Ethics Committees ................................. 89 
10.2. 
Financial Disclosure ................................................................................................... 89 
10.3. 
Informed Consent Process ......................................................................................... 89 
10.4. 
Study Monitoring ....................................................................................................... 90 
10.5. 
Confidentiality and Data Protection .......................................................................... 90 
10.6. 
Study Documentation and Data Archive ................................................................... 91 
10.7. 
Quality Control and Quality Assurance ..................................................................... 92 
10.8. 
Record Retention ....................................................................................................... 92 
10.9. 
Long-Term Retention of Samples for Additional Future Research ........................... 93 
10.10. 
Compensation ............................................................................................................ 94 
10.11. 
Study and Site Start and Closure ............................................................................... 94 
10.11.1. 
Study Termination ..................................................................................................... 94 
10.11.2. 
Trial Site Termination ................................................................................................ 94 
10.12. 
Publication Policy ....................................................................................................... 95 
 
 
 
 

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11. 
REFERENCES ............................................................................................................... 96 
APPENDIX 1. GRADING SCALE FOR ADVERSE EVENTS RELATING TO LAB TEST 
ABNORMALITIES, INFUSION-RELATED REACTIONS AND ADVERSE EVENTS AT 
THE INJECTION SITE ................................................................................................... 99 
 
LIST OF TABLES 
Table 1: 
Part A Schedule of Assessments (SOA) ...................................................................... 20 
Table 2: 
Part A Pharmacokinetic, ECG, ADA and Urine Collection .......................................... 23 
Table 3: 
Part B Schedule of Assessments (SOA) ...................................................................... 24 
Table 4: 
Part B Pharmacokinetic, ECG, VS, ADA and Urine collection .................................... 28 
Table 5: 
Estimated NOAEL and Starting Dose Safety Margins ................................................ 35 
Table 6: 
Safety Management Rules for Related AEs ............................................................... 46 
Table 7: 
Part A Cohort Dose Levels ......................................................................................... 54 
Table 8: 
Part B Cohort Dose Levels .......................................................................................... 54 
Table 9: 
Muscular Impairment Rating Scale ............................................................................ 62 
Table 10: 
Monitoring and Dosing Rules for Asymptomatic Participants with Confirmed 
Isolated Elevations of ALT or AST >3× ULN (or > 3x Baseline or >300 U/L 
[Whichever is Lower] in Participants with Elevated Baseline), with No 
Alternative Cause Identified ...................................................................................... 82 
Table 11: 
Hepatic Assessments in Participants Who Experience Elevated 
Transaminases ........................................................................................................... 83 
 
LIST OF FIGURES 
Figure 1: 
Design of AOC 1001 ................................................................................................... 32 
 
 
 
 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Synopsis 
Name of 
Sponsor/Company 
Avidity Biosciences 
Name of Investigational 
Product 
AOC 1001 
Protocol Title 
A Randomized, Double-Blind, Placebo-Controlled, Phase 1/2 Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and 
Multiple-Doses of AOC 1001 Administered Intravenously to Adult Myotonic Dystrophy 
Type 1 (DM1) Patients 
Short Title 
A Phase 1/2 Study to Evaluate AOC 1001 in Adult Patients with DM1 
Study Sites(s) 
Study will be conducted at 8 study sites in the USA  
Study Phase 
1/2 
Objectives 
Endpoints 
Primary Objective 
• To evaluate the safety and tolerability of single and 
multiple ascending doses of AOC 1001 in DM1 
patients 
Primary Endpoint 
• Frequency of treatment emergent adverse events 
(TEAEs) 
Secondary Objectives 
• To evaluate the pharmacokinetic profile of single 
dose and multiple doses of AOC 1001 in DM1 
patients 
• To evaluate the pharmacodynamic profile of single 
dose and multiple doses of AOC 1001 in muscle 
biopsies in DM1 patients 
• To evaluate the efficacy of multiple doses of 
AOC 1001 in DM1 patients as measured by 
spliceopathy  
Secondary Endpoints 
• AOC 1001 levels in plasma, urine, and muscle tissue 
• Estimation of PK parameters, including Cmax, tmax, t1/2, 
AUC, and fraction excreted in urine 
• Change and percentage change from baseline in 
DMPK mRNA levels  
• Change and percentage change from baseline in 
spliceopathy 
Exploratory Objectives 
• To evaluate the exploratory efficacy of multiple 
doses of AOC 1001 in DM1 patients on measures of 
mobility, muscle strength, muscle function, and 
patient-reported outcomes 
• To evaluate immunogenicity and metabolite PK of 
AOC 1001 
 
 
Exploratory Endpoints 
Change from Baseline in: 
• Myotonia 
• Ankle dorsiflexion strength by QMT 
• Multiple Muscle Strength by Quantitative Myometry 
Test (QMT) 
• Grip Strength 
• Pinch Strength 
• 10-Meter Walk/Run Test (10MWRT) 
• Timed Up and Go (TUG) 
• Timed 4 Stair Climb  
• Timed 4 Stair Descend 
• Pulmonary Function Parameters by Spirometry  
• Multiple Muscle Strength by Manual Muscle Test 
(MMT)  
• 9-Hole Peg Test 
• % of participants needing myotonia medications 
after dosing 
• Muscular Impairment Rating Scale 
• DM1-Neuromuscular Severity Measure (DM1-NSM) 
• Myotonic Dystrophy Health Index (MDHI)  
• DM1-Activ  
 
 
 
 

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• DM1-NSM Patient Global Impression of Severity 
(DM1-NSM-PGIS) 
• DM1-NSM Patient Global Impression of Change 
(DM1-NSM-PGIC) 
• Fatigue and Daytime Sleepiness Scale 
• Clinician Global Impression of Severity (CGIS) 
• Clinician Global Impression of Change (CGIC) 
• EQ-5D-5L 
• Columbia-Suicide Severity Rating Scale 
PK endpoints: 
• Measurement of ADA 
• Measurement of potential metabolites  
Additional Safety Objectives 
• To further characterize the safety and tolerability 
profile of AOC 1001 
• Laboratory parameters 
• Vital signs 
• Infusion related reactions (IRR) 
• Electrocardiographic measures 
• Echocardiographic measures 
Study Design 
This study is designed to evaluate the safety, tolerability, PK, PD, and clinical activity of 
AOC 1001 in a randomized, placebo-controlled, double-blind manner and will be 
conducted in two parts in patients with adult onset DM1.  Part A is designed to test 
the safety and tolerability of a single dose, while Part B will test single and multiple 
ascending doses in a nested manner. These cohorts will be initiated in a staggered 
fashion based on safety data review of preceding cohort(s). 
 
Part A – The length of participation in Part A is approximately 7.5 months that includes 
an up to 6-week screening period, a one-day dosing period, a 6-month post-treatment 
period. Muscle needle biopsies will occur at Baseline, Day 43, and Day 92 to 
characterize the PK and PD profile of AOC 1001. 
 
Part B – The length of participation in Part B is approximately 7.5 months, which 
includes an up to 6-week screening period, a 3-month of treatment period, and a 
3-month post-treatment period. Part B is designed to have both single-dose and 
multiple-dose treatment periods in a nested design.  Participants will receive a single 
dose of study drug (AOC 1001 or placebo) on Day 1 followed by safety assessments 
through Day 29, which will comprise the single dose treatment period.  Given an 
acceptable safety profile, as determined by the principal investigator (PI) and the 
sponsor medical monitor (MM) (or designee), participants will enter the multiple-dose 
treatment period and receive 2 additional doses on Days 43 and 92.  After the third 
dose, participants will enter a 3-month post-treatment period. Muscle needle biopsies 
will occur at Baseline, Day 92, and Day 183 to characterize the PK and PD profile of 
AOC 1001. 
 
Extended Follow-Up –Eligible participants will have the option to enroll into an open 
label extension (OLE) trial following completion of this study. However, participants 
who are not eligible or decline to participate in the OLE will be monitored for safety by 
quarterly telehealth visits for a total of 9 months from the last dose of study drug, 
which corresponds to 5 half-lives of AOC 1001 in tissue.   
 
Dose Escalation and Safety Review – From initiation of the study up through protocol 
version 4.0 a Safety Review Committee (SRC) was involved in the decision to dose 
escalate between successive cohorts and trial continuation and ad hoc evaluation of 
AEs meeting criteria for safety management (Section 4.2). After  AOC 1001-CS1 
 
 
 
 

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protocol version 5.0 is implemented, this responsibility will transition to an 
Independent Data Monitoring Committee. The SRC will continue to fulfill their 
oversight role until the IDMC is in place. 
Number of Participants 
Part A will enroll 8 participants in one single dose cohort.  Part B consists of 3 nested 
single and multiple ascending dose cohorts with 12 participants planned per dose level 
and the option to expand enrollment in one or more cohorts to obtain additional data. 
The maximum enrollment for the trial will be limited to 52 participants.  Dose 
escalation between cohorts will not exceed a two-fold increase over the previous 
cohort. Maximum dose will not exceed 8 mg/kg by siRNA component weight of 
AOC 1001 (see below). This protocol will refer to those enrolled in this trial as 
participants. 
Study Population  
The study will include adult patients with DM1 aged 18 to 65 years (inclusive) with a 
genetic diagnosis of DM1 with DMPK CTG repeat length ≥ 100. 
A full list of eligibility criteria is presented in Section 5.1. 
Treatment Groups 
Doses of AOC 1001 are presented in terms of the siRNA component of AOC 1001. For 
conversion into total AOC 1001 weight, please see Section 6.1. 
 
Part A:  Single Dose  
There is 1 planned dose level in Part A that will evaluate a single dose in 8 participants 
(Cohort A1). Participants will be randomized 3:1 (6 active and 2 placebo). A sentinel 
group will be randomized 1:1 active: placebo, then remaining participants are 
randomized to 5:1 active: placebo. Participants will receive a single dose of study drug 
(AOC 1001 or placebo) by IV infusion on Day 1 and will be monitored for at least 
24 hours in clinic or on an inpatient basis and then enter the 6-month post-treatment 
period.  
Part B: Nested Single and Multiple Ascending Dose  
There are 3 planned dose levels in Part B. Participants in each cohort will be 
randomized at a planned ratio of 3:1. Each cohort will include a sentinel group which is 
randomized 1:1 active: placebo. Participants will receive a total of three doses of study 
drug (AOC 1001 or placebo) by IV infusion on Day 1, 43, and 92. On Day 1 participants 
will be monitored for at least 24 hours in clinic or on an inpatient basis.   
  
Enrollment in Part B cohorts will proceed once the Day 29 safety and tolerability data 
for at least 75% of the preceding cohorts has been reviewed by either the SRC or 
IDMC, with decisions to escalate to 2 mg/kg and 4 mg/kg being made by the SRC and 
the decision to escalate above 4 mg/kg being made by the IDMC.  
 
For each participant, the 2nd dose on Day 43 for an individual can only proceed after 
the sponsor MM (or designee) and PI have reviewed the participant’s accumulated AE 
and safety lab data through Day 29. After the 3rd dose on Day 92, participants will 
enter a 13-week post-treatment period. 
 
Part A and B Sentinel Groups 
For each dose cohort in Parts A and B there will be 2 sentinel participants (one treated 
with AOC 1001 and one treated with placebo) and a period of at least 1 day is required 
between administering the first dose of study drug to the sentinel participants and the 
remaining participants in the cohort. The decision to initiate dosing for the rest of the 
cohort will be made based on the review of the safety data through the first 24 hours 
by the sponsor medical monitor (or designee), with the PIs of each of the two 
participants. 
 
 
 
 

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1.2. 
Study Design and Treatment Schema 
 
 
 
• 
Dosing of Study Drug is indicated by black dots. Part A: Day 1; Part B: Days 1, 43 and 92. 
• 
Part A will consist of a single dose treatment period (dark grey) and a post-treatment period (white).  The SRC will review 
data through Day 29 to determine if it is safe to proceed to Cohort B1. 
• 
Part B will consist of a single dose treatment period (dark grey), a multiple dose treatment period (light grey) and a 
post-treatment period.  The decision to continue from the single to multiple dose period for each participant in Part B will 
be made after reviewing data through Day 29 for each participant (indicated by stars).  
• 
The SRC or IDMC (indicated by crosses) will review all safety data through Day 29 for Cohort B1 and B2 in at least 
9 participants to determine if dose escalation is acceptable. 
• 
For each cohort, safety data through 24 hours after dosing from two sentinel participants will be reviewed to allow dosing 
for the rest of the cohort. 
• 
Randomization for the planned 12 participants per Part B cohort will be 9 active:3 placebo.  If additional participants are 
enrolled in a cohort, the same randomization scheme will be implemented. 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 

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TREATMENT SCHEMA 
Part A  
 
EOT = End of Treatment; EOPT = End of Post-Treatment 
• 
Extended follow up will continue until 9 months after the last dose. 
  
 
 
 
 
 
 
 
 
 
   
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 

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Part B 
 
EOT = End of Treatment; EOPT = End of Post-Treatment 
• 
Extended follow up will continue until 9 months after the last dose. 
  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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(e) Pre-screening Informed Consent (Optional): Can be used for DMPK genetic testing and/or to remote pre-screen participants in advance of 1st in-clinic visit to reduce patient burden 
and time requirements for preliminary eligibility confirmation.  
(f) 
Medical History: Changes from Screening to Randomization to be collected unless an event fulfills the criteria of an SAE. 
(g) Randomization: May be performed on Day -1 to allow scheduling flexibility for muscle needle biopsy and unblinded pharmacy preparation of study drug. Dose will be calculated 
based on body weight recorded at Baseline. 
(h) Physical Exam: Full physical exam to be given at Screening. At all other specified visits, an abbreviated physical exam (assessment of heart, lungs, abdomen, and symptom directed 
examination, if any symptoms) to be given as indicated to assess changes from Screening. 
(i) 
Vital Signs: BP, HR, RR, temperature 
(j) 
12-lead ECG (triplicate): All ECGs are 12-lead in triplicate using study provided equipment. Timing of assessments is shown in Table 2. When ECG and blood sample collection occur at 
the same time for PK, ECGs should be performed prior to drawing of blood samples.  
(k) Echocardiogram: Baseline may be performed up to one month prior to Day 1 after confirmation of eligibility. Day 183 (or EOPT) may be performed up to one month prior to Day 183. 
(l) 
AE Monitoring: SAEs should be reported starting at time of informed consent. AEs should be reported starting at time of study drug administration (Day 1), or if related to protocol-
mandated assessments prior to start of study drug administration. 
(m) Pregnancy Test: For women who are not post-menopausal and/or surgically sterile. Serum pregnancy test is performed at Screening and all other non-dosing visits after Day 1. Urine 
pregnancy test is performed on Baseline visit and the day of dosing. During Extended Follow Up period, a urine pregnancy test should be performed ONLY at the last visit either in-
clinic or remotely by home visit. 
(n) FSH: For post-menopausal women to confirm post-menopausal status. 
(o) DMPK Genetic Test: All participants will have a blood sample analyzed by the AOC 1001-CS1 genetic testing lab to determine DMPK CTG repeat length and the sample may be 
collected at any time throughout the study. The sample may be collected via home health or in-clinic. For eligibility, historical genetic test results may be used after discussion with 
the medical monitor. The sample may be collected prior to screening, after signing a prescreening consent form. 
(p) Archive for DNA: Participants who give additional consent (optional) consent will have an archived blood sample collected any time on trial after randomization for DNA isolation. 
Future potential analyses will be limited to further characterizing the disease (DM1), the drug (AOC 1001), and/or their interactions. 
(q) Day 15 PK sampling: Only collected if participant attends the visit in-clinic. 
(r) 
DM1-NSM (daily) and DM1-NSM-PGIS (weekly) and DM1-NSM-PGIC: Completed between 6:00-10:00pm at home. There are 4 assessment periods: before Day 1, 43, 92, and 183. 
DM1-NSM must be completed daily for at least 7 days prior to Day 1 (Day -7 to Day -1). DM1-NSM-PGIS is performed on Day -1. DM1-NSM will be completed daily for 14 consecutive 
days prior to the visits on Day 43, 92, and 183.  DM1-NSM-PGIS will be completed at the end of each week after DM1-NSM is performed (Day 7 of each week). DM1-NSM-PGIC is 
completed after DM1-NSM-PGIS on the last day of each assessment period after baseline. 
(s) 
PROs (in-clinic): Perform in the same order each time and before all other clinic procedures on the same day.  
(t) 
Measures of function and strength: Assessments will be performed once at Screening and once at Baseline and cannot be performed on the same day. The following assessments will 
be collected in the order specified in Section 7.4, including:  MMT of selected muscle groups, QMT of selected muscle groups, Pinch Strength, 10-meter walk/run test (10MWRT), 
Timed up and go (TUG), Timed 4 stair climb, Timed 4 stair descend, 9-hole peg test, spirometry, and myotonia. Measures of function and strength should be performed after PROs but 
before laboratory and biopsy procedures on the same day.  
(u) Remote hand grip strength: To be performed during baseline via remote visit, Day 29 by patient reporting, Day 71 by remote visit, Day 120 by patient reporting. Windows for the 
procedure on Day 29, 71, and 120 are ± 4 days. 
(v) CGIC: Change scale not to be assessed at Baseline. 
(w) Muscle needle biopsy: If multiple assessments are performed on a single day, biopsy should be performed as the last assessment of the day.  Time of day for biopsies should be kept 
similar across successive biopsies for each patient.  
 
