Clinical trial NCT04141670
Conditions: RYR-1 Myopathy
Keywords: RYR1 Myopathy
Sponsor: Armgo Pharma, Inc.
Start date: 2020-08-25; Completion date: 2023-07-30
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study proposes to test S 48168 (ARM210) in a Phase 1 trial in RYR1-RM patients, specifically. The objectives of this study are to explore the safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD)/target engagement (TE) of S 48168 (ARM210), as well as effects on muscle/motor function, and fatigue in RYR1-RM patients. The study population will include adult patients (≥18 years of age) who have demonstrated leaky RyR1 channels that are responsive to S48168 (ARM210) ex vivo.

Detailed description:
RYR1- related myopathy comprises a group of rare neuromuscular diseases. Affected individuals generally present with delayed motor milestones, muscle weakness, impaired ambulation, and, in severe cases, scoliosis, ophthalmoplegia, and respiratory distress all due to skeletal muscle weakness.

Causative variants in RYR1, which encodes the major calcium (Ca2+) release channel in skeletal muscle, RyR1, exert different effects on the RyR1 channel. They generally disrupt the normal Ca2+ flow between the sarcoplasmic reticulum (SR) and muscle cell cytosol and commonly result in excessive Ca2+ leak into the cytosol. Persistent Ca2+ leaks reduce its availability in the SR that is necessary for excitation-contraction coupling leading to the muscle weakness characteristic of this disease.

This open-label study consists of ten participants, randomized to two dose groups. All participants will have a diagnosis of RYR1-RM. In addition they have a prior muscle biopsy demonstrating a leaky RYR1 channel which responds to S48168 (ARM210) ex vivo. The first group of three participants will receive a low dose of S 48168 (ARM210) daily for 28 days. The second group of seven participants will receive a higher dose for 28 days. The decision to escalate to the higher dose will be made by an independent Data and Safety Monitoring Board (DSMB) after review of safety, tolerability and PK of the low daily dose. Safety and tolerability will be the primary objective in this study. In addition, exploratory objectives will include PK, PD/TE as well as measures of muscle/motor function and fatigue.

Arms: arm 1: Experimental: 120 mg S48168 (ARM210; 6 x 20 mg tablets) daily for 29 days arm 2: Experimental: 200 mg S48168 (ARM210; 10 x 20 mg tablets) daily for 28 days (1 participant) or 29 days (3 participants)
Interventions: intervention 1: S48168
Intervention descriptions: intervention 1: A novel oral small molecule which is designed to repair leaky RYR1 channels

Protocol documents:
Prot_000.pdf: 


S 48168 (ARM210) 
Phase 1 – Safety, PK, PD 
ARMGO Pharma Inc. 
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PROTOCOL REVISION HISTORY 
 
Amendment 1:  
Page(s) Summary of change 
20, 52 
Schedule of activites:  
Timeframe of screening tests changed to “Within 28 days prior to the first dose of 
study drug with the exeption of HIV, HCV, HbsAg, and CYP2C8 tests” 
20, 58 
Schedule of activities:  
Clarification that FSH and HbA1C tests are only required at baseline “FSH and 
HbA1c are only required at screening.” 
18 
Schedule of activities:  
Added pulse oximetry to vital signs measurements of d28 to make consistent with 
prior visits 
31 
Dose Justification:  
Description of dose for Figure 2 corrected to state “240 mg” and Figure numbering 
changed to reflect “Figure 2”. 
36, 37, 
40, 45, 
53, 73,  
Language pertaining to local blood draws (screening and follow-up): 
Language specifying local “facility” was removed and replaced with flexible 
language to allow for in-home blood draws. Example: “The blood sample for 
CYP2C8 analysis will be collected locally to the participant”. 
52 
Screening: 
Reference to appendices 19 and 20 were corrected. 
60 
AE severity:  
Clarified the severity rating based on CTCAE v5 here to make consistent with the 
remainder of the protocol 
61 
SAE reporting: 
Language was amended to refer to the Medical Monitoring Plan for SAE 
reporting: “All SAEs will be reported to the Sponsor  per the medical monitoring 
plan (Appendix # 17)” 
63 
Blood Sampling and Processing: 
Language was amended to reflect use of -80 freezer, rather than a -20 freezer. “The 
plasma aliquots will be frozen at -80 ± 10°C within 30 minutes maximum from 
the end of centrifugation”. 
 
Amendment 2: 
Page(s) 
Summary of change 
6 
Additional key contacts for the study:  
Genelex has been replaced with ARUP Laboratories as the CLIA-certified 
vendor of choice for CYP2C8 genotyping 
13 
Precis:  
The term “seven” in reference to the second dose group has been removed. 
The approximate number of participants has been changed from 10 to 8-20. 
14 
Synopsis:  


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The phrase “clinically significant” has been removed.  
16 
Synopsis (continued):  
Target accrual number has been revised to “ approximately 8-20 completers 
(pre-screening accrual ceiling n= 50)”. Randomization is no longer applicable 
and has been removed from Figure 1 (study design). The n for the dose group 
2 has been left undefined. 
17 
Synopsis (continued - dose regimen): 
The term “seven” in reference to the second dose group has been removed. 
31 
Dose justification:  
The term “seven” in reference to the second dose group has been removed. 
32 
Dose justification (continued): 
The term “seven” in reference to the second dose group has been removed. 
38 
Investigational Plan: 
Number of individuals was changed to “8 individuals with RYR1-RM 
completing the study.” The study design in Figure 1 has been updated 
(removal of randomization and n for dose group 2 left undefined). 
 
The phrase “up to 14 participants with RYR1-RM” has been removed. 
39 
Investigational Plan (continued):  
The pre-screening accrual ceiling and target number of completers have been 
clarified as n= 50 and n= 8-20, respectively. 
49 
Treatments administered:  
The term “seven” in reference to the second dose group has been removed. 
50 
Method of assigning subjects to treatment: 
The following language has been removed: 
 
(1): “Once 8-20 individuals are identified who meet the telephone and 
genotyping screen criteria, randomization will be conducted. This 
randomization will dictate the order in which these 8-20 individuals are 
invited to the NIH to finish screening procedures”. 
 
(2): The following language has been removed “individuals from the 
originally screened 8-20 subjects” and “per the randomized order”. 
  
(3): The following language has been removed “Dosing will continue until 10 
patients complete the study or the study is terminated”. 
51 
Interim analysis (PK): 
The phrase “if this is the case, then” has been replaced with “subsequently”. 
53 
Recruitment:  
Expected number of participants to be recruited within 6-12 months has been 
changed from 10 to approximately 8-20. 
55 
CYP2C8 genotyping: 
The phrase “sample submission form” has been removed. 
56 
Safety assessments: 
The phrase “clinically significant” has been removed. 


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Phase 1 – Safety, PK, PD 
ARMGO Pharma Inc. 
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Celerion Project No.: 
US IND No.: 
 
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Safety assessments continued: 
The phrase “by telephone” has been removed. 
59 
Cannulation and Phlebotomy:  
Number of participants has been updated from 10 to 8. 
65 
Blood sampling and processing: 
The term “lithium” has been removed. 
68 
Determination of Sample Size: 
Sample size changed from 10 to 8. 
71 
Subject information and consent: 
The first paragraph has been revised to clarify that blood obtained under the 
telephone consent will be used to test for CYP2C8 and serology. 
72-73 
Management of data and samples: 
NINR Tissue Injury Branch has been added as a location for sample storage. 
 
The following language has been removed: 
(1): “De-identified, unlinked skeletal muscle tissue samples will be collected 
and transported to the NINDS Neurogenetics Branch (building 35) for 
storage, ahead of analyses described in the biopsy manual”  
 
(2): “after the completion of the first 5 patients and after the completion of 
the 5 last patients”. 
 
(3): “and/or submitted to NIH designated repositories and databases” 
 
(4): “repositories receiving data and/or samples from this protocol may be 
open-access or restricted access”  
 
(5): “Submissions to NIH-sponsored or supported databases and repositories 
will be reported at the time of Continuing Review. Submission to non-NIH 
sponsored or supported databases and repositories will be submitted for 
prospective IRB approval.” 
Amendment 3 (expedited) 
4, 12-16, 
21, 30-31, 
35, 37, 48-
49, 55-57, 
64, 67, 69 
Dosing period was changed from “28 days” to “28 not to exceed 30 days” 
throughout the protocol 
Amendment 4 
12, 16, 41-
43, 51, 66 
Muscle biopsy RyR1-calstabin1 assay (inclusion criterion) was deleted and 
reference to this removed throughout the protocol 
Amendment 5 
17, 41, 43-
44, 51, 56 
Removal of skeletal muscle needle biopsy procedure for subject 0007 and 
subsequent participants, including all reference to this 
47 
Muscle biopsy-specific inclusion/exclusion criteria removed 


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15, 18, 40, 
41, 65 
Removal of 24hour PK study for subjects who have been previously dosed 
and are therefore not drug naïve 
15, 17, 23, 
39-41 
Switch in-person study visit on Day 14 to remote assessments and labs 
19, 33 
Removal of Day 14 EKG 
67 
Anticipated blood draw volumes added for re-enrolled subjects 
17, 21, 22, 
39 41 
Switch Day 42 remote follow-up to an in-person study visit with efficacy 
assessments. Schedule of activities was updated accordingly 
15, 20, 22, 
37, 43 
Addition of quantitative muscle assessment (QMA) to the battery of physical 
therapy tests 
54, 55 
Updated description of consent process for re-enrolled subjects  
17, 39  
Updated Figure 1 to reflect Amendment 5 changes 
30, 31, 59 
Updated reference to the IB to 2020 version 
20 
Schedule of activities updated to reflect 8 rather than 11 PK timepoints 
46 
Inclusion criterion added: Evidence  of functional deficit (defined by MFM-
32 < 80% maximum score) or  demonstratable deficits in at least one of the 
baseline muscle/motor function assessments 
 




S 48168 (ARM210) 
Phase 1 – Safety, PK, PD 
ARMGO Pharma Inc. 
Sponsor Project No.: 
Celerion Project No.: 
US IND No.: 
 
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3 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious Adverse 
Event Reporting 
Medical Monitor 
Protocol Authors 
 
Certified Clinical Laboratory for 
CYP2C8 Genotyping 
ARUP Laboratories 
500 Chipeta Way,  
Salt Lake City,  
UT 84108, USA 
Tel.:  +1 801 583-2787 
 
Bioanalytical Laboratory 
Nuvisan Pharma Services, 
NUVISAN GmbH 
Wegenerstrasse 13 
89231 Neu-Ulm, Germany 
 
 
 


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Celerion Project No.: 
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Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.:  +1 514 744-9090 
Fax:  +1 514 744-8700 
 
and/or 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.:  +1 402 476-2811 
Fax:  +1 402 939-0428 
 


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TABLE OF CONTENTS 
1 PROTOCOL REVISION HISTORY .............................................................................. 2 
2 PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ......................... 6 
3 ADDITIONAL KEY CONTACTS FOR THE STUDY ................................................. 7 
4 TABLE OF CONTENTS .................................................................................................. 9 
5 PRÉCIS ............................................................................................................................ 13 
6 SYNOPSIS ....................................................................................................................... 14 
7 STUDY EVENTS FLOW CHART ................................................................................ 19 
8 ABBREVIATIONS ......................................................................................................... 24 
9 INTRODUCTION AND BACKGROUND ................................................................... 28 
9.1 
Introduction ............................................................................................................. 28 
9.2 
Study Rationale ........................................................................................................ 28 
9.3 
Scientific Basis ........................................................................................................ 28 
9.4 
S 48168 (ARM210) – Research Drug ..................................................................... 30 
9.5 
Dose Justification .................................................................................................... 32 
9.6 
S 48168 (ARM210) Research Studies to Date (including potential 
interactions) ............................................................................................................. 35 
9.6.1 
S 48168 (ARM210) Pre-Clinical Studies in RYR1-RM ............................ 35 
9.6.2 
S 48168 (ARM210) Clinical Studies ........................................................ 35 
10 STUDY OBJECTIVES AND ENDPOINTS ................................................................. 37 
10.1 Study Objectives ...................................................................................................... 37 
10.2 Study Endpoints ....................................................................................................... 37 
11 INVESTIGATIONAL PLAN ......................................................................................... 39 
11.1 Overall Study Design and Plan ................................................................................ 39 
11.2 Risks and Discomforts ............................................................................................. 42 
11.3 Human Subjects Protection ..................................................................................... 43 
11.3.1 
Subject Selection ....................................................................................... 43 
11.3.2 
Justification for Exclusion of Children ..................................................... 44 
11.3.3 
Justification for Exclusion of Other Vulnerable Subjects ......................... 44 
11.3.4 
Safeguards for Vulnerable Populations and Sensitive Procedures ............ 44 
11.4 Anticipated Benefit/Classification of Risk .............................................................. 44 
11.5 Alternative to Participation ...................................................................................... 44 
11.6 Selection of Study Population ................................................................................. 45 
11.6.1 
Inclusion Criteria ....................................................................................... 45 


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US IND No.: 
 
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11.6.2 
Exclusion Criteria ...................................................................................... 46 
11.6.3 
Early Termination of Subjects from the Study .......................................... 48 
11.7 Study Restrictions .................................................................................................... 48 
11.7.1 
Prohibitions and Concomitant Medications .............................................. 48 
11.7.2 
Meals ......................................................................................................... 49 
11.7.3 
Activity ...................................................................................................... 49 
11.8 Treatments ............................................................................................................... 49 
11.8.1 
Treatments Administered .......................................................................... 49 
11.8.2 
Method of Assigning Subjects to Treatment ............................................. 50 
11.8.3 
Blinding ..................................................................................................... 51 
11.8.4 
Interim Analysis (PK) ............................................................................... 51 
11.8.5 
Stopping Rules .......................................................................................... 51 
12 STUDY ACTIVITIES AND PROCEDURES ............................................................... 53 
12.1 Recruitment ............................................................................................................. 53 
12.2 Screening ................................................................................................................. 53 
12.3 CYP2C8 Genotyping ............................................................................................... 55 
12.4 Medical History ....................................................................................................... 55 
12.5 Quality of Life Assessment ..................................................................................... 55 
12.6 Review of Inclusion/Exclusion Criteria .................................................................. 55 
12.7 Concomitant Medications ........................................................................................ 56 
12.8 Videotaping and/or Photography ............................................................................. 56 
12.9 Motor Function Measure 32 (MFM) ....................................................................... 56 
12.10 Safety Assessments .................................................................................................. 56 
12.10.1.1 Physical Examination ............................................................... 57 
12.10.1.2 Pulmonary Function Tests ........................................................ 57 
12.10.1.3 Vital Signs ................................................................................ 57 
12.10.2 Cardiac Monitoring ................................................................................... 58 
12.10.3 Cannulation and Phlebotomy .................................................................... 58 
12.10.4 Temperature Check ................................................................................... 58 
12.10.5 The Columbia-Suicide Severity Rating Scale (C-SSRS) .......................... 59 
12.10.6 Clinical Laboratory Tests .......................................................................... 60 
12.10.7 Adverse Events .......................................................................................... 61 
12.10.7.1 Adverse Event Definition and Grading .................................... 61 
12.10.7.2 Expected Adverse Events ......................................................... 61 
12.10.7.3 Monitoring ................................................................................ 61 
12.10.7.4 Reporting .................................................................................. 62 
12.10.7.5 Serious Adverse Event ............................................................. 63 


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US IND No.: 
 
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12.10.7.6 Reporting of Unanticipated Problems, Adverse Events, 
and Protocol Deviations ........................................................... 63 
12.10.7.7 AE’s of Special Interest ............................................................ 64 
12.10.7.8 End of Participation .................................................................. 64 
12.10.8 Pharmacokinetic Assessments ................................................................... 65 
12.10.9 Blood Sampling and Processing ................................................................ 65 
12.10.10 Interim PK Analysis .................................................................................. 65 
12.10.11 Analytical Method ..................................................................................... 65 
12.11 Blood Volume Drawn for Study Assessments ........................................................ 66 
13 DATA ANALYSIS .......................................................................................................... 68 
13.1 Pharmacokinetic Parameters .................................................................................... 68 
13.2 Statistical Methods .................................................................................................. 69 
13.2.1 
Determination of Sample Size ................................................................... 69 
13.2.2 
Subjects to Analyze ................................................................................... 70 
13.2.3 
Descriptive Statistics ................................................................................. 70 
13.3 Safety Evaluation ..................................................................................................... 70 
13.4 Pharmacodynamic/Target Engagement ................................................................... 71 
13.5 Muscle/Motor Function ........................................................................................... 71 
13.6 Quality of Life Assessment ..................................................................................... 71 
14 STUDY ADMINISTRATION ........................................................................................ 72 
14.1 Ethics ....................................................................................................................... 72 
14.1.1 
Institutional Review Board ........................................................................ 72 
14.1.2 
Ethical Conduct of the Study .................................................................... 72 
14.1.3 
Subject Information and Consent .............................................................. 72 
14.2 Termination of the Study ......................................................................................... 73 
14.3 Management of Data and Samples .......................................................................... 73 
14.3.1 
Storage ....................................................................................................... 73 
14.3.2 
Data and Sample Sharing Plan .................................................................. 73 
14.4 Data Collection ........................................................................................................ 74 
14.5 Data Quality Assurance ........................................................................................... 74 
14.6 Direct Access to Source Data/Documents ............................................................... 75 
14.7 Drug Supplies, Packaging and Labeling .................................................................. 75 
14.8 Record Keeping ....................................................................................................... 75 
14.9 Report Format .......................................................................................................... 75 
14.10 Publication Policy .................................................................................................... 75 
14.11 Research and Travel Compensation ........................................................................ 76 
15 PRIVACY AND CONFIDENTIALITY ........................................................................ 77 


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15.1 Research Data and Investigator Medical Records ................................................... 77 
15.2 Stored Samples ........................................................................................................ 77 
15.3 Special Precautions .................................................................................................. 77 
15.3.1 
Hard Copy Data/Records .......................................................................... 77 
15.3.2 
Samples without identifiers (coded or unlinked) ...................................... 77 
16 CONFLICT OF INTEREST AND TECHNOLOGY TRANSFER ............................ 78 
17 REFERENCES ................................................................................................................ 79 
18 APPENDICES ................................................................................................................. 81 
 
 
LIST OF TABLES 
Table 1: Approximate Blood Volume During the Study (drug naïve participants)……….66 
      Table 2:   Approximate Blood Volume During the Study (re-enrolled participants……….67 
 
 
 
 


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ARMGO Pharma Inc. 
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US IND No.: 
 
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5 
PRÉCIS 
Ryanodine receptor isoform 1-related congenital myopathies (RYR1-RM) comprise a group of 
rare neuromuscular diseases estimated to affect at least 1/90,000 pediatric individuals in the 
United States (Amburgey et al. 2011). Affected individuals generally present with delayed 
motor milestones, muscle weakness, impaired ambulation, and, in severe cases, scoliosis, 
ophthalmoplegia, and respiratory distress all due to skeletal muscle weakness (Witherspoon 
and Meilleur, 2016). Causative variants in RYR1, which encodes the major calcium (Ca2+) 
release channel in skeletal muscle, RyR1, exert different effects on the RyR1 channel. They 
generally disrupt the normal Ca2+ flow between the sarcoplasmic reticulum (SR) and muscle 
cell cytosol and commonly result in excessive Ca2+ leak into the cytosol. Persistent Ca2+ leaks 
reduce its availability in the SR that is necessary for excitation-contraction coupling. 
Additionally, chronic SR Ca2+ leak results in elevated cytosolic Ca2+ concentration, and 
mitochondrial-related oxidative stress and cellular injury (Görlach et al. 2015). The oxidative 
stress, in turn, can further contribute to RyR1 Ca2+ leak by channel oxidation and nitrosylation. 
Although RYR1-RM have been associated with significant morbidities and early mortality, 
there remains no FDA-approved treatment. 
A new class of Ca2+ channel stabilizers, Rycals®, were developed by Dr. Andrew Marks at 
Columbia University.  Under normal physiological conditions, Calstabin1 binds and stabilizes 
the RyR1 closed state. Rycals function as Ca2+ channel stabilizers by restoring RyR1-
Calstabin1 binding when it is deficient, thereby stabilizing the RyR1 closed state. To date, Dr. 
Marks laboratory has tested Rycals pre-clinically in at least 20 RYR1-RM patient muscle 
biopsies in vitro, including ten obtained during a previous clinical trial (NCT02362425). All 
untreated samples initially showed decreased RyR1-Calstabin1 binding (<10- 40% of healthy 
control muscle), which improved to 70-90% of control levels upon treatment with Rycals ex 
vivo. This work has demonstrated that Rycal treatment can restore RyR1-Calstabin1 binding 
and rescue leaky RyR1 channels in human biopsies ex vivo. In addition, a few muscle disease 
mouse models demonstrated that Rycal treatment improved muscle strength and muscle cell 
survival and may therefore offer a promising treatment for RYR1-RM (Andersson and Marks, 
2010; Capogrosso et al. 2018; Waning et al. 2015). S 48168 may also have benefit for 
malignant hyperthermia susceptibility, a condition allelic to RYR1-RM, by restoring the 
conformational integrity of mutant RyR1 channels. The lead Rycal, S 48168 (ARM210), has 
completed Phase I clinical studies in healthy volunteers. In those studies, S 48168 (ARM210) 
was safe and well tolerated in single and multiple dose studies and has now been tested in six 
(6) patients with RYR1-RM. This study continues to test S 48168 (ARM210) in a Phase I trial 
in RYR1-RM patients.  
The objectives of this study are to explore the safety and tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD)/target engagement (TE) of S 48168 (ARM210), as well as effects on 
muscle/motor function, and fatigue in adult RYR1-RM patients. The open-label study design 
consists of approximately 8-20 participants and two dose groups. The first three participants  
received 120 mg S 48168 (ARM210) daily for approximately 28 (not to exceed 30) days. Three 
participants have been enrolled in the second group and received 200 mg S 48168 (ARM210) 
daily for approximately 28 (not to exceed 30) days. The decision to escalate to a top dose 
of 200 mg daily was made by an independent Data and Safety Monitoring Board (DSMB) after 


S 48168 (ARM210) 
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ARMGO Pharma Inc. 
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US IND No.: 
 
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review of safety, tolerability and PK of the 120 mg daily dose. Interim data analysis suggested 
improvement in hand grip and pinch strength and improvement in manual muscle strength 
testing. Participants in the high dose group also reported decreased fatigue based on the patient 
reported outcome measure standardized tool (PROMIS-fatigue). Based on these findings and 
in preparation for the planned phase II trial, for the remainder of the trial, the post-intervention 
efficacy measures will be repeated after drug withdrawal to better assess the durability of 
observed benefits in participants. In addition, to maximize equitability and potential for 
maximum benefit, participants previously enrolled at the low dose will be invited to re-enroll 
at the high dose with the modified post-intervention and pharmacokinetic schedule. Safety and 
tolerability will remain the primary objective in this study. Exploratory objectives, including 
PK, PD/TE as well as measures of muscle/motor function and fatigue are being modified based 
on interim analysis.   
6 
SYNOPSIS 
 
Compound: S 48168 (ARM210) 
Clinical 
Indication: 
Ryanodine receptor 1-related congenital myopathy (RYR1-RM) 
Study 
Phase and 
Type: 
Phase 1– Safety and Tolerability, pharmacokinetic (PK), and pharmacodynamic/target 
engagement (PD/TE) 
Primary 
objective: 
To determine safety and tolerability of S 48168 (ARM210) treatment in RYR1-
RM affected individuals.  
Hypothesis: S 48168 (ARM210) treatment will have no safety concerns that limit 
further development and will be generally well tolerated in RYR1-RM patients.  
Primary endpoint: Composite safety and tolerability profile 
(Frequencies of the following: TEAEs ≥ grade 2 in severity (CTCAE version 5), all 
SAEs, and all AESIs). 
Methods: Safety and tolerability of S 48168 (ARM210) will be determined by 
monitoring Adverse Events (AEs) over approximately 28 (not to exceed 30) days of 
treatment via patient interviews, patient diary reviews, physical examinations, 
echocardiograms, electrocardiograms (ECGs), vital signs, and laboratory safety tests. 
A reference dataset of AEs/SAEs obtained from a natural history study of RYR1-RM 
will also be available to assist in interpretation of safety events. The Columbia-Suicide 
Severity Rating Scale (C-SSRS) will be administered pre- and post-intervention. The 
frequency and severity of AEs will be compared between treatment and historical 
controls including a previously conducted natural history study at the NIH. 
Exploratory 
objectives: 
1. To determine PK of a 28 day (not to exceed 30-day) administration of S 48168 
(ARM210) in RYR1-RM affected individuals. 


