Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study Analyzing Pharmacokinetics at Three Dose Levels In Children and Adolescents With Assessment of Safety and Tolerability of Omigapil (CALLISTO)
Phase: PHASE1
Conditions: Congenital Muscular Dystrophy
Sponsor: Santhera Pharmaceuticals

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
1 
 
  
Congenital Muscular Dystrophy Ascending Multiple Dose Cohort 
Study anaLyzing Pharmacokinetics at three dose Levels In Children and 
Adolescents with Assessment of Safety and Tolerability of Omigapil 
(CALLISTO) 
 
   
 
 
 
 
 
 
 
 
Clinical Research Protocol 
 
Abbreviated Title: CALLISTO 
NIH Protocol Number: 15-N-0018 
Santhera Protocol Number: SNT-I-015 
Date of This Submission/Version (see header) 
IND Number: 113,370 
Eudract Number: 2012-002700-40 
Compound: Omigapil Hydrogen Maleate 
CRADA 2012-0097 (expiration 2020) 
 
 
 
 
 
 
 
 
 
 
Confidential 
Property of Santhera Pharmaceuticals (Switzerland) Ltd. 

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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Synopsis 
 
Study Title 
Congenital Muscular Dystrophy Ascending Multiple Dose Cohort 
Study anaLyzing Pharmacokinetics at three dose Levels In Children and 
Adolescents with Assessment of Safety and Tolerability of Omigapil 
Study Number 
SNT-I-015 
Study Phase 
1 
Study Acronym 
CALLISTO 
Planned Study Duration 84 weeks (16 weeks recruitment, 68 weeks study conduct). The above 
duration is assuming cohorts are dosed in staggered parallel.  
Patient participation will be up to 28 weeks (up to 4 weeks screening, 4 
weeks run-in, 12 weeks treatment and a follow-up visit 8 weeks post last 
dose taken) 
Investigational Product 
Dosage and Route of 
Administration 
Omigapil oral solution (0.1 and 0.25 mg/ml in Humco® Cherry Syrup)  
Dosage: 0.02, 0.08 and 0.2 mg/kg/day; maximum daily dose: 5 mg  
Oral administration once per day after breakfast 
Vehicle 
Humco Cherry Syrup 
Indication 
Congenital Muscular Dystrophy (CMD) 
Study Objectives 
 The primary objective is to establish the pharmacokinetic profile 
of omigapil at a range of doses in pediatric and adolescent patients 
with CMD 
 The secondary objective is to evaluate the safety and tolerability of 
omigapil at a range of doses in pediatric and adolescent patients  
 The tertiary objective is to establish the feasibility of conducting 
disease-relevant clinical assessments in pediatric and adolescent 
patients with CMD to aid in the design of future studies 
Study Endpoints 
 The Primary Endpoint is the pharmacokinetic profile of omigapil 
and metabolites quantified by Cmax, Cmin, tmax, t1/2, AUC0-t, AUC0-8h, 
AUC0-24h, λz (terminal phase rate constant) and Ro (the extent of 
accumulation in plasma) 
 The Secondary Endpoint is safety and tolerability of omigapil at 
the doses tested, established through the collection of Adverse 
Events (AEs) and Serious Adverse Events (SAEs), vital signs, 
oxygen saturation, standard lab parameters and electrocardiogram 
(ECG) assessments. 
 The Tertiary Endpoint is the outcome of disease-relevant clinical 
assessments.  
 
Hospital-based pulmonary function tests (PFTs) by standard spirometry.  
 
Home-based pulmonary function tests using a child-compatible hand-held device 
(ASMA-1).  
 
Hospital-based evaluation of muscle strength & function.    
 
Motor function scales.  

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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 
Time tests (ambulatory patients only).   
 
Functional Scales.  
 
Muscle Imaging (Muscle magnetic resonance imaging (MRI) and Muscle Ultrasound) 
 
Collection of biomarkers 
Number of Centers 
1 
Number of Subjects 
Patient Population 
Approximately 20 eligible patients will be randomly assigned to ensure 
a minimum of 16 patients who have completed all study procedures (3 
cohorts of 4, 4, and 8-12 patients) 
Inclusion Criteria 
 Ambulatory and non-ambulatory patients from age 5 - 16 years (5 
years old and <17 years old) at time of screening with a clinical 
picture (see below) consistent with COL6-related dystrophy 
(COL6-RD) or LAMA2-related dystrophy (LAMA2-RD) 
 Under regular review at a neuromuscular center  
 On adequate double-barrier contraception (if of child-bearing 
potential (CBP)) 
 Stable on any allowed concomitant medications for 1 month prior to 
run in phase 
 Forced Vital Capacity (FVC) 30-80% of the predicted value and 
confirmed at Screening and Baseline visit(s)  
 
For patients with Collagen VI-related dystrophy (COL6-RD)– required 
clinical picture 
 Muscle weakness: inability to walk or, if patient is still ambulatory, 
inability to run and > 5 s for 10 m walk 
 