Time-points: 
(1) 
Predose 
(2) 
24 hours after start of infusion 
 
 
 
 

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(e) Day 50 and Day 99 Visit Windows for PK: For PK purposes, Day 50 and Day 99 visits must be 7 days (+/-1 day window) from the infusion day the previous week. As an 
example: if -3 day window is utilized for D43 infusion, the D50 visit should also utilize -3 day window (+/- 1 day) so PK is collected 6-8 days after the previous infusion.  
(f) 
Clinic Visit or Remote Visit: Visits may be performed in clinic or remotely. Remote visits may utilize telemedicine with site personnel in conjunction with mobile home nurse 
contracted by sponsor. If a clinic visit cannot occur due to unforeseen circumstances (e.g., pandemic travel restrictions), a home health visit or local lab collection may be 
scheduled to obtain laboratory samples per discussion with Sponsor. 
(g) Pre-screening Informed Consent: Optional, can be used for DMPK genetic testing and/or to remote pre-screen participants in advance of 1st in-clinic visit to reduce patient 
burden and time requirements for preliminary eligibility confirmation. 
(h) Medical History: Changes from Screening to Randomization to be collected unless an event fulfills the criteria of an SAE. 
(i) 
Randomization: May be performed on Day -1 to allow scheduling flexibility for muscle needle biopsy and unblinded pharmacy preparation of study drug. Dose will be 
calculated based on body weight recorded at Baseline. 
(j) 
Physical Exam (Abbreviated or Full): Full physical exam to be given at Screening. At all other specified visits, an abbreviated physical exam (assessment of heart, lungs, 
abdomen and symptom directed examination, if any symptoms) to be given as indicated to assess changes from Screening.   
(k) Vital Signs: BP, HR, RR, temperature.  Blood pressure should initially be measured on both arms.  The arm with the higher systolic measurement should be used at all future 
visits. VS should be collected every 15 minutes from start of infusion until 2 hours after the end of infusion. Participants should also be asked “how do you feel?” whenever 
vital signs are collected during and after the infusion and any newly emergent neurological symptoms should be assessed by a clinician. 
(l) 
12-lead ECG (triplicate): All ECGs are 12-lead in triplicate using study provided equipment. Timing of assessments is shown in Table 4. When ECG and blood sample 
collection occur at the same time for PK, ECGs should be performed prior to drawing of blood samples.  
(m) Echocardiogram: Baseline may be performed up to one month prior to Day 1 after confirmation of eligibility. Day 183 (or EOPT) may be performed up to one month prior to 
Day 183. Echo not required at EOPT if performed at EOT. 
(n) AE Monitoring: SAEs should be reported starting at time of informed consent. AEs should be reported starting at time of study drug administration (Day 1), or if related to 
protocol-mandated assessments prior to start of study drug administration. 
(o) MRI of brain and MRA of brain and neck and full Neurological exam: To be performed prior to first dose for new participants and as soon as possible for current 
participants.  See Section 7.1.8 for more detail. 
(p) Pregnancy Test: For women who are not post-menopausal and/or surgically sterile. Serum pregnancy test is performed at Screening and all other non-dosing visits after 
Day 1. Urine pregnancy test is performed on Baseline visit and dosing days (Days 1, 43 and 92). During Extended Follow Up period, a urine pregnancy test should be 
performed ONLY at the last visit either in-clinic or remotely by home visit 
(q) FSH: For post-menopausal women to confirm post-menopausal status 
(r) DMPK Genetic Test: All participants will have a blood sample analyzed by the AOC 1001-CS1 genetic testing lab to determine DMPK CTG repeat length and the sample may 
be collected at any time throughout the study. The sample may be collected via home health or in-clinic. For eligibility, historical genetic test results may be used after 
discussion with the medical monitor. The sample may be collected prior to screening, after signing a prescreening consent form.  
(s) Archive for DNA: Participants who give additional consent (optional) consent will have an archived blood sample collected any time on trial after randomization for DNA 
isolation. Future potential analyses will be limited to further characterizing the disease (DM1), the drug (AOC 1001), and/or their interactions. 
(t) Day 15 PK/ADA sampling: Only collected if participant attends the visit in-clinic. 
(u) DM1-NSM and DM1-NSM-PGIS and DM1-NSM-PGIC: Completed between 6:00-10:00pm at home. There are 4 assessment periods: before Day 1, 43, 92, and 183. 
DM1-NSM must be completed daily for at least 7 days prior to Day 1 (Day -7 to Day -1). DM1-NSM-PGIS is performed on Day -1. DM1-NSM will be completed daily for 
14 consecutive days prior to the visits on Day 43, 92, and 183.  DM1-NSM-PGIS will be completed at the end of each week after DM1-NSM is performed (Day 7 of each 
week). DM1-NSM-PGIC is completed after DM1-NSM-PGIS on the last day of each assessment period after baseline. 
(v) PROs (in-clinic): Perform in the same order each time and before all other clinic procedures on the same day.  
(w) Measures of function and strength: Assessments will be performed once at Screening and once at Baseline and cannot be performed on the same day. The following 
assessments will be collected in the order specified in Section 7.1 including:  MMT of selected muscle groups, QMT of selected muscle groups, Pinch Strength, 10-meter 
walk/run test (10MWRT), Timed up and go (TUG), Timed 4 stair climb, Timed 4 stair descend, 9-hole peg test, spirometry, and myotonia. Measures of function and strength 
should be performed after PROs but before laboratory and biopsy procedures on the same day.  
 
 

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(x) Remote hand grip strength: To be performed during baseline via remote visit, Day 29 by patient reporting, Day 71 by remote visit, Day 120 by patient reporting. Windows 
for the procedure on Day 29, 71, and 120 are ± 4 days.  
(y) CGIC: Change scale not to be assessed at Baseline. 
(z) Muscle needle biopsy: If multiple assessments are performed on a single day, biopsy should be performed as the last assessment of the day.  For Day 92 assessments when 
both dosing and muscle biopsy are scheduled, muscle biopsy should be performed on the day prior to dosing. Time of day for biopsies should be kept similar across 
successive biopsies for each patient. 
 
Time-points: 
(1) Predose 
(2) 24 hours after start of infusion 
(3) Predose; From start of infusion through 2 hours post end of infusion every 15 minutes; After infusion at 4, and 6 hours post end of infusion. 
(4) Predose; From start of infusion through 2 hours post end of infusion every 15 minutes. 
 
 

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d  VS should be collected every 15 minutes from start of infusion until 2 hours after the end of infusion. Participants should also 
be asked “how do you feel?” whenever vital signs are collected during and after the infusion and any newly emergent 
neurological symptoms should be assessed by a clinician. 
*When ECG, VS and PK are collected at the same time point, ECG should be conducted first, followed by VS, and PK draw last
**For PK purposes, Day 50 and Day 99 visits must be 7 days (+/-1 day window) from the infusion day the previous week. As an 
example: if -3 day window is utilized for D43 infusion, the D50 visit should also utilize -3 day window (+/- 1 day) so PK is 
collected 6-8 days after the previous infusion. The same logic should be applied to other similar visits as outlined. 
*** Two pre-dose triplicate ECGs are required.  The first should be approximately 0.5 hours pre-dose but timing can be adjusted 
as long as the measurements are separated by at least 10 minutes 
 
 
 
 

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2. 
BACKGROUND AND RATIONALE  
2.1. 
Disease Overview 
DM1 is a rare, monogenic, autosomal dominant, trinucleotide repeat expansion disorder that 
affects between 40,000 and 156,000 patients in the US (Udd 2012, Johnson 2019, 
Johnson 2021).  It is a progressive disorder that affects multiple organ systems including 
skeletal and smooth muscle, heart, eye, and the endocrine and central nervous systems 
(Bird 2019).  DM1 is typically characterized by myotonia and muscle weakness leading to 
immobility, respiratory insufficiency, dysarthria, and dysphagia (Udd 2012, Meola 2015).  Other 
common manifestations include cardiac conduction defects, extreme fatigue, excessive daytime 
sleepiness, and gastrointestinal (GI) disturbances (includes irritable bowel syndrome, acid 
reflux, abdominal pain and constipation (Hilbert 2017).  The congenital and childhood forms 
include intellectual disabilities and psychosocial problems. 
DM1 patients often present with abnormal laboratory values (Heatwole 2006), including 
elevated hemoglobin A1c and triglyceride consistent with insulin resistance, elevated FSH and 
LH due to hypogonadism, abnormal lactate dehydrogenase and creatinine kinase due to 
muscular dysfunction, and both elevated or decreased hemoglobin values. In addition, up to 
44% of DM1 patients have elevated transaminases. Out of these, 87% can be attributed to 
nonalcoholic fatty liver disease (Shieh 2010). Other liver enzymes detected in the blood, 
including gamma-glutamyltransferase and alkaline phosphatase, are also found to be elevated. 
Interestingly, these abnormalities are not thought to be progressive, and are not correlated to 
muscle weakness nor CTG repeat size (Achiron 1998). In fact, the consensus statement for DM1 
adults states that chronic liver enzyme elevation is typical and does not necessarily indicate the 
need for obtaining a liver biopsy (Ashizawa 2018). 
Disease manifestations are highly variable with respect to disease severity, presentation, and 
age of onset.  It shows anticipation, such that successive generations present with increased 
disease severity and earlier age of onset.  Severity can range from lethal effects in infancy to 
mild symptoms in late-onset adults.  As with other triplet repeat disorders, severity of disease is 
correlated with the extent of the repeat expansion, with a higher number of repeats correlating 
with more severe disease.  Based on age of onset and severity of symptoms, DM1 is often 
categorized into four overlapping phenotypes: late-onset, classical (or adult-onset), childhood 
and congenital DM1 (cDM1).  The classical form accounts for approximately 75% of diagnosed 
DM1 patients and the cDM1 form accounts for approximately 15% (Thornton 2014). 
DM1 is associated with high disease burden and premature mortality.  Excluding neonatal 
deaths, life expectancy ranges from 45-60 years with 70% of early mortality caused by 
cardiorespiratory complications.  Respiratory failure due to muscle weakness (especially 
diaphragmatic weakness), causes at least 40% of early mortality and cardiac abnormalities 
including conduction defect (~40% of patients with DM1) (Kaminsky 2013), cardiomyopathy, 
and sudden death which accounts for approximately 30% of the deaths (Turner 2014).  Due to 
the multisystemic disease manifestations, DM1 leads to significant decreases in quality of life as 
a consequence of physical impairment, activity limitations, loss of independence, and 
decreased participation in social activities and work (Landfeldt 2019, Hermans 2010). Common 
challenges to daily life activities reported by DM1 patients include handling objects, performing 
 
 
 
 

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housework, preparing meals, going up and down stairs and standing (Hagerman 2019).  There is 
also a significant impact on caregivers who report providing “moderate” or “major” assistance 
on a daily basis.  Most common forms of support are emotional, household tasks, attending 
doctor appointments, and financial (Hagerman 2019).  A large proportion (47%) of DM1 
patients do not work as a consequence of their disease (Landfeldt 2019).  The family burden is 
amplified due to the anticipation component of the disease where successive generations 
manifest symptoms at progressively earlier ages and with more severity.  Thus, it is common for 
several members of the same family to be affected, with the older DM1 patients also serving as 
the caregiver for the younger generation. 
The pathogenesis of DM1 is thought to include the following steps.  In patients with DM1, one 
of the alleles encoding the DMPK gene contains an expansion of the CTG triplet repeat in the 3’ 
non-coding region.  The expansion ranges from <35 in healthy people to many thousands in 
DM1 patients and correlates to the severity of disease at a population level. When the mutant 
DMPK gene containing the CTG expansion is transcribed into mRNA, the self-complementary 
CUG repeats fold into large hairpin loops and form discrete foci in the nucleus. Although this 
leads to the mutant mRNA not being translated into protein (Furling 2003), the decrease in 
DMPK protein level (or haploinsufficiency) is not thought to be the pathogenic driver of DM1 
(Brook 1992, Lee 2009, Salvatori 2005).  Although mutant mRNA is not expressed in an elevated 
level, the CUG-repeat containing RNA binds to RNA-binding proteins such as muscleblind-like 
protein (MBNL) family members and CELF1 (CUGBP Elav-like family member 1) and sequester 
them into the foci. MBNL and CELF1 physiologically play important roles in regulating mRNA 
processing (Lee 2009, Chau 2015).  However, when bound to the CUG repeats within the 
nuclear-retained DMPK mRNA, MBNL exhibits a loss of function whereas CELF1 activity is 
abnormally upregulated. This leads to a downstream mis-splicing of hundreds of mRNAs which 
translate into altered proteins with abnormal functions. This spliceopathy profile represents the 
molecular hallmark of DM1. The resulting atypical proteins are the ultimate cause of the 
disease manifestations (Gourdon 2017). As examples, some of the abnormal proteins include 
the skeletal muscle chloride channel, the insulin receptor, Troponin T, and the sodium channel, 
contributing to myotonia, insulin resistance, cardiac dysfunction, and conduction defects 
respectively (Pang 2018). 
The pathogenesis of DM1 described above is supported by the following evidence. 1) Another 
clinically similar disease, DM2 (myotonic dystrophy type 2), is caused by tetra-nucleotide 
expansion within a different gene, ZNF9 (zinc finger 9), a transcription factor. Thus, both types 
of myotonic dystrophy are caused by mutant RNA transcripts located in two different genes 
which aberrantly cause spliceopathy of the same downstream targets (Meola 2015). 2) Loss of 
function of DMPK or neighboring genes do not manifest features of DM1 (Berul 1999, 
Carrell 2016). 3) Expanded CTG repeats by themselves aggregate in nuclear foci and inhibit 
myogenesis (Orengo 2008). 4) Compound heterozygote MBNL1 and MBNL2 mice manifest 
features of DM1 (Lee 2013). Taken together, mutant CTG repeats, independent of the rest of 
the DMPK gene causes sequestration of key RNA regulating proteins such as MBNLs into 
discrete nucleus foci and prevent their proper function which then lead to downstream 
spliceopathy. 
 
 
 
 

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2.2. 
AOC 1001 Background 
AOC 1001 is an antibody oligonucleotide conjugate (AOC).  
It is composed of a human transferrin receptor 1 (TfR1) targeting, effector function-null, 
humanized IgG1 antibody (AV01mAb) conjugated via a linker to a double stranded small 
interfering ribonucleic acid (siRNA) oligonucleotide against DMPK (siDMPK.19, referred to 
hereafter as the siRNA component of AOC 1001).   
Figure 1: 
Design of AOC 1001 
Antibody-siRNA conjugate
Passenger strand
Guide strand
Linker
S
 
The AV01mAb facilitates delivery of AOC 1001 to muscle and cardiac tissue through 
TfR1-mediated endocytosis.  Although the TfR1 protein is widely expressed, Avidity’s nonclinical 
studies demonstrate that the primary site of activity of siRNAs delivered using AV01Ab is in 
skeletal and cardiac muscle.  Once AOC 1001 is inside the endolysosomal compartment, the 
antibody is degraded, and the siRNA is released into the cytosol and distributes to the nucleus.  
The pharmacological activity of AOC 1001 is derived from the guide strand of the siRNA which is 
loaded into the RNA-induced silencing complex (RISC) and results in the hydrolysis of DMPK 
mRNA located in both the cytosol and nuclear compartments.  The guide strand is 
complementary to a sequence in the 3’ untranslated region in exon 15 of the DMPK mRNA and 
degrades both wild-type and mutant DMPK mRNA transcripts. 
2.3. 
Therapeutic Rationale 
Because the disease-causing CUG repeats in the mutant DMPK mRNA form hairpin loops and 
aggregate in the nucleus, the mRNA is not translated into DMPK protein. Instead, the toxic 
mRNA sequesters RNA processing proteins such as MBNL and CELF1 that are crucial for proper 
splicing of many downstream genes. Thus, decreasing the levels of toxic DMPK mRNA with 
AOC 1001 should free the RNA processing proteins to perform their normal functions, and 
correct the downstream spliceopathy that is the cause of the disease manifestations. It is 
expected that AOC 1001 has the potential to modify the clinical course of DM1 and improve or 
stabilize muscle strength and performance, cardiac conduction defects and structural 
abnormalities, as well as respiratory function, irrespective of disease stage and CTG repeat size.  
There are currently no FDA approved drug therapies to treat DM1 and current treatment is 
focused largely on symptom management.  Hence, there remains a high unmet need for the 
development of disease modifying therapies to treat the underlying cause of DM1. 
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2.4. 
AOC 1001 Preclinical Experience 
Clinical development of AOC 1001 is based on a robust nonclinical program. Detailed 
information concerning the pharmacology, pharmacokinetics, and toxicology of AOC 1001 can 
be found in the current Investigator’s Brochure.   
2.5. 
AOC 1001 Clinical Experience  
AOC 1001 has not been evaluated in any clinical setting other than this trial and its extension 
trial AOC 1001-CS2.   
As of 30 Sept 2022, 38 participants (8 in cohort A1 and 12 in cohort B1, 18 in cohort B2) have 
been dosed.  
2.6. 
Rationale for Study Design 
This is a randomized, double-blind, placebo-controlled, phase 1/2 study, including a single dose 
arm (Part A) and a nested single and multiple ascending dose arm (Part B), to evaluate the 
safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AOC 1001 
administered intravenously to adult DM1 patients.  
Part A of the study assesses a single dose of AOC 1001 in adult DM1 patients to characterize the 
safety, tolerability, muscle and plasma PK and extent and time course of DMPK knockdown 
following a single dose. The safety data through Day 29 after a single dose will be reviewed to 
enable the initiation of the first MAD cohort in Part B.  
Part B will assess single and multiple ascending doses in DM1 patients in a nested design. The 
first dose in Part B will be based on initial safety data from Part A, and subsequent doses for 
each participant will be based on review of individual safety data following the first dose. 
Escalation to the next cohort in Part B requires approval of the SRC (for cohorts B1 and B2, per 
protocol versions 2.0 and 3.0) or IDMC (for cohort B3, per protocol version 5.0.) In addition to 
the primary objectives of safety and tolerability, secondary and exploratory objectives will 
include assessments of the correction of spliceopathy in muscle tissues to evaluate the 
downstream pharmacologic effect of AOC 1001, as well as measures of mobility, muscle 
strength, and muscle function in DM1 patients.  
Eligible participants from both parts will have the option to enroll into an open label extension 
(OLE) trial after regulatory approval(s), to enable long term follow-up both for safety and 
efficacy. For those patients unable to participate in the OLE, the duration of extended follow-up 
period after the last dose will be 9 months. This assumes appropriate tissue washout of 
AOC 1001 after five half-lives in humans as predicted from nonclinical studies.   
This trial design is based on the current published scientific understanding of the DM1 disease 
pathogenesis, manifestation, and progression as discussed in Section 2.1, input from clinician 
experts specialized in DM1 on clinical endpoint assessments, regulatory authority guidance, and 
DM1 patient feedback. In addition to individual patient interviews, a patient advisory board was 
convened on 10 December 2020 with six patients, ages ranging from 21 to 60 years old, with 
various stages of ambulation.  
 