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Hypothesis: There will be no clinically meaningful difference in S 48168 (ARM210) 
exposure at steady state in RYR1-RM affected individuals when compared to existing 
data established in healthy volunteers. 
Endpoints: 
S 48168 (ARM210) pharmacokinetics 
Day 1 composite PK profile (drug naïve individuals only) 
(Comprised of the following: AUC0-t, AUC0-inf, Cmax, Tmax, and t½).  
Day 28 (not to exceed Day 30) composite PK profile 
(Comprised of the following: AUCtau, Cmax, Tmax, Cmin, RAAUC, and RACmax). 
Methods: For participants who have not been dosed previously (i.e., drug naïve 
individuals), bloods for PK assessments will be drawn at study visit one (Day 0, 24h 
PK), study visit two (Day 28; not to exceed Day 30, 24h PK),. For individuals who 
have been dosed previously, a 24hr PK assessment at Day 0 will not be required. 
Whole blood will be processed, and the plasma fraction stored for PK analyses.  
2. To explore if S 48168 (ARM210) treatment increases RyR1-calstabin1 binding 
in skeletal muscle of RYR1-RM affected individuals. 
Hypothesis: S 48168 (ARM210) treatment will increase RyR1-calstabin1 binding, 
compared to baseline, as determined by co-immunoprecipitation of RyR1 and 
calstabin1 and decrease relative Fluo-4 signal compared to baseline. 
Endpoints: Change from baseline in relative RyR1-calstabin1 binding (AU) and 
(pending sufficient tissue yield) change from baseline in relative Fluo-4 signal (AU). 
Methods: Skeletal muscle tissue was obtained from the first six participants by needle 
biopsy. This tissue has been assessed for RyR1-calstabin1 binding by co-
immunoprecipitation followed by protein detection. Additional biopsies are not 
needed. 
3. To explore if S 48168 (ARM210) treatment improves muscle function, motor 
activity, and fatigue in RYR1-RM affected individuals. 
Hypothesis: Treatment with S 48168 (ARM210) will increase grip and pinch strength, 
increase strength as determined by quantitative muscle assessment, decrease the time 
it takes to complete graded functional tests, increase the total MFM-32 % maximum 
score, and decrease the PROMIS-fatigue subscale score, when compared to baseline. 
Endpoints: Grip strength (kg), pinch strength (kg), quantitative muscle strength 
assessment (kg), time taken to complete each of the following (seconds): walk 10-
meters, supine to stand, ascend 4 stairs, and descend 4 stairs, MFM-32 score for 
domains 1, 2, 3, and total (% of maximum score), PROMIS-fatigue subscale score (t-
score). 
Methods: 


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Grip and pinch strength: Participants will be seated comfortably with his/her elbow 
flexed to 90 degrees, with the forearm and wrist in neutral position. Participants will 
then be asked to squeeze the dynamometer and pinch the gauge. This process will be 
repeated three times with the best effort used for final analyses. A physical therapist 
will administer these study procedures. 
Quantitative muscle strength assessment: Participants will undergo assessment of 
muscle strength in standardized seated and supine positions. Participants will be asked 
to exert force against an elastic strap-based force transducer. A physical therapist will 
administer this study procedure. 
Graded Functional Tests: Participants will complete a timed 10-meter walk test, supine 
to stand, ascend 4 stairs, descend 4 stairs, pre- and post- intervention. A physical 
therapist will administer these study procedures. 
MFM-32: The MFM-32 scale, a validated measure of motor function, will be 
administered pre- and post-intervention by a physical therapist. The participant is 
asked to roll, sit, lift head from prone and supine position, get up from a lying position, 
prop on arms, kneel, crawl, stand and step.  
Fatigue Questionnaire: The validated PROMIS-fatigue subscale will be administered 
using the NIH toolbox app on an iPad. Participants will be asked to enter responses 
for fatigue-related quality of life questions pre- and post-intervention. 
Summary 
of Trial 
Design: 
Trial phase and type: Phase 1 safety and tolerability, PK, and PD/TE 
Sites: Single site (NIH/NINDS, Bethesda MD, USA) 
Randomization: Not applicable 
Study population: RYR1-related myopathy 
Target participant accrual number:  approximately 8-20 completers (pre-screening 
accrual ceiling n= 50) 
Investigational drug: S 48168 (ARM210) 
Dose and duration: ≤ 200 mg/day for approximately 28 days (not to exceed 30 days) 
Sponsor: ARMGO Pharma Inc. 


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participant in the proper dosing instructions for home administration when drug 
supplies are dispensed. 
Study drug (S 48168 [ARM210]) tablets will be provided to the participant in a bottle. 
All participants will be instructed to self-administer the study medication daily with 
water in the morning. Compliance will be assessed during each phone/e-mail contact. 
Compliance will be verified at in-person visits for residual pill counts and by a 
participant diary. 










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  a: 
For details on Procedures, refer to Section 12. 
  b: 
Within 28 days prior to the first dose of study drug with the exeption of HIV, HCV, HbsAg, and CYP2C8 tests. Screening safety evaluations will occur during 
the first visit and will be within 24-48 hours of first dose, therefore not repeated unless deemed necessary by the PI pre-dose Day1. 
  c: 
Symptom-driven physical examination may be performed at other times, at the PI or designee’s discretion. 
  d: 
Samples for serum chemistry will be obtained following a fast of at least 10 hours, however, in case of dropouts or rechecks, subjects may not have fasted for 
8 hours before the serum chemistry sample is taken. FSH and HbA1c are only required at screening. 
  e: 
AE’s will be monitored throughout the study. Study Investigators will attempt to contact all subjects who received at least one dose of study drug (including 
subjects who terminate the study early) using their standard procedures on Days 7 and 21 (± 2 days) whilst on study drug and on Days 35 ± 2 and 42± 2 
(Follow-up) to determine if any AE has occurred since the last study visit. A compliance assessment will be conducted as a part of the Day 7 and Day 21 
contact. Subjects will enter daily log of symptoms as well as study drug intake in a diary for the days when direct communication is not done. 
  f: 
To be performed within 24 hours prior to dosing. 
  g: 
Baseline 24hr PK will only be conducted on study drug naïve individuals. 
  h: 
Prior to dosing. 
  i: 
Participants will return to NIH CC on Day 27 for scheduled events. Participants will be observed and examined one day post cessation of dosing, for any 
withdrawal effects. Administration of the final dose and 24 hour PK will occur following approximately 28 days dosing (not to exceed 30 days). 
  j:      Approximately 14 days (± 2 days) following cessation of S 48168 (ARM210), participants will have follow-up safety laboratory tests. 
 
 
Abbreviations: Admin = Administration, AE = Adverse event(s), C-I = Check-in, Chem = Chemistry, CYP = Cytochrome P450, FU = Follow-up, HIV = Human 
immunodeficiency virus, NIH CC = National Institutes of Health Clinical Center, PI = Principal Investigator, PK = Pharmacokinetics. 
 
 


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8 
ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC%extrap 
Percent of AUC0-inf extrapolated  
AUC0-t 
Area under the concentration-time curve, from time 0 to the last observed 
non-zero concentration (t) 
AUC0-inf 
Area under the concentration-time curve, from time 0 extrapolated to 
infinity 
AUCtau 
The area under the concentration-time curve during a dosing interval (tau) 
at steady state 
BCRP 
breast cancer resistance protein 
BMD 
Becker Muscular Dystrophy 
BMI 
Body mass index 
°C 
Degrees Celsius 
Ca2+ 
Calcium ion(s) 
CD 
Clinical Director NINDS 
CDM 
Clinical Data Management 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
Cm 
Centimeter 
Cmax 
Maximum observed concentration  
Cmax,u 
Maximum plasma unbound concentration 
Cmin 
Minimum concentration at steady state 
CNS 
Central nervous system 
CRF 
Case report form 
Ctrough 
Concentration observed at the end of the dosing interval 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D 
Day 
DICR 
depolarization-induced Ca2+ release 


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DMD 
Duchenne Muscular Dystrophy 
DSMB 
Data and Safety Monitoring Board 
ECC 
Excitation-contraction coupling 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EDL 
Extensor Digitorum Longus 
FKBP12 
12 kDa FK506-binding protein-Calstabin1 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume at 1 second 
FIM 
First-in-man 
FWA 
Federal Wide Assurance 
G 
Gram 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GR 
Gastro-resistant 
H 
Hour 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPLC-MS-MS High performance liquid chromatography with tandem mass spectrometry 
HRPP 
Human Research Protection Program  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
Kel 
Apparent terminal elimination rate constant 
Kg 
Kilogram 
m2 
Meters squared 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
MFM 
Motor Function Measure 32 


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mIU 
Milli-international units 
Mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
N 
Sample size 
NCA 
Non-compartmental analysis 
NIH 
National Institute of Health 
NIH CC 
NIH Clinical Center 
NINDS 
National Institute of Neurological Disorders and Stroke 
NMD 
Neuromuscular diseases 
No. 
Number 
NOEL 
No observed effect level 
Oz 
Ounce 
PD 
Pharmacodynamics(s) 
PFT 
Pulmonary Function Tests 
PI 
Principal Investigator 
PII 
Personally identifiable information 
PK 
Pharmacokinetic(s) 
QA 
Quality assurance 
RAAUC 
Ratio of accumulation for AUC 
RACmax 
Ratio of accumulation for Cmax 
RyR 
Ryanodine receptor 
RYR1 
Ryanodine receptor isoform-1 
RYR1-RM 
RYR1-related myopathies 
RYR2 
Ryanodine receptor isoform-2 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Plan 
SERCA 
Sarco/endoplasmic reticulum calcium-ATPase 
SR 
Sarcoplasmic reticulum 
t½ 
Apparent terminal elimination half-life 
Tau 
Dosing interval 


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TE 
Target engagement 
TEAE 
Treatment Emergent Adverse Events 
Tlag 
Lag time 
Tmax 
Time to reach maximum observed concentration 
Tmin 
Time to Cmin 
ULN 
Upper limit of normal 
US 
United States 
USA 
United States of America 
VC 
Vital capacity 
WHO 
World Health Organization 


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9 
INTRODUCTION AND BACKGROUND 
9.1 
Introduction 
Ryanodine receptor isoform 1-related congenital myopathies (RYR1-RM) are rare, slowly 
progressive neuromuscular diseases estimated to affect at least 1/90,000 pediatric individuals 
in the United States (Amburgey et al. 2011). Causative RYR1 variants lead to a spectrum of 
RYR1-RM histopathological subtypes and clinical phenotypes. The most common clinical 
phenotype of RYR1-RM is a congenital myopathy.  Affected individuals usually present with 
delayed motor milestones, proximal muscle weakness, impaired ambulation, and, in severe 
cases, scoliosis, ophthalmoplegia, and respiratory distress (Witherspoon and Meilleur, 2016). 
RYR1-RM may also cause rhabdomyolysis or atypical periodic paralysis and is associated with 
malignant hyperthermia. Histopathological subtypes include central core disease, multi-
minicore disease, congenital fiber-type disproportion, centro-nuclear myopathy and core-rod 
myopathy. Although RYR1-RM have been associated with significant morbidities and early 
mortality, there remains no FDA-approved treatment. 
Ryanodine receptor isoform-1 (RyR1) is the major skeletal muscle Ca2+ release channel. RyR1 
is embedded within the sarcoplasmic reticulum (SR) membrane and is a principal component 
of skeletal muscle excitation-contraction coupling (ECC). Causative RYR1 variants can have 
different effects on the RyR1 channel function. Some of these mutations result in chronic SR 
Ca2+ leak while others primarily impair ECC. Chronic Ca2+ leak into the sarcoplasm may result 
in increased mitochondrial-related oxidative stress, RyR1 channel oxidation, and cellular 
injury (Görlach et al. 2015). 
9.2 
Study Rationale 
Under typical physiological conditions, SR Ca2+ flux is tightly regulated to facilitate effective 
ECC. RyR1 interacting proteins contribute to this regulation. In particular, Calstabin1 (also 
referred to as FKBP12) modulates SR Ca2+ release by stabilizing the RyR1 closed state (Zalk, 
Lehnart et al. 2007). In those with RYR1-RM, there is evidence of decreased RyR1-Calstabin1 
binding and increased RyR1 Ca2+ leak (unpublished data) supporting the concept of a drug trial 
that targets this pathomechanism in the aforementioned population. 
9.3 
Scientific Basis 
Excitation-Contraction Coupling 
ECC is initiated when depolarization of the skeletal myocyte plasma membrane causes 
activation of L-type Ca2+ channels on the transverse T-tubule, which then activates the 
juxtaposed ryanodine receptors (RyR) through a direct interaction between both ion channels 
(Marty, Robert et al. 1994). This interaction induces Ca2+ release from the sarcoplasmic 
reticulum (SR) to the sarcoplasm, a phenomenon also called depolarization-induced Ca2+ 
release (DICR) (Murayama and Kurebayashi 2011). DICR enables the actin-myosin 
cross-bridge formation and sarcomere shortening that results in muscle contraction. During 
skeletal muscle relaxation, Ca2+ is sequestered in the SR by an ATP-dependent Ca2+ pump 


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(sarco/endoplasmic reticulum calcium-ATPase, SERCA), thus lowering the sarcoplasmic Ca2+ 
concentration and removing Ca2+ from the troponin complex. RyR1, the main RyR isoform in 
skeletal muscle, forms a large sarcoplasmic membrane complex, consisting of four monomers 
that constitute a Ca2+ release channel associated with several proteins, such as Calstabin1, 
kinases, phosphatases, phosphodiesterases, and other regulatory subunits (Marx, Reiken et al. 
2000, Lehnart 2007). This assembly allows for tight regulation and gating of intracellular Ca2+ 
release for the control of skeletal muscle function. In RYR1-RM, this process can be disrupted 
owing to chronic SR Ca2+ leak, excitation-contraction uncoupling, and decreased RyR1 
expression (Lawal et al. 2018). 
Calstabin1 Binding 
The 12 kDa FK506-binding protein, Calstabin1 (also known as FKBP12) is encoded by 
FKBP1A and is located in the sarcoplasm. There are four Calstabin1 subunits that bind to the 
homotetrameric RyR1 protein in a 1:1 manner. Calstabin1 prevents leaky RyR1 signaling 
under sub-optimal ligand concentrations, and therefore serves as a molecular gradient reader. 
Calstabins are suggested to have a stabilizing effect on RyR1 channel function by lowering 
open probability and preventing sub-conductance state gating, which leads to fewer leaky 
RyR1 channels and fewer aberrant Ca2+ release events (Venturi et al. 2014). 
Decreased Calstabin1 binding is in part caused by pathologic RyR1 post-translational 
modifications such as excessive PKA-phosphorylation (Marx, Reiken et al. 2000; Reiken, 
Lacampagne et al. 2003) and/or hypernitrosylation (Bellinger, Reiken et al. 2009; Gonzalez, 
Treuer et al. 2010). The resulting dissociation of Calstabin1 from RyR1 may exacerbate the 
deleterious increase in RyR1 open probability under resting conditions in RYR1-RM affected 
individuals. 
The RYR1-RM (dyspedic) mouse model has a low survival rate and other knock-in RYR1-RM 
mouse models either more closely reflect a malignant hyperthermia (Y522S) phenotype or 
have a severe phenotype (I4895T) that may not reflect RYR1-RM as a slowly progressive 
myopathy. In part due to this limitation, the majority of preclinical Rycals research has been 
conducted in the Duchenne Muscular Dystrophy (DMD) mouse model (mdx mice). RyR1 
channels isolated from mdx mice were shown to be hypernitrosylated as a potential 
consequence of altered nitric oxide signaling downstream of dystrophin loss resulting in 
increased SR Ca2+ leak. Hypernitrosylation of RyR1 coupled to depletion of Calstabin1 from 
RyR1 in mdx mice, increased spontaneous RyR1 openings, as determined by Ca2+ sparks, and 
reduced specific muscle force (Bellinger, Reiken et al. 2009). Preventing Calstabin1 depletion 
from RyR1 with Rycals treatment inhibited SR Ca2+ leak, decreased biochemical and 
histological evidence of muscle damage, improved muscle function, and increased exercise 
performance in mdx mice (Bellinger, Reiken et al. 2009). 
Hypernitrosylation of RyR1 has also been observed in muscle biopsies from Becker Muscular 
Dystrophy (BMD) patients, disrupting the RyR1/Calstabin1 complex (Gentil, Leturcq et al. 
2012). Moreover, elevated intracellular Ca2+ was found sufficient to cause a dystrophic 
phenotype even when dystrophin remained intact suggesting that some of the muscle damage 
observed in dystrophin–glycoprotein complex (DGC)-related muscular dystrophies may be 


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attributed to downstream defects in Ca2+ homeostasis (Millay, Goonasekera et al. 2009; 
Gumerson and Michele 2011). 
9.4 
S 48168 (ARM210) – Research Drug 
Overview 
S 48168 (ARM210) is the lead compound in a new pharmacological class of specific calcium 
release channel stabilizers, termed Rycals. Rycals are thought to stabilize leaky RyR channels 
through restoration of Calstabin binding. S 48168 (ARM210) is proposed for the treatment of 
genetically determined diseases of muscle including DMD and RYR1-RM. S 48168 (ARM210) 
acts on both skeletal and cardiac RyRs (RyR1 and RyR2, respectively) if dysfunctional, and 
correct channel dysfunction due to Calstabin dissociation. This may in turn restore Ca2+ 
homeostasis at the sarcoplasmic and cytosolic levels, improving muscle fiber survival and 
function. S 48168 (ARM210) repairs dysfunctional RyRs but should have no effect on normal 
RyRs (Liu et al., 2012). Thus, in muscle diseases such as DMD where RyR1 and RyR2 are 
affected, S 48168 (ARM210) would repair both types of the channel. In RYR1-RM, where only 
RyR1 is affected, the therapeutic effect would be on RyR1 in skeletal muscle only. The new 
therapeutic approach embodied by Rycals targets a pathophysiological mechanism that is 
implicated in the skeletal muscle function dysfunction observed in muscular degenerative 
diseases. S 48168 (ARM210) is being manufactured and formulated under cGMP conditions 
by Servier Laboratories, France. 
Refer to the Investigator’s Brochure (IB) for more background information on S 48168 
(ARM210)
 
Formulation 
S 48168 (ARM210) Phase I formulations are oral gastro-resistant (GR) tablets dosed at 5 mg, 
20 mg, 40 mg or 200 mg of S 48168 (ARM210) (as hemifumarate salt). Two formulations 
have been developed: the adult First-In-Man (FIM) study formulation dosed at 20, 40 and 
200 mg (adult formulation A) and the formulation suitable for pediatric administration, at, 
5 mg and 20 mg (pediatric/adult formulation B). These two formulations have been shown to 
be equivalent in exposure in a clinical study 
. The latter 
formulation will be used for this study. The formulations contain no excipients with known 
effect. 
Pharmacodynamics 
In mdx mice, S 48168 (ARM210) was administered daily for 3 or 4 weeks in drinking water 
(ad lib.). This treatment was shown to have a beneficial effect: (i) on in vivo muscular function 
(i.e., significant improvement of voluntary wheel activity at 10 and 50 mg/kg/day after 3 weeks 
of treatment, no decline in treadmill exhaustion test performance compared to vehicle-treated 
mice); (ii) on in vivo muscle force (i.e., improvement of forelimb grip strength); and (iii) on ex 
vivo Extensor Digitorum Longus (EDL) specific force (3-week treatment) and diaphragm 
specific tetanic force at 50 mg/kg/day (4-week treatment) (Capogrosso et al., 2018). Two in 


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vitro parameters of intracellular Ca2+ homeostasis (i.e., mechanical threshold and resting 
cytosolic Ca2+ level) were improved by a 4-week treatment of S 48168 (ARM210) at 50 
mg/kg/day.
Pharmacokinetics 
After single oral administration in young healthy males of 20, 40, 80, 160, 240 and 400 mg of 
S 48168 (ARM210), rapid absorption was observed, after a lag time consistent with the GR 
properties of the tablet administered. There was no evidence of non-linearity with the dose. 
After 14-days of repeated once daily oral administrations of 20 mg of S 48168 (ARM210), the 
Cmax was reached with a median Tmax between 3 and 3.5 hours. Steady-state was attained 
after 3-7 days of daily treatment with S 48168 (ARM210). After 14-days of repeated 
administration of 20, 60,120 and 240 mg of S 48168 (ARM210), accumulation ratios are 
around 1.5-1.8 for Cmax and AUC24, consistent with the half-life (20 hours) of S 48168 
(ARM210) and its dose regimen.  
The effect of food on the absorption of S 48168 (ARM210) has been tested in a three-period 
crossover study, comparing fasted with administration with a high fat breakfast, and with 
administration of a light breakfast 
. The results showed that there is minimal 
effect on the exposure of S 48168 (ARM210) when administered with food when compared to 
fasted. The inclusion of food can delay the Tmax and blunt the Cmax so when PK is to be 
measured in the trial, S 48168 (ARM210) should be given fasted. However, on all other days 
S 48168 (ARM210) can be given without regard to food, i.e. fasted or with food.  
In human liver microsomes, S 48168 (ARM210) did not inhibit the metabolism of selective 
substrates for CYP1A1/2, 2A6, 2B6, 2C9, 2C19, 2E1, 2D6 and 3A4 iso-enzymes. However, 
S 48168 (ARM210) showed an inhibitory potential towards CYP2C8 and a low inducer 
potential towards CYP3A4. The involvement of the CYP2C8 as one of the main metabolic 
pathway of S 48168 (ARM210) metabolism has been confirmed in vivo via an interaction study 
with the CYP2C8 inhibitor gemfibrozil 
. 
Toxicology 
A complete safety pharmacology program was performed. No major safety concern was raised. 
S 48168 (ARM210) was devoid of genotoxic potential in the three regulatory genotoxicity 
studies. 
 
 
Overall, non-clinical safety studies showed potential dose limiting findings with respect to: 
• Central Nervous System (CNS) toxicity with tremors in isolated animals at the 
highest tested doses of 540 and 250 mg/kg/day in the regulatory 4-week rat study and 
in the regulatory 39-week dog study, respectively, and convulsions after single 
administration at 500 mg/kg in the exploratory (non-regulatory) intra-duodeno-jejunal 
administration study in dog and in one dog at the high dose of 250 mg/kg/day in the 


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regulatory 39-week dog study. In the regulatory 26-week rat study, CNS signs were 
limited to decreased activity at the highest tested dose of 540 mg/kg/day.  
• Testicular toxicity [characterized by decreased testis weights associated to 
depletion/sloughing 
of 
germ 
cells 
leading 
to 
aspermia 
or 
increased 
hypospermatogenesis (correlated to low sperm counts) and minimal germ cells 
degeneration and/or cellular debris in the epididymides] observed in the exploratory 8-
week (+10-week recovery) study at the highest dose of 250 mg/kg/day in sexually 
mature dogs and in the regulatory 13- and 39-week (+10-week recovery period) studies 
at the highest dose of 250 mg/kg/day or from the mid-dose of 50 mg/kg/day, 
respectively, where the dogs were not sexually mature at the start of dosing (maturation 
under treatment). Following the 10-week recovery period in both studies, these changes 
were no longer apparent and considered to be reversible.  
• Gastric toxicity (minimal neck cell hyperplasia in the fundic mucosa) observed at the 
highest dose of 100 mg/kg/day in the regulatory 4-week dog study but not in any 
S 48168 (ARM210) dosed-animals in the regulatory 13- and 39-week dog studies, the 
risk for human is considered to be low since the gastro-resistant formulation developed 
for the overall clinical development program would limit the contact with stomach.  
9.5 
Dose Justification 
The initial proposed dose for this study was 120 mg S 48168 (ARM210) daily for 
approximately 28 days (not to exceed 30 days) for the first three participants (6 x 20 mg tablets) 
(see details outlining dose modification in Section 9.6). An additional three participants were 
dosed with 200 mg S 48168 (ARM210) (10 x 20 mg tablets) daily for approximately 28 days 
(not to exceed 30 days) after DSMB evaluation of the interim safety and PK data. The 
remainder of participants will be dosed at the same high dose ≤ 200 mg S 48168 (ARM210) 
(10 x 20 mg tablets) daily for approximately 28 days. The projected exposure at 200 mg/day 
dose remains below preclinical safety margins (Cmax<35 ug/ml), as well as below the highest 
dose tested in healthy volunteers (240 mg/day for 14 days). Preclinically, the one finding that 
is not monitorable in humans is the proconvulsant risk, with convulsions rarely observed at 
highest dose level in dogs in the 39-week study. The convulsions occurred at the high dose of 
250 mg/kg/day in the 39-week GLP chronic study. The Cmax of that dose for both genders is 
374 ug/ml. This concentration range is associated with an in vivo unbound fraction of 3.5%, 
which is greater than 20-fold higher than the in vivo fraction unbound (0.16%) in the human at 
240 mg. It is likely that this high unbound fraction, which is able to penetrate tissues, including 
the brain, was responsible for the rare convulsions seen in 1 of 20 dogs (i.e. 1/12 dogs from 
the 39-week study and 0/8 dogs from the 13-week study, both studies at 250 mg/kg/day). The 
FDA has determined that the high dose (250 mg/kg/day from 13-week dog study) sets the 
NOEL for convulsions for this trial. The Cmax at the NOEL (from the 250 mg/kg high dose) 
from the 13-week dog study is a mean of 320 ug/ml for both sexes. In consultation with the 
FDA, the current dose cap is at 35 ug/ml for Cmax to provide a significant margin to the NOEL 
Cmax from the dog.  