 
 
 

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Key lessons from this meeting were incorporated into our design, including incorporation of 
patient reported outcome (PRO) and creation of a DM1 specific PRO to characterize the 
symptom severity and impact on function, and logistic planning to decrease in person clinic 
visits where appropriate and to utilize tele-health and home-health visits.  
The use of strategic muscle biopsies allows for AOC 1001 PK/PD profiles and subsequent 
analysis of molecular mechanism and clinical manifestations. A survey was conducted at 
University of Rochester in 60 DM1 patients regarding their experience with muscle biopsies 
(Dr Charles Thornton, unpublished data). Ninety-five percent of the patients had previously had 
a needle biopsy taken in the lower leg in the tibialis anterior muscle. Eighty percent of the 
patients rated the pain of muscle biopsy after a couple of days as 2 out of 10 (10 being most 
severe). Over 97% of the patients rated the needle biopsy experience as “not bad at all” or 
“bother me a little”, and <2% rated it as “horrible”. Over 96% of the patients were willing to 
undergo another muscle biopsy to allow follow up of their disease or as part of a clinical trial. In 
summary, patients did not find the muscle biopsy procedure to be overly burdensome and 
appreciated the importance of comprehensive characterization of the individual’s clinical 
presentations and molecular profile due to the inherent variability of the disease.  
2.7. 
Dose Rationale  
Study drug doses mentioned in this section are referred to by siRNA component weight, not the 
total AOC 1001 weight given that the siRNA component is the pharmacologic moiety of 
AOC 1001. To translate into total AOC 1001 weight, please see Section 6.1. 
2.7.1. 
Starting Dose in Part A  
The strategy for selecting the first in human starting dose (1 mg/kg per siRNA component 
weight) was based on the safety margin relative to the NOAEL in animal toxicity studies, as well 
as ensuring that this dose level was on the low end of the pharmacologically active range for 
DM1 patients. Safety margins were calculated using multiple approaches.  
The NOAEL of 45 mg/kg based on siDMPK.19 component weight is derived from the 
cynomolgus monkey GLP toxicity study. Thus, the starting dose of 1 mg/kg is 15-fold below the 
human equivalent dose of 15 mg/kg (per siRNA component weight) based on a conservative 
estimate of a safety margin assuming body surface area (BSA; mg/m2) scaling from animals to 
humans (Table 5). This approach of selecting a human starting dose at least 10-fold below the 
monkey toxicity study NOAEL in the most sensitive species is consistent with FDA guidance on 
maximum recommended starting dose (MRSD) selection (FDA 2005). 
Based on predicted plasma PK exposures for a 70 kg patient, a safety margin of > 50-fold exists 
for Cmax and >100-fold for AUC (Table 5) relative to the NOAEL (45 mg/kg based on siRNA 
component weight).  
The toxicity of oligonucleotide drugs translates to humans on a body weight (mg/kg) basis 
(FDA 2005, Geary 1997); therefore, this yields a safety margin of 45-fold for the starting dose of 
1 mg/kg (per siRNA component weight). 
Thus, a starting dose of 1 mg/kg provides adequate safety margins. 
 
 
 
 
 
 

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Table 5: 
Estimated NOAEL and Starting Dose Safety Margins 
Species 
NOAEL 
(siDMPK.19 / 
AOC 1001)a, c 
Estimated Safety Margin 
(First-in-human dose, 1 mg/kg siDMPK.19 (12 mg/kg AOC 1001)c 
BSA 
Weight-based 
Cmax-basedb 
AUC-basedb 
Cynomolgus 
Monkey 
45 / 537.4 mg/kg 
~15X 
~45X 
~57X 
~142X 
AUC = area under the drug concentration versus time curve; BSA = body surface area; Cmax = maximum plasma 
concentration; FIH = first in human; NOAEL = no-observed-adverse-effect-level; source for HED calculation: 
FDA 2005.  
a The NOAEL was determined from the 13-week GLP toxicity study in cynomolgus monkeys. 
b The cumulative systemic exposure (plasma cumulative AUC) after 3 doses total was used to project the exposure 
margin.  The Cmax and cumulative AUC following IV infusion in the cynomolgus monkey were approximately 
80,000 nM and 355,600 nM*d, respectively.  For a typical 70 kg patient, predicted human systemic Cmax and plasma 
AUC values following single IV dosing of AOC 1001 at 1 mg/kg are approximately 1400 nM and 2500 nM*d, 
respectively.   
c NOAEL and the FIH starting dose are expressed as siDMPK.19 component and total AOC 1001 dose 
2.7.2. 
Dose Escalation and Maximal Dose 
The strategy for selecting the doses of 2, 4 and 8 mg/kg (based on siRNA component weight) in 
Part B is based on achieving robust mutant DMPK mRNA reduction in muscle tissue while 
maintaining a 2-fold dose escalation schema. Although preclinical data shows that substantial 
knockdown of wild-type DMPK mRNA may occur at lower doses, modeling suggests that 
dose-dependent reduction of mutant DMPK mRNA is expected between 2 mg/kg and 8 mg/kg 
in patients with DM1.   
The selection of the maximal dose of 8 mg/kg is based on preclinical data that suggests higher 
doses may be required to achieve optimal mutant DMPK mRNA reduction relative to wild-type 
DMPK mRNA, in part, because the mutant form is sequestered in the nucleus. This is supported 
by data that show higher siRNA doses were required to achieve mutant DMPK mRNA 
knockdown in in vitro studies utilizing DM1 patient-derived myotubes relative to wild-type 
DMPK mRNA, and that higher doses of a mouse surrogate siRNA targeting DMPK 
(mTfR1Ab-siDMPK.45) were required to achieve comparable reduction of mutant DMPK mRNA 
compared to wild-type DMPK mRNA in a mouse model. Please see the Investigator’s Brochure 
for a detailed summary. Thus, dose levels of 2 to 8 mg/kg will be tested in Part B as these doses 
are predicted to result in graded mutant DMPK mRNA reductions that are anticipated to lead to 
potential clinical benefit.   
A sufficient margin of safety is predicted for the high dose of 8 mg/kg relative to the NOAEL 
(45 mg/kg; maximal feasible dose) in the cynomolgus monkey toxicity study:  ~2-fold margin of 
safety is predicted based on BSA scaling while a >5-fold margin is predicted based on 
body-weight-based scaling. Further, a 3-fold margin is predicted based on plasma PK exposures 
in a 70 kg subject after 3 doses.  
The quarterly (administration every 3-months) regimen proposed for MAD part is supported by 
observed durable DMPK mRNA lowering following a single dose in cynomolgus monkeys. 
Predictions from PK/PD modeling indicate that, at a quarterly dose regimen, AOC 1001 dose 
levels of ≥ 2 mg/kg will achieve the targeted PD in skeletal muscle tissues. However, time to 
steady state is predicted to be up to 9 months after quarterly dose administration. To 
 
 
 
 

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accelerate attainment of steady state levels, a single booster dose at Day 43 is planned in the 
MAD portion of the study. The quarterly regimen with a booster at Day 43 is supported by the 
animal toxicity studies that tested an every 6-week dosing regimen (3 doses total in 13 weeks). 
The anticipated half-life of AOC 1001 in human tissue is approximately 50 days, allometrically 
scaled from observed tissue half-life in cynomolgus monkey.  The siDMPK.19 tissue levels are 
expected to be cleared in approximately 9 months (five tissue half-lives), which is the proposed 
length of safety follow-up for participants not entering the OLE.  
2.8. 
Benefit-Risk Assessment 
Due to limited human experience with AOC 1001, there are no identified risks associated with 
AOC 1001 administration to date. This section summarizes the potential benefits, potential 
risks, and risk mitigation of AOC 1001. More information may be found in the Investigator’s 
Brochure. 
2.8.1. 
Benefit Assessment 
AOC 1001 has the potential to decrease the accumulation of the disease-causing mRNA of 
mutant DMPK gene and modify the disease progression of DM1.  
It is anticipated that AOC 1001 will knockdown the mutant DMPK mRNA in DM1 patients, 
potentially leading to correction of spliceopathy, improving or stabilizing muscle strength and 
performance, cardiac conduction defects and structural abnormalities, as well as respiratory 
function. However, DM1 patients in this study may not benefit from the study drug, due to 
either the short duration of the trial, receiving a lower than optimal dose, or being in the 
placebo arm. Patients completing this study may be able to enroll in the open-label extension 
trial during which long term effects of AOC 1001 will be assessed. 
2.8.2. 
Risk Evaluation 
The potential risks associated with participation in this trial include infusion related reactions 
and hypersensitivity reaction as have been observed with other monoclonal antibodies, 
changes to iron homeostasis through interaction with Tfr1, and risk from the muscle biopsy 
procedure.  In addition, one participant in the 4 mg/kg dose cohort (siRNA component weight) 
in Study AOC 1001-CS1 has experienced a suspected unexpected serious adverse reaction 
(SUSAR) with the verbatim term of “bilateral hemorrhagic lesions in the thalamus.” Symptoms 
from this event include memory loss and sever blurred vision which began approximately 
20 minutes after the end of the first infusion of study drug. 
Appropriate risk mitigation measures have been put in place including addition of exclusion 
criteria related to iron deficiency, guidance for safety monitoring during infusions, guidance for 
managing infusion related reactions, incorporation of safety monitoring and stopping rules 
related to hemoglobin levels, and additional monitoring for neurologic complications. These 
potential risks are considered monitorable and manageable.  Details of each risk and 
corresponding mitigations are provided in Section 6.6 Risk Summary and Recommended 
Mitigation of the Investigator Brochure.   
 
 
 
 

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Other mechanistic risks listed below are described in more detail in the Investigator Brochure: 
• AOC 1001 binds to both wild-type and mutant DMPK mRNA, leading to their 
degradation. However, knockdown of the DMPK wildtype protein is expected to have an 
acceptable safety profile.  
• The potential off-target risk of AOC 1001 is low based on the platform experience in 
siRNA therapeutics and humanized monoclonal antibodies.  
• Off-target hybridization by the siRNA has been minimized and confirmed in preclinical 
studies.  Drug-drug interactions are not expected for the siRNA platform. 
Safety will be monitored throughout the trial with both in clinic visits and remote visits with 
home health care and/or telehealth support. Study assessments and visit schedules have been 
designed with the goal to minimize the burden of the study on participants without risking 
safety. Safety will be monitored and reviewed by the investigator(s), the sponsor medical 
monitor and designees, as well as an SRC/IDMC (as applicable). From initiation of the study 
through protocol version 4.0, SRC was responsible for  dose escalation decisions,  review of 
ongoing safety data and reviewing any cases meeting predefined safety monitoring and 
stopping rules throughout both Part A and Part B of the trial (see Section 4.3, Section 8).  After 
AOC 1001-CS1 protocol version 5.0 is implemented, these responsibilities will transition to the 
IDMC.  The SRC will continue to fulfill the oversight role until the IDMC has been implemented.  
The following safety processes are built into this trial: 
• Participants will be monitored closely during and after the first dosing for at least 
24 hours. 
• Brain imaging and neurologic exam will be completed for all participants as soon as 
possible to allow comparison in situations when neurologic symptoms manifest and 
work up required. 
• Sentinel dosing is employed for all cohorts. The safety data through 24 hours after the 
first dose in the first two participants of each cohort will be reviewed by site PI and 
sponsor medical monitor (or designee) to allow dosing of subsequent participants in the 
same cohort.  
• Dose escalation decisions will be made after reviewing Day 29 safety and tolerability 
data of at least 75% of the participants in the prior cohort. The 29-day monitoring 
period provides sufficient time to monitor for acute safety events (such as immune 
reaction) during and after first dose administration. In monkeys, rapid DMPK mRNA 
lowering was observed in tissues, with near maximal reduction observed within 4 weeks 
post first dose. Thus, the Day 29 evaluation period between cohorts will allow for safety 
assessment at maximal DMPK mRNA lowering.  
• In multiple ascending dose cohorts, nested SAD/MAD design is employed in that safety 
and tolerability data through Day 29 for each participant after the first dose will be 
reviewed by the site PI and sponsor medical monitor (or designee) to allow subsequent 
dosing for each individual. 
 
 
 
 

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• In addition to collecting triplicate ECGs during this period when AOC 1001 plasma Cmax is 
expected to be the highest, triplicate ECGs will be collected throughout the trial to 
examine the relationship of PK, PD, and electrocardiographic parameters when 
AOC 1001 is expected to be in cardiomyocytes. Because patients with DM1 often have 
electrical and structural cardiac changes, echocardiogram and highly sensitive cardiac 
troponin will be monitored as well.  
• Because AOC 1001 is expected to knockdown DMPK mRNA in muscles, serum levels of 
muscle proteins that are considered biochemical markers of muscular injury will be 
monitored throughout the duration of the trial, including creatine kinase, aspartate 
aminotransferase, and myoglobin. 
• In preclinical studies, the distribution of AOC 1001 is observed in liver, kidney, and bone 
marrow, in addition to muscle containing organs. Eligibility criteria have been placed to 
exclude participants with baseline abnormalities to reduced potential risks while taking 
into consideration the ranges of lab abnormalities expected in the DM1 population. 
Additionally, safety monitoring rules are designed to provide guidance related to the 
potential risks described below.  
• Although siDMPK.19 is distributed to reproductive organs, reproductive effects are not 
expected given the lack of meaningful DMPK mRNA reduction in these tissues and lack 
of any histopathology findings in the 13-week monkey GLP toxicity study. To limit 
embryofetal risk, female participants of child-bearing potential are required to have a 
negative pregnancy test, cannot be breast feeding, and must be willing to use a highly 
effective method of contraception as specified in Section 6.4. Exposure level in the 
partners of male participants is expected to be negligible for the following reasons. First, 
AOC 1001 is not genotoxic per standard battery of nonclinical studies conducted and 
described in the IB. Second, AOC 1001 is a relatively large molecule to be able to cross 
the blood-testis barrier and administered infrequently with short duration of meaningful 
plasma concentration. Third, the amount of unconjugated siRNA in the circulation is 
expected to be very low and are likely to be renally cleared rapidly. Fourth after 
AOC 1001 is internalized through transferrin receptor mediated endocytosis, the 
antibody portion of the molecule is degraded, leaving only the unconjugated siRNA. 
Unconjugated siRNAs are highly polar and, they do not readily cross cell membranes 
without receptor-mediated endocytosis. This means any unconjugated siRNAs present 
in the seminal fluid would be unable to be taken up by cells of the female partner. Fifth, 
it is unlikely that AOC 1001 would be exposed to the placenta and for those drugs 
actually in contact with the placenta, it would be unlikely to cross the placenta due to its 
large size. Sixth, negligible amount of the unconjugated siRNAs is expected to be in the 
sperm and whatever present is not expected to lead to meaningful DMPK reduction in 
maternal tissues or in the conceptus. Nonetheless, male participants and their female 
partners of child-bearing potential, will be required to use contraception as specified in 
Section 6.4.  
• Any participant who does not enroll in the OLE will be followed for at least 9 months 
after the last dose, which is predicted to be at least 5 tissue half-lives. 
 
 
 
 

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2.8.3. 
Risks and Mitigation Due to the COVID-19 Pandemic 
This study has been designed to reduce the likelihood of COVID-19 spread for participants and 
healthcare personnel, to maintain safe and continuous study conduct, and to analyze the data 
for potential effects of COVID-19 illness on results. 
Study participants will be tested for COVID-19 per site and local regulatory requirements. 
Participants with a history of COVID-19 based on clinical presentation and/or COVID-requiring 
medical management within 1 week of Day 1; or presence of clinically relevant post-COVID 
symptoms/conditions after discussion with medical monitor are also excluded. It is possible 
that this process may lead to more screen failures, but overall, the pandemic is not expected to 
significantly impact recruitment.  
Recent or future vaccination is not excluded or prohibited as patients with DM1 are at high risk 
for severe COVID-19 and poor outcome (Dhont 2020) and have a high priority for vaccination 
due to cardiorespiratory risk factors. Previous clinical trials with siRNA therapeutics have not 
excluded vaccine administration to trial participants in general. It is believed that there 
COVID-19 vaccines would have minimal impact on the effect of AOC 1001. COVID-19 illness or 
vaccination status will not affect the length of follow-up. 
The impact of COVID-19 on concomitant medications and clinical monitoring should not be 
significantly different in this study. It is not known if there are any treatments for COVID-19 
(e.g., remdesevir or monoclonal antibody infusions) that would affect DM1 patients differently 
than the general population, nor of any interaction between these medications and AOC 1001. 
To assess the potential for virus/drug interactions, participants enrolled in the trial who 
contract COVID-19 will be monitored per standard of care, and per trial schedule as well as per 
investigator judgment. It is not expected that AOC 1001 would affect COVID-19 disease 
progression. It is possible that AOC 1001 could improve muscular strength of the DM1 patients, 
in which case it may improve respiratory function in DM1 patients. 
Careful risk mitigation steps have been instituted at the clinical sites to decrease the risk of 
participants and healthcare providers contracting COVID-19 during the study, per local and 
institution regulation and guidance. Risk mitigation will include working closely with sites and 
rearranging schedules if site personnel require isolation. These measures will be agreed in 
advance between the sponsor and clinical trial site. Telehealth visits are allowed if travel is 
restricted. The schedule of assessments and visit windows have been designed to allow 
flexibility for trial conduct. Use of remote and telehealth visits and home health lab collections 
have been built in, as well as telephone visits for patient monitoring. Protocol deviations due to 
COVID-19 will be recorded to allow analysis of impact due to COVID-19. Similarly, screen failure 
and treatment discontinuation due to COVID-19 will be recorded and monitored. These will be 
reviewed to assess for the need for a protocol amendment. 
Should the overall duration of the study be extended, this should not affect the availability of 
study drug as stability testing is ongoing. 
Overall, the risk benefit balance of conducting the trial during the COVID-19 pandemic is 
considered to be positive, due to the ability to mitigate risks and conduct the study safely, and 
to provide potential benefit to a vulnerable population. 
 
 
 
 

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2.8.4. 
Overall Assessment of Benefit: Risk 
Based on preclinical results and analysis, it is predicted that the dose range tested will exhibit 
acceptable safety and tolerability profile in adult DM1 patients, and knockdown of the mutant 
DMPK mRNA may potentially lead to correction of spliceopathy in DM1 patients. 
The potential safety concerns associated with AOC 1001 treatment can be monitored by clinical 
signs and/or lab tests, and this study has been designed with appropriate exclusion criteria, 
dose escalation, safety monitoring and review to minimize potential risks to study participants. 
The information obtained during this study is critical to further development of AOC 1001 for 
DM1, a rare disease with high unmet need for an effective treatment.  Key opinion leaders in 
the field of DM1 were consulted and agreed that, given the high unmet need, the trial has a 
favorable risk/benefit profile. Thus, exposure of participants in this study is justified by the 
anticipated benefits that may be afforded to the wider population of patients by continued 
development of AOC 1001. 
 
 
 
 

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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary Objective 
• 
To evaluate the safety and tolerability 
of single and multiple ascending doses 
of AOC 1001 in DM1 patients 
Primary Endpoint 
• 
Frequency of treatment emergent adverse 
events (TEAEs) 
Secondary Objectives 
• 
To evaluate the pharmacokinetic profile 
of single dose and multiple doses of 
AOC 1001 in DM1 patients 
• 
To evaluate the pharmacodynamic 
profile of single dose and multiple 
doses of AOC 1001 in muscle biopsies in 
DM1 patients 
• 
To evaluate the efficacy of multiple 
doses of AOC 1001 in DM1 patients as 
measured by spliceopathy  
Secondary Endpoints 
• 
AOC 1001 levels in plasma, urine, and muscle 
tissue 
• 
Estimation of PK parameters, including Cmax, 
tmax, t1/2, AUC, and fraction excreted in urine 
• 
Change and percentage change from baseline 
in DMPK mRNA levels  
• 
Change and percentage change from baseline 
in spliceopathy 
 
 
 
 

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Exploratory Objectives 
• 
To evaluate the exploratory efficacy of 
multiple doses of AOC 1001 in DM1 
patients on measures of mobility, 
muscle strength, muscle function, and 
patient-reported outcomes 
• 
To evaluate immunogenicity and 
metabolite PK of AOC 1001 
 
 
Exploratory Endpoints 
Change from Baseline in: 
• 
Myotonia 
• 
Ankle dorsiflexion strength by QMT 
• 
Multiple Muscle Strength by Quantitative 
Myometry Test (QMT) 
• 
Grip Strength 
• 
Pinch Strength 
• 
10-Meter Walk/Run Test (10MWRT) 
• 
Timed Up and Go (TUG) 
• 
Timed 4 Stair Climb  
• 
Timed 4 Stair Descend 
• 
Pulmonary Function Parameters by 
Spirometry  
• 
Multiple Muscle Strength by Manual Muscle 
Test (MMT)  
• 
9-Hole Peg Test 
• 
% of participants needing to start myotonia 
medications after dosing 
• 
Muscular Impairment Rating Scale 
• 
DM1-Neuromuscular Severity Measure 
(DM1-NSM) 
• 
Myotonic Dystrophy Health Index (MDHI)  
• 
DM1-Activ  
• 
DM1-NSM Patient Global Impression of 
Severity (DM1-NSM-PGIS) 
• 
DM1-NSM Patient Global Impression of 
Change (DM1-NSM-PGIC) 
• 
Fatigue and Daytime Sleepiness Scale 
• 
Clinician Global Impression of Severity (CGIS) 
• 
Clinician Global Impression of Change (CGIC) 
• 
EQ-5D-5L 
• 
Columbia-Suicide Severity Rating Scale 
PK Endpoints: 
• 
Measurement of ADA 
• 
Measurement of potential metabolites  
Additional Safety Objectives 
• 
To further characterize the safety and 
tolerability profile of AOC 1001 
• 
Laboratory parameters 
• 
Vital signs 
• 
Infusion related reactions (IRR) 
• 
Electrocardiographic measures 
• 
Echocardiographic measures 
 
 
 
 

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4. 
INVESTIGATIONAL PLAN 
4.1. 
Study Design 
AOC 1001-CS1 is a first in human, double-blind (participant and trial site personnel), 
placebo-controlled multicenter study in two parts. Part A is a single dose design, enrolling 
approximately 8 adult DM1 patients, whereas part B is a nested single and multiple ascending 
dose (MAD) design enrolling up to 44 adult DM1 participants.  
For participants who withdraw from the study prematurely, additional participants may be 
enrolled at sponsor discretion so that minimal evaluable participants are achieved for dose 
escalation. The maximum enrollment will be limited to 52 participants, including replacement 
participants.  
Consistent with the pathogenesis of DM1 and the mechanism of action of AOC 1001, one of the 
pharmacodynamic parameters for this study will be the knockdown of the DMPK mRNA. The 
safety of AOC 1001 will be monitored in an ongoing fashion throughout the study including 
safety labs from blood/urine samples, ECGs, physical examinations, vital signs, and adverse 
events. Exploratory efficacy endpoints to measure participants’ mobility, muscle strength, 
muscle function, and patient-reported outcomes will be assessed. 
Detailed information regarding study procedures is outlined in the Schedules of Assessments 
(SOA) (Table 1, Table 2, Table 3, and Table 4). 
The end of study is defined as the last participant last visit. 
The study will continue until all treated participants have completed the last study visit.  
4.1.1. 
Part A 
The minimum length of participation in Part A is approximately 7.5 months that includes an up 
to 6-week screening period, a one-day dosing period, and a 6-month post-treatment period.  
The duration of the study is designed to capture the maximal DMPK mRNA knockdown, and to 
follow the duration of the knockdown as well as safety profile associated with the drug action.  
Baseline assessments will be collected after participant is deemed eligible for Part A prior to 
Day 1. Participants will receive study drug by IV infusion on the morning of Day 1 and will be 
monitored overnight. After at least 24 hours of observation, they will be discharged on Day 2 
after completing the Day 2 study assessments. The participant will return to the trial site for 
additional safety evaluations during the 6-month post-treatment period per Table 1. 
At the end of the 6-month post-treatment period, eligible participants may directly enroll into 
an open label extension trial (OLE).  Participants not willing or eligible to enroll in the OLE will 
be followed in the extended follow-up period for an additional 3 months, for a total of 9 
months post-dose, which is estimated to be 5 tissue half-lives of the drug.  The extended follow 
up will consist of communication between the site and participant via telephone, telehealth or 
other applicable means.   
A muscle needle biopsy from the tibialis anterior will be obtained at Baseline, on Days 43, and 
92.  
 
 
 
 

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If a participant discontinues prior to completing the required assessments, perform the 
Day 183/End of Post-Treatment (EOPT) assessments, if possible (Table 1 and Table 2). 
4.1.2. 
Part B 
The length of participation in Part B is approximately 7.5 months, which includes an up to 
6-week screening period, a 3-month treatment period, and a 3-month post-treatment period.
Pending approval by the regulatory agencies, all eligible participants will have the option to
enroll into the OLE.
Baseline assessments will be collected after participant is deemed eligible for Part B prior to 
Day 1.  Participants will receive study drug by IV infusion on the morning of Day 1 and will be 
monitored overnight. After at least 24 hours of observation, they will be discharged on Day 2 
after completing the Day 2 study assessments.  The participant will return to the trial site for 
additional safety evaluations during the 3-month treatment period per Table 3. They will 
receive IV infusions on Day 43 and 92 and will be followed for an additional 13 weeks in the 
post-treatment period after the 3rd dose. 
For each participant in Part B, continuation of the second dose will require the review of Day 29 
safety and tolerability data by the participant’s PI, and the sponsor medical monitor or 
designee. The decision will be documented on the Dose Continuation Approval form. 
A muscle needle biopsy from the tibialis anterior will be obtained at Baseline, on Days 92, and 
183.  
If a participant discontinues prior to completing Day 92 (3rd infusion), every effort should be 
made to complete End of Treatment (EOT) assessments, then have the participant begin the 
13-week post-treatment period. See Section 5.3, Section 5.4, and Section 5.5. Detailed
information regarding study procedures is outlined in Table 3 and Table 4.
For participants who terminate treatment early and/or do not enroll into the OLE trial, 
participants will be followed in the extended follow-up period to be monitored for safety every 
3 months until they have been followed for 9 months from the last dose. 
4.2. 
Safety Oversight 
4.2.1. 
Safety Review Committee (SRC) 
An SRC will perform ongoing blinded reviews of safety, tolerability data collected in all study 
parts (Parts A and B) with the primary purpose of protecting the safety of participants.  
SRC will be responsible for recommending decisions to dose escalate from Part A to Part B and 
from cohort B1 to cohort B2 based on safety and tolerability data of preceding cohorts.  SRC 
may also participate in ad hoc meetings for decisions related to AEs meeting criteria listed in 
Section 4.3.  After the Data Monitoring Committee (IDMC) (see Section 4.2.2) has been put in 
place, the SRC safety oversight responsibilities will be transferred to the IDMC.      
The details regarding meeting frequency, data to be reviewed, the data review process, and 
information dissemination to clinical sites, are included in the SRC charter. 
 
 
 
 

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4.2.2. 
Independent Data Monitoring Committee (IDMC) 
An IDMC will be responsible for recommending the decision to dose escalate from cohort B2 to 
cohort B3 (upon implementation as of protocol version 5.0).  The IDMC will also conduct regular 
meetings to review the safety and tolerability. The IDMC will also approve resumptions in 
dosing as described in Table 6.  
The details regarding membership, responsibilities, meeting frequency, data to be reviewed, 
and process for communication with the Sponsor are included in the IDMC charter. 
4.3. 
Cohort Safety Management Rules 
Individual participant, dosing cohort, and study dose suspension and stopping rules are 
presented in Table 6.  
AE severity and seriousness are assessed independently, according to the definitions listed in 
Section 8.2 and Section 8.4.1, but are considered together for the purpose of applying the 
suspension and stopping rules described here.   
Abnormal laboratory and other test results should always be repeated at a central laboratory, if 
possible, before evaluating clinical relevance and grading AEs to ensure consistency and to 
exclude technical errors.  If applicable, diurnal variations in laboratory parameters and other 
measurements as well as baseline status should be considered when grading AEs and assessing 
whether abnormal laboratory values constitute a drug-related AE. 
Participants who discontinue dosing because they have met a stopping rule will be asked to 
undergo scheduled study assessments until completion of the study or until resolution or 
stabilization of the AE, whichever is later.  Participants who meet stopping rules will be 
managed as clinically indicated, with appropriate consultation and referral to their primary 
physicians, as necessary.   
 
 
 
 
 
 

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5. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
5.1. 
Inclusion and Exclusion Criteria  
5.1.1. 
Inclusion Criteria  
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be willing and able to comply with all study requirements  
2. Males or females aged 18 to 65 years (inclusive) at the time of informed consent  
3. Genetic diagnosis of DM1 with DMPK CTG repeat length ≥ 100 during screening, if not 
done prior  
4. Ability to walk independently (orthoses and ankle braces allowed but not cane or 
walker) for at least 10 meters at screening   
5. 10mWRT velocity at Screening 
a. Part A: 10mWRT velocity 0.7 -3.3 m/sec (3-14 seconds) 
b. Part B: 10mWRT velocity 0.7 -2.63 m/sec (3.8-14 seconds) 
6. Muscular Impairment Rating Scale (MIRS) score  
a. Part A: MIRS score ≥2 
b. Part B: MIRS score ≥3 
5.1.2. 
Exclusion Criteria  
1. Females who are pregnant, planning a pregnancy, or breast-feeding  
2. Males or Females not willing to comply with contraceptive requirements as described in 
Section 6.4. 
3. Screening laboratory results as follows, or any other clinically significant abnormalities in 
screening laboratory values that would render a participant unsuitable for inclusion.  
a. ALT, AST >2.5x ULN, alkaline phosphatase >2x ULN  
b. Total bilirubin > 1.5 mg/dL. Total bilirubin between 1.5 and ≤ 3 mg/dL with clinical 
diagnosis of Gilbert’s syndrome as determined by the investigator may also be 
eligible if approved by sponsor medical monitor or designee  
c. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 calculated 
by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
d. Platelet count < 100x109/L 
e. Hemoglobin < 10 g/dL 
f. TSH outside reference range and thyroid panel including reflexive TT3 and FT4 
consistent with clinically significant abnormalities per investigator judgment  
g. HbA1c > 9%  
4. Diabetes that is not, in the opinion of the investigator, adequately controlled with diet 
and/or antidiabetic medication(s)  
5. PR interval >240 milliseconds at screening (except those with appropriately 
programmed cardiac rhythm management devices after discussion with the medical 
monitor) or planned pacemaker procedure during study period. Clinically significant and 
unstable heart disease including decompensated heart failure within 3 months of 
screening (such as New York Heart Association (NYHA) Classification III or more), atrial 
flutter, atrial fibrillation, ventricular arrhythmias, or receiving medication for the 
treatment of a cardiac arrhythmia, in the opinion of the investigator. (Patients 
 
 
 
 

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presenting with Stable ventricular dysfunction without congestive heart failure, 
pre-existing pacemaker or ICD are not excluded from this study.)  
6. Uncontrolled hypertension (BP > 160/100 mm Hg)  
7. BMI > 35 kg/m2  
8. Congenital DM1 
9. Have unstable medical conditions that affect the musculoskeletal system (other than 
DM1) that could affect interpretability of the outcome measures  
10. History of tibialis anterior biopsy 3 months within the first biopsy of the trial or planning 
to undergo tibialis anterior biopsies over the duration of the trial. History of bleeding 
disorders, significant keloid or other skin or muscle conditions (eg. Severe muscle 
wasting) that in the opinion of the investigator make the participant unsuitable for serial 
muscle biopsy.  
11. Anticipated survival less than 2 years   
12. Evidence of current active or chronic infection with hepatitis C, hepatitis B, or HIV 
(including chronic infection requiring ongoing treatment to maintain viral suppression) 
13. Malignancy within 5 years, except for basal or squamous cell carcinoma, melanoma in 
situ of the skin, or carcinoma in situ of the cervix that has been successfully treated. 
Participants with a history of other malignancies that have been treated with curative 
intent and which have no recurrence within 5 years may also be eligible if approved by 
sponsor medical monitor or designee  
14. Treatment with another investigational drug or biological agent within one month of 
screening, or 5 half-lives of the drug, whichever is longer. Participation or plan to 
participate in another intervention trials with investigational devices, or other types of 
interventional trials (including trials studying behavioral modification and/or physical 
therapy) 
15. Treatment with an oligonucleotide within 9 months of screening   
16. Treatment with anti-myotonic medication within 14 days prior to dosing.  May include, 
but not limited to: phenytoin, carbamazepine, procainamide, disopyramide, nifedipine, 
acetazolamide, clomipramine, imipramine, amitriptyline, taurine, quinine, mexiletine  
17. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1   
18. Recent history of, or current drug or alcohol abuse  
19. Have any other conditions (e.g., medical concern, neuropsychiatric or intellectual 
disabilities), which, in the opinion of the investigator or sponsor would make 
the participant unsuitable for inclusion, could interfere with participating in, or 
completing the Study.  
20. History of multiple drug allergies or history of allergic reaction to any component of, or 
excipient in, the study drug.  
21. COVID-19 based on clinical presentation and/or COVID-requiring medical management 
within 1 week of Day 1; or presence of clinically relevant post-COVID 
symptoms/conditions after discussion with medical monitor.  (Screening and Baseline 
periods may be extended without the need for rescreen after discussion with Sponsor 
medical monitor.)   
 
 
 
 

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22. Unwillingness to receive COVID-19 testing per local or site COVID-19 guidance. 
5.2. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized due to not meeting eligibility criteria outlined in Section 5.1. 
Screening labs can be repeated without the need to screen fail if the investigator feels the lab 
results are out of range due to technical issues or mild or reversable clinical conditions. 
Select information regarding screen failure is required in the EDC. Please refer to eCRF 
Completion Guidelines.  
Participants who fail screening can be rescreened if the investigator documents that the reason 
for screen failure has reversed and after consultation with medical monitor. However, for 
10mwrt velocity, participant should not be rescreened unless the transient medical condition 
affecting the performance of 10mwrt has reversed. A participant can be rescreened twice. If 
rescreened, the participant will keep the originally assigned screening number. Assessments 
performed prior to reconsent but within the current screening period may be used for eligibility 
upon approval from Sponsor (or designee). 
5.3. 
Discontinuation of Study Drug  
In some instances, it may be necessary for a participant to permanently discontinue study drug.  
If study drug is permanently discontinued, the participant should, if at all possible, remain in 
the study to be evaluated for post-treatment visits, and the extended follow-up visits, if 
applicable, unless they have specifically withdrawn consent for any further involvement with 
the study.   
The reason for discontinuing study drug should be recorded in the EDC.  Reasons could include, 
but are not limited to, the following: 
• Withdrawal of consent 
• Significant violation of the protocol (including participant unwilling or unable to comply 
with the protocol) 
• Adverse Event 
• Pregnancy 
• Meets protocol specified treatment discontinuation criteria 
If possible, the investigator will confer with the medical monitor or designee before 
discontinuing study drug administration. Medical monitor (or designee) should be involved in 
the planning of subsequent follow up to ensure patient safety and trial integrity.  
Participants who are pregnant will be discontinued from study drug dosing immediately (see 
Section 8.8 for reporting and follow-up of pregnancy).  
If a participant discontinues study drug due to an AE or SAE, the event should be reported as 
described in Section 8.4. The primary reason must be recorded in the appropriate section of the 
eCRF. Safety data will be captured for the entire duration of the study for participants who 
discontinue study drug. 
 