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US IND No.: 
 
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In the first in man study 
 40 male healthy volunteers (5 groups, 
approximately 8 participants p
: placebo) completed the study part I (single 
escalating dose). Five dose levels were tested successively: 20 mg, 60 mg, 120 mg, 240 mg 
and 400 mg. In part II, a four dose levels were studied with daily doses for 14 days (20 mg/day, 
60 mg/day, 120 mg/day and 240 mg/day) all of which were well tolerated.  
Using total PK to determine the safety margin, the Cmax should be limited to 35 ug/ml per the 
FDA partial clinical hold comments. This limit is based on a 10-fold safety margin to the Cmax 
of the high dose of the 13-week dog toxicology study. We propose to dose the first three 
participants at 120 mg/ day. The mean Cmax for healthy volunteers at this dose was 17 ug/ml. 
Assuming the safety, tolerability and PK are acceptable
 to the DSMB, a top dose of ≤
(not to exceed 30 days) is proposed for the remaining participants. 
Preliminary human PK of 14 days of dosing at 240 mg/day S48168 (ARM210) shows a mean 
Cmax of 35 ug/ml 
). The Cmax at steady state has been dose 
proportional, with no evidence of non-linearity, with low variability (13.5%). The projected 
Cmax for 200 mg/day at steady state is 28 ug/ml. Assuming that the PK at 120 mg/day dose is 
similar to the previous numbers seen in heathy volunteers, then a dose ≤ 200 mg/day should 
remain below the dose cap of 35 ug/ml.  
Staggered dosing was implemented for the first three participants at the low dose level, starting 
each participant on drug after the previous participant had finished 14 days of dosing. At the 
high dose level (200 mg/day), Cmax at steady state of each participant was measured before 
dosing the next participant. S48168 (ARM210) reaches steady state typically after five days of 
dosing, consistent with its terminal half life. PK profiles have been established in RYR1-RM 
trial participants at both low and high dose levels and are consistent with healthy volunteer 
studies. In addition, none of the subjects tested so far have exceeded the FDA Cmax limit of 
35 ug/ml at steady state and no clear safety signals have been observed to date in safety labs, 
EKG, or other safety related assessments.  
Although testes toxicity was observed in dogs (see above), it was not seen in the 4-week dog 
study, which is the duration of dosing in this protocol. In the 13-week dog studies in mature 
dogs the NOEL = 50 mg/kg/day with an expected safety margin of 22-fold in terms of unbound 
plasma exposure (AUC). Thus, high safety margins are expected in adult population for a 
28-day (not to exceed 30-day) treatment duration as in this study. These findings in the dogs 
were reversible with cessation of treatment. Furthermore, no clinically meaningful effects on 
sperm counts numbers have been observed to date in the ongoing 14-day multiple dose studies 
in young healthy males.  
The gastric toxicity observed in animals is mitigated by a gastric-resistant formulation, which 
will not undergo dissolution at pH below 5. In order to avoid chronic increases in gastric pH, 
which may allow gastric dissolution, proton pump inhibitors and histamine 2 receptor blockers 
are not allowed in the study. Antacids may be used only at night, with S 48168 (ARM210) 
dosed in the morning. Numerous studies have shown that antacids only affect gastric pH for 
1-2 hours after administration (Decktor et al., 1995). Antacids cannot be dosed at the same 
time as S 48168 (ARM210).  


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Sponsor Project No.: 
Celerion Project No.: 
US IND No.: 
 
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The target exposure at the level of the muscle can be estimated from a number of sources. The 
measured level of unbound muscle exposure of the 120 mg/day dose in healthy volunteers at 
steady state from muscle biopsies ranges from 1.15-3.59 µg.h/mL, which overlaps with the 
target unbound AUC in mdx mouse muscle, estimated to be 2.47 µg.h/mL. There was efficacy 
in 4 weeks seen in the mdx mouse model, at these concentrations (Capogrosso et al., 2018). 
The ≤ 200 mg daily dose is likely to ensure that the muscle concentration in all patients will 
be similar or higher than the efficacious level in mdx mice.  
S 48168 (ARM210) has orphan designation for RYR1-RM and a phase II clinical trial is in the 
planning stages. Preliminary analysis of the exploratory outcome measures of the trial so far 
suggests improvement in hand grip and pinch strength and improvement in manual proximal 
muscle strength. Participants in the high dose group also reported decreased fatigue as assessed 
by the standardized patient reported outcome measure (PROMIS-fatigue), consistent with the 
efficacy expectations at the high dose of 200 mg daily.   
The PK profile of the 240 mg dose at steady state in healthy volunteers shows a slow decline 
over several days at the end of drug administration (Figure 2). This gradual decline in exposure 
reduces the risk of a sudden effect at the end of the dosing period due to withdrawal.  
 
 
Figure 2. PK profile of S 48168 (ARM210) at day 1 and day 14 in healthy volunteers 
dosed at 240mg/day. 
Modification of the Dose and/or Dosing Regimen 
This protocol is written with some flexibility to accommodate the inherent dynamic nature of 
early clinical trials. Modifications to the dose and dosing regimen currently outlined below 
may be required to achieve the scientific goals of the trial objectives and/or to ensure 
appropriate safety monitoring of the trial subjects.  


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Sponsor Project No.: 
Celerion Project No.: 
US IND No.: 
 
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As such, lowering the currently outlined dose may be permitted based on newly available data, 
but the dose may not exceed 200 mg per day. 
• 
Decrease in the dose of the trial drug administered during the study 
The current top dose of ≤ 200 mg/day (10 X 20 mg tablets) is not expected to exceed 
the Cmax limit of 35 ug/ml (projected mean from healthy volunteer data of 28 ug/ml) 
However if PK monitoring reveals that the limit could be exceeded, then 180 mg/day 
will be given (9 X 20 mg tablets). This dose would be projected to have a Cmax of 
25.75 ug/ml.  
• 
Decrease in the duration of trial drug administration (e.g., number of days) in 
the study 
• 
Addition of a pharmacokinetic data review 
9.6 
S 48168 (ARM210) Research Studies to Date (including potential interactions) 
9.6.1 S 48168 (ARM210) Pre-Clinical Studies in RYR1-RM 
To date, we have utilized extra skeletal muscle tissue collected from RYR1-RM patients at the 
NIH CC for testing Rycals preclinically in this population. Skeletal muscle tissue was obtained 
via needle biopsy in a previous RYR1-RM clinical trial (NCT02362425). Skeletal muscle 
samples were tested in Dr. Marks’ lab for RyR1-Calstabin1 binding. All biopsies demonstrated 
decreased Calstabin1 binding, which was rescued with Rycal treatment ex vivo. Seven samples 
had sufficient material to evaluate channel function in a Ca2+ leak assay as well. All seven 
samples exhibited increased leakiness compared with control muscle RyR1, and decreased 
channel leakiness upon Rycal treatment ex vivo. 
9.6.2 S 48168 (ARM210) Clinical Studies 
To date, unblinded data are available for a total of 107 adult subjects that participated in Phase 
I clinical studies (including single and multiple dose-escalation) where 90 participants were 
exposed to S 48168 (ARM210) treatment. S 48168 (ARM210) has been safe and well-tolerated 
in single doses (up to 240 mg) and in 14 days of multiple dosing up to 240 mg daily. The study 
drug has been well tolerated. No serious AEs were reported. There were no clinically 
significant, dose dependent changes in vital signs, physical examination, laboratory data, ECG 
and telemetric data. 
S 48168 (ARM210) has been used in four Phase I clinical studies,
 with two further described below. All studies to date have been in adult healthy male 
Caucasian volunteers aged 18- 45 years. The FIH study
was divided into two 
parts; part 1 is a randomized placebo-controlled blind
ose escalation study 
where 5 dose levels were tested (40 mg, 80 mg, 160 mg, 240 mg and 400 mg), and part 2 is a 
four-panel rising multiple dose study (20 mg/day, 60 mg/day, 120 mg/day and 240 mg/day) 
for 14 days of dosing. The single dose level of 400 mg and the repeated dose level of 240 
mg/day for 14 days of S 48168 (ARM210) were tested in a second step with a study 
amendment. The data are unblinded for all dose levels. S 48168 (ARM210) has been safe and 


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Phase 1 – Safety, PK, PD 
ARMGO Pharma Inc. 
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Celerion Project No.: 
US IND No.: 
 
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well-tolerated in part 1 and part 2. No serious AEs were reported. All AEs were of mild 
intensity including an increase in transaminases which occurred 14 days after cessation of drug 
in the 20 mg dose panel at the post study follow up visit. These elevations were considered not 
related to the study drug by the investigator and were not related to any signs and symptoms. 
There were no elevations in the dosing period. There were no clinically significant changes in 
vital signs, physical examination, ECG and telemetric data. No other laboratory changes apart 
from this mild increase in transaminases was observed. 
In this study, additional monitoring was performed for two theoretical risks, based on prior 
animal studies. First, pre- and post-dose sperm levels were measured in all panels and there 
were no clinically significant changes seen in sperm numbers. Secondly, gastroscopies were 
performed to ensure that the gastric restrictive formulation was protective for the transient 
gastric toxicity (minimal neck cell hyperplasia in the fundic mucosa) seen in the four-week 
(but not 13-week) dog toxicology studies. Here, two minor erosions reported as mild adverse 
events not considered as related to the product by the investigator were seen in the 60 mg/day 
cohort, which resolved at 8 weeks. No erosions were seen at the 20 or 120 mg dose level in 
any subjects. 
The IND opening study 
is complete. A total of 18 subjects received single doses 
of 40 mg of S 48168 (ARM210). This was an open-label, 2-cohort study. Cohort 1 was a 
randomized, 3-period, 3-way crossover study in extensive CYP2C8 metabolizers to examine 
the effect of food on the rate and extent of absorption of S 48168 (ARM210). Administration 
of S 48168 (ARM210) 40 mg was compared between fasted, high fat meal and a light meal 
after a brief delay. The lighter meal was meant to be a “real world” assessment, as patients in 
future clinical studies, are likely to eat a lighter meal than the high-fat meal, a worst-case 
scenario.  
As described above, there is no clinically meaningful difference in AUC when S 48168 
(ARM210) is given fasted or fed.  
Cohort 2 is a 1-period study in intermediate CYP2C8 metabolizers. All studies to date have 
been conducted in CYP2C8 extensive metabolizers. Approximately 1/3 of the population is 
likely to be intermediate metabolizers. These levels of metabolism have been classified on the 
basis of in vitro assays. Subjects who are poor CYP2C8 metabolizers are expected to exhibit a 
similar S 48168 (ARM210) PK profile as observed in the presence of a CYP2C8 inhibitor in 
CYP2C8 extensive metabolizers. Surprisingly, several CYP2C8 sensitive substrates (i.e. 
increased by gemfibrozil treatment), when examined in vivo for their clearance with extensive 
versus intermediate metabolizers have had the opposite results; namely that intermediate 
metabolizers had higher clearance and therefore lower exposure than their wild type 
counterparts. It is therefore possible that these classifications, based on in vitro data, are not 
meaningful. This study examined the single-dose PK in extensive versus intermediate 
metabolizers. The results showed that intermediate metabolizers did not have higher levels of 
Cmax or AUC than extensive metabolizers and are therefore safe to include. In the current 
protocol rare (~1% of the population) poor CYP2C8 metabolizers are excluded as a precaution.  


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Sponsor Project No.: 
Celerion Project No.: 
US IND No.: 
 
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No serious AEs were reported in this study. All AEs were of mild intensity and resolved. There 
were no clinically significant changes in vital signs, physical examination, laboratory and ECG 
data. 
10 STUDY OBJECTIVES AND ENDPOINTS 
10.1 Study Objectives 
Primary objective: To determine safety and tolerability of S 48168 (ARM210) treatment in 
RYR1-RM affected individuals.  
Hypothesis: S 48168 (ARM210) treatment will have no safety concerns limiting further 
development and will be generally well tolerated in RYR1-RM patients. 
Exploratory objectives: 
1. To determine PK of a 28-day (not to exceed 30-day) administration of S 48168 (ARM210) 
in RYR1-RM affected individuals. 
Hypothesis: There will be no clinically meaningful difference in S 48168 (ARM210) 
exposure at steady state in RYR1-RM affected individuals when compared to existing data 
established in healthy volunteers. 
2. To explore if S 48168 (ARM210) treatment increases RyR1-calstabin1 binding in skeletal 
muscle of RYR1-RM affected individuals. 
Hypothesis: S 48168 (ARM210) treatment will increase RyR1-calstabin1 binding, compared 
to baseline, as determined by co-immunoprecipitation of RyR1 and calstabin 1, and decrease 
relative Fluo-4 signal compared to baseline 
3. To explore if S 48168 (ARM210) treatment improves muscle function, motor activity, and 
fatigue in RYR1-RM affected individuals. 
Hypothesis: Treatment with S 48168 (ARM210) will increase hand grip, pinch, and 
quantitative muscle assessment strength, decrease the time to complete graded functional 
tests, increase the total MFM-32 % maximum score, and decrease the PROMIS-fatigue 
subscale score, when compared to baseline. 
10.2 Study Endpoints 
Primary endpoint:  
Composite safety and tolerability profile 
(Frequencies of the following: TEAEs ≥ grade 2 in severity (CTCAE version 5), all SAEs, and 
all AESIs). 
 
Exploratory Endpoints: 
S 48168 (ARM210) pharmacokinetics 
Day 1 composite PK profile (for study drug naïve participants only) 


S 48168 (ARM210) 
Phase 1 – Safety, PK, PD 
ARMGO Pharma Inc. 
Sponsor Project No.: 
Celerion Project No.: 
US IND No.: 
 
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(Comprised of the following: AUC0-t, AUC0-inf, Cmax, Tmax, and t½). 
 
Day 28  (not to exceed Day 30) composite PK profile 
(Comprised of the following: AUCtau, Cmax, Tmax, Cmin, RAAUC, and RACmax). 
 
S 48168 (ARM210) pharmacodynamics 
RyR1-calstabin1 binding 
(Change from baseline in RyR1-calstabin1 binding (arbitrary units)). 
 
RyR1 channel integrity 
(Change from baseline in RyR1-mediated Ca2+ leak (arbitrary units)). 
 
Muscle/motor function and fatigue 
Hand grip strength (kg), pinch strength (kg). 
Time taken to complete each of the following (seconds): walk 10-meters, supine to stand, 
ascend 4 stairs, and descend 4 stairs. 
MFM-32 score for domains 1, 2, 3, and total (% of maximum score). 
PROMIS-fatigue subscale score (t-score). 
Quantitative muscle strength (kg) 


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Phase 1 – Safety, PK, PD 
ARMGO Pharma Inc. 
Sponsor Project No.: 
Celerion Project No.: 
US IND No.: 
 
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Safety will be monitored throughout the study by repeated clinical and laboratory evaluations. 
Discontinued subjects may be replaced at the discretion of the Sponsor in consultation with the 
PI and DSMB. The pre-screening accrual ceiling will be up to 50 subjects with a target number 
of approximately 8-20 completers. 
Overview of study visits: 
Pre-screening of individuals will be conducted by the study coordinator who will use prior 
medical records and biospecimen data and/or an IRB-approved script (Appendix # 2). During 
pre-screening, interested individuals may be asked pre-specified questions pertaining to the 
inclusion and exclusion criteria if needed.  
Informed consent will be obtained before any study procedures begin, including formal 
screening procedures. Formal screening will initiate remotely, upon completion of a telephone 
consent form for a blood draw. Remote analysis of CYP2C8 genotype will be done at this 
initial stage of consent to avoid unnecessary burden for the particants who do not meet this 
inclusion criterion. 
The first study visit will begin with the completion of an in-person consent form, covering 
screening procedures to be conducted at the NIH Clinical Center (e.g. PE, safety laboratory 
assessments, PFT, ECG) and all remaining study procedures. Participants that complete the 
study screening assessments at NIH and meet all the eligibility criteria (per an IRB-approved 
eligibility checklist, Appendix # 3) will receive an allocation number. This number will be 
distinct from the participant’s baseline number. Next, participants will undergo muscle/motor 
function assessments. They will fast overnight. The following morning, administration of the 
first dose will begin and participants will remain at the NIH CC for at least 24 hours for single-
dose PK (baseline 24hr PK for drug naïve participants only), safety labs, ECG, vital signs and 
physical examination. Participants will then be discharged, provided with a lifestyle 
recommendations sheet (Appendix # 4) and contacted approximately one week later for AE 
assessment (Appendix # 5) by a study investigator (Day 7 ± 2 days). Re-enrolled participants 
will be assigned a new allocation number. Re-enrolled participants will not undergo baseline 
24hr PK studies and will be discharged and instructed to take the study drug after all baseline 
safety assessments (safety labs, ECG, vital signs and physical examination) are completed.  
Participants will attend a phone call on Day 14 (± 2 days). This will include review of any 
concomittant medication, TEAE assessment, and C-SSRS and PROMIS-fatigue questionaires. 
Safety labs will be obtained remotely or at NIH CC if the participant is local to the study site. 
Participants will return to the NIH CC on Day 28 (± 2 day) for repeat safety labs, ECG, vital 
signs, physical examination, and 24hr PK. In addition, participants will be observed and 
examined  one day post cessation of dosing, for any withdrawal effects, although none are 
expected.  
A study investigator will contact participants by telephone weekly when not on site to remind 
them of upcoming, scheduled local phlebotomy appointments and perform remote TEAE 
assessments, if applicable. 


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Phase 1 – Safety, PK, PD 
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Sponsor Project No.: 
Celerion Project No.: 
US IND No.: 
 
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The final onsite study visit (Day 42 ± 2 Days) will consist of muscle/motor function 
assessments, PROMIS-fatigue questionnaire, AE assessment, vital signs, physical 
examination, safety labs, and a blood draw.  
Daily subject diaries will be used to capture both time of dose administered as well as any 
symptoms they may feel in between remote TEAE assessments.  
Confinement, Return Visits, and Follow-Up 
Participants will be admitted to the NIH CC on the evening of Day -1 for drug administration. 
Drug naïve participants will undergo baseline 24hr PK sample collection the next morning. 
Participants will attend a phone call on Day 14 (± 2 days). This will include review of any 
concomittant medication, TEAE assessment, and C-SSRS and PROMIS-fatigue questionaires. 
Safety labs will be obtained remotely or at NIH CC if the participant is local to the study site. 
Participants will return to the NIH CC on Day 28 (± 1 day) for repeat safety labs, PE, ECG, 
vital signs, and a 24hr PK sample collection.  
Participants will return to the NIH CC for Day 42 ± 2 days for  vital signs, AE assessment, 
exploratory efficacy assessments, safety labs, and a blood draw. 
At all times, a subject may be required to remain at the NIH CC for longer at the discretion of 
the Principal Investigator (PI) or designee (e.g. when deemed necessary for safety reasons). 
Participants will be contacted by telephone/secured email for a follow up regarding TEAEs 
approximately weekly when not on site and will also have a blood draw for safety clinical 
laboratory tests at day 14. This will include participants who terminate the study early. 
Participants local to the study site will have the option of completing AE assessments  and 
safety clinical laboratory tests at the NIH. 
Participants will also be able to enter any symptoms they experience in a participant diary 
(Appendix # 6). 
11.2 Risks and Discomforts 
Medical History 
There may be some psychological distress associated with providing medical and family 
history. Frequent breaks may be taken to decrease the risk of distress. 
Suicidality assessment  
There may be some psychological distress associated with completing the suicidality 
assessment. Frequent breaks may be taken to decrease the risk of distress. There is a risk that 


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US IND No.: 
 
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the suicidality assessment will be positive. If positive, we will take steps to assure the 
participant’s safety and well-being.  
Physical Examination 
There is minimal medical risk and discomfort from the physical examination.  
 
Videotaping 
Risks are minimal. The patient may be identified if a face is featured. When possible, the 
patient’s face and other identifying marks will not be included in the recording or photograph 
in order to protect confidentiality. 
Pulmonary Function Tests 
There are minimal risks. Participants may feel tired after the procedures.  
Cardiac assessment (ECG and Echocardiogram) 
Patients may experience slight discomfort from laying still. These are minimal risk procedures 
however patients may experience discomfort with removal of the electrodes or a topical 
reaction to the adhesive on the electrodes. 
Cannulation and phlebotomy 
Participants may have some discomfort and bruising at the site of cannulation/needle entry. 
There is a minimal risk of fainting. Infection in the area of the cannulation/needle insertion is 
rare. To address this risk cannulation and phlebotomy will be conducted by clinicians / 
phlebotomists.  
Pregnancy testing 
There is a risk that a pregnancy test will be positive. This may be upsetting to the participant. 
A clinician will be present the results to the participant and be available for any questions. 
Urine collection 
There is minimal risk associated with urine collection.  
Motor Function Measure 32 
Participant self-limiting tests with minimal risk and discomfort. Participants may become 
fatigued.  
Graded Functional Tests 
These are patient self-limiting tests with minimal risk and discomfort.  Participants may 
become fatigued. 
Grip/Pinch Strength: These are patient self-limiting tests with minimal risk and 
discomfort.  Participants may become fatigued. 
Quantitative Muscle Assessment: Participant self-limiting test with minimal risk and 
discomfort. Participants may become fatigued.  
PROMIS-fatigue: 


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This is a minimal risk procedure. 
 
Remote TEAE reporting 
There may be some psychological distress associated with recalling adverse events. A clinician 
will conduct remote TEAE reporting data collection and be available for any questions the 
participant may have relating to their responses. Participants local to the study site will have 
the option of completing TEAE assessments at the NIH. 
Post-study follow-up blood draw 
The risks associated with phlebotomy (detailed above) apply. A study investigator will contact 
participants by telephone to remind them of upcoming, scheduled local phlebotomy 
appointments. 
Administration of study drug 
As this is a phase 1 study, and the first time S 48168 will be administered to a patient 
population, we consider administration of study drug to be greater than minimal risk. To date 
however, data are available for a total of 107 adult healthy male Caucasian participants aged 
18- 45 years that participated in Phase 1 clinical studies. Of these participants,  90 were exposed 
to S 48168 (ARM210) treatment. S 48168 (ARM210) has been safe and well-tolerated in 
single doses up to 240 mg and in 14 days of multiple dosing up to 240 mg daily (un-blind data), 
and in single dose of 400 mg and 14 days of multiple dosing of 240 mg daily (blinded data). 
No serious AEs were reported. There were no clinically significant, dose dependent changes 
in vital signs, physical examination, laboratory data, ECG and telemetric data. 
Risk to the participant from study drug administration will be minimized through 24h inpatient 
monitoring following administration of the first dose and AE monitoring scheduled throughout 
the intervention phase as well as 1 day, 7 ± 2 days, and  14 ± 2 days post-intervention. As a 
precaution, all participants will be provided with a malignant hyperthermia alert bracelet and 
asked to wear this throughout the study and two-week follow-up. 
11.3 
Human Subjects Protection 
11.3.1 Subject Selection 
Subject selection will be equitable considering the rarity of RYR1-RM. Pediatric RYR1-RM 
affected individuals are not being considered for this trial since clinical trials of S 48168 
(ARM210) have only been completed in adult healthy volunteers to date. All ages within the 
specified range, races, and both sexes will be accepted. Individuals over 65 years of age will 
be excluded from participation in this study to avoid potential increased risks due to pre-
existing conditions or confounding factors (e.g. from concomitant medication use and age-
related muscle weakness (sarcopenia)). 


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11.3.2 Justification for Exclusion of Children 
Children (individuals below 18 years of age) will be excluded from participating in this trial 
since clinical trials of S 48168 (ARM210) have only been completed in adult healthy 
volunteers to date. 
11.3.3 Justification for Exclusion of Other Vulnerable Subjects 
Those unable to provide consent due to cognitive issues will be excluded, due to the 
requirement to be able to respond to remote TEAE reporting. 
11.3.4 Safeguards for Vulnerable Populations and Sensitive Procedures 
For women of childbearing age, we will do pregnancy testing to exclude those who are 
pregnant at the beginning of the study. We will also exclude women who are breastfeeding. 
Women who are sexually active will require contraception. Acceptable contraception includes 
hormonal methods (oral contraceptives, the patch, shot/injection, and vaginal ring), 
implantable devices (implantable rods and intrauterine devices), and permanent birth control 
methods (sterilization implant and surgical sterilization). 
11.4 Anticipated Benefit/Classification of Risk 
Anticipated Benefits: This study may offer a temporary direct benefit to participants allocated 
to receive S 48168 (ARM210), such as improved skeletal muscle function owing to enhanced 
RyR1-Calstabin1 binding and, in turn, improved excitation-contraction coupling. The short 
nature of this study may limit these benefits. 
Overall Risk and Benefit Ratio: The risks are reasonable in relation to the anticipated benefit 
in this adult patient population. 
11.5 Alternative to Participation 
As this study is a clinical trial to determine the effects of S 48168 (ARM210) on patients with 
RYR1-RM, it is necessary for participants in the trial to take S 48168 (ARM210). S 48168 
(ARM210) is used under an IND. For patients who do not wish to take S 48168 (ARM210) the 
alternative is to not participate in the trial. There are no approved therapeutic alternatives. 
11.6 Selection of Study Population 
11.6.1 Inclusion Criteria 
Patients must meet all the following conditions to be eligible for enrollment into the study: 
1. Adult males and females, 18 – 65 years of age, inclusive, at screening. 
2. Body mass index (BMI) ≥ 18.0 and ≤ 36.0 kg/m2 at screening. 