 
 
 

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A participant may also be discontinued for protocol violations or if the protocol specified 
treatment discontinuation criteria are met for cohort/study (see Section 4.3, Table 6).  
For Part B participants who permanently discontinue study drug, they should complete End of 
Treatment (EOT) assessments prior to initiating post treatment visits. 
5.4. 
Declining of Study Procedure 
Participants who decline protocol assessments (e.g., muscle biopsy) should not be 
automatically removed from study unless the participant specifically withdraws consent for any 
further involvement with the study. Participants should be encouraged to continue with the 
remaining protocol assessments, especially safety monitoring.   
If a participant declines some or all of the study assessments, the investigator must discuss with 
the participant options for continuing Schedule of Assessments including different levels for 
follow-up and collection of data, including endpoints and AEs. These options may include in 
person clinic or remote visits, by phone, by mail, through family or friends, or options not 
involving direct contact, such as communication with other treating physicians or from review 
of medical records. Investigator should document this decision in the participant’s medical 
records. 
Medical monitor (or designee) should be informed. 
5.5. 
Participant Discontinuation/Withdrawal from the Study 
A participant is considered to have completed the study if the participant has completed the 
post treatment period and complete either of the following: 
• Enroll in the OLE, or 
• Extended Follow-up through 9 months after the last dose 
A participant may withdraw from the study at any time. However, study integrity and 
interpretation are optimal if all randomized participants continue study assessments and 
follow-up. Participants considering withdrawing from the study should be informed that they 
can discontinue study drug administration and complete the remaining scheduled study visits 
or agree to alternative follow-up processes as described in Section 5.4. 
If a participant still chooses to withdraw consent from study participation, every effort should 
be made to conduct the assessments performed at the EOPT visit prior to the withdraw of 
consent.   
After withdrawal of consent from further participation in the study, participants will have no 
additional study procedures performed and no additional data collected.  The information and 
samples that he or she has provided prior to withdrawal may be kept and continue to be used, 
transferred, and processed. 
The investigator should notify the medical monitor or designee of all discontinuations of 
participants from the study, preferable before the discontinuation. Medical monitor (or 
designee) should be involved as applicable in the planning of subsequent follow up to ensure 
 
 
 
 

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patient safety and trial integrity.  In addition, the investigator should follow the following 
guidance’s: 
• Discontinuation due to AE should occur AFTER proper follow up of the AE.  
• If a participant withdraws due to a serious adverse event (SAE), the SAE should be 
followed as described in Section 8.5. See SOA for data to be collected at the time of 
study discontinuation (Table 1, Table 3). 
If the participant withdraws from the study, the information and samples that he or she has 
provided prior to withdrawal may be kept and may continue to be used, transferred and 
processed. 
5.6. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the trial site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• Medical monitor (or designee) should be informed. 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get study intervention. Public sources may be searched for vital status 
information.  If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information. 
 
 
 
 

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reactions (IRRs) in the opinion of the IDMC (or SRC until the IDMC is implemented). See 
Section 8.9.2. 
6.1.1. 
Packaging and Labeling 
The sponsor will provide the investigator with packaged AOC 1001 labeled in accordance with 
specific country regulatory requirements. Placebo will be provided by the study site. 
6.1.2. 
Study Drug Accountability 
The unblinded pharmacist will maintain accurate records of receipt and the condition of 
AOC 1001 including dates of receipt. In addition, accurate records will be kept of the 
participants’ baseline weights used to calculate each dispensed dose, and when and how much 
AOC 1001 is dispensed and used by each participant in the study. Any reasons for departure 
from the protocol dispensing regimen must also be recorded. Please refer to Pharmacy Manual 
for more detail. 
6.2. 
Randomization and Blinding 
Eligible participants will be randomly assigned on Day -1 or Day 1 to AOC 1001 or placebo via 
IRT. Participants within each cohort will be randomized in a 3:1 AOC 1001:placebo allocation.  A 
sentinel group of 2 participants (1:1 active: placebo) will be utilized in each cohort. 
Investigators and site personnel will remain blinded to each participant’s assigned study 
intervention (AOC 1001 vs placebo) throughout the course of the study. The site pharmacy and 
the sponsor will be unblinded to study drug treatment. The study drug will be administered 
under the supervision of the blinded investigator. To maintain this blind, an otherwise 
uninvolved pharmacist will be responsible for the reconstitution and dispensation of study drug 
and will endeavor to ensure that site personnel and participants remain blinded to the 
treatment. 
Once assigned, randomization numbers will not be re-used.   
6.2.1. 
Unblinding 
The IRT system will be programmed with blind-breaking instructions. In case of a medical 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s treatment assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should contact the sponsor prior to unblinding a participant’s 
treatment assignment, unless this could delay emergency treatment of the participant. The 
date, time, and reason that the blind was broken must be recorded in the source document and 
filed in the eTMF.  
6.3. 
Dosing 
6.3.1. 
Part A: Single Dose  
There is 1 planned dose level in Part A with 8 participants in the cohort (Table 7 ). Participants 
will receive a single dose of study drug (AOC 1001 or placebo) by IV infusion on Day 1 and will 
 
 
 
 

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CONTRACEPTION REQUIRED: None 
b. Female participants of childbearing potential (WOCBP) who anticipate being sexually 
active with a male during the trial (from one complete menstrual cycle prior to the first 
study drug administration until the last visit):  
CONTRACEPTION REQUIRED: Highly effective contraception must start one complete 
menstrual cycle prior to the first day of dosing and continue until the end of the 
systemic exposure of the study drug (defined as 5 tissue half-lives or 9 months from the 
last dose). Highly effective contraception methods for WOCBP include:  
• Combined i.e. (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
− oral  
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of 
ovulation 
− oral  
− injectable  
− implantable  
• Intrauterine hormone-releasing system (IUS) 
• Intrauterine device (IUD)  
• Bilateral tubal occlusion 
• Infertile male partner (e.g., vasectomized, permanently sterile following bilateral 
orchidectomy, or any other documented cause of infertility) 
c. WOCBP who agree to remain abstinent for the duration of the trial (from one complete 
menstrual cycle prior to the first study drug administration until the last visit): 
CONTRACEPTION REQUIRED: Abstinence (Note: sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the trial treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the participant. Calendar, symptothermal and 
post-ovulation methods of contraception are not considered to be equivalent to 
abstinence).  
d. Male participants, who agree to remain abstinent for the duration of the trial (from first 
study drug administration until the follow-up visit): 
CONTRACEPTION REQUIRED: Abstinence (Note: sexual abstinence is considered a highly 
effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the trial treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the participant).  
 
 
 
 

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If the situation changes after randomization during the trial, participants must use a 
condom with or without spermicide for the duration of the trial and for 9 months after 
the end of the trial. 
e. Male participants, who anticipate being sexually active during the trial period (from first 
study drug administration until the last follow-up visit):  
CONTRACEPTION REQUIRED: from start of dosing until 9 months after the last dose. 
Male participants should use a condom with or without spermicide.  Female partners of 
male participants who are WOCBP should use highly effective contraception per point b 
above.  
6.5. 
Disallowed Therapy 
Therapies disallowed and excluded during the eligibility process are prohibited during the trial. 
These include:  
• Participation in interventional trials with another investigational drug, biological agent, 
device, or other types of interventional trials (including trials studying behavioral 
modification and/or physical therapy) 
• Treatment with an oligonucleotide other than study drug (this does not include 
COVID-19 RNA vaccines) 
• Treatment with anti-myotonic medication which includes, but is not limited to: 
phenytoin, carbamazepine, procainamide, disopyramide, nifedipine, acetazolamide, 
clomipramine, imipramine, amitriptyline, taurine, quinine, mexiletine. They should be 
washed out 14 days prior to first dose of study drug. If treatment with anti-myotonic 
medication is started during the trial, it should be recorded as a concomitant medication 
(see Section 7.1.1). 
6.6. 
Lifestyle Considerations 
Energy drinks or drinks containing taurine, glucuronolactone (e.g., Red Bull), or alcohol should 
be withheld 24 hours before visits that include dose administration and/or muscle biopsy 
procedures, if possible. 
If participants take a stimulant or caffeine to prepare for clinic visit, the same regimen should 
be maintained before each visit and recorded in source each visit. 
If participants are in physical therapy or follow an exercise routine, it should be consistent 
throughout the trial. 
Strenuous physical activity should be avoided 72 hours before visits that include dose 
administration, measures of functions and strength, and/or muscle biopsy procedures. 
Blood and plasma donation should be avoided for 16 weeks before the planned first study drug 
administration and throughout the trial. 
Vaccinations should not be given within 5 days before dosing and for two weeks after dosing. 
Participants should refrain from starting new supplements, herbal preparations, over the 
counter medications, vitamins, or minerals for the length of the trial. 
 
 
 
 

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6.6.1. 
Spirometry 
For spirometry to assess pulmonary function: Participants can continue taking daily medications 
prior to testing unless told otherwise. Participants should not smoke for at least six hours prior 
to testing. 
For a participant who uses short-acting inhaler on a “as needed” basis: Participants should not 
use for eight hours prior to testing, if possible. Participants should not eat or drink for at least 
30 minutes prior to spirometry testing. 
 
 
 
 

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7. 
STUDY ASSESSMENTS  
7.1. 
General Assessments 
The schedules of assessments (SOA) for Part A are provided in Table 1 and Table 2, and for 
Part B in Table 3 and Table 4.  
No study-specific procedures or tests will be performed prior to the participant voluntarily 
signing the ICF. Procedures or tests performed per standard-of-care routine medical care prior 
to a participant signing the ICF may be used to fulfill eligibility requirements. These conditions 
are specified in the SOA. 
Additional assessments may be performed at any point as clinically indicated for safety.  
As applicable, additional details for assessments will be described in the Study Operations 
Manual (SOM) and instructions for entering the data into EDC are included in the eCRF 
Completion Guidelines. 
In general, pre-dose laboratory testing and muscle biopsy should be performed after all other 
assessments during a clinical visit except for dosing. PROs should be the first assessments to be 
performed. 
7.1.1. 
Medications 
The investigator or qualified designee will review past and current medication use to assess for 
eligibility according to the inclusion and exclusion criteria. Current medications as well as 
medications taken in the two months prior to screening should be recorded in EDC.   
Use of all concomitant medications and treatments will be reviewed by the investigator and 
recorded in the eCRF during the trial. This will include all prescription drugs (including 
vaccination), herbal preparations, over the counter medications, vitamins, and minerals. Any 
changes in medications during the study will also be recorded in the EDC. 
Participants are required to discontinue use of any anti-myotonic medication at least 14 days 
prior to dosing. However, if, in the opinion of the Investigator, start of anti-myotonic 
medication is clinically warranted due to symptom recurrence or worsening after dosing has 
started, it should be recorded as a concomitant medication. 
7.1.2. 
Demographics  
At the Screening Visit, demographic data will be collected and include gender, year of birth, 
age, race, and ethnicity (where allowed, per local regulations).  
7.1.3. 
Medical History and Disease History 
A complete medical (including a comprehensive neurologic history) and surgical history will be 
obtained by the investigator or a qualified designee.  
All clinically significant medical history (including any significant surgical procedures) must be 
recorded in the EDC for each participant. Each participant’s full medical history will be obtained 
through direct questioning and the medical assessment during the Screening Period and 
 
 
 
 

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updated prior to dosing unless they are considered Serious Adverse Events (SAE, see 
Section 8.3). 
A structured medical/disease history will be used to capture DM1 phenotypes in the EDC as 
outlined in the eCRF Completion Guidelines. Data will include age of onset, presence or absence 
of common DM1 symptoms, such as myotonia, muscle weakness, cataracts, cognitive or sleep 
symptoms. Common comorbidities will be documented, including sleep apnea, use of 
non-invasive ventilatory support, presence of a pacemaker or ICD, history of bowel obstruction 
or pseudo-obstruction, and presence of thyroid disease or diabetes mellitus. Information of 
prior participation in any DM1 natural history study will be recorded in the EDC. 
7.1.4. 
Physical Examinations 
The physical examination performed at Screening will include an assessment of the following: 
general appearance, skin, eyes, ears, nose, neck, lymph nodes, throat, heart, lungs, abdomen, 
musculoskeletal system, extremities, and neurological/psychiatric assessments. At all other 
clinic visits, an abbreviated physical exam (assessment of heart, lungs, abdomen, and symptom 
directed examination, if any symptoms) is administered to assess changes in symptoms from 
last visit. For infusion reaction monitoring, see Section 8.9. For abnormalities that are deemed 
clinically significant by the investigator, report as AE per Section 8.4. 
For new participants, a detailed neurological examination should be conducted as part of the 
full PE during the screening period and include assessment of mental status, cranial nerves 
2-12, motor and sensory function, deep tendon reflexes, coordination, and gait/station.  For 
ongoing participants, this examination should be done prior to or during the next visit and prior 
to the next dose. 
During infusions, a focused neurological exam should be conducted if participants report any 
neurological symptoms.  If neurological symptoms are reported, a focused neurological exam 
should be conducted prior to subsequent doses. 
7.1.5. 
ECG 
Triplicate 12-lead ECGs using trial specific machines will be recorded at the time-points 
described in the SOA (Section 1.3 and Section 1.4). Procedural details will be described in the 
central ECG manual. Participants should be resting in a supine position for at least 5 minutes, 
then triplicate ECGs will be performed at approximately 1-minute intervals and each ECG 
recording (trace) will last 10 seconds.  
Participants should remain supine between ECGs. The participants will avoid postural changes 
during the ECG recordings and site personnel will ensure that participants are awake during the 
ECG recording.  
Repeat ECGs will be performed until at least three 10-second ECG records per scheduled 
time-point meet the quality criteria outlined in the central ECG manual. 
When ECG and blood sample collection occur at the same time for PK, ECGs should be 
performed prior to drawing of blood samples. 
 
 
 
 

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7.1.6. 
Vital Signs, Height, and Weight 
Height (cm) will be recorded at screening only. Height will be measured in cm and weight in 
kilograms. Measurements should be taken with participants wearing light clothing and without 
shoes using calibrated scales for all measurements. BMI will be calculated from the height and 
weight.  
Vital signs (body temperature, blood pressure, heart rate, respiratory rate) will be measured 
pre-dose and at specified post-dose times. Vital signs should be measured in the seated 
position after the participant has rested comfortably for 10 minutes. Heart rate will be 
measured for 30 seconds and the number multiplied by 2 and recorded in beats per minute, 
and respiration rate will be counted for a full minute and recorded in breaths per minute. Blood 
pressure should be measured using an oscillometric device and will initially be recorded in both 
of the participant’s arms unless a concomitant condition favors the use of a particular arm. The 
arm with the higher systolic reading at screening will then be used for blood pressure 
determinations throughout the study (including for determination of eligibility) and recorded in 
the EDC. The appropriate size cuff should be used. Participants must rest before blood pressure 
measurements. 
On study drug administration days in Part B vital signs should be measured: 
• Pre-dose 
• From start of infusion through 2 hours post end of infusion every 15 minutes 
• At 4 and 6 hours post end of infusion on Day 1  
In addition, qualified site staff will ask the participant “how do you feel?” along with pre-
infusion vitals prior to the start of infusion, and then every 15 minutes during and for 1 hour 
after the infusion along with the collection of vital signs. The question should also be asked 
every time ad hoc vitals are collected. If a participant complains of any newly emergent 
neurological symptoms during an infusion, the clinician (PI or sub-Investigator) is required to 
assess the participant and then, per clinical judgement, determine if a dose pause and 
additional work up and/or monitoring is indicated. If the clinician cannot assess a participant 
with emerging symptoms immediately, dosing should be paused until an assessment can be 
made.   
7.1.7. 
Echocardiogram 
Echocardiographic parameters will be used for assessment of cardiac structure and function.  
Qualified personnel will be required to administer echocardiograms as specified in the 
echocardiogram manual. Echocardiograms will be performed at the timepoints specified, per 
Table 1 and Table 3 analyzed at a central cardiac imaging lab. 
7.1.8. 
MRI 
All participants are required to have one non-contrast brain magnetic resonance imaging (MRI) 
and one time-of-flight MR angiogram (MRA) of the head and neck collected to establish a 
baseline.  
 
 
 
 

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The MRI/MRA should include: 
• MRI of the brain without contrast including T1, T2/FLAIR, diffusion-weighted (DWI), and 
gradient echo (GRE)/susceptibility weighted (SWI) sequences  
• MRA of the head and neck  
For participants who have not yet received study drug, MRI/MRA should be performed prior to 
the first dose.  For all other participants, MRI/MRA should be performed as soon as possible, 
preferably before the next dose.  
For participants who are unable to undergo an MRI, a CT brain with contrast and CT angiogram 
head and neck should be performed. 
If the participant has had imaging as specified above in the 3 months prior to enrollment, this 
requirement may be waived by the medical monitor. 
7.1.9. 
Telehealth Visits 
During the Extended Follow-Up Period, participants will be contacted by telephone (or other 
adequate communication method) per SOA to remind participant of study requirements, to 
assess overall health status, and to proactively plan subsequent in-clinic visit details. 
7.1.10. 
Considerations Relating to COVID-19 Pandemic 
As permitted per local regulation, select study assessments may be conducted remotely if 
travelling is restricted. If participant cannot travel to the clinic due to the COVID-19 pandemic, 
the site is encouraged to modify visit schedule after discussion with medical monitor or 
designee.  
Asymptomatic COVID-19 test positivity should be reported in the EDC per eCRF completion 
Guidelines. 
7.2. 
Assessments by Clinicians 
7.2.1. 
Muscular Impairment Rating Scale (MIRS) 
The DM1-specific muscular impairment rating scale (MIRS) will be captured at screening (as 
part of the inclusion criterion) and per SOA (Table 1 and Table 3). It is an ordinal five-point 
rating scale, established in accordance with clinically recognized distal to proximal progression 
of the muscular involvement in DM1 (Mathieu 2001) (Table 9). It is based on manual muscle 
testing of 11 muscle groups (neck flexors and six proximal [shoulder abductors, elbow flexors, 
elbow extensors, hip flexors, knee extensors, knee flexors] and four distal muscle groups 
bilaterally [wrist extensors, digits flexors, ankle dorsiflexors, ankle plantar flexors]).  
 