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3. Confirmed genetic diagnosis of RYR1-RM and supporting clinical phenotype with 
demonstrable deficits on at least one of the baseline study assessments. 
4. Evidence  of functional deficit (defined by MFM-32 < 80% maximum score) or  
demonstratable deficits in at least one of the baseline muscle/motor function assessments. 
5. Ambulatory. Able to walk ten meters (with or without assistance e.g. with a cane).  
6. Must have a CYP2C8 extensive or intermediate metabolizer genotype. 
7. Daily use of medicines and dietary supplements need to be approved by the PI and 
Sponsor, or a drug/supplement-dependent wash-out prior to inclusion.  
8. For male subjects: is sterile or agrees to use an appropriate method of contraception, 
including a condom with spermicide, from study drug administration on the first day of 
dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study 
drug administration. No restrictions are required for a vasectomized male subject 
provided the subject is at least 1-year post–bilateral vasectomy procedure prior to study 
drug administration on first day of the first dose. A male subject whose vasectomy 
procedure was performed less than 1 year prior to study drug administration on the first 
day of dosing must follow the same restrictions as a non-vasectomized male. Appropriate 
documentation of surgical procedure should be provided. 
9. For male subjects: agrees to not donate sperm from study drug administration on the first 
day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of 
study drug. 
10. For female subjects of childbearing potential: uses one of the following highly effective 
birth control methods (from the first dose until 5 half-lives plus 90 days (approximately 
94 days): 
• Prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch. 
• Intrauterine device (IUD). 
• Intrauterine hormone-releasing system (IUS). 
• Depot/implantable hormone (e.g., Depo-provera®, Implanon). 
• Bilateral tubal occlusion/ligation. 
• Sexual abstinence:   
o Refraining from heterosexual intercourse during the entire period of risk 
associated with the study requirements. 
o If the participant decides to become sexually active during the study, then one 
of the highly effective birth control methods must be used.  
11. For female subjects of non-childbearing potential; defined by at least 1 of the following 
criteria: 


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• Postmenopausal defined as 12 months of spontaneous amenorrhea and 
follicle-stimulating hormone (FSH) serum level > 40mIU/mL. Appropriated 
documentation of FSH levels is required.  
• Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure. 
• Has a congenital condition resulting in no uterus. 
12. Willingness and ability to comply with scheduled visits, drug administration plan, 
laboratory tests, study restrictions, and study procedures 
13. Able to provide written informed consent and understands the study procedures in the 
informed consent form (ICF). 
11.6.2 Exclusion Criteria 
The presence of any of the following conditions will exclude a patient from study enrollment: 
1. Patient is mentally or legally incapacitated at the time of the screening visit or during the 
conduct of the study. 
2. History or presence of alcoholism or drug abuse within the past 2 years prior to the first 
dose of study drug. 
3. History or presence of hypersensitivity or idiosyncratic reaction to the study drug, related 
compounds, or inactive ingredients. 
4. Positive urine drug or alcohol results at screening.  
5. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), or hepatitis C virus (HCV). 
6. Patients with baseline ALT levels three times above the upper limits of normal (ULN) or 
baseline AST levels five times the ULN (isolated elevations of total bilirubin <2 X ULN 
with direct bilirubin below the ULN will be included). 
7. Patients with severe pulmonary dysfunction at screening (Forced Vital Capacity (FVC) < 
50% predicted) or evidence of pulmonary exacerbation. Pulmonary exacerbations refer to 
an acute worsening of respiratory symptoms that result from a decline in lung function. 
8. Patients with a history of a seizure. 
9. Subject has a history of cancer (malignancy) Exceptions:  (1) Subjects with adequately 
treated non-melanomatous carcinoma or carcinoma in situ of the cervix may participate in 
the trial (2) Subjects with other malignancies who have been successfully treated 
> 10 years prior to the screening where in the judgment of the investigator has revealed no 
evidence of recurrence from the time of treatment through the time of the screening except 
those identified at the beginning of the exclusion criterion or (3) Subjects who in the 


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opinion of the investigator are highly unlikely to sustain a recurrence for the duration of 
the trial. 
10. Patients with uncontrolled diabetes defined as HbA1c > 7% or diabetic neuropathy. 
11. Estimated creatinine clearance <40 mL/minute at screening, which may be calculated 
using the Chronic Kidney Disease Epidemiology Collaborative method (CKD-EPI), due 
to reduced muscle mass often seen in RYR1-RM patients. 
12. Patients with a clinically significant abnormality on their ECG other than hypertensive 
related, or heart failure (ejection fraction <30%) or other clinically significant structural 
heart disease on echocardiogram.  
13. Patients with a history of myocardial infarction in the last five years, or evidence of 
congestive heart failure. 
14. Pregnant and breastfeeding women. 
15. Unable to refrain from or anticipates the use of: 
• Any non-approved medicines and/or dietary supplements beginning 14 days prior to 
the first dose of study drug and throughout the study. Thyroid hormone replacement 
medication may be permitted if subject has been on same stable dose for the last 
3 months prior to the first dose of study drug.  
• Any drugs known to be significant inducers or inhibitors of CYP2C8 enzymes for 
28 days prior to the first dose of study drug and throughout the study. Any substrates 
of breast cancer resistance protein (BCRP). 
16. Is currently taking any drug which raises gastric pH, including proton pump inhibitors or 
H2 antagonists. Antacids may be used if taken at night. 
17. Donation of blood or significant blood loss within 56 days prior to the first dose of study 
drug. 
18. Plasma donation within 7 days prior to the first dose of study drug. 
19. Participation in clinical trials for other therapeutic investigational drugs simultaneously or 
within the 4 weeks prior to the first dose of study drug.  
20. Ongoing medical condition that is deemed by the Principal Investigator to interfere with 
the conduct or assessments of the study or safety of the subject.  
21. Is an NIH employee who is a subordinate/relative/coworker of a study investigator.  


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11.6.3 Early Termination of Subjects from the Study 
All participants have the right to withdraw from the study at any time. 
In addition, subjects may be withdrawn from the study by the PI or designee for the 
following reasons: 
• AEs. 
• Subject has a positive urine drug or alcohol result. 
• Difficulties in blood collection. 
• Pregnancy. 
• Disease progression which requires discontinuation of the study intervention. 
• If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
The PI, in consultation with the Medical Monitor, may withdraw any subject from the study 
treatment, if, in the investigator’s opinion, it is not in the subject’s best interest to continue. A 
subject may be withdrawn by the PI (or designee) or the Sponsor/Medical Monitor if 
enrollment into the study is inappropriate, the study plan is violated, or for safety reasons. 
If withdrawn from the study, participants will be required to return all remaining study drug. 
A mailing address will be provided to the participant upon withdrawal. If withdrawn, the 
participant will still need to provide a blood sample locally and have a remote TEAE 
assessment 7 ± 2 days post-withdrawal from the study. A study investigator will contact 
participants by telephone to remind them of upcoming, scheduled local phlebotomy 
appointments. The participant will also need to have a remote TEAE assessment 14 ± 2 days 
post-withdrawal from the study. Participants local to the study site will have the option of 
completing AE assessments at the NIH. If a participant is withdrawn for a safety reason(s), 
more intensive safety monitoring may be undertaken as clinically indicated.    
 
11.7 Study Restrictions 
11.7.1 Prohibitions and Concomitant Medications 
Consumption of foods and beverages containing the following substances will be prohibited 
as indicated: 
• Xanthines/Caffeine: 24 hours before administration of the first and final S 48168 doses 
continuing through the last PK sample collection for that day (small amounts of 
caffeine derived from normal foodstuffs e.g., 250 mL/8 oz./1 cup decaffeinated coffee 
or other decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. 
chocolate bar, per day, would not be considered a deviation to this restriction); 


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• Alcohol: 48 hours before administration of the first and final S 48168 doses continuing 
through the last PK sample collection for that day; 
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 11.6.2. 
Once the subject has been dosed, acetaminophen (up to 2 g per 24 hours) may be administered 
at the discretion of the PI or designee. 
If deviations occur, the PI or designee will decide on a case-by-case basis whether the subject 
may continue participation in the study and may consult the Sponsor if needed. 
All medications taken by subjects during the course of the study will be recorded. 
11.7.2 Meals 
Water and other fluids (except water provided with each dosing) will be restricted 1 hour prior 
to and 1 hour after their first and final S 48168 dose administrations but will be allowed ad 
libitum at all other times. 
Subjects will fast overnight for at least 10 hours prior to their first and final S 48168 dose 
administrations and will continue the fast for at least 4 hours post-dose. 
When confined in the NIH CC, meals and snacks will be provided at appropriate times, except 
when subjects are required to fast. 
During confinement, each meal and/or snacks served at the NIH CC will be similar in caloric 
content and composition and will be taken at approximately the same time for all participants. 
11.7.3 Activity 
Subjects will remain ambulatory or seated upright for the first 4 hours following S 48168 
(ARM210) dosing, except when they are supine or semi-reclined for study procedures.  
However, should AEs occur at any time, subjects may be placed in an appropriate position or 
will be permitted to lie down. 
Depending on the NIH CC rules and regulations, subjects may be prohibited from smoking 
during their confinement or during portions of their confinement. 
11.8 Treatments 
11.8.1 Treatments Administered 
Research with an investigational drug 
S 48168 (ARM210) requires an IND, and the FDA approved IND number is: 
 (See 
Appendix # 7). The company manufacturing S 48168 (ARM210) is Laboratoires Servier. 
Study drug will be shipped by Laboratoires Servier directly to the NIH Pharmacy as therapeutic 
units. The study sponsor is ARMGO Pharma Inc. 


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S 48168 (ARM210) will be supplied as 20 mg gastro-resistant tablets.  
Study visits will be scheduled such that no more than two participants receive their initial dose 
in the same week (See Section 12.11.10 of this protocol for details). The first three participants 
were dosed with 120 mg S 48168 (ARM210) (6 x 20 mg tablets) daily for approximately 
28 days (not to exceed 30 days). After DSMB review of the safety, tolerability and PK of the 
120 mg dose, the remaining participants were dosed with 200 mg S 48168 (ARM210) 
(10 x 20 mg tablets) daily for approximately 28 days (not to exceed 30 days).  All subsequent 
participants are planned to be dosed with ≤ 200 mg S 48168 (ARM210) (10 x 20 mg tablets) 
daily for approximately 28 days (not to exceed 30 days). The tablets are small in size (5 mm 
diameter).  
Study investigators will administer S 48168 (ARM210) during the time the participant is 
confined to the NIH CC for 24h PK assessments (first and final dose administrations). S 48168 
(ARM210) should be administered orally following an overnight fast (at least 10 hours) with 
approximately 240 mL of water on all PK days. A mouth check will be performed by the 
qualified designee to ensure that the subjects have swallowed the study drug. The exact clock 
time of dosing will be recorded using a standardized network clock. 
Study investigators will instruct the participant in the proper dosing instructions for home 
administration when drug supplies are dispensed (Appendix # 8). Study drug (S 48168 
[ARM210]) will be provided in tablet form. All participants will be instructed to self-administer 
the study medication daily with water in the morning. Compliance will be assessed during each 
phone/e-mail contact. Compliance will be verified at in-person visits for residual pill counts as 
well as with diary. Adequate compliance will be defined as taking 80% of the study drug. If a 
participant completely misses a dose (e.g. missed one day of drug), we will have them take the 
next dose and contact the site. 
11.8.2 Method of Assigning Subjects to Treatment 
Individuals who have expressed an interest in participating and meet the pre-screening 
eligibility criteria will be contacted for telephone screening as detailed in Appendix # 2. Each 
individual will be assigned a unique identification number (baseline number) at this time.  
The individuals who complete the study screening assessments at NIH and meet all the 
eligibility criteria (Appendix # 3) will receive an allocation number. The allocation number 
will be different from the baseline number. If replacement subjects are used, the replacement 
subject number will be 100 more than the original (e.g., Subject No. 101 will replace Subject 
No. 1). Eligible participants will be started on  ≤ 200 mg/day dose.   
11.8.3 Blinding 
This is an open label study.  
11.8.4 Interim Analysis (PK) 
Interim PK analysis was conducted by Nuvisan (contract vendor) as follows: 


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First dose group (120 mg/day): Full PK analysis once the first three participants completed 
dosing for approximately 28 days (not to exceed 30 days). This allowed verification that the 
observed PK results from these RYR1-RM affected individuals agreed with PK results from 
previous studies in healthy volunteers and that the Cmax limit of 35 ug/mL was not exceeded. 
At this stage of drug development, a PK value that would not require a dose adjustment would 
be considered as similar. This would mean 50% lower or 200% higher than that of healthy 
volunteers.  
Based on PK results and safety data from the first dose group, the dose to be administered in 
subsequent participants was increased to 200 mg/day. This was based on DSMB 
recommendations and investigator and sponsor’s joint decision. 
Second dose group (200 mg/day): PK analysis for Cmax once the first three participants have 
completed dosing for approximately 28 days (not to exceed 30 days). This will allow 
verification that the Cmax limit of 35 ug/mL was not exceeded. Subsequently, all remaining 
samples will be shipped to the contract laboratory for analysis at the end of the study, when 
full PK analysis beyond the Cmax measurement will occur for all of the samples obtained from 
this group  
11.8.5 Stopping Rules 
A decision to stop dose administration or terminate the study will be made jointly by the 
Sponsor, Medical Monitor, Data and Safety Monitoring Board (DSMB), and the PI following 
the review of all pertinent safety/tolerability data and PK data (if available). However, the 
DSMB may independently decide to pause, halt,  or terminate the study. In addition, the DSMB 
may independently decide to pause or stop dose administration in an individual.  
To stop or temporarily halt dose administration in any subject: 
• Participant has a SAE that is possibly or definitely related to drug. 
• Participant has a non-serious adverse event that is possibly or definitely related to 
drug and is severe (on a scale of mild, moderate, or severe) per the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
• Participant has an AE special interest (AESI) that is considered serious as defined 
by 21 CFR 312.32. AESIs for this study are as follows:  
 
Large increases in transaminases, Aspartate aminotransferase or Alanine 
aminotransferase. If the subject’s baseline transaminases were within normal limits, 
then a change of 3X ULN is the criteria. If the subject’s baseline transaminases are 
above the ULN at baseline, then 5X ULN would be the criteria. Baseline elevations in 
transaminases have been known to occur in some patients with RYR1-RM, likely due 
to muscle injury as a consequence of the disease and normal activity. 
 
CNS toxicity (tremors/convulsions seen in safety assessment animals) - consider 
tremors and any symptoms of seizure as the events to monitor for. 
 


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Gastric toxicity - severe gastric or epigastric pain or severe vomiting. 
 
Plasma Cmax (S 48168) >35 µg/mL. 
 
Dosing may be temporarily halted in any subject for medically important non-serious AE that 
is possibly or definitely related to drug and requires medical intervention. Dosing may be 
halted until the AE resolves and then may be resumed with careful observation for 
reoccurrence. The PI, IRB, CD, the Sponsor (ARMGO Pharma Inc.), DSMB, or the FDA may 
pause, halt, or terminate the study at any time following review of any safety concerns.  
The study will be terminated if: 
• ≥ 2 subjects have a SAE that is possibly, probably, or definitely related to drug. 
 
• ≥ 2 subjects have a medically important non-serious TEAE that is probably or 
definitely related to drug and is severe (on a scale of mild, moderate, or severe) per 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
 
• ≥ 3 subjects have a medically important non-serious TEAE that is possibly related 
to drug and is severe (on a scale of mild, moderate, or severe) per the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
 


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12 STUDY ACTIVITIES AND PROCEDURES 
The Study Events Flow Chart (Section 7) summarizes the clinical procedures to be performed 
at each visit. Individual clinical procedures are described in detail below. All procedures in 
this protocol are for research purposes. Additional evaluations/testing may be deemed 
necessary by the PI or designee and/or the Sponsor for reasons related to individual subject 
safety. If required for all subjects, such procedures will be added to the protocol via 
amendment. 
For this study, the blood collection for S 48168 (ARM210) is the critical parameter and needs 
to be collected as close to the exact time point as possible. All other procedures should be 
completed as close to the prescribed/scheduled time as possible but can be performed prior or 
after the prescribed/scheduled time. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
  
12.1 Recruitment 
Although RYR1-RM constitute a rare disease, investigators on the protocol work closely with 
this patient population and with advocacy groups such as the Muscular Dystrophy Association, 
the RYR-1 Foundation and Cure CMD. The RYR1-RM population is highly motivated and 
there is significant interest surrounding S48168 (ARM210) as a potential therapy. As such, we 
expect to recruit approximately 8-20 participants within six to twelve months of opening the 
study with an accrual ceiling of up to 50 to allow for dropouts. 
We will implement a strategy that promotes equitable subject recruitment as follows:  
• IRB-approved letters providing an overview of the study will be emailed to staff at 
neuromuscular disease clinics (Appendix # 10). In particular, clinics that are known to 
have previously sent tissue for RyR1-Calstabin1 binding assay or referred patients to 
NCT02362425. This will be provided with the abovementioned study advertisement 
for distribution to patients at the clinician’s discretion.  
• An IRB-approved letter and study advertisement will be provided to patient advocacy 
groups, such as the RYR-1 Foundation, for circulation (e.g. via email or posting 
online). The advertisement includes contact details for the study coordinator as well as 
key inclusion and exclusion criteria (Appendix # 9). 
12.2 Screening 
Pre-screening 
Interested participants will contact the study team directly or may be referred by their 
physicians. Pre-screening of individuals will be conducted by the study coordinator who will 
use prior medical and research records and biospecimen data in accordance with the revised 


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common rule and/or an IRB-approved script (Appendix # 2). During pre-screening, interested 
individuals may be asked pre-specified questions pertaining to the inclusion and exclusion 
criteria, if needed. The study coordinator will then contact the potentially eligible individuals 
to initiate the telephone consent process as detailed below and in Section 14.1.3.  
Formal screening procedures 
Formal screening will be conducted in two parts.  
Part 1: Telephone consent for blood draw and tests.  
Participants will be required to have a local blood draw for CYP2C8, HIV and hepatitis testing 
(inclusion criteria) prior to attending the NIH. A telephone consent (Appendix # 19) will be 
used to cover this procedure. A study investigator will contact participants by telephone to 
remind them of upcoming, scheduled local phlebotomy appointments.  
CYP2C8 genotyping will be performed at a contract laboratory. Individuals that are deemed 
to be rare (1% of the population) poor CYP2C8 metabolizers will be excluded. To assess 
eligibility criteria, informed consent will also be obtained to access additional medical and 
research records, if applicable.  
Part 1 continued: Telephone consent for blood draw and tests (re-enrolled subjects) 
Participants who are re-enrolling from the low dose cohort to the high dose, will not require 
re-assessment of CYP2C8 metabolizer genotype since this is a non-modifiable factor. Thus, 
re-enrolled subjects will not have to complete a separate telephone consent and instead will be 
able to provide samples for HIV and hepatitis screening at their first study visit under the study 
consent form (Appendix #20). 
Part 2: In-person consent (for final screening procedures and for the trial).  
Clinical Laboratory Assessments, Echocardiogram, ECGs, PFTs, general medical history, and 
physical exams will be done at the first study visit. Part 2 procedures will be completed within 
28 days of the first dose administration. 
The second consent form (Appendix # 20) will be sent to the participant prior to the NIH study 
visit to give the participant sufficient time to read the information. This consent form will cover 
the remaining screening procedures (e.g. PFTS, ECG, echocardiogram) as well as all other 
study-related procedures. 
Prior to the first dose of study drug, several tests and procedures will be performed to assess 
and mitigate the risk to participants with pre-existing medical conditions. Medical history and 
demographic data, including name, age, body weight (kg), height (cm), BMI (kg/m2), and 
tobacco use (including number of cigarettes smoked per day) will be reported. Each subject 
will also have a physical examination, vital sign measurements (heart rate, blood pressure, 
temperature, and respiratory rate), 12-lead ECG, echocardiogram, PFTs, and the clinical 
laboratory tests of hematological, hepatic and renal function. Additional research blood 


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samples (e.g. serum, plasma, DNA, and PAX tubes) will also be obtained. These samples are 
all noted in Section 12.11.6 and Table 1.  
Part 2 continued: In-person consent (process for re-enrolled subjects). 
Individuals interested in re-enrolling to receive the high dose will be reconsented to the most 
recent study consent and must meet all inclusion and exlusion crtieria prior to dosing. For re-
enrolled participants, an interim medical history will be performed and a subset of research 
blood samples obtained (e.g., plasma only).  
12.3 CYP2C8 Genotyping 
A blood sample (1 × 4 mL polypropylene K2EDTA Vacutainers® tubes) for CYP2C8 
genotyping will be collected from all subjects as outlined in the Study Events Flow Chart 
(Section 7), to confirm subject eligibility for the study. The blood sample for CYP2C8 analysis 
will be collected locally to the participant.  
These samples will only be used for CYP2C8 genotyping and will be discarded after subject 
eligibility has been confirmed. 
Each sample must be labeled with a unique identifier that is present on the sample container. 
Good Laboratory Practice (GLP) requires a chain-of-custody that is traceable to the sample 
donor. Labels must be legible and waterproof. 
On the same day as collection, samples will be packaged and shipped at ambient temperature 
(fresh sample) or on dry ice (stored sample), as per the clinical site’s standard operating 
procedures, to the appropriate laboratory (listed in Section 3) for analysis. 
12.4 Medical History 
Study physicians or nurses will obtain medical history information. 
12.5 Quality of Life Assessment 
Participants will complete a PROMIS-fatigue questionnaire at each study visit following 
screening (Appendix # 11).  
12.6 Review of Inclusion/Exclusion Criteria 
For each study visit following screening, the study staff will review the inclusion and exclusion 
criteria with each participant to affirm that the inclusion and exclusion criteria have not been 
violated since the last study visit. 


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12.7 Concomitant Medications 
Use of concomitant medications will be documented throughout the study at the time of each 
study visit including the follow-up visit and at the time of each phone/e-mail contact during 
the study. 
12.8 Videotaping and/or Photography 
Videotaping or photography will be performed during portions of the physical examination to 
accurately document the condition. When possible, the patient’s face and other identifying 
marks will not be included in the recording or photograph in order to protect confidentiality.  
12.9 Motor Function Measure 32 (MFM) 
The MFM is a generic scale which provides a measurement of the effects of muscle weakness 
in neuromuscular diseases (NMD) (Appendix # 14). Assessments are based on posture and 
movements of the whole body. It is applicable to both ambulant and non-ambulant patients 
with a wide range of disease severity. The patient is asked to roll, sit, lift head from prone and 
supine position, get up from a lying position, prop on arms, kneel, crawl, stand and step. This 
test will be combined with timed tests (floor to stand, ascend/descend 4 steps). Time to 
complete both tests: approximately 60 minutes. 
12.10 Safety Assessments 
Safety and tolerability of S 48168 (ARM210) will be determined by monitoring Adverse 
Events (AEs) over approximately 28 days (not to exceed 30 days) of treatment via physical 
examinations, electrocardiograms (ECGs), vital signs, and laboratory safety tests. A reference 
dataset of AEs/SAEs obtained from a natural history study of RYR1-RM will also be available 
to assist in interpretation of safety events. Per FDA requirements for a drug with a novel 
mechanism that has not been evaluated in patients, the Columbia-Suicide Severity Rating Scale 
(C-SSRS) (Appendix # 15) will be administered pre- and post-intervention. The frequency and 
severity of AEs will be compared between treatment and historical controls including a 
previously conducted natural history study at the NIH. 
The aggregate review of AEs, discontinuations and other safety findings from diaries and AE 
monitoring, will determine participant tolerability. A participant will be considered to have 
tolerated a dose if the participant experiences no clinically significant drug-related AE or 
laboratory abnormality. Conversely, a participant will not be considered to have tolerated the 
dose if he/she experiences a clinically significant drug-related AE or laboratory abnormality 
during the study drug administration or post-administration follow-up period. Clinically 
meaningful changes in vital signs (heart rate, blood pressure, and breathing rate) and cardiac 
function tests (ECGs and echocardiography) will be assessed by the medical monitor in 
conjunction with investigators. Further interpretation of such tests by a specialist (e.g. 
cardiologist) may be requested if deemed necessary by the medical monitor and PI. 
S 48168 (ARM210) has been safe and well tolerated to date. However, in normal healthy 
volunteers, there is not likely to be an effect on muscle function. In patients with RYR1-RM, 


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even in this short study, there may be improvement in muscle function and strength with 
approximately 28 days (not to exceed 30 days) of dosing with S 48168 (ARM210). Although 
there are no mechanistic reasons to assume that removal of the drug after the proposed dosing 
period would have any consequences other than a return to baseline function, post-dose 
monitoring has been included in the study. These measures include observation and 
examination after 24 hours off drug, as well as remote TEAE monitoring and a blood draw for 
safety labs on day 35 ± 2 days, approximately one week off drug and a remote TEAE 
assessment on day 42 ± 2 days, approximately two weeks off drug.  A study investigator will 
contact participants to remind them of upcoming, scheduled local phlebotomy appointments. 
Participants local to the study site will have the option of completing AE assessments and 
safety laboratory tests at the NIH. 
 
12.10.1.1 
Physical Examination 
A full physical examination will be performed as outlined in the Study Events Flow Chart 
(Section 7). Symptom-driven physical examinations may be performed at other times, if 
deemed necessary by the PI or designee. 
Height, weight, and BMI will be obtained by trained staff (including study investigators, 
nurses, nurse practitioners, and physicians). Study physicians or nurse practitioners will 
perform a physical examination including the evaluation of cranial nerves, reflexes, sensation, 
strength, gait, movement, motor function and coordination.  
12.10.1.2 
Pulmonary Function Tests 
Each participant will perform pulmonary function testing (PFTs) to assess vital capacity (VC) 
at screening. To measure VC the participant will be asked to take the deepest breath they can, 
and then exhale into a flow sensor. During the test, soft nose clips may be used to prevent air 
escaping through the nose (patients will use their own flow sensors, so filters will not be 
needed). Measures to be obtained include VC (both forced and slow) and forced expiratory 
volume at 1 second (FEV1). 
12.10.1.3 
Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate, will 
be measured as outlined in the Study Events Flow Chart (Section 7). Additional vital signs 
may be taken at any other times, if deemed necessary. 
Blood pressure and heart rate measurements will be performed with subjects in a seated 
position, except when they are supine or semi-reclined because of study procedures and/or AEs 
(e.g. nausea, dizziness) or if deemed necessary by the PI or designee. 
Blood pressure and heart rate will be measured within 24 hours prior to first and final S 48168 
dose administrations.  


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12.10.2Cardiac Monitoring 
Cardiac evaluations will be performed in an effort to identify cardiac conditions or 
abnormalities which may preclude the participant from being able to participate in the study. 
It will also monitor them for any adverse reactions to the investigational drug, although cardiac 
specific side effects are not anticipated. These assessments will include ECGs and 
echocardiograms.  
ECG: Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 7). Additional ECGs may be taken at any other times, if deemed necessary by the PI 
or designee. ECGs will be performed with subjects in a supine position. ECGs take 10 minutes 
or less to perform and will be reviewed and interpreted by a cardiologist. ECGs will be 
measured within 24 hours prior to the first and final S 48168 dose administrations. 
Echocardiogram: Screening echocardiography will be performed as outlined in the Study 
Events Flow Chart. Particular focus will be given to overall ventricular systolic function 
(ejection fraction) and major structural heart and valve abnormalities. Echocardiogram is 
expected to be performed in 30-45 minutes.  
Abnormal cardiac test results may be followed by cardiology consultation and/or additional 
cardiac testing such as event monitoring or cardiac MRI, if clinically indicated.  
 