 
 
 

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• Days 43, 92, 183/EOT/EOPT – During the two-week period leading up to these visits, 
DM1-NSM should be completed daily for 14 days prior to the planned study day/visit.  
Example: 
 If Day 43 uses a -3 (day) visit window for a Day 40 visit, the DM1-NSM should be 
completed daily on Days 25-39; PGIS on Days 32 and 39; PGIC on Day 39. 
 If Day 43 uses a +3 (day) visit window for a Day 46 visit, the DM1-NSM should be 
completed daily on Days 31-45; PGIS on Days 38 and 45; PGIC on Day 45. 
7.3.3. 
DM1-NSM Patient Global Impression of Severity and Change (DM1-NSM-PGIS, 
DM1-NSM-PGIC) 
These questionnaires will evaluate the global severity and rate of change for both symptoms 
and activity impact. This information will be used as an anchoring procedure to evaluate 
responsiveness and determine minimally important clinical difference. For detail instruction, 
see the Study Operations Manual. Generally: 
• DM1-NSM-PGIS will be performed on Day 7 and 14 (every 7th day) of each DM1-NSM 
assessment period. 
• DM1-NSM-PGIC will be performed on Day 14 (the last day) of each of the 
3 post-baseline DM1-NSM assessment periods 
The order of questionnaire completion should be DM1-NSM, DM1-NSM-PGIS, and lastly 
DM1-NSM-PGIC. 
7.3.4. 
Fatigue and Daytime Sleepiness Scale (FDSS) 
This is a combined scale of Fatigue Severity Scale and Daytime Sleepiness Scale designed and 
validated for patients with DM1 (Hermans 2013). 
7.3.5. 
DM1 Activity and Participation Scale for Clinical Use (DM1-Activ) 
This questionnaire will assess impact of DM1 on daily life (Hermans 2015). 
7.3.6. 
EuroQol 5 Dimension 5 Level Quality of Life Scale (EQ-5D-5L) 
This brief questionnaire will assess overall health and impairment. 
7.3.7. 
Myotonic Dystrophy Health Index (MDHI) 
The MDHI is a standardized questionnaire to quantify DM1-related symptoms and disease 
severity (Heatwole 2014). 
7.3.8. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS (Baseline and Since Last Visit) will be administered to the participant by trained 
study personnel in clinic visits. This is meant to guide the investigators to monitor and follow up 
per standard of care. 
7.4. 
Efficacy Assessments – Measures of Function and Strength  
• The following exploratory efficacy assessments will be collected. Exploratory efficacy 
assessments will be performed per the SOA (Table 1 and Table 3). The assessments done 
 
 
 
 

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during the screening period are included to decrease the impact of a learning effect and 
will not be included in the change from baseline efficacy analysis. 
• Detailed descriptions for these assessments are outlined in the Clinical Endpoints 
Manual.   
• For all measures of muscle strength and function, the same therapist should conduct 
the assessments for an individual participant throughout the study.  All therapists must 
receive central endpoint training prior to evaluating any participants on study.   
• Testing should be done at approximately the same time of day throughout the study.   
• For 10-meter walk/run test, timed up and go, and timed 4 stair climb and 4 stair 
descend assessments, orthotics and ankle braces are allowed but should be kept 
consistent and documented for each test.   
• For the grip strength, myotonia, 9-hole peg test, and quantitative myometry testing 
(QMT), testing will be done only on one side of the body which preferably should 
correspond to the side with the dominant hand.  The same side of the body must be 
tested throughout the study and documented in the EDC.  
• The assessments should be conducted in the following order as much as possible when 
performed together.  If the order is altered, the same order of assessments used at 
baseline should be used throughout the trial. 
1. MMT 
2. QMT 
3. Grip strength  
4. Pinch strength 
5. 10 meter walk/run test (10MWRT) 
6. Timed Up and Go (TUG) 
7. Timed 4 stair climb 
8. Timed 4 stair descend 
9. 9 hole peg test (9HPT) 
10. Myotonia Video Recording (vHOT). 
Spirometry assessments may be completed at any point during or after the above listed 
assessments, but timing relative to other assessments should be consistent across visits. 
• Select assessments are done remotely per SOA.  
1. Remote Hand Grip strength 
7.4.1. 
Manual Muscle Testing (MMT) 
Both sides of the body will be used for MMT testing and will be tested throughout the trial.  
Each muscle group will be scored using a modified Medical Research Council Scale (MRC) scale, 
in accordance with a protocol that standardizes the participant’s position, direction of 
movement, and joint angle for resistance, as well as the examiners stabilization and hand 
placement. MMT will be performed on the following muscle groups:   
• Neck extensors and flexors 
• Shoulder abductors 
• Elbow flexors and extensors 
 
 
 
 

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• Wrist flexors and extensors 
• Thumb flexors 
• Hip flexors, extensors and abductors 
• Knee flexors and extensors 
• Ankle dorsiflexors 
• Plantar flexors 
7.4.2. 
Quantitative Myometry Testing (QMT) 
At screening, dominant side of the body will be chosen for QMT testing and will be the side 
tested throughout the trial.  Quantitative Myometry Testing (QMT) will be performed using a 
force transducer attached to an inelastic strap as previously described (Personius 1994, 
(Quantitative Muscle Assessment (QMA) system (Computer Source, Atlanta, GA). Standardized 
positions for isometric force testing will be used on the following muscle groups. These muscles 
were selected for showing good test-retest reliability in previous natural history studies. 
• Elbow flexion  
• Ankle dorsiflexion 
• Elbow extension 
• Knee flexion  
• Knee extension 
• Hand grip 
7.4.3. 
Pinch Strength by dynamometer 
Key (lateral) pinch will be measured using a standalone hand dynamometer. Three successive 
trials will be recorded for the dominant hand. 
7.4.4. 
10-Meter Walk/Run Test (10MWRT) 
From a standing start, the participant will be asked to go 10 meters as quickly as possible, 
whether by walking or running.  Timing will start at “Go” and stop when the first full foot 
crosses the 10-meter mark. Orthotics and ankle braces are allowed. The time in seconds to 
complete the task will be recorded.   
7.4.5. 
Timed Up and Go (TUG) 
Participants will be asked to rise from a chair, walk 3 meters, turn around, return to the chair 
and sit.  The time it takes to complete the task will be recorded.  The TUG will be performed 
twice, once at a comfortable pace and once at a maximum pace. Assistive devices, orthoses, 
and ankle braces will be allowed. 
7.4.6. 
Timed 4 Stair Climb and Timed 4 Stair Descend 
Participants will be asked to climb up and down (timed as separate tests) 4 stairs as quickly as 
possible, using steps with a six-inch rise and ten-inch run.  Quality grades will be captured for 
this test to record the use of railings and manner of ascent (i.e., step-to or step-over-step 
pattern).  The time it takes to complete the task will be recorded. 
 
 
 
 

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7.4.7. 
9-Hole Peg Test (9HPT) 
The 9-hole peg test is a quantitative measure of distal upper extremity function.  Participants 
will be asked to place 9 pegs in the 9 holes on the board and then remove them as quickly as 
possible, using their dominant hand.  Two trials will be recorded using the participant’s 
dominant hand. The total time to complete the task will be recorded. 
7.4.8. 
Myotonia Video Recording (vHOT) 
To eliminate “warm-up” of myotonia, participants will rest the dominant hand for five minutes 
before each vHOT trial.  The participant will be asked to squeeze their hand for three seconds 
then open as quickly as possible.  A video recording of the procedure will be obtained showing 
the forearm and hand but not the face.  All recordings will later be evaluated, and hand opening 
times determined by independent, blinded reviewers.   
7.4.9. 
Spirometry  
Spirometry will be performed in the sitting and supine positions using standardized, calibrated 
equipment.  Pulmonary parameters including forced vital capacity (FVC), peak cough flow, 
maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) will be assessed 
and reviewed centrally.  
7.5. 
Muscle Needle Biopsy for Pharmacokinetic, Pharmacodynamic and Spliceopathy 
Evaluations 
Muscle needle biopsy sample from the tibialis anterior at each time point (per SOA in Table 1 
and Table 3), will be used to determine levels  of DMPK mRNA and spliceopathy.  Please refer to 
the Muscle Biopsy Manual for additional details. Location of biopsy should alternate between 
two sides of the body at each visit to allow tissue healing. Sites of prior biopsies should be 
avoided. The investigators will utilize a 14-gauge, 10 mm length Supercore biopsy instrument or 
similar device to take up to 5 passes from the same site. The muscle tissues will be 
homogenized, RNA will be purified from the muscle tissue and analyzed for DMPK mRNA levels 
as well as alternative exon usage across many splicing events. Change from baseline in splicing 
events will be quantified, and details of relevant splicing events and computation of 
spliceopathy will be provided in the SAP.  
Additional exploratory biomarkers related to DM1 may be evaluated in tissue, blood, and urine 
samples.  
Please refer to the Muscle Biopsy Manual and Laboratory Manual for details on preparation, 
location of biopsy, processing of samples, and documentation. 
7.6. 
Pharmacokinetic and Immunogenicity Evaluations 
Blood and urine samples (24-hour and spot urine samples) will be collected for assessment of 
PK of AOC 1001 (total AV01mAb, total siRNA component, and intact AOC 001). Select plasma PK 
samples are paired with triplicate ECG assessment. When ECG and blood sample collection 
occur at the same time, ECGs should be performed prior to drawing of blood samples.  
The amount of siDMPK.19 present in muscle needle biopsies from the tibialis anterior will be 
evaluated.  
 
 
 
 

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Potential metabolites may be quantified in these samples.  
The concentration of analytes will be determined using validated assays. Details for handling of 
these samples including processing, storage, and shipment will be provided in the Laboratory 
Manual. Timepoints for PK, ECG, anti-drug antibodies (ADA), 24-hour and spot urine collections 
are outlined on the SOA, Table 2 and Table 4.  
7.7. 
DMPK Gene Analysis 
Blood will be drawn and DMPK gene analyzed for CTG repeat size. Historical report of DMPK 
gene analysis for enrollment needs to be approved by sponsor MM or designee. 
Archival DNA from blood may be used for batched genetic analysis specifically for the DMPK 
gene at the end of the trial to allow characterization including presence of DMPK single 
nucleotide polymorphisms (SNPs) and other variants such as CCG or CGG repeats within the 
CTG repeat tract. 
7.8. 
Clinical Laboratory Tests 
7.8.1. 
Guidance for Clinically Relevant Abnormal Labs 
Clinically relevant abnormal laboratory values should be repeated for confirmation as soon as 
possible per investigator judgment for patient safety (ideally within 3 days when possible). 
Those meeting monitoring and/or stopping criteria (Section 8.12, Section 8.13) should be 
monitored with weekly or more frequent laboratory draws. Evaluation for etiology should be 
performed. Sponsor medical monitor or designee should be notified.  
7.8.2. 
Pregnancy Test 
A positive urine pregnancy test should be confirmed by a serum pregnancy test prior to 
discontinuing the study drug. 
 
 
 
 
 
 

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7.8.3. 
Laboratory Analyte List 
Clinical 
Chemistry 
Hematology 
Urinalysis 
Blood screening 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonat
e 
• 
Blood urea 
nitrogen 
(BUN) 
• 
Creatinine, 
eGFR 
• 
Glucose 
• 
Calcium 
• 
Magnesiu
m 
• 
Phosphoru
s  
• 
Total 
protein 
• 
Albumin 
• 
Aspartate 
transamina
se (AST) 
• 
Alanine 
transamina
se (ALT) 
• 
Alkaline 
phosphatas
e (ALP) 
• 
Total 
bilirubin 
(TB) 
• 
Direct 
(conjugate
d) bilirubin 
(reflexively 
measured 
if TB > 
ULN) 
• 
Indirect 
(unconjuga
ted) 
bilirubin 
(reflexively 
measured 
if TB > 
ULN) 
• 
Hematoc
rit 
• 
Hemoglo
bin (Hb) 
• 
MCV, 
MCH, 
MCHC 
• 
Red 
blood cell 
(RBC) 
count 
• 
RDW 
• 
Reticuloc
yte count 
• 
Platelet 
count 
• 
White 
blood cell 
(WBC) 
count 
• 
Neutroph
ils, 
absolute 
and % 
• 
Lymphoc
ytes, 
absolute 
and % 
• 
Monocyt
es, 
absolute 
and % 
• 
Eosinophi
l, 
absolute 
and % 
• 
Basophil, 
absolute 
and % 
• 
Mean 
Platelet 
Volume 
 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Blood  
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic examination (reflexive for 
abnormal findings) 
• 
Hepatitis B Surface 
antigen 
• 
Hepatitis C 
antibody 
• 
HIV antibody 
• 
FSH (women only) 
• 
HbA1c 
Other  
• 
Cardiac troponin 
(highly sensitivity 
cardiac troponin T 
(Hs-cTnT)) 
• 
aPTT, PT, INR 
• 
Iron 
• 
Ferritin 
• 
Transferrin 
saturation  
• 
Transferrin 
• 
Total iron binding 
capacity (TIBC) 
• 
bHCG (female only) 
• 
Thyroid panel (TSH 
with reflexive TT3, 
FT4)  
• 
Haptoglobin 
(reflexive) 
• 
LDH (reflexive) 
  
Urine Chemistry 
• 
Urinary protein: creatinine ratio (UPCR) 
 
 
 
 

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• 
Gamma 
glutamyl 
transferase 
(GGT) 
• 
Creatine 
kinase 
• 
Myoglobin 
• 
Uric acid 
• 
Glutamate 
Dehydroge
nase 
(GLDH) 
 
Infusion-related reaction (unscheduled collection per Section 8.9.2) 
 
Hypersensitivity assessments (as needed per Section 8.10.1) 
Hepatic assessments (as needed per Section 8.12.3) 
 
 
 
 

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Pharmacokinetics  
• AOC 1001 levels in plasma, urine, and muscle 
Immunogenicity  
• Anti-AOC 1001 antibodies (ADA) 
Pharmacodynamics 
• DMPK mRNA levels in muscle 
• Spliceopathy in muscle 
 
Archived Blood  
• An archived blood sample will be collected for measurement of cytokine, CRP and 
complement testing or other analyses as needed to characterize DM1, safety and 
efficacy profile of AOC 1001, and /or interactions between the disease and drug as 
applicable. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
• SiRNA therapeutics permits the highly specific targeting of investigational therapies 
based on genetic sequence. It is possible that variations in the target genetic sequence 
will result in variations in drug effect. More generally, genetic variations may account for 
the well-described heterogeneous manifestations of disease in patients with DM1, as 
well as their responses to treatment. Where allowed per local regulations, ethics 
committee (IRB/IEC) approval, and patient consent, samples will be collected as part of 
this study to permit exploratory investigations and the application of novel approaches 
to bioanalyses that may further elucidate the outcomes of this study, or potentially 
advance understanding of the safety, mechanism of action, and/or efficacy of AOC 1001. 
Biological specimens will be collected at the intervals indicated in the SOA. These 
specimens will be analyzed at a central lab. Potential exploratory investigations may 
include DNA, RNA, or biochemical metabolite assessments as they relate to disease 
progression, efficacy or safety. The biospecimen repository will also include residual 
material from routine samples (safety laboratory samples, PK samples, etc.) that are 
obtained during the study. These specimens will be securely stored in a central 
biorepository for up to 10 years following the completion of this clinical study (ie, last 
patient last visit), or as per local regulations. After 10 years have elapsed, samples will 
be destroyed. Details regarding the collection, processing, storage, and shipping of the 
samples will be provided in the laboratory manual. Exploratory analysis of these 
biospecimens will be performed by the sponsor or its designees. When biobanking is 
permitted by local regulation, study participants will be advised during the informed 
consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
 
 
 
 

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8. 
SAFETY DATA AND ADVERSE EVENT COLLECTION AND REPORTING 
The collection, evaluation and reporting of AEs arising from this clinical study will be performed 
in accordance with the following where applicable: 
• Detailed guidance on the collection, verification and presentation of adverse 
event/reaction reports arising from clinical trials on medicinal products for human use 
(‘CT-3’) (2011/C 172/01). 
• ICH harmonized tripartite guideline on clinical safety data management: “Definitions 
and standards for expedited reporting” E2A.  
• ICH harmonized tripartite guideline on development safety update report: E2F.  
• ICH guideline E2F “Note for guidance on development safety update reports (DSUR)”. 
8.1. 
Definition of Adverse Events (AE) 
• An AE is defined as any untoward medical occurrence in a clinical trial participant. The 
event does not necessarily have a causal relationship with study treatment. An AE can 
therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the clinical trial whether or not considered related to the study drug.  
• An AE can include intercurrent illnesses or injuries, and exacerbation or worsening of 
preexisting conditions. Worsening indicates that the pre-existing medical condition (eg, 
diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration, and/or has an association with a significantly worse outcome. 
• Clinical laboratory, vital sign, or physical examination abnormalities will only be 
reported as AEs if they are deemed clinically significant by the investigator (e.g., 
associated with signs and symptoms, require treatment or adjustment in current 
therapy, or require follow-up).  
• Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. The investigator should attempt to establish a diagnosis of the 
event based on signs, symptoms, and/or other clinical information. In such cases, the 
diagnosis will be documented as the AE and not the individual signs/symptoms. 
• Any laboratory, physical exam, or vital sign abnormality assessed as clinically significant 
by the investigator during the screening period will be recorded as medical history.  
• All Infusion Related Reactions (IRR) will be recorded as an AEs. 
• A pre-existing condition that has not worsened during the study or involves an 
intervention such as elective cosmetic surgery or a medical procedure while on study, is 
not considered an adverse event.  
• Medical or surgical procedure (e.g., endoscopy, appendectomy) is not an AE. The 
condition that leads to the procedure is an AE if new or worsening. 
• Hospitalization not intended to treat an acute illness is not an adverse event. 
• Participants should be encouraged to report to the trial site as soon as possible events 
that required medical attention or are concerning to participants. 
 
 
 
 

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• The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the participant are recorded in the participant’s medical 
record.  
• Symptoms and signs that are being recorded as part of PROs or functional assessments 
should not be additionally recorded as AEs, unless it leads to the participant’s 
withdrawal from dosing or it is one symptom of another diagnosis.   
• A worsening of symptoms due to DM1 disease progression in the scientific opinion of 
the investigator is not considered an AE unless more severe than expected for the 
participant’s condition.  
8.2. 
Definition of Serious Adverse Events (SAE) 
A serious adverse event is defined as an adverse event that meets at least 1 of the following 
serious criteria: 
• Fatal. Death is an outcome of an AE and not an AE itself. All events leading to death, 
regardless of causality, must be reported. 
• Life threatening  
o It places the participant at immediate risk of death 
o It does not refer to an event which hypothetically might have caused death if it were 
more severe 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
o Necessitated medically an admission to a health care facility  
o Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
o ≤ 24-hour holds in the emergency room do not meet the criteria for hospitalization. 
Hospital admissions for circumstance that carries no bearing on health status and 
requires no significant medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason) are not 
considered SAEs 
• Results in persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Other medically important serious event 
o If an AE does not meet any of the serious criteria but an investigator considers an 
event to be clinically important or may require an intervention to prevent one of the 
other outcomes listed above, the event could be classified as a serious adverse 
event under the criterion of “other medically important serious event”.  
 
 
 
 

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o Examples of such events could include allergic bronchospasm, convulsions, blood 
dyscrasias, drug-induced liver injury (DILI), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
8.3. 
Serious Adverse Reaction and Suspected Unexpected Serious Adverse Reactions 
A Serious Adverse Reaction (SAR) is any adverse event that fulfils the criteria of seriousness, as 
defined above and is deemed related to study drug by the investigator.  
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a serious adverse reaction that is 
unexpected. The ‘expectedness’ of a serious adverse reaction is assessed in the light of the 
reference safety information.  
The expectedness of a SAR is determined by the Sponsor. The list of ‘expected SARs’ should be 
based on ‘suspected’ SARs that were previously observed and not on the basis of what might be 
anticipated from the pharmacological properties of a medicinal product or the compound class. 
An ‘expected’ SAR is therefore one that is listed in the RSI. For this protocol, the reference 
document for the assessment of expectedness is the Investigator’s Brochure for AOC 1001; 
however, at the time of writing, no clinical data is available for this compound. Therefore, any 
serious adverse reaction will be reported as a SUSAR, until any RSI is available in the IB. 
8.4. 
Reporting Procedures for Adverse Events (AE and SAE)  
• SAEs should be reported starting at time of informed consent.  
• AEs should be reported starting at time of study drug administration (Day 1), or if 
related to protocol-mandated assessments prior to start of study drug administration. 
Additionally, spontaneously reported SAEs will be collected up until 30 days after the final visit. 
SAEs experienced after this 30-day period will only be reported if the Investigator suspects a 
causal relationship with the study drug. 
The investigator will evaluate all AEs. The investigator will attempt to establish a diagnosis of 
the event based on signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE. 
The investigator must assign the following adverse event attributes: 
• Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
• Dates of onset and resolution (if resolved) 
• Severity and seriousness 
• Assessment of relatedness to study drug  
• Action taken: If dosing of study drug is modified due to an AE, this information must be 
submitted to the sponsor as soon as possible  
• Outcome  
8.4.1. 
Assessment of Severity  
Adverse events are to be graded according to the categories below. 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
 
 
 
 

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Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (eg, preparing meals, shopping for groceries or clothes, 
using the telephone, managing money) 
Severe: medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living (ie, 
bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; OR death related 
to an adverse event 
Please note the following: 
• The severity of AEs and SAEs relating to laboratory tests, infusion related reactions and 
adverse events at the injection site will be graded based on the Grading Scale for 
Adverse Events Relating to Lab Test Abnormalities, Infusion Related Reactions and 
Adverse Events at the Injection Site (Appendix 1).  Analytes not listed in the table should 
be graded based on criteria described above. 
• Severity of Infusion Related Reactions should be assessed as defined in Section 8.9.1. 
• Changes in severity should be documented in the medical record to allow assessment of 
the duration of the event at each level of severity. Adverse events characterized as 
intermittent require documentation of the start and stop of each incidence.  
• AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the 
intensity of an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the 
Sponsor for defining regulatory reporting obligations (see definition for SAE). 
8.4.2. 
Assessment of Causality 
• Investigator should assess the relationship of each AE to study procedure by asking “Is 
there a reasonable possibility that the event may have been caused by a study 
procedure?” A “yes” response indicates that the event is considered as related to the 
study procedure. 
• Investigator should assess the relationship of each AE to study drug by asking: “is there 
a reasonable possibility that the event may have been caused by the study drug?” A 
“yes” response indicates that the event is considered as related to the study drug. 
The investigator will use clinical judgment to determine the relationship. The investigator will 
also consult the Investigator’s Brochure (IB) in his/her assessment. The following factors should 
be considered in assessing relatedness: 
• Whether the AE can be explained by other causative factors or the pharmacological 
effect of the study drug 
• Temporal relationship to study drug exposure 
• Event is known to be associated with the study drug class  
• Event improved on discontinuation or dose reduction of study drug  
• Event reoccurred on re-challenge of study drug 
• Biological plausibility 
• Event attributed to concomitant medication (provide details of the concomitant 
medication). 
 
 
 
 

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• Event attributed to the concurrent disease (s) / condition(s) (provide details of the 
disease/condition).  
• Events expected in the study indication and/or target population 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. Therefore, 
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is 
very important that the investigator always assess causality for every event before the 
initial transmission of the SAE data to the sponsor or designee. 
• The investigator may change his/her opinion of causality considering follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
The investigator should also comment on the source document whether an AE is not 
related to the study treatment but is related to study participation (eg, study 
procedures, wash-out periods etc.). 
8.4.3. 
Action Taken with Study Drug 
• If dosing of study drug is modified due to an AE, this information must be submitted to 
the sponsor as soon as possible. 
• Action taken in regards to study drug will be defined as the following. If infusion is 
modified, total dose given needs to be recorded in the eCRF. 
o Not applicable 
o None 
o Infusion interrupted but completed 
o Dosing incomplete 
o Infusion not done 
8.4.4. 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the AE 
eCRF.  Treatment should also be recorded on the concomitant treatment or ancillary 
procedures as appropriate. 
8.4.5. 
Outcome of Adverse Events 
• AE Persists:  participant terminates from the trial and the AE continues 
• Recovered:  participant recovered completely from the AE 
• Recovered but with sequelae: The signs/symptoms of the reported SAE have improved 
but not completely resolved, and a new baseline for the participant is established since 
full recovery is not expected 
8.5. 
Follow up of Adverse Events 
• The investigator is expected to follow reported adverse events until stabilization or 
resolution. If the severity of an adverse event worsens from the date of onset to the 
 
 
 
 

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date of resolution, record a single event for each altered level of severity on the Adverse 
Event eCRF. 
• All serious adverse events that have not resolved by the end of the study, or that have 
not resolved upon discontinuation of the participant's participation in the study, must 
be followed until any of the following occurs:  
o The event resolves, stabilizes, or return to baseline. 
o The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct. 
o It becomes unlikely that any additional information can be obtained (participant or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts). 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor or designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.  
8.6. 
Reporting Procedures for Serious Adverse Events 
• Investigators or designee should record any new or updated SAE case details that can be 
gathered immediately (i.e., within 24 hours after learning of the event) on the SAE 
report form and submit the report via email or fax (please refer to the SOM).  
• New or updated information will be recorded in the originally submitted documents. 
• SAEs that are assessed by the investigator as related to study drug and occurring after 
the SAE reporting period will also be reported to the sponsor or designee immediately 
without undue delay, under no circumstances later than 24 hours following knowledge 
of the event. 
• Reporting of SAEs to the IRB/IEC will be done in accordance with the standard operating 
procedures (SOPs) and policies of the IRB/IEC. Adequate documentation must be 
provided to the sponsor showing that the IRB/IEC was properly notified. 
• The sponsor assumes responsibility for appropriate reporting of adverse events to the 
regulatory authorities. The sponsor will also report to the investigator all serious 
adverse events that are unexpected and associated with the use of the study drug.  
• SUSARs will be notified to the Competent Authority by sponsor or designee and to the 
relevant IECs by the sponsor within 7 (for fatal and life-threatening SUSARs) or 15 days 
(all other SUSARs).  
8.7. 
COVID-19 Specific Guidance 
• COVID-19 symptoms, signs, sequalae should be reported as an AE per Reporting 
Procedures for AEs (Section 8.4) 
• Medications for prevention or treatment of COVID-19 should be entered as concomitant 
medications 
• Please refer to eCRF Completion Guidelines for further detail 
 
 
 
 

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8.8. 
Pregnancy and Lactation Reporting 
• Pregnancy is not regarded as an AE, unless there is a suspicion that study drug may have 
interfered with the effectiveness of a contraceptive medication. However, complications 
of pregnancy and abnormal outcomes of pregnancy are AEs, and many may meet 
criteria for an SAE, such as ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly.  Elective abortions without 
complications should not be handled as an AE. 
• If a pregnancy occurs in a female participant or female partner of a male participant 
while the participant is taking study drug, the Pregnancy Report Form should be 
completed by the investigator or designee no more than 24 hours after learning of the 
pregnancy and submitted using the same process as for SAEs (please refer to 
Section 8.6). The female participant will discontinue further study treatment. Contact 
information of the health care provider taking care of the pregnancy should be obtained 
so that the outcome of the pregnancy can be followed. 
• Male participants may continue in the trial if an accidental pregnancy of their female 
partner occurs despite adequate contraception. 
• Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required for a female participant and the partner of a male 
participant, even if the participant terminates from the trial. The investigator will 
request consent from the female partner of a male participant to collect the required 
information. If additional follow-up of the female partner is required, the investigator 
will be requested to provide the information. 
• If a lactation case occurs while the female participant is taking study drug, report the 
lactation case to the sponsor or designee within 24 hours of the investigator’s 
knowledge of event.  
8.9. 
Guidance for Infusion-Related Reactions (IRR) 
Participants will be monitored during and after IV administration for infusion related and/or 
allergic reactions. The participant’s infusion site should be assessed for signs of any localized 
reaction during the infusion and for 120 minutes after the end of the infusion. The participant 
will remain at the trial site for at least 24 hours for observation after first dose. In Part B, 
participants should remain on site for minimally 2 hours after completion of 2nd and 3rd dosing 
for observation. Participants will be instructed to contact the investigator if they experience 
symptoms such as fever, chills, myalgia, skin rash, or nausea/vomiting after discharge from the 
site. 
Trained site personnel at the trial site should be prepared to intervene in case of any infusion 
reactions occurring, and resources necessary for resuscitation (eg, agents such as epinephrine 
and aerosolized bronchodilator, also medical equipment such as oxygen tanks, tracheostomy 
equipment, and a defibrillator) must be available at the bedside. Attention to staffing should be 
considered when multiple participants will be dosed at the same time.  
 
 
 
 

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8.9.1. 
Categorization of Infusion-Related Reaction 
IRR is defined as an adverse reaction that the investigator deems to be related to the study 
infusion.  Adverse events deemed by the investigator to be IRR will be indicated by the 
Investigator checking in the ‘IRR’ field in the EDC.  
Signs and symptoms of an IRR may include: allergic reaction / hypersensitivity (including drug 
fever), rigors / chills, arthralgia (joint pain), myalgia (muscle pain), bronchospasm, wheezing, 
cough, dizziness, dyspnea (shortness of breath), fatigue (asthenia, lethargy, malaise), headache, 
hypertension, hypotension, tachycardia, nausea, vomiting, pruritus / itching, rash / 
desquamation, sweating (diaphoresis), urticaria (hives, welts, wheals).  
Investigators should avoid reporting events deemed related to infusion generically as IRR. 
Instead, the individual symptoms/signs should be reported as separate adverse events, with 
relationship and severity assessed separately for each event. 
Categorization of IRRs is as follows and can also be found in Appendix 1(adapted from CTCAE 
version 5.0): 
• Mild: Mild transient reaction; infusion interruption not indicated; intervention not 
indicated 
• Moderate: Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hrs 
• Severe reaction: Prolonged (e.g., not rapidly responsive to symptomatic medication 
and/or brief interruption of infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical sequelae 
8.9.2. 
Management of Infusion-Related Reactions 
Participants who experience adverse events during the infusion must be treated according to 
the investigator’s judgment and best clinical practice. Premedication, infusion interruption or 
infusion rate decrease should be considered based on the severity of symptoms. Please refer to 
current Study Drug Infusion Guidance. Participants should be closely monitored until resolution 
of the reaction. The following guidelines may apply. 
• Participants may be treated with acetaminophen /paracetamol, antihistamine, or 
corticosteroids. Intravenous saline may be indicated. For bronchospasm, urticaria, or 
dyspnea, participants may require antihistamines, oxygen, corticosteroids, or 
bronchodilators. For hypotension, participants may require vasopressors. 
• Vital signs and oxygen saturation should be monitored until resolution of IRR. 
• Study drug administration will not be resumed for any participant following a severe 
IRR. Close observation for 24 h is recommended after a severe reaction. Please refer to 
Section 4.3 for cohort safety management rules. 
• No rechallenge should be undertaken for IgE mediated anaphylaxis or for 
life-threatening IRRs. Aggressive symptomatic treatment should be applied. (see next 
section). 
 
 
 
 

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• If an infusion is interrupted or the infusion rate is decreased, then a longer-than-
anticipated infusion time may occur. Overnight stays at the study site because of slow 
infusion times should not be reported as a serious adverse event. However, if the 
underlying cause of the delayed infusion time is an adverse event or serious adverse 
event, then that should be reported as such. 
Cohort level safety management guidance is provided in Section 4.3. Sponsor medical monitor 
or designee should be notified as soon as possible and be involved in the work up and follow up 
of the participant. Unscheduled plasma PK, add-on labs (see Section 8.10.1), and triplicate ECG 
should be obtained for each infusion-related reaction. If an infusion-related reaction is 
observed in the current or prior cohorts, site should consider premedication, and/or starting 
the infusion at a reduced rate per discussion with sponsor medical monitor. 
8.10. 
Guidance for Hypersensitivity Reactions 
Participants should be closely monitored during and after study drug administration for any 
symptoms of anaphylaxis and other hypersensitivity reactions. Treatment should be instituted 
per standard of care.  
Hypersensitivity reaction will be recorded in the EDC, including documentation of timing 
relative to start of infusion, type and duration of symptoms, timing and type of intervention, 
and action to study drug administration.  
Study drug infusion should be stopped if there is a suspected IgE-mediated allergic event 
related to IP.  
Study drug should be permanently discontinued if: 
• Serious adverse event of hypersensitivity reaction considered related to study drug.  
• Non-serious but severe in intensity, such as bronchospasm requiring medication or 
intravenous intervention. 
• Likely IgE mediated allergic event 
8.10.1. 
Evaluation and Reporting of Hypersensitivity Reactions 
Please contact medical monitor as soon as possible. 
The following add-on tests should be taken: (please use central lab as much as possible) 
• Unscheduled PK sample 
• Serum tryptase (alpha and beta) and histamine 
o At 30 and 120 minutes after the onset of symptoms 
o At 2-3 days after onset of symptoms 
• Anti-drug antibodies (ADA) within 15 minutes to 3 hours after onset of reaction 
• C3a, C5a, and CH50, SC5b-9 2-4 hours after onset of reaction 
• Cytokine levels (including IL2, IL6, IL8, IL10, IL13, TNF-α, INF-ϒ) 2-4 hours after onset of 
reaction 
• Archive sample for additional safety labs 
 
 
 
 

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• Additional tests may be performed at the request of the sponsor, including consultation 
with an allergist 
If IgE mediated anaphylaxis is thought to be the cause of IRR subsequently, the verbatim term 
should be revised as such. 
8.11. 
Guidance for Adverse Events with Cutaneous Involvement 
• Adverse events with cutaneous involvement of ≥ moderate severity which are obviously 
of allergic origin and which are deemed to be related to study drug by the investigator 
should be evaluated by a dermatologist as soon as possible, and preferably within one 
week of the site first becoming aware of the event. The investigator should evaluate the 
participant for possible etiologies (new medications, etc.) and extra-cutaneous 
symptoms and signs.  
• An unscheduled laboratory assessment for hematology, chemistry, PK, and ADA should 
be obtained.  
• If it is possible, the site will take photographs of the skin lesions in order to provide the 
participant with them for the dermatologist’s visit. If the photos are obtained, then 
copies should be kept as source documents.  
• In addition to photographs of the skin lesions, the investigator should provide a 
summary of the participant’s case, reason for consultation, and information being 
requested to the consulting dermatologist.  
• The dermatologist should be asked to generate a full consultation report to the 
investigator. The full report should contain, at a minimum, the following information:  
o A detailed description of the rash (such as the morphology [lesion type], shape of 
individual lesions, arrangement of multiple lesions [eg, scattered, grouped, linear, 
etc.], distribution, color, consistency, presence of pruritus or pain, and other 
clinical signs).  
o In case a skin biopsy (including histopathology and immunofluorescence) was done 
(if it was deemed necessary as per the dermatologist’s or investigator’s medical 
judgment), the results of this investigation with, if applicable, a specific diagnosis 
of the AE.  
• The investigator will send the full dermatologist report to the sponsor medical monitor 
or designee within 24 hours. 
8.12. 
Guidance for Liver Function Test Abnormality 
8.12.1. 
Monitoring Rule 
• If multiple baseline liver function test (LFT) measurements are available, baseline LFTs 
will be defined as the average of the 2 most recent LFT measurements prior to the first 
dose administered. 
• ALT or AST > 3 x ULN (or > 3x baseline or > 300 U/L [whichever is lower] in participants 
with elevated baseline): repeat test (at a central laboratory, if possible) and obtain total 
bilirubin, direct and indirect bilirubin, alkaline phosphatase, INR, and GLDH weekly or 
more frequent depending on the clinical severity. Sponsor medical monitor or designee 
 
 
 
 

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should be informed within 24 hours of the site’s awareness. The monitoring should 
continue until the values recover (Table 10) or stabilize per consultation with sponsor 
medical monitor or designee (Balwani 2020, FDA 2009). 
• Evaluate for etiologies based on clinical presentation, including viral or autoimmune 
hepatitis, concurrent diseases, concomitant drugs or supplements, environmental 
exposure, other infectious etiology. Refer to Table 11. 
8.12.2. 
Criteria for Withholding or Stopping Study Drug 
The study drug withholding or stopping rules are designed to minimize the risk of drug-induced 
liver injury. Confirmatory liver function tests should be performed through the central 
laboratory. 
Criteria for withholding and stopping study drug are as follows: 
• For ALT or AST > 8x ULN (or > 8x baseline or > 500 U/L [whichever is lower] in 
participants with elevated baseline), which is confirmed, without alternative cause, 
permanently discontinue dosing. 
• For ALT or AST >3× ULN (or > 3x baseline or > 300 U/L [whichever is lower] in 
participants with elevated baseline), which is confirmed and without alternative cause 
that is accompanied by clinical symptoms consistent with liver injury (e.g., nausea, right 
upper quadrant abdominal pain, jaundice), elevated bilirubin to >2× ULN, or 
international normalized ratio (INR) >1.5, permanently discontinue dosing. 
• For ALT or AST elevations >3× ULN (or > 3x baseline or > 300 U/L [whichever is lower] in 
participants with elevated baseline), which is confirmed and without alternative cause 
and not accompanied by symptoms consistent with liver injury or elevated bilirubin 
≥2× ULN or INR ≥1.5, see Table 10 . 
• Meeting any of the liver criteria for permanent discontinuation of study drug, listed 
above or in Table 10 , should be considered a SAE. The rules for cohort and study dosing 
suspension and stopping presented in Section 4.3 should be followed. 
 