12.10.3  Cannulation and Phlebotomy 
Cannulation will be performed by the phlebotomy service or nurses at the NIH CC. Clinicians 
will obtain blood samples for clinical laboratory tests as well as PK throughout the study. 
Bloods for PK assessments will be drawn at baseline (Day 1, 24h PK; drug naïve participants 
only), at the second in-person study visit (Day 28 – not to exceed Day 30, 24h PK). Whole 
blood will be processed, and the plasma fraction stored for PK analyses. 
Although there is not a specific hypothesis for the comparison of the PK of RYR1-RM patients 
with that of normal healthy volunteers, the expectation is that the difference should not be 
clinically meaningful. At this stage of the development of S 48168 (ARM210) the program 
bounds for exposure are not clear until efficacy is established. However, an increase of roughly 
two-fold in exposure or a decrease of approximately 50% in exposure would be considered 
clinically meaningful. Given the very low variability in Phase 1 to date for S 48168 (ARM210) 
(coefficient of variability- %CV ~15%) it is likely that 8 participants would be sufficient for 
this comparison since six subjects were sufficient to provide 80% power in a parallel design 
comparison in healthy volunteers (Study CL1-210-01 described in the IB 2020).   
12.10.4 Temperature Check 
Participants will be instructed on how to take their temperature using a thermometer for the 
follow-up assessment at approximately 7 days post-drug withdrawal. Participants will record 


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their temperature the morning of their remote TEAE assessment and report the result to the 
study team. Participants local to the study site will have the option of completing their 
temperature check at the NIH. 
12.10.5 The Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a suicidal ideation and behavior assessment instrument. The FDA 
recommends assessment of suicidal ideation and behavior for all clinical trials where the 
drug has central nervous system activity per Guidance for Industry Suicidal Ideation and 
Behavior: Prospective Assessment of Occurrence in Clinical Trials. Although S 48168 
(ARM210) at this dose will have minimal brain penetration, the requirement extends to novel 
mechanisms that have not previously been evaluated in patients.  
The C-SSRS is a detailed interview, but the full interview is needed only if the initial 
screening questions about suicidal ideation and behavior are positive. Although the screening 
questions should be completed at baseline and at every visit for every patient, they are not by 
themselves burdensome, typically taking only 1 to 2 minutes for patients who have no 
positive findings.  Even for a patient with multiple positive findings, the full interview 
typically takes less than 10 minutes. Investigators administering the C-SSRS will be required 
to have completed training provided by The Columbia Lighthouse Project: 
http://cssrs.columbia.edu/training/training-research-setting/.  
Management of participants positive for suicidal ideation and behavior:  
• Result of C-SSRS is positive for suicidal ideation and behavior 
• Principal Investigator is informed of the positive C-SSRS 
• NIH Psychiatry Service is consulted 
• Participant is managed in accordance with standard clinical care and suicide risk 
assessment. This may include social work consultation, referral to local psychiatric care, 
or psychiatric admission when clinically indicated. 
 


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12.10.6 Clinical Laboratory Tests 
All tests listed below will be performed as per Study Events Flow Chart (Section 7). In 
addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the PI or designee.  
Hematology 
 
Serum Chemistry* 
• 
Hemoglobin 
• 
Hematocrit  
• 
Total and differential leukocyte count 
• 
Red blood cell count 
• 
Platelet count 
• 
HbA1C (screening only) 
 
 
• 
Blood Urea Nitrogen 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase 
• 
Aspartate aminotransferase 
• 
Alanine aminotransferase 
• 
Gamma-glutamyl transferase 
• 
Creatine Kinase 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Glucose (fasting) 
• 
Creatinine** 
• 
Cystatin C 
Urinalysis 
 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Protein*** 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood*** 
• 
Nitrite*** 
• 
Urobilinogen 
• 
Leukocyte esterase*** 
 
• 
HIV test 
• 
HBsAg 
• 
HCV 
• 
Urine drug screen 
Ø Opiates 
Ø Amphetamines 
Ø Cocaine 
Ø Cannabinoids 
• 
Urine alcohol screen 
• 
Serum pregnancy test**** 
(for females only) 
• 
FSH (for postmenopausal females at screening 
only) 
 
* 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours before the serum chemistry sample is taken. 
Participants will be encouraged to drink water as usual during the fast. 
** 
At screening, creatinine clearance will be calculated using the CKD-EPI formula. 
*** 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination (for red blood cells, white blood cells, bacteria, casts, and epithelial cells) will be 
performed. 
**** Pregnancy tests must be confirmed as negative prior to administering the first dose. Contraception 
will be required for women of childbearing potential who are sexually active. If a pregnancy test is 
positive, the study participant will be notified of the results. Women who become pregnant during 
the study will be withdrawn and followed through their pregnancy and birth. 
 


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12.10.7 Adverse Events 
12.10.7.1 
Adverse Event Definition and Grading 
Adverse events (as defined per 21 CFR 312.32) will be tracked and submitted to the IRB as 
outlined NIH Policy 801. 
All adverse events will be reviewed by a safety monitor and graded in accordance with CTCAE 
version 5 (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm)  
12.10.7.2 
Expected Adverse Events 
 
Previous adverse events include stomach pain, diarrhea, vomiting, constipation, nausea, dry 
mouth, loss of taste, catheter site pain, fatigue, nose and throat pain, muscle stiffness, lower 
back pain, dizziness, headache, local numbness, and excessive sweating. A complete list of 
previous adverse events, which may be expected in this trial, are provided in the Investigator’s 
Brochure.  
12.10.7.3 
Monitoring 
Data and safety monitoring for this study will be conducted in accordance with the “NINDS 
Guidelines for Monitoring in Clinical Trials”. Safety will be monitored on a weekly basis 
during the intervention phase of the study either at study visits or via remote TEAE 
assessments. Moreover, safety will be assessed approximately one-week post-intervention by 
a remote TEAE assessment and safety labs. A study investigator will contact participants by 
telephone to remind them of upcoming, scheduled local phlebotomy appointments. An 
additional remote TEAE assessment will also be made approximately two-weeks post-
intervention. For remote TEAE assessments, if study investigators are unable to make contact 
with the participant on the first attempt, at least two further attempts will be made. Participants 
local to the study site will have the option of completing TEAE assessments and safety 
laboratory tests at the NIH. 
 
A DSMB will be established and provide independent medical oversight for this study. The 
DSMB will act in an advisory capacity to the study Principal Investigator (PI) and the NINDS 
Clinical Director (CD) and Medical Monitor to monitor participant safety, data quality and 
evaluate the progress of the study. This will also include deciding if stopping rules should be 
triggered. To ensure oversight, the DSMB may independently pause, halt, or terminate the 
study. The DSMB may also pause or stop dose administration in an individual. DSMB 
activities will be governed as detailed in the DSMB Charter (Appendix # 16). There will be 
four DSMB members with expertise in neurology, clinical trials, clinical pharmacology, and 
biostatistics. The DSMB will meet monthly after the first subject is dosed and acutely if a 
significant safety concern is raised by the PI or medical monitor. Additional meetings may be 
scheduled when necessary for adequate monitoring. Any member of the DSMB may request a 
meeting if they believe data provided within interim reports warrant an additional meeting. 
Subjects will be monitored throughout the study and during confinement for adverse reactions 
to the study drug and/or procedures. Prior to release from confinement, subjects will be asked 
how they are feeling. At each subsequent visit, subjects will be queried with an open-ended 


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question such as: ‘How have you been feeling since your visit or last telephone and/or email 
contact?’  
Participants will be contacted by a study investigator by telephone and/or e-mail four times 
during the study for AE assessments. The investigator will ask a series of open-ended and 
focused questions relating to safety and tolerability of S 48168 (ARM210). On rare occasions, 
additional participant contact may be made by telephone or secure email to ensure 
comprehensive monitoring. Examples include contacting participants to inform them of 
important new safety-related information, changes in key study personnel, and clarification of 
medical information. 
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test 
value(s) will be evaluated by the PI or designee and treated and/or followed up until the 
symptoms or value(s) return to normal, or acceptable levels, as judged by the PI or designee.  
Treatment of SAEs will be performed by a licensed independent provider, either at NIH CC or 
at a nearby hospital emergency room. Where appropriate, medical test(s) and/or examination(s) 
will be performed to document resolution of event(s). Outcome may be classified as resolved, 
improved, unchanged, worse, fatal, or unknown (lost to follow-up). 
12.10.7.4 
Reporting 
All AEs that occurred during this clinical study will be recorded on the AE CRF using a 
recognized medical term or diagnosis that accurately reflects the event. For each adverse event, 
the investigator will provide the onset date, end date, intensity, treatment required, outcome, 
seriousness, and action taken with the investigational drug. The PI or designee will review each 
event and assess its relationship to drug treatment (likely, probably, possibly, unlikely or 
unrelated). Each sign or symptom reported will be graded in accordance with CTCAE (version 
5), and the date of onset, time of onset, and outcome of each event will be noted. To fulfil the 
regulatory requirements for expedited safety reporting, the sponsor evaluates whether a 
particular AE is "listed" (i.e. known side effect of the drug or not). Medical judgment should 
be used to determine the causal relationship of adverse event, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history. Serious 
AEs that are considered related to S48168 will be considered a suspected unexpected serious 
adverse reaction (SUSAR). Assessment of causal relationship must also be recorded on the 
CRF.  If an AE has not resolved at the end of the study reporting period it will be documented 
as ongoing on the corresponding CRF. 
Prompt reporting of adverse events is the responsibility of the PI or designee. The reporting 
period for AEs is the period immediately following each study administration through 28 days 
after each dose. AEs must be followed until resolution or stabilization, the subject is lost to 
follow-up, even if this extends beyond the 28-day post-dosing reporting period (for the purpose 
of obtaining a stop date for the event).  
If an AE has not resolved at the end of the study reporting period it will be documented as 
ongoing on the corresponding CRF. 


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Each AE will be reviewed with the medical monitor, 
 and 
discussed with the PI. AEs will be reported to the DSMB, regardless of PI classification for 
review.   
The AE severity definitions of CTCAE version 5 will be used for rating the severity of all 
AEs (Grade 1-5).  
12.10.7.5 
Serious Adverse Event 
If any AEs are serious, as defined by the FDA Code of Federal Regulations (CFR), Chapter 
21, special procedures will be followed. All SAEs will be reported to the Sponsor per the 
medical monitoring plan (Appendix # 17) and adhere to 21 CFR 312.32 for Investigational 
New Drugs (IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 2012 (FDA 2012). Reporting of SAEs to 
the IRB will be consistent with NIH Policy 801.   
A SAE is any AE or suspected adverse reaction that in the view of either the PI (or designee) 
or Sponsor, results in any of the following outcomes:  Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the above definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the PI 
(or designee) or Sponsor, its occurrence places the patient or subject at immediate risk of death. 
It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the IB or is 
not listed at the specificity or severity that has been observed; or is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application, as amended. 
12.10.7.6 
Reporting of Unanticipated Problems, Adverse Events, and Protocol 
Deviations 
The Principal Investigator is responsible for detecting, documenting, and reporting 
unanticipated problems, AEs, including SAEs, and deviations in accordance with NIH policy, 
IRB requirements, and federal regulations. Relatedness to the research of all serious adverse 
events will be determined by the PI in consultation with the medical monitor. 
Reporting of unanticipated problems, adverse events, and protocol deviations will be reported 
to the IRB as detailed in NIH Policy 801.  


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Within 24 hours of identifying a SAE, regardless of the presumed relationship to the study 
product, the PI must complete the serious adverse event (SAE) case report form and email it 
to
 as ARMGO representative according to the requirements of 21 
CFR 312.64(b) and as agreed upon with the sponsor.  
The PI will record nonserious AEs and report them to the Sponsor as agreed upon in the 
Medical Monitoring Plan (Appendix # 17). All expedited AE reports will be processed by 
ARMGO with Celerion. 
12.10.7.7 
AE’s of Special Interest  
An AE of Special Interest (serious or nonserious) is one of scientific and medical concern 
specific to the compound or program, 
AEs of special interest in this trial include: 
o Large increases in transaminases, Aspartate aminotransferase or Alanine 
aminotransferase. If the subject’s baseline transaminases were within normal 
limits, then a change of 3X ULN is the criteria. If the subject’s baseline 
transaminases are above the ULN at baseline, then 5X ULN would be the 
criteria. Baseline elevations in transaminases have been known to occur in some 
patients with RYR1-RM, likely due to muscle injury as a consequence of the 
disease and normal activity. 
 
o CNS toxicity (tremors/convulsions seen in safety assessment animals) - 
consider tremors and any symptoms of seizure as the events to monitor for. 
 
o Gastric toxicity - severe gastric or epigastric pain or severe vomiting. 
 
o Plasma Cmax (S 48168) >35 µg/mL. 
 
12.10.7.8 
End of Participation 
Participants will remain under the care of their local clinicians and/or primary neurologists 
while in this study. Participants will be informed of any clinically relevant findings identified 
during the study via secure e-mail. Participants will also be provided with a letter to give to 
their primary care provider detailing such findings. Participation in this study will be 
considered to have ended once the participant has completed the Day 42 post-intervention 
TEAE assessment (exceptions to this may be made on a case-by-case basis e.g. if an individual 
has an ongoing AE/SAE at Day 42). 


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12.10.8 Pharmacokinetic Assessments 
12.10.9 Blood Sampling and Processing 
For all subjects, blood samples for the determination of S 48168 (ARM210) will be collected 
into polypropylene heparinized tubes at scheduled time points as delineated in the Study Events 
Flow Chart (Section 7). All attempts will be made to collect the blood samples at, or within ± 
15 minutes of the scheduled time point. Actual sample times will be recorded. 
Within 30 minutes from collection, PK blood samples will be centrifuged at approximately 
2000 g for 10 minutes, at approximately 4°C. 
After centrifugation, plasma will be transferred into aliquots (polypropylene tubes) containing 
approximately 0.3 mL/tube. The plasma aliquots will be frozen at  -80 ± 10°C within 
30 minutes maximum from the end of centrifugation. Samples will be stored at this temperature 
until shipped to the bioanalytical laboratory.  
12.10.10 
Interim PK Analysis 
Interim PK analysis was conducted by the contract vendor (Nuvisan) as follows:  
Full PK once the first dose group (120 mg/day) have completed dosing for approximately 28 
days (not to exceed 30 days) (Section 13.1). 
Interim analysis of Cmax once the first 3 participants in the second dose group (≤ 200 mg/day) 
have completed dosing for approximately 28 days (not to exceed 30 days). 
Provided that the Cmax limit of 35 ug/mL is not exceeded in the above samples, all  remaining 
PK analyses will be conducted upon study completion. 
12.10.11 
Analytical Method 
Samples will be assayed for plasma S 48168 (ARM210) using a validated HPLC-MS-MS 
bioanalytical method. The subjects to include in the analysis are specified in Section 13.2.2. 
This analysis will be conducted by the contract vendor, Nuvisan. Since this is the first study of 
S 48168 (ARM210) in the RYR1-RM population, and profiling of S 48168 (ARM210) 
metabolism is currently ongoing in healthy volunteers, the remaining portions of plasma 
samples collected for PK analysis may be preserved for S 48168 (ARM210) metabolite 
analysis. 


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12.11 Blood Volume Drawn for Study Assessments  
Table 1: Approximate Blood Volume During the Study (drug naïve participants) 
Sample Type 
Number of 
Time 
Points 
Approximate 
Volume per Time 
Point * (mL) 
Approximate Sample 
Volume Over Course 
of Study (mL) 
Screening laboratory safety tests (including 
hematology, serum chemistry, serology) 
FSH (for postmenopausal female subjects 
only), and serum pregnancy (for female 
subjects only) 
1 
12.5 
12.5 
Screening CYP2C8 genotyping 
1 
4 
4 
On-study (including follow-up) hematology, 
serum chemistry, and serum pregnancy (as 
scheduled for female subjects only)  
3 
12.5 
37.5 
Blood for S 48168 (ARM210) 
16 
2 
32 
Baseline blood (future research use)  
1 
50.0 
50.0 
Post-intervention blood (future research use) 
1 
10.0 
10.0 
Total Blood Volume (mL)→ 
146.0** 
* 
Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** 
If additional safety or PK analysis is necessary or if larger collection tubes are required to obtain sufficient 
plasma/serum for analysis, additional blood may be obtained (up to a maximum of 50 mL). 


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Table 2: Approximate Blood Volume During the Study (re-enrolled participants) 
Sample Type 
Number of 
Time 
Points 
Approximate 
Volume per Time 
Point * (mL) 
Approximate Sample 
Volume Over Course 
of Study (mL) 
Screening laboratory safety tests 
(including hematology, serum chemistry, 
serology) FSH (for postmenopausal 
female subjects only), and serum 
pregnancy (for female subjects only) 
1 
12.5 
12.5 
Screening CYP2C8 genotyping 
0 
0 
0 
On-study (including follow-up) 
hematology, serum chemistry, and serum 
pregnancy (as scheduled for female 
subjects only)  
3 
12.5 
37.5 
Blood for S 48168 (ARM210) 
8 
2 
16 
Blood for future research use  
2 
10.0 
20.0 
Total Blood Volume (mL)→ 
86.0** 
* 
Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** 
If additional safety or PK analysis is necessary or if larger collection tubes are required to obtain sufficient 
plasma/serum for analysis, additional blood may be obtained (up to a maximum of 50 mL). 
 
 


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13 DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of GCP. 
13.1 Pharmacokinetic Parameters 
The following PK parameters for plasma S 48168 (ARM210) will be calculated, as 
appropriate: 
Day 1 
 
AUC0-24: 
 
The area under the concentration-time curve, from time 0 to the 
24 hours post dose, as calculated by the linear trapezoidal 
method. 
AUC0-t: 
 
The area under the concentration-time curve, from time 0 to the 
last observed non-zero concentration, as calculated by the linear 
trapezoidal method. 
AUC0-inf: 
The area under the concentration-time curve from time 0 
extrapolated to infinity. AUC0-inf is calculated as the sum of 
AUC0-t plus the ratio of the last measurable plasma concentration 
to the elimination rate constant. 
AUC%extrap: 
Percent of AUC0-inf extrapolated, represented as 
(1 - AUC0-t/AUC0-inf)*100. 
Cmax: 
Maximum observed concentration. 
Tmax: 
Time to reach Cmax. If the maximum value occurs at more than 
one time point, Tmax is defined as the first time point with this 
value. 
Kel: 
Apparent first-order terminal elimination rate constant calculated 
from a semi-log plot of the plasma concentration versus time 
curve. The parameter will be calculated by linear least-squares 
regression analysis using the maximum number of points in the 
terminal log-linear phase (e.g., three or more non-zero plasma 
concentrations). 
t½: 
Apparent first-order terminal elimination half-life will be 
calculated as 0.693/Kel. 
Tlag: 
Lag time – the time delay between drug administration and the 
onset of absorption; where onset of absorption can be defined as: 
the time point prior to the first observed/measured non-zero 
plasma concentration. 


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Day 28 (not to exceed Day 30) 
 
AUCtau 
The area under the concentration-time curve during a dosing 
interval (tau) at steady state. 
Cmax: 
Maximum observed concentration. 
Tmax: 
Time to reach Cmax. If the maximum value occurs at more than 
one time point, Tmax is defined as the first time point with this 
value. 
Cmin 
Minimum observed concentration. 
Tmin 
Time to reach Cmin. 
RAAUC 
The ratio of accumulation for AUC calculated as the ratio of the 
AUCtau Day 28 (not to exceed Day 30)/AUC0-24 Day 1. 
RACmax 
The ratio of accumulation for Cmax calculated as the ratio of the 
Cmax Day 28 (not to exceed Day 30)/Cmax Day 1. 
Concentration observed at the end of the dosing interval on Day 13 Ctrough (associated with 
Day 14 pre-dose) will be ascertained for the first six subjects. Additional parameters may be 
calculated as appropriate. 
No value for Kel, AUC0-inf, AUC%extrap, or t½ will be reported for cases that do not exhibit 
a terminal log-linear phase in the concentration-time profile. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive time points with 
detectable concentrations. 
Individual and mean plasma concentration time curves (both linear and log-linear) will be 
included in the final report. 
13.2 Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP) (Appendix # 18). The SAP will be 
prepared by Celerion and agreed upon with the Sponsor. This document may modify the plans 
outlined in the protocol; however, any major modifications of the primary endpoint definition 
and/or its analysis will also be reflected in a protocol amendment. Additional statistical 
analyses other than those described in this section may be performed if deemed appropriate.  
13.2.1 Determination of Sample Size 
The sample size (n= 8) was determined based on the number of RYR1-RM affected individuals  
expected to have loss of RyR1-calstabin1 binding. This sample size is expected to be sufficient 
for analysis of the primary endpoint (safety and tolerability). The accrual ceiling for this study 
is n = 50 subjects to allow for dropout. 


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13.2.2 Subjects to Analyze 
Safety Population: All subjects who received at least one dose of the study drug will be 
included in the safety evaluations. 
PK Population: All subjects who comply sufficiently with the protocol (see Section 11.8.1) 
and display an evaluable PK profile (e.g., exposure to treatment, availability of measurements 
and absence of major protocol violations) will be included in the statistical analyses. 
Pharmacodynamic/Target Engagement: All subjects who complete the study will be included 
in the pharmacodynamics/target engagement analysis. 
Muscle/Motor Function (Grade Functional Tests and MFM32): All subjects who complete the 
study will be included in the muscle/motor function assessments. 
Quality of Life: All subjects who complete the study will be included in the quality of life 
assessments. 
13.2.3 Descriptive Statistics 
Values will be calculated for the plasma concentrations and the PK parameters listed in 
Section 13.1 using appropriate summary statistics to be fully outlined in the SAP.  
PK data from
will be utilized for comparisons between healthy subjects and 
RYR1-RM patients. 
13.3 Safety Evaluation 
All safety data will be populated in the individual CRFs. All safety data will be listed by 
subjects. 
Dosing dates and times will be listed by subject in their diary when not confined to the NIH CC. 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion and summarized by cohort and treatment for the 
number of subjects reporting the Treatment Emergent Adverse Events (TEAE) and the number 
of TEAEs reported. A by-subject AE data listing including verbatim term, coded term, 
treatment, severity, and relationship to treatment will be provided.  
Safety data including ECGs, vital signs assessments, clinical laboratory evaluations, will be 
summarized by treatment and point of time of collection. 
Descriptive statistics using appropriate summary statistics will be calculated for quantitative 
safety data as well as for the difference to baseline, when appropriate.  
Concomitant medications will be listed by subject and coded using the most current version of 
WHO drug dictionary available at Celerion. Medical history will be listed by subject. 


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13.4 Pharmacodynamic/Target Engagement 
% RyR1-Calstabin1 binding of normal control muscle will be listed by subject and compared 
between pre- and post-treatment biopsies. If there is sufficient remaining tissue, % RyR1-
mediated Ca2+ leak may be determined, using muscle membrane preparations, and listed by 
subject and compared between pre- and post-treatment biopsies.  
13.5 Muscle/Motor Function 
A physical therapist will administer these study procedures. 
Graded functional tests will be completed by participants at each in-person study visit. These 
will include 10-meter walk test, supine to stand, ascend 4 stairs, descend 4 stairs. The 
recorded time will be listed by subject and summarized descriptively for each test to compare 
between pre- and post-treatment  results. 
Day 1 versus Day 28 (not to exceed Day 30) motor function will be documented and listed 
for each subject quantitatively (% of maximum score) using the scoring of the MFM32 for 
the following: total score, domain 1 (standing and transfers), domain 2 (axial and proximal 
motor function), and domain 3 (distal motor function). The resulting scores will be listed by 
subject and summarized descriptively to compare between pre- and post-treatments results. 
Grip and pinch strength: Participants will be seated comfortably with his/her elbow flexed to 
90 degrees, with the forearm and wrist in neutral position. Participants will then be asked to 
squeeze the dynamometer and pinch the gauge. This process will be repeated three times 
with the best effort used for final analyses. 
Quantitative muscle strength assessment: Participants will undergo assessment of muscle 
strength in standardized seated and supine positions. Muscle strength testing will focus on each 
participant’s dominant side for shoulder abductors, elbow flexors/extensors, hip flexors and 
knee extensors/flexors. Participants will be asked to exert force against an elastic strap-based 
force transducer. A physical therapist will administer this study procedure and the best of 
multiple efforts used for final analyses.  
 
13.6 Quality of Life Assessment 
The PROMIS-fatigue subscale (questionnaire) will be completed during each study visit. 
Results (t-scores) for each individual (Day 1 and Day 28 – not to exceed Day 30) will be 
summarized descriptively. 
 
 


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14 STUDY ADMINISTRATION 
14.1 Ethics 
14.1.1 Institutional Review Board 
This protocol will be reviewed by the NIH Intramural Institutional Review Board, and the 
study will not start until the IRB has approved the protocol or a modification thereof. The IRB 
is constituted and operates in accordance with the principles and requirements described in the 
US Code of Federal Regulations (21 CFR Part 56). The IRB is compliant to International 
Council for Harmonisation (ICH) guidelines. 
 