 
 
 

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8.13.2. 
Dosing Pause Rule  
Pause study drug administration and initiate workup if: 
• Confirmed Hb > 2 g/dL decrease from baseline, and MCV < LLN, without alternative 
etiology, OR 
• Confirmed Hb < 8.5 g/dL, and MCV < LLN, without alternative etiology 
Resumption of dosing may occur per discussion with sponsor medical monitor or designee. 
 
 
 
 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Analysis Plan 
A detailed Statistical Analysis Plan (SAP) will be developed and finalized before database lock 
and will provide additional information surrounding all statistical considerations. 
9.2. 
General Considerations 
Data collected during the study will be presented in summary tables and graphical figures, as 
appropriate.  In tabular presentations, continuous variables will be summarized using 
descriptive statistics including mean, standard deviation (SD), median, minimum, and 
maximum. Categorical variables will be summarized using percentages and frequency 
distributions. Where appropriate, confidence intervals (CI) may be presented.  As the primary 
objective is to evaluate the safety and tolerability of single and multiple ascending doses of 
AOC 1001 in DM1 patients, no formal hypothesis testing will be performed.  Tabulations will be 
produced for appropriate disposition, demographic, baseline, safety, and efficacy parameters. 
Data collected will be presented in by-subject data listings. 
In general, data summaries will be presented separately for Part A and Part B.  Summaries will 
be grouped by dose level and overall for AOC 1001 and a single pooled placebo group.  
9.3. 
Sample Size Determination 
The sample size was selected based on practical considerations and is consistent with this type 
of early phase study. The cohort size is chosen considering the detectable event rate and the 
safety management rule (Buöen 2003).  This sample size is deemed to be able to provide 
sufficient evidence of safety and tolerability of AOC 1001 in DM1 patient participants while 
limiting unnecessary participant exposure:  
• In Part A, there is 1 planned dose level with 8 participants (6 active and 2 placebo). 
• In Part B, there are 3 planned dose levels with at least 12 participants planned per 
cohort  
The maximum enrollment for the trial will be limited to 52 participants. The sample size for this 
study was not based on statistical power considerations.   
 
 
 
 

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9.4. 
Analysis Sets 
The following analysis sets will be used in this study: 
• Safety Analysis Set: The Safety Analysis Set will include all participants who received at 
least one dose of study drug. Participants will be grouped according to the dose level 
they received. The Safety Analysis Set will be used for all safety analyses.   
• Full Analysis Set (FAS): All participants who were randomized and have received any 
amount of study drug and had a baseline measurement and at least 1 post-baseline 
assessment. Participants will be grouped as randomized.  Additional analysis subset(s) 
may be formed based on different outcome measures as appropriate. 
• Pharmacokinetic (PK) Analysis Set: The PK Analysis Set will include all participants who 
receive any amount of study drug and provide a sufficient number of plasma sample(s) 
for PK analysis. Participants will be grouped according to the dose level they received. 
• Pharmacodynamic (PD) Analysis Set: The PD Analysis Set will include all participants who 
receive any amount of study drug and had a baseline PD assessment and at least one 
post-baseline pharmacodynamic assessment. Participants will be grouped according to 
the dose level they received. 
All Analysis Sets will generally be maintained separately for Part A and Part B due to the 
different study design and treatment schedules. Analysis of Part A and Part B will primarily be 
executed on the Safety Analysis Set for baseline and safety parameters and PK and PD Analysis 
Sets, respectively for PK and PD analyses. Efficacy analysis performed will be executed on the 
Full Analysis Set.  Additional analysis details will be specified in the SAP. 
9.5. 
Interim Analysis (IA) 
No formal interim analyses are planned within this study. 
The Sponsor may perform administrative analyses while the study is ongoing. 
 
 
 
 

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9.6. 
Safety Evaluations 
Safety results will be provided for adverse events, use of concomitant medications, body 
weight/BMI, clinical laboratory safety tests, vital sign measurements (blood pressure, heart 
rate, body temperature and respiratory rate), ECGs, echocardiogram, and C-SSRS. 
Safety summaries will include incidence of AEs, summarized according to system organ class 
and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). An overall 
summary of AEs will include the incidence of AEs, serious AEs, treatment-related AEs, and 
severe AEs. Summaries of AEs by system organ class and preferred term will be presented for 
all AEs occurring or events worsening on or after first dose, serious AEs, AEs by relationship to 
study drug. Listings of AEs leading to death, discontinuation from study drug, and for serious 
AEs will be presented. 
Concomitant medications will be classified by WHO Drug Anatomic Therapeutic Chemical (ATC) 
and will be presented in data listings. Observed values for body weight and BMI will be 
summarized at each time point. 
Observed values and changes from baseline in clinical laboratory parameters will be 
summarized at each assessment. Shift tables may be presented for changes from baseline to 
worst value on study and from baseline to last value recorded. Laboratory data will be 
presented in standard units. 
Vital signs will be summarized as observed values and changes from baseline. 
ECG data (PR, QRS, QT, QTcB, QTcF and HR) and overall ECG evaluation will be listed. ECG data, 
along with changes from baseline will be summarized using descriptive statistics and categorical 
data on QTc will be summarized. Relationship between plasma PK and QTc will be explored. 
All safety data will be presented in by-subject data listings. 
9.7. 
Pharmacokinetic and Immunogenicity Evaluations 
Summaries of PK and ADA data will be presented separately for Part A and Part B. 
Non-compartmental analysis will be used for estimation of plasma PK parameters, including 
Cmax, tmax, t1/2, and AUC. Additional parameters may be estimated. PK measures will be reported 
over time and summarized using descriptive statistics.  Graphical displays may be presented. 
Exploratory analyses of PK data and their relationship to PD and safety endpoints may be 
investigated.  
The fraction excreted in urine will be estimated from 24-hour urine collections.  
Immunogenicity analysis will be determined at baseline, during treatment and follow up. 
Impact of ADA on PK will be explored.  
Tissue PK will be summarized and the relationship to PD endpoints will be explored.  
Further details will be provided in the SAP.  
9.8. 
Pharmacodynamic Evaluations 
Summaries, including change and percentage change from baseline, of PD data (DMPK mRNA 
levels and spliceopathy) will be presented descriptively.  
 
 
 
 

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9.9. 
Efficacy Evaluations 
The exploratory efficacy analysis, including clinical assessments and patient reported outcome 
measures, will be performed to evaluate further aspects of participant mobility, muscle 
function related to the extent of treatment distribution over time in descriptive summaries.  
Additional details will be specified in the SAP.  
 
 
 
 
 
 

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10. 
REGULATORY, LEGAL, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1. 
Obligations to Regulatory Authorities and Ethics Committees 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable country-specific laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) will be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations 
The sponsor is responsible for reporting to the investigators of serious adverse events (SAEs), 
including SUSARs, per ICH guidelines E2A and ICH E6.  
Any substantial amendments to the protocol will require health authority approval prior to 
initiation except for changes necessary to eliminate an immediate hazard to study participants. 
10.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.  
10.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study (aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail) to the participant or his/her legally 
authorized representative and answer all questions regarding the study. 
 
 
 
 

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• Participants or their legally authorized representative will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study site. 
• Participants must be informed that their participation is voluntary and that they may 
withdraw consent to participate at any time. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
• A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within 30 days from the previous ICF signature date. 
10.4. 
Study Monitoring 
• All aspects of the trial will be carefully monitored by the sponsor, or designee, for 
compliance with all applicable government regulations with respect to Good Clinical 
Practice (GCP) and current standard operating procedures. 
• The monitoring of this trial will be performed by the sponsor’s monitor(s) or a designee 
in accordance with the principles of GCP as laid out in the International Council on 
Harmonisation (ICH) Good Clinical Practice Guideline E6(R2) (2016). 
• The clinical monitor, as a representative of the sponsor, has an obligation to follow the 
trial closely. In doing so, the monitor may visit the investigator and site periodically as 
well as maintain frequent telephone and email contact. The monitor will maintain 
current personal knowledge of the trial through observation, review of trial records and 
source documentation, and discussion of the conduct of the trial with the investigator 
and site personnel. Further details will be described in the Clinical Monitoring Plan or 
SOM as appropriate. 
10.5. 
Confidentiality and Data Protection 
• The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to the Sponsor and in compliance with applicable data privacy 
deprotection laws and regulations.  
• Participants are to be identified by a unique subject identification number. Where 
permitted, date of birth is to be documented and formatted in accordance with local 
laws and regulations. Any participant records or datasets that are transferred to the 
sponsor will contain the identifier only; participant names or any information which 
would make the participant identifiable will not be transferred. 
 
 
 
 

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• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data 
to be used as described in the informed consent. 
• Sponsor personnel whose responsibilities require access to personal data for 
study-related monitoring, audit, IEC/IRB review, and regulatory inspection agree to keep 
the identity of participants confidential.  
• This consent also addresses the transfer of the data to other entities and to other 
countries. The participant has the right to request through the investigator access to his 
or her personal data and the right to request rectification of any data that are not 
correct or complete. Reasonable steps will be taken to respond to such a request, taking 
into consideration the nature of the request, the conditions of the study, and the 
applicable laws and regulations. 
• Exploratory biomarker/PK/immunogenicity research is not conducted under standards 
appropriate for the return of data to participants. In addition, the sponsor cannot make 
decisions as to the significance of any findings resulting from exploratory research. 
Therefore, exploratory research data will not be returned to participants or 
investigators, unless required by law or local regulations. Privacy and confidentiality of 
data generated in the future on stored samples will be protected by the same standards 
applicable to all other clinical data.   
10.6. 
Study Documentation and Data Archive 
• All participant data relating to the study will be recorded in the EDC unless transmitted 
to the sponsor or designee electronically (e.g., laboratory data). The investigator should 
ensure that all appropriately qualified persons to whom he/she has delegated trial 
duties are recorded on a sponsor-approved Delegation of Site Responsibilities Form.  
• The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
• Guidance on completion of eCRFs will be provided in eCRF Completion Guidelines. 
• Source documents are original documents, data, and records from which the 
participant’s eCRF data are obtained. Source documents provide evidence for the 
existence of the participant and substantiate the integrity of the data collected in the 
eCRF. Source documents are filed at the investigator’s site. These can be either paper or 
electronic and include but are not limited to trial assessment/activity records, hospital 
records, clinical and office charts, laboratory, imaging, and pharmacy records, diaries, 
and correspondence. Case report form trial activities may be considered source data if 
the case report form is the site of the original recording (i.e., there is no other written or 
electronic record of data). 
• The investigator and site personnel are responsible for maintaining a comprehensive 
and centralized filing system of all study-related (essential) documentation, suitable for 
 
 
 
 

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inspection at any time by representatives from sponsor or designee, and/or applicable 
regulatory authorities. For this study, elements include: 
o Participant files containing completed informed consent and any other forms, and 
participant identification list. 
o Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation, and all correspondence to and from the 
IRB/IEC. In addition, all original source documents supporting entries in the EDC 
must be maintained and be readily available. 
o If drug supplies are maintained at the study site, proof of receipt, study drug 
Accountability Record, Return of study drug for Destruction, final study drug 
reconciliation, and all drug-related correspondence. 
• Retention of study documents will be governed by the Clinical Trial Agreement, but in 
general for a retention period in compliance with local regulations or institutional 
policies, if they require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
• Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These pre-defined 
parameters will be monitored during the study and important deviations from the QTLs 
and remedial actions taken will be summarized in the clinical study report. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data to ensure accuracy, consistency, completeness, and 
adherence to the protocol and GCP. To resolve any questions arising from the clinical 
data management review process, data queries will be sent to the trial site for 
completion and return to the sponsor or designee. Updates to eCRFs will be 
automatically documented through the “audit trail”. 
10.7. 
Quality Control and Quality Assurance 
• In the event of a Quality Assurance audit, the auditor(s) will be allowed access to 
unblinded study intervention records at the sites to verify that 
randomization/dispensing has been done accurately. 
• A regulatory inspection of this trial may be carried out by regulatory agencies. Such 
audits/inspections can occur at any time during or after completion of the trial. If an 
audit or inspection occurs, the investigators for all sites agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate their time and 
the time of their site personnel to the auditor/inspector to discuss any findings or 
relevant issues.  
10.8. 
Record Retention 
• The Investigator Site File is part of the Trial Master File (TMF) and retention of the 
documents within the TMF and the medical records of study participants is a legal 
requirement.  After completion of the trial, all documents and data relating to the trial 
will be kept in an orderly manner and securely by the investigator in a secure file and/or 
 
 
 
 

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electronically. The data will be available for inspection by the sponsor or their 
representatives. Essential documents must be retained for 25 years after the final 
marketing approval in an EU region or at least 25 years have elapsed since the formal 
discontinuation of clinical development of AOC 1001. The PI or delegate must contact 
the sponsor before destroying any trial-related documentation and it is the 
responsibility of the sponsor to inform the investigative site of when these documents 
can be destroyed. In addition, all participant records and other source documentation 
will be kept as required by the applicable regulatory requirements.  
• For trial sites in the US, an investigator shall retain records required to be maintained 
under this part for a period of 2 years following the date a marketing application is 
approved for the drug for the indication for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for such indication, until 
2 years after the investigation is discontinued and FDA is notified. 
• The ultimate responsibility for the documents to be retained by the investigator or 
institution resides with the investigator or institution. If the investigator becomes 
unable to be responsible for their essential documents (eg, relocation, retirement, etc.) 
the sponsor should be notified in writing of this change and informed as to whom the 
responsibility has been transferred. 
• The Investigator Site File should never be sent to the sponsor. However, where the 
investigator cannot meet their archiving requirements, the sponsor can arrange 
archiving on behalf of the investigator and their institution, subject to the following 
being implemented: 
o The archive arrangements are formally agreed and documented between the 
sponsor and investigator or institution. 
o A formal procedure is in place such that the documents are only released from the 
external archive with the approval of the investigator or institution. In such cases, 
permission from the investigator or assigned host, is required to permit access to 
the contents of investigator site archived materials at the archive facility. 
o The records go directly between the investigator site and an archive facility 
independent of the sponsor, thereby ensuring that the sponsor does not have 
uncontrolled access to the investigator files. 
• It is important that where an organization has centralized records that may be relevant 
to a number of studies, for example, SOPs, staff training records or maintenance and 
calibration records for equipment used in the study, that these are also considered in 
the arrangements for archiving and retention (including superseded versions or 
obsolete records for example training records of personnel who have left the 
organization) as they may be required to be produced in addition to the TMF to 
demonstrate compliance. 
10.9. 
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional exploratory research. Samples will only be used to understand 
profiles of study drug and/or DM1, to understand differential drug responders, and to develop 
tests/assays related to AOC 1001 and/or DM1. The research may begin at any time during the 
 
 
 
 

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study or the post-study storage period. Stored samples will be coded throughout the sample 
storage and analysis process and will not be labeled with personal identifiers. Participants may 
withdraw their consent for their samples to be stored for research. 
10.10. 
Compensation 
Any arrangements for compensation to participants for injury or illness that arises in the study 
is described in the Compensation for Injury section of the Informed Consent Form. 
10.11. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
10.11.1. 
Study Termination 
The sponsor or designee reserves the right to terminate the study.  The investigator reserves 
the right to terminate their participation in the study, according to the terms of the site 
contract.  The investigator/sponsor or designee as appropriate should notify the IEC/IRB, in 
writing, as appropriate per local requirements, of the trial’s completion or early termination 
and send a copy of the notification to the sponsor or designee. 
10.11.2. 
Trial Site Termination 
The sponsor or designee reserves the right to close the trial site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Trial sites will be closed upon study 
completion. A trial site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the sponsor or investigator may include but are 
not limited to the following: 
• For study termination: Discontinuation of the clinical study due to reasons including 
unacceptable risk to participants, failure to enroll at an acceptable rate, plans to modify 
development strategy, or recommendation by regulatory authorities. 
• For site termination: 
o Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
o Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
o Total number of participants enrolled earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
 
 
 
 

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10.12. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors (http://www.icmje.org/) authorship 
requirements. 
 
 
 
 

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11. 
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