14.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration 
of 
Helsinki, 
GCP, 
and 
the 
ICH 
harmonized 
tripartite 
guideline 
regarding 
GCP (E6 Consolidated Guidance, April 1996). 
14.1.3 Subject Information and Consent 
Two consent forms (Appendix # 19 and Appendix # 20) will be used in this study (1) telephone 
consent form that will cover a blood draw for CYP2C8 genotyping and serology (inclusion 
criteria), and informed consent to obtain prior research data and PII for participants in 
NCT02362425 and (2) in-person consent form that will cover all screening procedures that 
will be conducted at the NIH Clinical Center. The in-person consent form will also cover all 
additional procedures associated with the study.  
Telephone (screening) consent: Only adults (greater than 18 years of age) are being considered 
for this study. Participants will be mailed a telephone consent form for completion during a 
scheduled telephone appointment with an investigator authorized to obtain consent. A pre-paid 
return label will be included so the participant can return the signed form.  
In-person consent: this consent form will be completed upon arrival of each participant at the 
NIH Clinical Center. 
All participants will receive a verbal explanation in terms suited to their comprehension of the 
purposes, procedures and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review both consent forms and ask questions 
regarding this study prior to signing. The investigator obtaining consent will document the 
consent process in the participant’s medical record. A copy of the completed signed screening 
and, if applicable, study consent forms will be provided to the participant. 
For individuals who are not fluent in English, both blood draw and study consent documents 
will be translated to the individual’s native language with an interpreter present throughout the 
consenting process. 


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The consent forms contain all required elements. 
14.2 Termination of the Study 
NIH reserves the right to terminate the study in the interest of subject welfare. 
Sponsor reserves the right to suspend or terminate the study at any time. 
Termination of the Study shall be governed by Section 11.8.5 
14.3 Management of Data and Samples 
14.3.1 Storage 
Biological samples obtained during this study will be appropriately stored in a locked freezer 
at -20 ± 10°C or -80 ± 10°C located in the laboratory of the NINDS
or NINR
. Although the majority of biological 
samples will be shipped to contract laboratories for analyses, muscle biopsies, whole blood 
and blood products (serum/plasma) may be retained at the aforementioned locations for future 
use, if permitted by the participant as per their consent documentation. Contract laboratories 
will be instructed to dispose of samples once all analyses have been completed. Data obtained 
during this study will be stored in the Celerion’s EDC system, with full access granted to the 
NIH Investigators. Only listed study investigators will have the permissions required to access 
data. Paperwork relating to this study will be kept in a locked cabinet in the office of the 
NINDS
). Loss of samples and/or data will be reported to 
the IRB. 
14.3.2 Data and Sample Sharing Plan 
This protocol will not generate large-scale human or non-human genomic data, as defined by 
the NIH Genomic Data Sharing Policy, and is therefore not subject to this policy. Biological 
samples and data will not be submitted to a repository. There will be controlled access to study 
data (i.e. only listed study investigators will have access via a secure system). 
PD analyses will be conducted on a fee-for-service basis.. For S 48168 (ARM210) PK 
analyses, whole blood and blood product samples (serum/plasma) will be shipped to Nuvisan 
Pharma Services, Neu-Ulm, Germany. PK analyses will be conducted on a fee-for service 
basis. Coded data will be shared with ARMGO Pharma Inc. 
Data and samples may also be shared with collaborating laboratories at NIH or outside of NIH 
if consent for sharing was obtained.  
Samples and data will be stripped of identifiers and may be coded (“de-identified”) or unlinked 
from an identifying code (“anonymized”). When coded data is shared, the key to the code will 
not be provided to collaborators but will remain at NIH. Data and samples may be shared with 
investigators and institutions with a Federal Wide Assurance (FWA) or operating under the 


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Declaration of Helsinki (DoH) and reported at the time of continuing review. Sharing with 
investigators without an FWA or not operating under the DoH will be submitted for 
prospective IRB approval.  
Required approvals from the collaborating institution will be obtained and materials will be 
shipped in accordance with NIH and federal regulations. 
14.4 Data Collection 
Electronic CRFs will be supplied by Celerion. The investigators’ authorized site personnel 
must enter the information required by the protocol on the CRF, which will be housed within 
Celerion’s Electronic Data Capture (EDC) system. A study monitor will visit the site in 
accordance with the clinical monitoring plan (Appendix # 21) and review the CRF data against 
the source data (e.g. Rehabilitation Medicine Department paper CRF) for completeness and 
accuracy. Discrepancies between source data and data entered on the CRF will be addressed 
by qualified site personnel in accordance with GCP. When a data discrepancy warrants 
correction, the correction will be made by authorized site personnel.  
CRFs are printed off directly from the database. Each CRF is reviewed and signed by the PI. 
14.5 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant to 
the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure 
that the study is conducted, and that data are generated, documented and reported in 
compliance with the study protocol, GCP and GLP requirements as well as applicable 
regulatory requirements and local laws, rules and regulations relating to the conduct of the 
clinical study. A quality assurance audit/inspection of this trial may be conducted by the 
sponsor or sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality 
assurance auditor will have access to all medical records, the investigator’s trial-related files 
and correspondence, and the informed consent documentation of this clinical trial. 
The Clinical Study Report will be audited by the QA department (Sponsor’s CRO) and the QA 
audit certificate will be included in the study report. 
All clinical data will be entered by the site or uploaded into the EDC electronically.  Edit 
checks are built into the EDC. Clinical Data Management (CDM) will resolve all queries with 
the site via the EDC. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. Edit 
checks are then performed for appropriate databases as a validation routine using SAS® or 
comparable statistical program to check for missing data, data inconsistencies, data ranges, etc. 
Corrections are made prior to database lock. 


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14.6 Direct Access to Source Data/Documents 
NIH/Celerion will ensure that the Sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all study-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 6.10). In the event 
that other study-related monitoring should be done by other parties, they will be required to 
sign a confidentiality agreement prior to any monitoring and auditing. 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. Data 
entered in the eCRFs that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained by the site (i.e. PI may need to request 
previous medical records or transfer records). Current medical records must be available. For 
eCRFs all data must be derived from source documents. 
14.7 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of S 48168 (ARM210) tablets to allow 
completion of this study. The lot numbers and expiration dates of the study drugs supplied will 
be recorded in the final report. 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused study drugs will be retained by the pharmacy, returned to 
the Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies remain, this 
fact will be documented in the pharmacy product accountability records. 
14.8 Record Keeping 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained until at least 5 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 5 years have elapsed since the formal discontinuation 
of clinical development of the investigational product. These documents should be retained for 
a longer period however if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the Sponsor to inform the PI/Institution 
as to when these documents no longer need to be retained. 
14.9 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final report will be written according to the 
ICH E3 Guideline (Structure and Content of Clinical Study Reports).  
14.10 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 


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disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor or the NIH 
14.11 Research and Travel Compensation 
Research subjects will be reimbursed for travel. If coming from outside the US, travel to the 
port of entry will be reimbursed by non-NIH sources. NIH will cover the costs of travel to and 
from the Clinical Center within the U.S., lodging and meals, per the NIH policy for 
Reimbursement of Travel and Subsistence Expenses for NIH Clinical Research Protocol 
Participants. If within the United States, the NIH will also cover the cost of the local blood 
draws. This will be paid directly by the NIH. If research subjects elect to have local blood 
draws outside the U.S., the cost of this will be reimbursed by non-NIH sources. 
 
 


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15 PRIVACY AND CONFIDENTIALITY  
Only investigators listed on the protocol will have access to records, data, and samples. If 
sponsors, monitors or auditors outside of study investigators require access, they will have 
access to coded data. Deidentified study results will be posted on clinicaltrials.gov. 
All research activities will be conducted in as private a setting as possible. 
15.1 Research Data and Investigator Medical Records 
Medical records will be stored in CRIS behind the NIH firewall. All electronic data will be 
stored on encrypted, password protected servers only accessible by authorized NIH associate 
investigators. For photographs and videos, when possible, the patient’s face and other 
identifying marks will not be included in the recording or photograph in order to protect 
confidentiality. Biological samples sent to contract laboratories for analyses will be de-
identified. 
15.2 Stored Samples 
Stored samples will be kept behind a double lock or will be coded and kept behind a single 
lock. Samples will be stored indefinitely and may be used for future research.  However, this 
is contingent upon each participant’s consent and a MTA being in place if future research is to 
be conducted outside of NINDS. Any loss or destruction of samples will be reported to the 
IRB.  
15.3 Special Precautions 
Samples and data will be stored using codes that are assigned. Data will be kept in password-
protected computers. Samples will be kept in locked storage. Only study investigators will 
have access to the samples and data. 
15.3.1 Hard Copy Data/Records 
Hard copies of data will be kept in locked file cabinets in locked offices at NINDS. All 
participant data will be coded for the purpose of data analysis and sharing between listed 
investigators. 
15.3.2 Samples without identifiers (coded or unlinked) 
A single lock will be used for samples without identifiers. 


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16 CONFLICT OF INTEREST AND TECHNOLOGY TRANSFER 
NIH guidelines on conflict of interest have been distributed to all investigators.  There are no 
conflicts-of-interest to report for NIH investigators. Non-NIH investigators will abide by the 
conflict-of-interest policies of their own institutions. 
 
 


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17 REFERENCES 
Amburgey K et al. Prevalence of congenital myopathies in a representative pediatric united 
states population. Ann Neurol. 2011;70(4):662-5. 
Andersson, D. C. and A. R. Marks (2010). "Fixing ryanodine receptor Ca leak - a novel 
therapeutic strategy for contractile failure in heart and skeletal muscle." Drug Discov Today 
Dis Mech 7(2): e151-e157. 
Bellinger, A. M., S. Reiken, et al. (2009). "Hypernitrosylated ryanodine receptor calcium 
release channels are leaky in dystrophic muscle." Nat Med 15(3): 325-330. 
Bushby K et al. DMD Care Considerations Working Group. Diagnosis and management of 
Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial 
management. Lancet Neurol. 2010;9(1):77-93. 
Capogrosso, RF, Mantuano,P, Uaesoontrachoon, K, Cozzoli, A, Giustino,A, Dow, T, 
Srinivassane, S, Filipovic, M, Bell,C, Vandermeulen, J, Massari,AM, De Bellis, M, Conte, E, 
Pierno, S, Camerino, GM, Liantonio, A, Nagaraju, K, De Luca, A. Ryanodine channel 
complex stabilizer compound S 48168/ARM210 as a disease modifier in dystrophin-deficient 
mdx mice: proof-of-concept study and independent validation of efficacy. FASEB J. 2018 
Feb;32(2):1025-1043. 
Decktor DL, Robinson M, Maton PN, et al. Effects of aluminum/magnesium hydroxide and 
calcium carbonate on esophageal and gastric pH in subjects with heartburn. Am J Ther. 
1995;(8):546-552. 
Food and Drug Administration, Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, Dec 2012. 
Gentil, C., F. Leturcq, et al. (2012). "Variable phenotype of del45-55 Becker patients 
correlated with nNOSmu mislocalization and RYR1 hypernitrosylation." Hum Mol Genet 
21(15): 3449-3460. 
Gonzalez, D. R., A. V. Treuer, et al. (2010). "Impaired S-nitrosylation of the ryanodine 
receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure." J 
Biol Chem 285(37): 28938-28945. 
Görlach, A., Bertram, K., Hudecova, S., et al. 2015. Calcium and ROS: A mutual interplay. 
Redox Biol. 6:260–271. 
Gumerson, J. D. and D. E. Michele (2011). "The dystrophin-glycoprotein complex in the 
prevention of muscle damage." Journal of biomedicine & biotechnology 2011: 210797. 
Lawal TA, Todd JJ, Meilleur KG. Ryanodine Receptor 1-Related Myopathies: Diagnostic 
and Therapeutic Approaches. Neurotherapeutics. 2018;15(4):885-899. 


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Lehnart, S. E. (2007). "Novel targets for treating heart and muscle disease - stabilizing 
ryanodine receptors and preventing intracellular calcium leak." Current Opinion in 
Pharmacology 7(2): 225-232. 
Liu, X., Betzenhauser, M.J., Reiken, S., et al. (2012). “Role of Leaky Neuronal Ryanodine 
Receptors in Stress-Induced Cognitive Dysfunction.” Cell 150 (5): 1055-1067. 
Marty, I., M. Robert, et al. (1994). "Biochemical evidence for a complex involving 
dihydropyridine receptor and ryanodine receptor in triad junctions of skeletal muscle." Proc 
Natl Acad Sci U S A 91(6): 2270-2274. 
Marx, S. O., S. Reiken, et al. (2000). "PKA phosphorylation dissociates FKBP12.6 from the 
calcium release channel (ryanodine receptor): defective regulation in failing hearts." Cell 
101(4): 365-376. 
Millay, D. P., S. A. Goonasekera, et al. (2009). "Calcium influx is sufficient to induce 
muscular dystrophy through a TRPC-dependent mechanism." Proc Natl Acad Sci U S A 
106(45): 19023-19028. 
Murayama, T. and N. Kurebayashi (2011). "Two ryanodine receptor isoforms in 
nonmammalian vertebrate skeletal muscle: possible roles in excitation-contraction coupling 
and other processes." Prog Biophys Mol Biol 105(3): 134-144. 
Reiken, S., A. Lacampagne, et al. (2003). "PKA phosphorylation activates the calcium 
release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure." 
J Cell Biol 160(6): 919-928. 
. 
Venturi E., Galfré E., O'Brien F., Pitt S.J., Bellamy S., Sessions R.B., Sitsapesan R. 2014. 
FKBP12.6 activates RyR1: investigating the amino acid residues critical for channel 
modulation. Biophys J. 106(4):824-33. 
Waning D. L., Mohammad K.S., Reiken, S. 2015. Excess TGF-β mediates muscle weakness 
associated with bone metastases in mice. Nat Med. 21(11):1262-71 
Witherspoon, J.W and Meilleur, K.G. 2016. Review of RyR1 pathway and associated 
pathomechanisms. Acta Neuropathol Commun. 4:121 
Zalk, R., S. E. Lehnart, et al. (2007). "Modulation of the ryanodine receptor and intracellular 
calcium." Annu Rev Biochem 76: 367-385. 
 
 


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18 APPENDICES 
1. Investigator’s brochure  
2. Pre-screening script 
3. Eligibility checklist 
4. Lifestyle recommendations 
5. Script for remote/in-person TEAE assessments 
6. Participant diary 
7. IND documentation 
8. Guide to taking study medications 
9. Study advertisement  
10. Neuromuscular clinic recruitment letters 
11. PROMIS-fatigue questionnaire 
12. Needle Aspiration Muscle Biopsy Procedure Information Sheet 
13. Skeletal muscle biopsy manual 
14. MFM-32 
15. Columbia suicidality scale 
16. DSMB charter 
17. Medical monitoring plan  
18. Statistical analysis plan 
19. Blood draw consent form 
20. Study consent form 
21. Clinical monitoring plan 
22. 
23. Data access and sharing plan 

SAP_001.pdf: 
Statistical Analysis Plan 
 
Safety and tolerability of S 48168 (ARM 210) for the treatment of RYR1-related myopathies 
(RYR1-RM) 
Sponsor Protocol No: 
 
Final Protocol Date: 11 September 2018 
Amendment 1 Date: 03 December 2018 
Amendment 2 Date: 15 March 2019 
Amendment 3 Date: 18 June 2019 
Amendment 4 Date: 31 October 2019 
 
US IND No.: 
 
 
Compound Name: S 48168 (ARM210) 
 
 
 
Draft Version 2.0 
Date:24 March 2020 
 
 
 
 
ARMGO Pharma Inc. 
PMB #260, 923 Saw Mill River Road 
Ardsley, New York 10502, USA 
 
Celerion 
621 Rose Street 
Lincoln, Nebraska 68502, USA 
and 
100 Alexis-Nihon Boulevard, Suite 360, Montreal, QC, H4M 2N8, Canada  
 
 


ARMGO Pharma Inc. 
S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 2 of 40 
Statistical Analysis Plan Signature Page 
Compound Name: S 48168 (ARM210) 
Protocol: 
 
Study Title: Safety and tolerability of S 48168 (ARM 210) for the treatment of RYR1-related 
myopathies (RYR1-RM) 
Issue Date: 24 March 2020 
 
Signature:_____________________________________ 
Date:_______________ 
 
 
 
 
 
 
Signature:_____________________________________ 
Date:_______________ 
 
 
 
 
 
 
 
 
Signature:_____________________________________ 
Date:_______________ 
 
 
 
 


ARMGO Pharma Inc. 
S 48168 (ARM210), Protocol Number 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 3 of 40 
Table of Contents 
1. 
INTRODUCTION ..............................................................................................................5 
2. 
OBJECTIVES AND ENDPOINTS ....................................................................................5 
2.1 
Objectives ..................................................................................................................5 
2.2 
Endpoints ..................................................................................................................6 
3. 
STUDY DESIGN ...............................................................................................................7 
4. 
ANALYSIS POPULATIONS ............................................................................................9 
4.1 
Analysis Populations .................................................................................................9 
4.2 
Preliminary Data and Interim Analysis .....................................................................9 
5. 
TREATMENT DESCRIPTIONS .....................................................................................10 
6. 
SAFETY ...........................................................................................................................11 
6.1 
Subject Discontinuation ..........................................................................................11 
6.2 
Demographics .........................................................................................................11 
6.3 
Adverse Events........................................................................................................11 
7. 
PHARMACOKINETIC ANALYSIS ...............................................................................12 
7.1 
Measurements and Collection Schedule .................................................................12 
7.2 
Bioanalytical Method ..............................................................................................12 
7.3 
Investigational Product and PK Analyte Information .............................................12 
7.4 
Pharmacokinetic Concentrations .............................................................................13 
7.5 
Noncompartmental Pharmacokinetic Analysis and Parameter Calculation ............13 
7.5.1 Plasma Pharmacokinetic Parameters...........................................................13 
7.6 
Data Summarization and Presentation ....................................................................15 
7.7 
Statistical Analysis of PK Parameters .....................................................................15 
8. 
PHARMACODYNAMICS/TARGET ENGAGEMENT AND MOTOR FUNCTIONS 15 
8.1 
Pharmacodynamic/Target Engagement: .................................................................15 
8.2 
Motor Functions and Quality of Life (Exploratory): ..............................................16 
8.3 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Urinalysis) ................16 
8.4 
Vital Signs ...............................................................................................................17 
8.5 
12-Lead Electrocardiogram .....................................................................................17 
8.6 
Concomitant Medications .......................................................................................17 
8.7 
Physical Examination ..............................................................................................17 
8.8 
The Columbia-Suicide Severity Rating Scale (C-SSRS) ........................................17 
8.9 
Pulmonary Function Test ........................................................................................18 
8.10 Medical and Surgical History..................................................................................18 
9. 
SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS ................18 
10. SUMMARY TABLES AND FIGURES ..........................................................................18 
10.1 In-text Summary Tables and Figures ......................................................................18 


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10.2 Section 14 Summary Tables and Figures ................................................................19 
11. TABLE AND FIGURE SHELLS .....................................................................................26 
11.1 In-text Summary Tables Shells ...............................................................................27 
11.2 Section 14 Summary Tables Shells .........................................................................28 
11.3 Figures Shells ..........................................................................................................35 
12. LISTING SHELLS ...........................................................................................................38 
 


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S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 5 of 40 
1. INTRODUCTION 
The following statistical analysis plan (SAP) provides the framework for the 
summarization of the data from this study. The SAP may change due to unforeseen 
circumstances. Any changes made from the planned analysis within protocol, after 
locking of the database will be documented in the clinical study report (CSR). The 
section referred to as Table Shells within this SAP describes the traceability of the 
tables, figures, and listings (TFLs) back to the data. Note that the header for this page 
will be the one used for the main body of the CSR.  
Any additional exploratory analyses not addressed within this SAP and/or driven by 
the data, or requested by the SPONSOR, will be considered out of scope and must be 
described in the CSR.  
2. OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary 
Hypothesis: S 48168 (ARM210) treatment will have no safety concerns that limit 
further development and will be generally well tolerated in RYR1-RM patients.  
Exploratory: 
1. To determine PK of a 28-day administration of S 48168 (ARM210) in RYR1-RM 
affected individuals. 
Hypothesis: There will be no clinically meaningful difference in S 48168 (ARM210) 
exposure at steady state in RYR1-RM affected individuals when compared to existing 
data established in healthy volunteers. 
2. To explore if S 48168 (ARM210) treatment increases RyR1-calstabin1 binding in 
skeletal muscle of RYR1-RM affected individuals. 
Hypothesis: S 48168 (ARM210) treatment will increase RyR1-calstabin1 binding, 
compared to baseline, as determined by co-immunoprecipitation of RyR1 and 
Calstabin 1 and decrease relative Fluo-4 signal compared to baseline. 
3. To explore if S 48168 (ARM210) treatment improves muscle function, motor 
activity, and fatigue in RYR1-RM affected individuals. 
Hypothesis: Treatment with S 48168 (ARM210) will increase grip and pinch strength, 
decrease the time to complete graded functional tests, increase the total MFM-32 % 
maximum score, and decrease the PROMIS-fatigue subscale score, when compared to 
baseline. 


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Celerion, Clinical Study Report No
 
 
Statistical Analysis Plan March 24, 2020 
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2.2 
Endpoints 
Primary: 
Composite safety and tolerability profile 
(Frequencies of the following: TEAEs ≥ grade 2 in severity (CTCAE version 5), all 
SAEs, and all AESIs). 
Methods: Safety and tolerability of S 48168 (ARM210) will be determined by 
monitoring Adverse Events (AEs) over 28 days of treatment via patient interviews, 
patient diary reviews, physical examinations, echocardiograms, electrocardiograms 
(ECGs), vital signs, and laboratory safety tests. A reference dataset of AEs/SAEs 
obtained from a natural history study of RYR1-RM will also be available to assist in 
interpretation of safety events. The Columbia-Suicide Severity Rating Scale (C-
SSRS) will also be administered pre- and post-intervention. The frequency and 
severity of clinically significant AEs will be compared between treatment and 
historical controls including a previously conducted natural history study at the NIH. 
Exploratory: 
1. To determine PK of a 28-day administration of S 48168 (ARM210) in RYR1-RM 
affected individuals. 
Endpoints: 
Day 1: AUC0 t, AUC0 inf, Cmax, Tmax, and t½ 
Day 28: AUCtau, Cmax, Tmax, Cmin, RAAUC, and RACmax 
Secondary PK parameters will include: AUC0-24, AUC%extrap, Tmin, Kel, Tlag, 
and Day 13 Ctrough (associated with Day 14 pre-dose). Additional parameters may 
be calculated as appropriate. 
Methods: Bloods for PK assessments will be drawn at baseline (Day 0, 24h PK), at 
the study mid-point (day 14 ± 2 days, trough PK), and at the final study visit (Day 28, 
24h PK). Whole blood will be processed, and the plasma fraction stored for batch PK 
analyses. 
2. To explore if S 48168 (ARM210) treatment increases RyR1-calstabin1 binding in 
skeletal muscle of RYR1-RM affected individuals. 
Endpoint: Change from baseline in relative RyR1-calstabin1 binding (AU) and 
(pending sufficient tissue yield) change from baseline in relative Fluo-4 signal (AU). 
Methods: Skeletal muscle tissue will be obtained from participants pre- and post-
intervention by needle biopsy. This tissue will be assessed for RyR1-calstabin1 




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S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 8 of 40 
National Institutes of Health (NIH) in the Neurogenetics Branch of NINDS in 
collaboration with ARMGO Pharma Inc (the Sponsor), and Les Laboratoires Servier. 
 
The overall design of the study is shown below  
 
For each participant, the study duration will be approximately 2 months from enrollment to 
completion. Overall there will be three inpatient visits at the NIH CC, Bethesda, MD; one 
prior to the first dose, one mid-intervention, and one at the end of the dosing period. Study 
participants will be contacted by telephone/ secured email approximately 1 week after each 
visit for a follow-up regarding AEs and can describe daily any symptoms in a subject diary. 
Follow-ups will also serve to encourage study compliance. The dosing interval S 48168 
[ARM210] will be 28 days. Biopsy samples obtained at NIH, during visit 1 (pre-treatment) 
and visit 3 (post-treatment) will be analyzed. Approximately 7 ± 2 days following cessation 
of S 48168 (ARM210), participants will be contacted by telephone/ secure email for a follow 
up regarding AEs and will have blood drawn locally, for follow up safety clinical laboratory 
tests, to be sent to NIH and analyzed by the NIH CC laboratory. A study investigator will 
contact participants by telephone to remind them of upcoming, scheduled local phlebotomy 
appointments. A final follow-up AE assessment will be conducted by telephone/ secure email 
14±2 days following cessation of S48168 (ARM210). 
Safety will be monitored throughout the study by repeated clinical and laboratory 
evaluations. 


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Statistical Analysis Plan March 24, 2020 
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Discontinued subjects may be replaced at the discretion of the Sponsor in consultation 
with the PI and DSMB. The pre-screening accrual ceiling will be up to 50 subjects 
with a target number of 8-20 completers. 
The FIH study 
 that will be the historical control was divided into two 
parts; part 1 is a randomized placebo-controlled blinded single rising dose escalation 
study where 5 dose levels were tested (
), 
and part 2 is a four-panel rising multiple dose study (
 for 14 days of dosing.  PK data from 
 the 
240 mg dose level will be utilized for comparisons between healthy subjects and 
RYR1-RM patients. 
4. ANALYSIS POPULATIONS
4.1 
Analysis Populations 
Safety Population: All subjects who received at least one dose of the study drug will 
be included in the safety evaluations. 
PK Population: All subjects who comply sufficiently with the protocol and display 
an evaluable PK profile (e.g., exposure to treatment, availability of measurements and 
absence of major protocol violations) will be included in the statistical analyses. 
Pharmacodynamic/Target Engagement: All subjects who complete the study will 
be included in the pharmacodynamics/target engagement analysis. 
Muscle/Motor Function (Grade Functional Tests and MFM32): All subjects who 
complete the study will be included in the muscle/motor function assessments. 
Quality of Life: All subjects who complete the study will be included in the quality 
of life assessments. 
4.2 
Preliminary Data and Interim Analysis 
Interim PK analysis will be conducted by Nuvisan (contract vendor) as follows: 
First dose group (120 mg/day): Full PK analysis (see Table 6:1 for PK parameters) 
once the first three participants have completed dosing for 28 days. This will allow 
verification that the observed PK results from these RYR1-RM affected individuals 
agree with PK results from previous studies in healthy volunteers and that the Cmax 
limit 
 was not exceeded. At this stage of drug development, a PK value 
that would not require a dose adjustment would be considered as similar. This would 
mean 50% lower or 200% higher than that of healthy volunteers. Based on PK results 
and safety data from the first dose group, the dose to be administered in subsequent 


ARMGO Pha1ma Inc. 
S 48168 (ARM210), 
Celerion, Clinical S 
pa11icipants may be increased to ::: 200 mg/day. This will be based on DSMB 
recommendations and investigator and sponsor's joint decision. 
Second dose group(::: 200 mg/day): PK analysis for Cmax once the first three 
pa11icipants have completed dosing for 28 days. This will allow verification that the 
Cmax limitllllllllllll was not exceeded. If this is the case, then all remaining 
samples wilt to the contract laboratory for analysis at the end of the study, 
when full PK analysis beyond the Cmax measurement will occur for all of the 
samples obtained from this group. 
5. TREATMENT DESCRIPTIONS
S 48168 (ARM210) requires an IND, and the FDA approved IND number is:-· 
The company manufacturing S 48168 (ARM210) is Laboratoires Servi er. Study drug 
will be shipped by Laboratoires Servier directly to the NIH Pha1macy as therapeutic 
lmits. The study sponsor is ARMGO Pha1ma Inc. 
S 48168 (ARM210) will be supplied as 20 mg gastro-resistant tablets -
). 
Tablt' 5.1 Dt'scription of Trt'atmt'nts 
Shor t Description (text, 
t ables, figures, li stings, 
T1-eatment 
SAS output) 
Sponsor Protocol: 
Single oral 120 mg 
A 
S 48168 (ARM210) QD 
for 28 days (patients) 
Single oral 200 mg 
B 
S 48168 (ARM210) QD 
for 28 days (patients) 
Sponsor Protocol: 
Single oral 120 mg 
C 
S 48168 (ARM210) QD 
for 14 days (healthy 
subjects) 
Single oral 240 mg 
D 
S 48168(ARM210) QD 
for 14 days (healthy 
subjects) 
Stati stical Analysis Plan March 24, 2020 
Abb1·eviated Descrip tion (foo tnotes) 
Single oral 120 mg S 48168 (ARM210) (6 x 20 mg 
tablets) daily for 28 days (patients) 
Single oral 200 mg S 48168 (ARM2 l 0) (l Ox 20 mg 
tablets) daily for 28 days (patients) 
Single oral 120 mg S 48168 (ARM210) (3 x 40 mg 
tablets) daily for 14 days (healthy subjects) 
Single oral 240 mg S 48168 (ARM2 l 0) (l x 200 mg 
and l x 40 mg tablets) daily for 14 days (healthy 
subjects) 
Page 10 of 40 


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Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 11 of 40 
6. SAFETY 
All case report form (CRF) data will be listed by subject and chronologically by 
assessment time points. This will include rechecks, unscheduled assessments, and 
early termination.  
Applicable continuous variables will be summarized using n, arithmetic mean, SD, 
minimum, median, and maximum. Frequencies and percentages will be used to 
summarize categorical variables. 
The level of precision will be presented as follows: minimum/maximum in the same 
precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be 
presented as an integer. 
Where individual data points are missing because of dropouts or other reasons, the 
data will be summarized based on reduced denominators. 
6.1 
Subject Discontinuation 
Subjects will be summarized by number of subjects enrolled, completed, and 
discontinued the study with discontinuation reasons by treatment and study overall. 
6.2 
Demographics 
Descriptive statistics will be calculated for continuous variables (age, weight, height, 
and body mass index) by treatment and study overall.  
Frequency counts will be provided for categorical variables (race, ethnicity, and sex) 
for each treatment and study overall.  
6.3 
Adverse Events 
All adverse events (AEs) reported during this clinical trial will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®), Version 21.0.  
All adverse events will be reviewed by the Medical Monitor and graded in 
accordance with CTCAE version 5 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm)  
All AEs captured in the database will be listed in by-subject data listings including 
verbatim term, coded term, treatment, severity, relationship to study medication, and 
action; however, only treatment-emergent AEs (TEAEs) will be summarized.  
A TEAE is defined as an AE that is starting or worsening at the time of or after study 
drug administration. Each TEAE will be attributed to a treatment based on the onset 
date and time of the AE.  


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Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
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An AE will also be considered treatment emergent if:  onset date of an AE is missing; 
if onset time of an AE is missing and the onset date is the same as the treatment 
dosing date; and if both AE onset date and time are missing. 
TEAEs will be tabulated by System Organ Class (SOC) and Preferred Term (PT). 
Summary tables will include number of subjects reporting the AE and as percent of 
number of subjects dosed by treatment and study overall. The number of AEs will be 
tabulated in a similar manner. Tables which tabulate the number of TEAEs by 
severity and relationship to study treatment will also be included.  
Serious adverse events (SAEs), if present, will also be listed. Applicable narratives 
will be included in the CSR.  
Frequencies of TEAEs ≥ grade 2 in severity (CTCAE version 5), all SAEs, and all 
AE of Special Interest (AESI) will be tabulated by SOC/TE. 
The frequency and severity of clinically significant AEs will be compared 
descriptively between treatment and historical controls including a previously 
conducted natural history study at the NIH. 
7. PHARMACOKINETIC ANALYSIS (EXPLORATORY) 
7.1 
Measurements and Collection Schedule 
All concentration data will be included in the calculation of the individual PK 
parameters, the individual concentration-time plots (based on actual sample times), 
and in the mean concentration-time plots (based on nominal sample times). However, 
if there are any significant deviations from nominal sample times, some concentration 
data may be excluded from mean concentration-time plots and/or additional 
concentration-time plots of the mean data may be provided. All deviations and 
excluded data will be provided and discussed in the CSR. 
7.2 
Bioanalytical Method 
Plasma sample analysis for S 48168 (ARM210) will be performed by Nuvisan 
Pharma Services (Germany) using validated procedures and methods.  
7.3 
Investigational Product and PK Analyte Information 
S 48168 (ARM210) can be described as follows. S 48168 (ARM210) in the 
hemifumarate salt formulation has an empirical formula C18H18NO3S·C2H2O2 and a 
molecular weight of 387.42 g/mol. The free base has a molecular weight of 
329.42 g/mol.  


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Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
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7.4 
Pharmacokinetic Concentrations 
Serial blood samples for the determination of plasma S 48168 (ARM210) will be 
collected at predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Days 1 
and 28. A predose sample will also be collected on Day 14. 
7.5 
Noncompartmental Pharmacokinetic Analysis and Parameter Calculation 
7.5.1 Plasma Pharmacokinetic Parameters 
The appropriate noncompartmental PK parameters will be calculated from the plasma 
S 48168 (ARM210) concentration-time data using Phoenix® WinNonlin® Version 7.0 
or higher sample times will be used in the calculations of the PK parameters. The 
calculation of the actual time for S 48168 (ARM210) will be in respect to the start of 
dose administration time of S 48168 (ARM210) on every PK day. All PK parameters 
included in the protocol are listed in Table 6.1 below, and are defined as appropriate 
for study design. 
Table 6.1. Noncompartmental Pharmacokinetic Parameters to be Calculated 
(Day 1) 
Parameter 
Definition 
Method of Determination 
AUC0-24 
Area under the concentration-time 
curve from time 0 to the 24 hours 
postdose 
Calculated using the Linear Trapezoidal 
with Linear Interpolation Method. If a 
value could not be obtained at 24 hours 
the parameter will be set to missing 
AUC0-t 
Area under the concentration-time 
curve from time 0 to the time of the 
last observed/measured non-zero 
concentration 
Calculated using the Linear Trapezoidal 
with Linear Interpolation Method  
AUC0-inf 
Area under the concentration-time 
curve from time 0 extrapolated to 
infinity 
AUC0-inf = AUC0-t + (Clast/kel) 
where Clast is the last 
observed/measured concentration  
AUC%extrap 
Percent of AUC0-inf extrapolated 
Calculated as (1 - AUC0-t/AUC0-
inf)*100 
Cmax 
The maximum observed concentration 
Taken directly from bioanalytical data 
Tmax 
The time to reach Cmax 
Taken from clinical database as the 
difference in the time of administration 
and the time of the blood draw which is 
associated with the Cmax. 
Kel 
Apparent first-order terminal 
elimination rate constant calculated 
from a semi-log plot of the plasma 
concentration versus time curve. 
The parameter will be calculated by 
linear least-squares regression analysis 
using the maximum number of points in 
the terminal log-linear phase (e.g., three 
or more non-zero plasma concentrations). 
t½: 
Apparent first-order terminal 
elimination half-life 
Calculated as 0.693/Kel 


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Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
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Parameter 
Definition 
Method of Determination 
Tlag 
Lag time – the time delay between 
drug administration and the onset of 
absorption; where onset of absorption 
Calculated as the time point prior to the 
first observed/measured non-zero plasma 
concentration 
Table 6.2. Noncompartmental Pharmacokinetic Parameters to be Calculated 
(Day 28) 
Parameter 
Definition 
Method of Determination 
AUC0-tau 
The area under the concentration 
versus time curve from the start of 
drug infusion over the final dosing 
interval (tau) 
Calculated using the linear trapezoidal 
method with linear interpolation. Tau is 
equal to 24 hours. 
Cmax,ss 
The maximum observed 
concentration at steady state 
Taken directly from bioanalytical data 
Tmax,ss 
The time of the maximum observed 
concentration at steady state 
Taken directly from bioanalytical data. 
Tmax,ss is the first time point if Cmax,ss 
occurs at 2 time points 
Cmin 
Minimum observed concentration at 
the end of the dosing interval 
Taken directly from bioanalytical data 
Tmin 
Time to reach Cmin 
Taken directly from bioanalytical data. 
Tmin is the first time point if Cmin occurs 
at 2 time points 
RA(AUC) 
Accumulation ratio for AUC (steady 
state versus single dose) 
Calculated as AUCtau Day 28/AUC0-24 
Day 1 
RA(Cmax) 
Accumulation ratio for Cmax (steady 
state versus single dose) 
Calculated as Cmax Day 28/Cmax Day 1. 
Ctrough_D13 
Day 13 Ctrough 
Taken directly from bioanalytical data. 
Day 13 Ctrough is the predose of Day 14 
Pharmacokinetic parameters will not be calculated for subjects with less than 
2 consecutive postdose time points with quantifiable concentrations. Subjects for 
whom there are insufficient data to calculate the PK parameters will be included in 
the concentration tables only and excluded from the descriptive statistics.  
Concentrations will be presented in the report at the same precision as received from 
the bioanalytical laboratory. Concentrations below the lower limit of quantification 
(LLOQ) will be assigned a value of zero if they occur between time zero (predose) 
and the first measurable plasma concentration after the first dose and missing 
thereafter, and will be treated as such for the purpose of calculating PK parameters 
and summary statistics.  
The Kel will be determined using linear regressions composed of least 3 data points. 
The Kel will not be assigned if 1) the terminal elimination phase is not apparent, 2) if 
Tmax is one of the 3 last data points, or 3) if the R2 value is less than 0.8. In cases 
where the Kel interval is not assigned, the values of t½, AUC0-inf and AUC%extrap 
are considered not calculable and will not be reported. Wherever the resulting t½ is 


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Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
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more than half as long as the sampling interval, the Kel values and associated 
parameters (t½, AUC0-inf and AUC%extrap) may not be presented as judged 
appropriate and in accordance with Celerion SOPs.  
7.6 
Data Summarization and Presentation 
All S 48168 (ARM210) PK concentration and PK parameter descriptive statistics will 
be generated using WinNonlin® Version 7.0 or higher and/or SAS Version 9.4. 
Summary statistics, including sample size (n), arithmetic mean (mean), standard 
deviation (SD), coefficient of variation (CV%), standard error of the mean (SEM), 
median, minimum, and maximum will be calculated for all nominal concentration 
time points. The plasma concentrations of S 48168 (ARM210) will be calculated by 
nominal time. Excluded subjects due to major protocol deviations will be included in 
the concentration table listing, but will be excluded from the summary statistics and 
noted as such in the tables. All BLQ values will be presented as “BLQ” in the 
concentration table listing and footnoted accordingly.  
The level of precision for each statistic will be presented as follows: mean, median, 
minimum, maximum, SEM, and SD in same precision as in bioanalytical data, n will 
be presented as an integer, and CV% will be presented to 1 decimal place. 
Summary statistics (n, mean, SD, CV%, SEM, median, minimum, and maximum, 
geometric means, and geometric CV%) will be calculated for plasma S 48168 
(ARM210) PK parameters. Excluded subjects will be included in the PK parameter 
table listing, but will be excluded from the summary statistics and noted as such in the 
tables. PK parameters will be tabulated by dose level and listed by subject and 
parameter. 
Mean and individual concentration-time profiles will be presented on linear and semi-
log scales. Linear mean plots will be presented with and without SD. 
7.7 
Statistical Analysis of PK Parameters 
All data will be summarized and compared descriptively with no formal statistical 
analysis performed in this study. 
8. PHARMACODYNAMICS/TARGET ENGAGEMENT AND MOTOR 
FUNCTIONS 
8.1 
Pharmacodynamic/Target Engagement (Exploratory):  
All participants will undergo two needle muscle biopsies during the study in order to 
determine S 48168 (ARM210) PD in the RYR1-RM population. Biopsy 1 will take 
place pre-dose during study visit 1 (Day -1/Day 1, pre-treatment). Biopsy 2 will take 
place during study visit 3 (Day 27/28, post-treatment). Baseline (pre-treatment) and 


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Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
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post-treatment biopsies will be assayed for RyR1-Calstabin1 interaction as % RyR1-
Calstabin1 binding of normal control muscle. % RyR1-Calstabin1 binding will be 
listed by subject with summary statistics calculated to compare between pre- and 
post-treatment biopsy results.  
If there is sufficient remaining tissue, % Ca2+ leak from RyR1 will be determined and 
listed by subject and compared between pre- and post-treatment biopsies. 
8.2 
Motor Functions and Quality of Life (Exploratory): 
Timed Functional Tests: Timed functional tests will be performed on Day -1 (pre-
treatment) and Day 27 (post-treatment) and include10-meter walk test, supine to 
stand, ascend 4 stairs, and descend 4 stairs. The recorded time will be listed by 
subject and summarized descriptively for each test to compare between pre- and post-
treatment biopsy results. 
Grip/Pinch Strength: Day -1 versus Day 27 hand grip and pinch strength will be 
documented quantitatively using dynamometry. This will also be assessed at trial 
mid-point (Day 14). The results will be listed by subject and summarized 
descriptively to compare hand grip and pinch strength (kg) between pre- and post-
treatment. 
Motor Function Measure 32:  
Day -1 versus Day 27 motor function will be documented quantitatively using the 
scoring of the MFM32 for the following: total score, domain 1 (standing and 
transfers), domain 2 (axial and proximal motor function), and domain 3 (distal motor 
function). The resulting scores will be listed by subject and summarized descriptively 
to compare between pre- and post-treatment. 
Quality of Life Questionnaire: PROMIS-fatigue subscale questionnaires will be 
completed by participants during study visits 1 (Day -1), 2 (Day 14), and 3 (Day 27) 
with a raw score, theta, t-score, and standard error reported. All results will be listed 
by subject and summarized descriptively, as applicable, to compare between pre- and 
post-treatments.  
8.3 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Urinalysis) 
Serum chemistry, hematology and urinalysis tests will be performed at Screening and 
on Days 14, 27 and 35 (Follow-up).  
Out-of-range values and corresponding recheck results will be listed.  
For all numeric laboratory values, descriptive statistics will be presented for each 
laboratory test by assessment time point and treatment. Change from baseline will be 
summarized in a similar manner. Baseline is defined as the screening result closest 


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Statistical Analysis Plan March 24, 2020 
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and prior to first dose which may include unscheduled or recheck results. Postdose 
unscheduled event and recheck results will not be included in summaries.  
For each laboratory test, a shift table will be developed to compare the frequency of 
the results at baseline (above normal, normal, or below normal) with the respective 
postdose results.  
8.4 
Vital Signs 
Blood pressure and pulse are assessed at Screening, predose on Day 1 and on Days 14 
and 28.  Respiratory rate, temperature and pulse oximetry are measured at Screening 
and on Days 14 and 28.   
Summary statistics will be calculated for all vital sign parameters by timepoint and 
treatment.  Change from baseline (Predose Day 1) for blood pressure and pulse will 
be summarized for post baseline by timepoint and treatment.   Baseline is defined as 
the result closest and prior to first dose on Day1 which may include unscheduled or 
recheck results. Postdose unscheduled event and recheck results will not be included 
in summaries. 
8.5 
12-Lead Electrocardiogram  
12-lead electrocardiogram (ECG) will be assessed at Screening and Days 14 and 28 
for HR, RR, PR, QRS, QT and QTcF. All ECG parameters will be listed by subjects 
with QTcF>450 msec flagged. Summary statistics will be calculated for each 
parameter and presented by timepoint and treatment. Postdose unscheduled event and 
recheck results will not be included in summaries. 
8.6 
Concomitant Medications 
All concomitant medications recorded during the study will be coded with the WHO 
Dictionary March 2018 B3 and listed. 
8.7 
Physical Examination 
Full physical examinations will be performed at Screening and on Days 14 and 27. 
Symptom driven physical examination may be performed at other times, at the PI or 
designee’s discretion. All data found in the CRF will be listed.  
8.8 
The Columbia-Suicide Severity Rating Scale (C-SSRS) 
C-SSRS will be administered at Screening, Day 14 and Day 27. Results recorded on 
the CRF will be listed. 


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Statistical Analysis Plan March 24, 2020 
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8.9 
Pulmonary Function Test 
Each participant will perform pulmonary function testing (PFTs) to assess vital 
capacity (VC) at screening.  Results recorded on the CRF will be listed. 
8.10 
Medical and Surgical History 
All medical and surgical history recorded during the study will be coded with the 
MedDRA 21.0 and listed. 
9. SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS 
The analyses described in this SAP are aligned with those analyses described in the 
protocol.  
10. SUMMARY TABLES AND FIGURES 
Summary tables and figures are numbered following the International Conference on 
Harmonization (ICH) structure but may be renumbered as appropriate during the 
compilation of the tables and figures for the CSR. Note that all summary tables and 
figures will be generated using SAS® Version 9.3 or higher, as appropriate.  
10.1 
In-text Summary Tables and Figures 
The following is a list of table and figure titles that will be included in the text of the 
CSR. Tables and figures will be numbered appropriately during compilation of the 
CSR. 
Section 10: 
Table 10-1 
Subject Disposition Summary  
Section 11: 
Table 11-1 
Demographic Summary 
Table 11-2 
Summary of Plasma S 48168 (ARM210) Pharmacokinetics Following 
Single Dose of 120 mg, 200 mg, and 240 mg S 48168 (ARM210) 
(Treatments A, B, C, and D) (Day 1) 
Table 11-3 
Summary of Plasma S 48168 (ARM210) Pharmacokinetics Following 
Single Dose of 120 mg, 200 mg and 240 mg S 48168 (ARM210) 
(Treatments A, B, C, and D) (Days 14 and 28) 
Figure 11-1 
Arithmetic Mean Plasma S 48168 (ARM210) Concentration-Time 
Profiles of Following Single Dose Administration of 120 mg, 200 mg, 


ARMGO Pharma Inc. 
S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 19 of 40 
and 240 mg S 48168 (ARM210) on Day 1 (Treatments A, B, C, and 
D) (Linear Scale) 
Figure 11-2 
Arithmetic Mean Plasma S 48168 (ARM210) Concentration-Time 
Profiles of Following Single Dose of 120 mg and 200 mg  S 48168 
(ARM210) in Patients (Day 28) and 120 mg and 240 mg S 48168 
(ARM210) in Healthy Subjects (Day 14) (Linear Scale) 
Note to Programmer: For Figures 11-2 superimpose both the Days 14 (Healthy)and 
28 (Patient). All figures are to be generated in color. 
Section 12: 
Table 12-1 
Adverse Event Frequency by Treatment - Number of Subjects 
Reporting the Event (% of Subjects Dosed) 
10.2 
Section 14 Summary Tables and Figures 
The following is a list of table and figure titles that will be included in Section 14 of 
the report. Table and figure titles may be renumbered as appropriate during the 
compilation of the report.  
14.1 
Demographic Data Summary Tables  
Table 14.1.1 Summary of Disposition (Safety Population) 
Table 14.1.2 Demographic Summary (Safety Population) 
14.2 
Pharmacokinetic/Pharmacodynamic Data Summary Tables and Figures  
14.2.1 Plasma S 48168 (ARM210) Tables 
Table 14.2.1.1 Plasma S 48168 (ARM210) Concentrations (<units>) 
Following Single Oral Administration of 120 mg S 48168 
(ARM210) (6 x 20 mg Tablets) for 28 Days (Patients) 
(Treatment A) (Days 1-28) (Pharmacokinetic Population)  
Table 14.2.1.2 Plasma S 48168 (ARM210) Concentrations (<units>) 
Following Single Oral 200 mg S 48168 (ARM210) (10 x 20 
mg Tablets) for 28 Days (Patients) (Treatment B) (Days 1-
28) (Pharmacokinetic Population)  
Table 14.2.1.3 Plasma S 48168 (ARM210) Concentrations (<units>) 
Following Single Oral 120 mg S 48168 (ARM210) (3 x 40 
mg Tablets) for 14 Days (Healthy Subjects) (Treatment C) 
(Days 1-14) (Pharmacokinetic Population) 
Table 14.2.1.4 Plasma S 48168 (ARM210) Concentrations (<units>) 
Following Single Oral 240 mg S 48168 (ARM210) (1 x 200 


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S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 20 of 40 
mg and 1 x 40 mg Tablets) for 14 Days (Healthy Subjects) 
(Treatment D) (Days 1 - 14) (Pharmacokinetic Population) 
Table 14.2.1.5 Plasma S 48168 (ARM210) Pharmacokinetic Parameters 
Following Single Oral Administration of 120 mg S 48168 
(ARM210) (6 x 20 mg Tablets) for 28 Days (Patients) 
(Treatment A) (Day 1) (Pharmacokinetic Population) 
Table 14.2.1.6 Plasma S 48168 (ARM210) Pharmacokinetic Parameters 
Following Single Oral Administration of 120 mg S 48168 
(ARM210) (6 x 20 mg Tablets) for 28 Days (Patients) 
(Treatment A) (Day 28) (Pharmacokinetic Population) 
Table 14.2.1.7 Plasma S 48168 (ARM210) Pharmacokinetic Parameters 
Following Single Oral 200 mg S 48168 (ARM210) (10 x 20 
mg Tablets) for 28 Days (Patients) (Treatment B) (Day 1) 
(Pharmacokinetic Population) 
Table 14.2.1.8 Plasma S 48168 (ARM210) Pharmacokinetic Parameters 
Following Single Oral 200 mg S 48168 (ARM210) (10 x 20 
mg Tablets) for 28 Days (Patients) (Treatment B) (Day 28) 
(Pharmacokinetic Population) 
Table 14.2.1.9 Plasma S 48168 (ARM210) Pharmacokinetic Parameters 
Following Single Oral 120 mg S 48168 (ARM210) (3 x 
40 mg Tablets) for 14 Days (Healthy Subjects) (Treatment C) 
(Day 1) (Pharmacokinetic Population) 
Table 14.2.1.10 Plasma S 48168 (ARM210) Pharmacokinetic Parameters 
Following Single Oral 120 mg S 48168 (ARM210) (3 x 
40 mg Tablets) for 14 Days (Healthy Subjects) (Treatment C) 
(Day 14) (Pharmacokinetic Population) 
Table 14.2.1.11 Plasma S 48168 (ARM210) Pharmacokinetic Parameters 
Following Single Oral 240 mg S 48168 (ARM210) (1 x 
200 mg and 1 x 40 mg Tablets) for 14 Days (Healthy 
Subjects) (Treatment D) (Day 1) (Pharmacokinetic 
Population) 
 
Table 14.2.1.12 Plasma S 48168 (ARM210) Pharmacokinetic Parameters 
Following Single Oral 240 mg S 48168 (ARM210) (1 x 
200 mg and 1 x 40 mg Tablets) for 14 Days (Healthy 
Subjects) (Treatment D) (Day 14) (Pharmacokinetic 
Population) 
Table 14.2.1.12 Intervals (Hours) Used for Determination of Plasma S 48168 
(ARM210) Kel Values (Pharmacokinetic Population) 


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S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 21 of 40 
14.2.2 Plasma S 48168 (ARM210) Figures 
Figure 14.2.2.1 Mean (SD) Plasma S 48168 (ARM210) Concentration-Time 
Profiles of Following Single Dose Administration of 120 mg, 
200 mg, and 240 mg S 48168 (ARM210) on Day 1 
(Treatments A, B, C, and D) (Linear Scale) (Pharmacokinetic 
Population) 
Figure 14.2.2.2 Mean Plasma S 48168 (ARM210) Concentration-Time 
Profiles of Following Single Dose Administration of 120 mg, 
200 mg, and 240 mg S 48168 (ARM210) on Day 1 
(Treatments A, B, C, and D) (Linear Scale) 
Figure 14.2.2.3 Mean Plasma S 48168 (ARM210) Concentration-Time 
Profiles of Following Single Dose Administration of 120 mg, 
200 mg, and 240 mg S 48168 (ARM210) on Day 1 
(Treatments A, B, C, and D) (Semi-Log Scale) 
Figure 14.2.2.4 Mean (SD) Plasma S 48168 (ARM210) Concentration-Time 
Profiles of Following Multiple Daily Doses 120 mg and 200 
mg S 48168 (ARM210) in Patients (Day 28) and 120 mg and 
240 mg S 48168 (ARM210) in Healthy Subjects (Day 14) 
(Linear Scale) (Pharmacokinetic Population) 
Figure 14.2.2.5 Mean Plasma S 48168 (ARM210) Concentration-Time 
Profiles of Following Multiple Daily Doses 120 mg and 200 
mg S 48168 (ARM210) in Patients (Day 28) and 120 mg and 
240 mg S 48168 (ARM210) in Healthy Subjects (Day 14) 
(Linear Scale) 
Figure 14.2.2.6 Mean Plasma S 48168 (ARM210) Concentration-Time 
Profiles of Following Multiple Daily Doses 120 mg and 200 
mg S 48168 (ARM210) in Patients (Day 28) and 120 mg and 
240 mg S 48168 (ARM210) in Healthy Subjects (Day 14) 
(Semi-Log Scale) 
 
Note to Programmer:  For Figures 14.2.2.4 through 14.2.2.6 
superimpose both the Days 14 and 28 for All figures are to be 
generated in color. 
14.2.3 Pharmacodynamic/Target Engagement Tables 
Table 14.2.3.1 Mean % RyR1-Calstabin1 Binding   
 
14.2.4 Motor Function and Quality of Life Tables 
Table 14.2.4.1 Summary of Timed Functional Tests   
Table 14.2.4.2 Summary of Motor Function Measure 32   
Table 14.2.4.3 Summary of Quality of Life Questionnaire   


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Statistical Analysis Plan March 24, 2020 
Page 22 of 40 
14.3 
Safety Data Summary Tables  
14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 Treatment-emergent Adverse Event Frequency by Treatment 
– Number of Subjects Reporting the Event (% of Subject 
Dosed) (Safety Population) 
Table 14.3.1.2 Treatment-emergent Adverse Event Frequency by Treatment 
– Number of Adverse Events (% of Total Adverse Events) 
(Safety Population) 
Table 14.3.1.3 Treatment-emergent Adverse Event Frequency by Treatment, 
Severity, and Relationship to Drug – Number of Adverse 
Events (Safety Population) 
Table 14.3.1.4 Frequency of Treatment-emergent Adverse Event with Grade 
2 or Greater Severity, are Serious, or Are of Special Interest  
by Treatment (Safety Population) 
14.3.2 
Listings of Deaths, other Serious and Significant Adverse Events 
Table 14.3.2.1 Serious Adverse Events (Safety Population)  
<if no serious adverse event occurred, a statement ‘No 
serious adverse event is reported’> 
14.3.3 
Narratives of Deaths, other Serious and Certain other 
Significant Adverse Events 
14.3.4 
Abnormal Laboratory Value Listing (each patient) 
Table 14.3.4.1 Out-of-Range Values and Recheck Results – Serum 
Chemistry (Safety Population) 
Table 14.3.4.2 Out-of-Range Values and Recheck Results – Hematology 
(Safety Population) 
Table 14.3.4.3 Out-of-Range Values and Recheck Results – Urinalysis 
(Safety Population) 
14.3.5 
Displays of Other Laboratory, Vital Signs, Electrocardiogram, 
Physical Examination, and Other Safety Data 
Table 14.3.5.1 Clinical Laboratory Summary and Change from Baseline – 
Serum Chemistry (Safety Population) 
Table 14.3.5.2 Clinical Laboratory Shift from Baseline – Serum Chemistry 
(Safety Population) 
Table 14.3.5.3 Clinical Laboratory Summary and Change from Baseline – 
Hematology (Safety Population) 


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Statistical Analysis Plan March 24, 2020 
Page 23 of 40 
Table 14.3.5.4 Clinical Laboratory Shift from Baseline – Hematology 
(Safety Population) 
Table 14.3.5.5 Clinical Laboratory Summary and Change from Baseline – 
Urinalysis (Safety Population) 
Table 14.3.5.6 Clinical Laboratory Shift from Baseline – Urinalysis (Safety 
Population) 
Table 14.3.5.7 Vital Sign Summary and Change from Baseline (Safety 
Population)  
Table 14.3.5.8 12-Lead Electrocardiogram Summary (Safety Population) 
14.4 
Section 16 Data Listings 
Data listings are numbered following the ICH structure but may be renumbered as 
appropriate during the compilation of the TFLs for the CSR. The following is a list of 
appendix numbers and titles that will be included as data listings: 
16.1 
Study Information 
Appendix 16.1.9 
Statistical Methods 
Appendix 16.1.10.1 
Clinical Laboratory Reference Ranges 
16.2 
Subject Data Listings 
16.2.1 
Subject Discontinuation 
Appendix 16.2.1 
Subject Discontinuation (Safety Population) 
16.2.2 
Protocol Deviations 
Appendix 16.2.2 
Protocol Deviations 
16.2.3 
Subjects Excluded from Pharmacokinetic Analysis 
Appendix 16.2.3 
Subjects Excluded from Pharmacokinetic Analysis 
Note: Appendices 16.2.2 and 16.2.3 are generated in MS Word for inclusion 
in the study report. 
16.2.4 
Demographic Data 
Appendix 16.2.4.1 
Subject Information (Safety Population) 
Appendix 16.2.4.2 
Demographics (Safety Population) 
Appendix 16.2.4.3 
Physical Examination - Full (Safety Population)  


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Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 24 of 40 
Appendix 16.2.4.4 
Physical Examination – Symptom Driven (Safety 
Population)  
Appendix 16.2.4.5 
Medical and Surgical History (Safety Population) 
Appendix 16.2.4.6 
Tobacco Use (Safety Population) 
Appendix 16.2.4.7 
CYP2C8 Genotyping (Safety Population) 
Appendix 16.2.4.8 
Echocardiogram (Safety Population) 
Appendix 16.2.4.9 
Pulmonary Function Test (Safety Population)  
16.2.5 
Compliance and/or Drug Concentration Data 
Appendix 16.2.5.1 
Inclusion/Exclusion Criteria not Met (Safety 
Population) 
Appendix 16.2.5.2 
Dose Administration Times (Safety Population) 
Appendix 16.2.5.3 
Pharmacokinetic Blood Sampling (Safety Population) 
Appendix 16.2.5.4 
Skeletal Muscle Needle Biopsy (Safety Population) 
Appendix 16.2.5.5 
Concomitant Medications (Safety Population) 
Appendix 16.2.5.6 
Subject Contact (Safety Population) 
Appendix 16.2.5.7 
Subject Diary (Safety Population) 
16.2.6 
Individual Pharmacokinetic/Pharmacodynamic Response Data 
Appendix 16.2.6.1 
Plasma S 48168 (ARM210) Concentrations Versus 
Time (Linear and Semi-Log Scale) for Subject # 
Appendix 16.2.6.2 
Percent (%) RyR1-Calstabin1 Binding 
(Pharmacodynamic Population) 
Appendix 16.2.6.3 
Motor Function Measure 32 (Safety Population) 
Appendix 16.2.6.4 
Graded Functional Testing (Safety Population)  
Appendix 16.2.6.5 
Grip and Pinch Strength (Safety Population)  
Appendix 16.2.6.6 
Fatigue Questionnaire (Safety Population)   
Appendix 16.2.6.7 
C-SSRS – Baseline – Suicidal Ideation (Safety 
Population)   
Appendix 16.2.6.8 
C-SSRS – Baseline – Intensity of Ideation (Safety 
Population)   
Appendix 16.2.6.9 
C-SSRS – Baseline – Suicidal Behavior (Safety 
Population)   
Appendix 16.2.6.10 
C-SSRS – Baseline – Actual Attempts (Safety 
Population)   
Appendix 16.2.6.11 
C-SSRS – Since Last Visit – Suicidal Ideation (Safety 
Population)   
Appendix 16.2.6.12 
C-SSRS – Since Last Visit – Intensity of Ideation 
(Safety Population)   
Appendix 16.2.6.13 
C-SSRS – Since Last Visit – Suicidal Behavior (Safety 
Population)   


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S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 25 of 40 
Appendix 16.2.6.14 
C-SSRS – Since Last Visit – Actual Attempts (Safety 
Population)  
16.2.7 
Adverse Events Listings 
Appendix 16.2.7.1 
Adverse Events (I of II) (Safety Population) 
Appendix 16.2.7.2 
Adverse Events (II of II) (Safety Population) 
Appendix 16.2.7.3 
Adverse Event Preferred Term Classification (Safety 
Population) 
16.2.8 
Listings of Individual Laboratory Measurements and Other 
Safety Observations 
Appendix 16.2.8.1.1 Clinical Laboratory Report - Serum Chemistry (Safety 
Population)  
Appendix 16.2.8.1.2 Clinical Laboratory Report - Hematology (Safety 
Population) 
Appendix 16.2.8.1.3 Clinical Laboratory Report - Urinalysis (Safety 
Population) 
Appendix 16.2.8.1.4 Clinical Laboratory Report - Urine Drug Screening 
(Safety Population) 
Appendix 16.2.8.1.5 Serology (Safety Population) 
Appendix 16.2.8.1.6 Pregnancy Test (Safety Population)  
Appendix 16.2.8.1.7 Serum FSH (Safety Population)  
Appendix 16.2.8.1.8 Urine Alcohol Test (Safety Population) 
Appendix 16.2.8.2 
Vital Signs (Safety Population) 
Appendix 16.2.8.3 
12-Lead Electrocardiogram (Safety Population) 
 
 


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Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan March 24, 2020 
Page 26 of 40 
11. TABLE AND FIGURE SHELLS  
The following table shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the tables that will be presented and included in the final report. Unless otherwise 
noted, all tables will be presented in Times New Roman font size 8. These tables will 
be generated off of the Celerion ADaM data structure. ADaM datasets are created in 
accordance with CDISC guidance (ADaM Model 2.1 and ADaM implementation 
guide 1.1). 
Safety table shells will be completed at a later date. 
 
 


ARMGO Pharma Inc. 
S 48168 (ARM210), 
 
Celerion, Clinical Study Report No
 
 
Statistical Analysis Plan March 24, 2020 
Page 27 of 40 
11.1 
In-text Summary Tables Shells 
In-text Tables 11-2 and 11-3 will be in the following format: 
 
Table 11-2  
Summary of Plasma S 48168 (ARM210) Pharmacokinetics Following Single 
Dose of 120 mg, 200 mg, and 240 mg S 48168 (ARM210)  
(Treatments A, B, C, and D) (Day 1) 
 
Pharmacokinetic Parameters 
Treatment <Y> 
Treatment <X> 
Param1 (units)   
XXX.X (XX.X) [n=xx] 
XXX.X (XX.X) [n=xx] 
Param2 (units)   
XXX.X (XX.X) [n=xx] 
XXX.X (XX.X) [n=xx] 
Param3 (units)   
XXX.X (XX.X) [n=xx] 
XXX.X (XX.X) [n=xx] 
Param4 (units)  
XXX.X (XX.X) [n=xx] 
XXX.X (XX.X) [n=xx] 
Treatment <Y>: <Label for Second Treatment>  
Treatment <X>: <Label for First Treatment> 
AUCs and Cmax values are presented as geometric mean and geometric CV%. 
Tmax values are presented as median (min, max). 
Other parameters are presented as arithmetic mean (± SD).  
Source: Tables <XXXX> and <YYYY> 
 
Notes for Generating the Actual Table: 
 
Treatments 
Treatment A: Single oral 120 mg S 48168 (ARM210) QD for 28 days (patients) 
Treatment B: Single oral 200 mg S 48168 (ARM210) QD for 28 days (patients) 
Treatment C: Single oral 120 mg S 48168 (ARM210) QD for 14 days (healthy subjects) 
Treatment D: Single oral 240 mg S 48168 (ARM210) QD for 14 days (healthy subjects) 
 
Presentation of Data: 
• 
The following PK parameters will be presented in the following order and with following 
units: Day 1: AUC0-t <unit>, AUC0-inf <unit>, AUC%extrap <unit>, Cmax <unit>, Tmax 
<unit>, Kel <unit>, t½ <unit>, and Tlag <unit> 
Day 28: AUC0-tau <unit>, Cmax,ss <unit>, Tmax,ss <unit>, Cmin <unit>, Tmin <unit>, 
RA(AUC) <unit>, RA(Cmax) <unit>, and Ctrough_D13 <unit> 
• 
n will be presented as an integer (with no decimal); 
• 
Summary statistics will be presented with same precision as defined in post-text shells  
• 
Table 11-2 source table is Tables 14.2.1.5, 14.2.1.7, 14.2.1.9, and 14.2.1.11. 
• 
Table 11-3 source table is Tables 14.2.1.6, 14.2.1.8, 14.2.1.10, and 14.2.1.12. 
 
 
 
Celerion Note: Per study design needs, the following changes are made to this table relative to 
Celerion’s standard shell. For Tables 11-2 and 11-3 there will be a column for each Treatment. 
Put the “Treatment” as well as the “Dose Level” administered. Also add the Day in brackets. 
 
Program:  /CAXXXXX/sas_prg/pksas/intext-pk-tables.sas   
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_intext_pkparam.sas   
DDMMMYYYY  HH:MM 
 


  
Statistical Analysis Plan 12 December 2019 
 
Page 28 of 40 
11.2 
Section 14 Summary Tables Shells 
Safety table shells will be provided in later version. 
 
 


  
Statistical Analysis Plan 12 December 2019 
 
Page 29 of 40 
Tables 14.2.1.1 through 14.2.1.4 will be in the following format. 
 
 
 
Page 1 of X 
 
 
 Table 14.2.1.1 
Plasma S 48168 (ARM210) Concentrations (<units>) Following Single Oral Administration of 120 mg S 48168 (ARM210) (6 x 20 mg 
Tablets) for 28 Days (Patients) (Treatment A) (Days 1-28) (Pharmacokinetic Population) 
 
 
 
 
-----------------------------------------Sampling Time (hr)-------------------------------------- 
Subject 
Number 
Treatment 
Sequence 
Study 
Period 
Predose 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
X 
XXXX 
X 
BLQ 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
X 
XXXX 
X 
BLQ 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
X 
XXXX 
X 
BLQ 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
X 
XXXX 
X 
BLQ 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
X 
XXXX 
X 
BLQ 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
X 
XXXX 
X 
BLQ 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
n 
 
 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
Mean 
 
 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
SD 
 
 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
CV% 
 
 
. 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SEM 
 
 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
XXX.XX 
Minimum 
 
 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Median 
 
 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
XXX.X 
Maximum 
 
 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
For the calculation of summary statistics, values that are below the limit of quantitation (BLQ) of <XX> are treated as <0> before the first quantifiable 
concentration and as missing elsewhere. 
. = Value missing or not reportable. 
 
 


  
Statistical Analysis Plan 12 December 2019 
 
Page 30 of 40 
 
Notes for Generating the Actual Table: 
 
Presentation of Data: 
• 
Concentrations will be presented to same precision as in bio data.  
• 
Summary statistics presentation with respect to the precision of the bio data: n = integer; Mean and Median +1; SD and SEM +2, Min 
and Max +0, CV% to 1 decimal 
 
Programmer Note:  
• 
Template to be used CPConc1. 
• 
See Section 6.4 for PK sample collection times.   
• 
Remove “Treatment Sequence” and “Study Period” columns from the table. 
• 
Footnote for BLQ should be updated following multiple doses see Section 6.5 for details. 
 
 
Program:  /CAXXXXX/sas_prg/pksas/pk-conc-tables.sas    
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/pk-conc-tables-sig.sas   DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_conc.sas   
 
 
DDMMMYYYY  HH:MM 
 
 
 
 


  
Statistical Analysis Plan 12 December 2019 
 
Page 31 of 40 
Tables 14.2.1.5 through 14.2.1.12 will be in the following format. 
 
Page 1 of X 
 
Table 14.2.1.5 
Plasma S 48168 (ARM210) Pharmacokinetic Parameters Following Single Oral Administration of 120 mg S 48168 
(ARM210) (6 x 20 mg Tablets) for 28 Days (Patients) (Treatment A) (Day 1) (Pharmacokinetic Population) 
 
 
 
 
Parameters 
Subject 
Number 
Treatment 
Sequence 
Study 
Period 
Param1 
(units) 
Param2 
(units) 
Param3 
(units) 
Param4 
(units) 
Param5 
(units) 
Param6 
(units) 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
X 
XXXX 
X 
XXXX 
X.XX 
XXX 
XXXX 
XX.X 
X.XXXX 
n 
 
 
XX 
XX 
XX 
XX 
XX 
XX 
Mean 
 
 
XXXX.X 
X.XXX 
XXXX.X 
XXXX.X 
XX.XX 
X.XXXXX 
SD 
 
 
XX.XXXX 
X.XXXX 
XX.XXXX 
XX.XXXX 
XX.XXX 
X.XXXXXX 
CV% 
 
 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
SEM 
 
 
XX.XXXX 
X.XX 
XX.XXXX 
XX.XXXX 
XX.XXX 
X.XXXXXX 
Minimum 
 
 
XXXX 
X.XXX 
XXXX 
XXXX 
XX.X 
X.XXXX 
Median 
 
 
XXXX.X 
X.XX 
XXXX.X 
XXXX.X 
XX.XX 
X.XXXXX 
Maximum 
 
 
XXXX 
X.XXX 
XXXX 
XXXX 
XX.X 
X.XXXX 
Geom Mean 
 
 
XXXX.X 
XXXX.X 
XXXX.X 
XXXX.X 
XXXX.X 
XXXX.X 
Geom CV% 
 
 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
 
. = Value missing or not reportable. 
 
 
 


  
Statistical Analysis Plan 12 December 2019 
 
Page 32 of 40 
Notes for Generating the Actual Table: 
 
Presentation of Data: 
• 
Template to be used CPPar1. 
• 
PK Parameters will be presented in the following order and with following units: Day 1: AUC0-t <unit>, AUC0-inf <unit>, AUC%extrap 
<unit>, Cmax <unit>, Tmax <unit>, Kel <unit>, t½ <unit>, and Tlag <unit>. Day 28: AUC0-tau <unit>, Cmax,ss <unit>, Tmax,ss <unit>, 
Cmin <unit>, Tmin <unit>, RA(AUC) <unit>, RA(Cmax) <unit>, and Ctrough_D13 <unit> 
• 
n will be presented as an integer (with no decimal); 
• 
Parameter values for exposure based parameters (i.e. AUCs, Cmax) will be presented with, at maximum, the precision of the bio data, 
and, at minimum, 3 significant figures (to be determined by the PKist once bio data are received). Summary statistics for exposure 
parameters will be presented as: Mean, Median, and Geom Mean+1; SD and SEM +2, Min and Max +0.  
• 
Values for time-based parameters (i.e. Tmax, t1/2) will be presented with 2 decimals. Summary statistics for time-based parameters 
will be presented as: Mean, Median, and Geom Mean +1; SD +2, Min and Max +0.  Accumulation ratios will be presented like time-based 
parameters. 
• 
Values for rate constants (i.e. Kel) will be presented with 3 significant figures. Summary statistics for Kel will be presented as: 
Mean, Median, and Geom Mean +1; SD and SEM +2, Min and Max +0.  
• 
CV% and Geom CV% for all parameters will be presented with 1 decimal. 
• 
Remove “Treatment Sequence” and “Study Period” columns from the table. 
 
 
Program:  /CAXXXXX/sas_prg/pksas/pk-tables.sas   
 
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_pkparam.sas   
DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan 12 December 2019 
 
Page 33 of 40 
Table 14.2.1.12 will be in the following format. 
 
Page 1 of X 
 
Table 14.2.1.13 
Intervals (Hours) Used for Determination of Plasma S 48168 (ARM210) Kel Values 
(Pharmacokinetic Population) 
 
 
Subject 
Treatment -------------  Treatment  <X>  -------------- 
-------------  Treatment  <Y>  -------------- 
Number 
Sequence 
Interval 
R2 
n 
Interval 
R2 
n 
                 ------------------------------------------------------------------------------------------------------------------------- 
X 
XX 
XX.X - XX.X 
X.XXX 
X 
XX.X - XX.X 
X.XXX 
X 
X 
XX 
XX.X - XX.X 
X.XXX 
X 
XX.X - XX.X 
X.XXX 
X 
X 
XX 
XX.X - XX.X 
X.XXX 
X 
XX.X - XX.X 
X.XXX 
X 
X 
XX 
XX.X - XX.X 
X.XXX 
X 
XX.X - XX.X 
X.XXX 
X 
X 
XX 
XX.X - XX.X 
X.XXX 
X 
XX.X - XX.X 
X.XXX 
X 
X 
XX 
XX.X - XX.X 
X.XXX 
X 
XX.X - XX.X 
X.XXX 
X 
                 ------------------------------------------------------------------------------------------------------------------------- 
                 Treatment <X>: <Label for First Treatment> 
                 Treatment <Y>: <Label for Second Treatment> 
                 R2 = Coefficient of determination  
                 n = Number of points used in Kel calculation 
                 . = Kel value not reportable. 
 
 


  
Statistical Analysis Plan 12 December 2019 
 
Page 34 of 40 
Notes for Generating the Actual Table: 
 
Treatments 
• 
Treatment A: Single oral 120 mg S 48168 (ARM210) QD for 28 days (patients) 
• 
Treatment B: Single oral 200 mg S 48168 (ARM210) QD for 28 days (patients) 
• 
Treatment C: Single oral 120 mg S 48168 (ARM210) QD for 14 days (healthy subjects) 
• 
Treatment D: Single oral 240 mg S 48168 (ARM210) QD for 14 days (healthy subjects) 
 
 
 
Presentation of Data: 
• 
Interval start and stop times will be presented to 1 decimal or 3 sig figures min; 
• 
R2 will be presented to 3 decimals; 
• 
n will be presented as an integer (with no decimal) 
 
Programmer Note: 
• 
Use template CPKel1 for generation of table. 
 
 
 
Program:  /CAXXXXX/sas_prg/pksas/kel-tables-parallel.sas   DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_kel.sas   
 
DDMMMYYYY  HH:MM 
 
 


  
Statistical Analysis Plan 12 December 2019 
 
Page 35 of 40 
11.3 
Figures Shells 
Note: In-text figures 11-1, 11-2, and mean figures of 14.2.2 will be in the following format.   
 
 
Figure 14.2.2.1 
 
 
Mean (SD) <Matrix Analyte> Concentrations Versus Time 
(Linear Scale) 
 
 
 


ARMGO Pharma Inc. 
S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan 12 December 2019 
Page 36 of 40 
Figure 14.2.2.2 
 
 
Mean <Matrix Analyte> Concentrations Versus Time 
(Semi-Log Scale) 
 
 
 
 
 
 
 


ARMGO Pharma Inc. 
S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan 12 December 2019 
Page 37 of 40 
Notes for Generating the Actual Mean Figure: 
 
• 
Legend will  
• 
Treatment A: Single oral 120 mg S 48168 (ARM210) QD for 28 days (patients) 
• 
Treatment B: Single oral 200 mg S 48168 (ARM210) QD for 28 days (patients) 
• 
Treatment C: Single oral 120 mg S 48168 (ARM210) QD for 14 days (healthy subjects) 
• 
Treatment D: Single oral 240 mg S 48168 (ARM210) QD for 14 days (healthy subjects) 
• 
Y axis label will be <Plasma S 48168 (ARM210)  Concentration (<unit>)” 
• 
X axis label will be “Time (Hours)” 
• 
More than 1 treatment day so add the footnote: “x Treatment(s)” administration is shifted to the right for ease of reading.  
• 
For footnote when there are more than 1 treatment add footnote to indicate if it is for healthy subjects or 
patients that are shifted. 
• 
Please generate figures in color. Please use the same color and symbol for each treatment throughout. 
 


ARMGO Pharma Inc. 
S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan 12 December 2019 
Page 38 of 40 
12. LISTING SHELLS 
The following listing shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the listings that will be presented and included in the final report. These listings 
will be generated off of the Celerion SDTM datasets (SDTM Tabulation Model 
Model 1.4 mapped in accordance with SDTM Implementation Guide 3.2).  All 
listings will be presented in Courier New size font 9. 
CRF listing shells will be completed at a later date. 
 
 
 


ARMGO Pharma Inc. 
S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan 12 December 2019 
Page 39 of 40 
Figures in Appendix 16.2.6.1 will be in the following format: 
 
Figure PFPConc5 
Appendix 16.2.6.1 
 
Individual <Matrix Analyte> Concentrations Versus Time  
for Subject X 
 


ARMGO Pharma Inc. 
S 48168 (ARM210), 
 
Celerion, Clinical Study Report No. 
 
 
Statistical Analysis Plan 12 December 2019 
Page 40 of 40 
Notes for Generating the Actual Individual Figure: 
 
Treatments 
• 
Treatment A: Single oral 120 mg S 48168 (ARM210) QD for 28 days (patients) 
• 
Treatment B: Single oral 200 mg S 48168 (ARM210) QD for 28 days (patients) 
• 
Treatment C: Single oral 120 mg S 48168 (ARM210) QD for 14 days (healthy subjects) 
• 
Treatment D: Single oral 240 mg S 48168 (ARM210) QD for 14 days (healthy subjects) 
 
• 
Y axis label will be <Matrix> <analyte> Concentration (unit) 
• 
X axis label will be “Hours From Dosing” 
• 
Reference line will not be included for the LOQ 
 
PKist Note: 
 
• 
Our standard is same scale for all subjects, but if one or 2 subjects are are driving the 
scale resulting in poor resolution for all other subjects, then it may be more 
appropriate to scale individual plots to each subject’s data. 
• 
Individual profiles will be generated with Days 1, 14, and/or 28 overlayed.  
• 
Please generate figures in color. Please use the same color and symbol for individual 
treatments/cohorts throughout. 
 
Program:  /CAXXXXX/sas_prg/pksas/indgraph-all.sas   
 
DDMMMYYYY  HH:MM 
Program:  /CAXXXXX/sas_prg/pksas/adam_indgraph.sas   
 
DDMMMYYYY  HH:MM