Genetics and Pathology: 
 Molecular diagnosis of COL6-RD, defined by one dominant or two 
recessive mutation(s) in COL6A1, COL6A2 or COL6A3 known to 
cause the clinical picture,  
OR  
 
Histological diagnosis showing (i) absent or significantly decreased 
expression of collagen VI in muscle (overall reduction or basal 
lamina specific) or (ii) absent or significantly abnormal matrix in 
skin fibroblast culture  
 
For patients with Laminin alpha 2 related dystrophy (LAMA2-RD)  – 
required clinical picture 
 Muscle weakness: Inability to walk; if patient is still ambulatory, 
inability to run and > 5 s for 10 m walk. 
Genetics and Pathology: 
 Either: 2 identified pathologic or probable pathologic mutations in 
LAMA2 gene 
     OR  
 1 identified pathologic or probable pathologic mutation in LAMA 2 
gene with evidence of decrease in laminin alpha 2 staining on 
muscle or skin biopsy  

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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      OR 
 
Evidence of decrease in laminin alpha 2 staining on muscle or skin 
biopsy with matching clinical phenotype and no suspicion of alpha 
dystroglycanopathy (aDG-RD) (clinically or by staining on muscle 
biopsy) 
Exclusion Criteria 
 Use of any investigational drug other than the study medication 
within 12 weeks of study start. 
 Recurrent hospitalization for chest infections in previous 2 years (≥ 
2 per year) 
 Patients with respiratory parameters (eg: low pulmonary function 
test value i.e. <30% predicted or need for daytime non-invasive 
ventilation) currently affected by short term medications, or acute 
illness/ conditions (conduct baseline assessments when the patient 
has recovered and is no longer taking acute medication) 
 Any need for surgery (i.e. scoliosis, gastrostomy, other) in the 
preceding 24 weeks or foreseen during the course of the study. 
 Patient has an intercurrent significant medical condition or situation 
which in the opinion of the Investigator or the study Medical 
Monitor may put the patient at significant risk, confound the study 
results or interfere significantly with the patient’s participation in the 
study. 
 Failure to thrive, defined as: 
 
Falling 20 percentiles (20/100) in body weight in the 12 weeks preceding 
Screening/Baseline (based on family report of weight loss and review of relevant 
medical records) 
 
In patients below the 3rd percentile, any further drop in body weight percentile in the 
12 weeks preceding Screening/Baseline (based on family report of weight loss and 
review of relevant medical records) 
 Weight less than 17 kg at Baseline 
 Morbidly obese or grossly overweight (≥ 86 percentile body mass 
index (BMI) in children)  
 History 
of 
epilepsy 
or 
on 
antiepileptic 
medication 
at 
Screening/Baseline 
 Diabetes 
 On daytime Non Invasive Ventilation (NIV)  
 Intake of prohibited medication (as listed in Appendix I)  
 Anticipated need for anesthesia during the course of this study 
 Patients with renal impairment defined as urinary protein 
concentration ≥ 0.2 g/L  
 Patients with moderate to severe hepatic impairment.  
 
ALT ≥ 8x upper limit of normal (ULN) and total bilirubin 2x ULN (plus >35% ‘direct’ 
bilirubin), or  
 
ALT ≥ 8x ULN and INR >1.5 or ALT >2x baseline levels, and total bilirubin > 2x 
ULN (plus >35% ‘direct’ bilirubin),  
 
      or 
 
ALT >2x baseline levels, and INR greater than 1.5,  

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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 
      or 
 
ALT ≥ 8 x ULN and associated with symptoms of hepatitis (e.g. onset or worsening 
of nausea, anorexia, jaundice or abdominal pain) or hypersensitivity (e.g. fever, rash, 
eosinophilia),  
 
      or 
 
GGT > 2-3x ULN and bilirubin 2x ULN (plus >35% ‘direct’ bilirubin) or  
 
GGT >2-3x ULN and INR >1.5 
Participation Period 
28 weeks per patient – up to 4 weeks screening, 4 weeks vehicle 
(Humco Cherry Syrup) run-in phase followed by 12 weeks on 
omigapil and a follow-up visit 8 weeks after last dose. 
Study Design 
This study will be an open-label, sequential group, ascending oral dose, 
continual reassessment method (CRM) based model, pharmacokinetic, 
cohort study.  
A Data and Safety Monitoring Board (DSMB) will be established to 
monitor patient safety throughout the study. 
Pharmacokinetics 
Pharmacokinetic (PK) parameters of omigapil and metabolites, such as 
Cmax, Cmin, tmax, t1/2, AUC0-t, AUC0-8h, AUC0-24h*, λz and Ro (*if 
sufficient data are available) will be calculated.  
 
During the first 8 hours following initial intake of the study 
medication (Visit 2) 
and 
 
After 4 weeks of daily dosing, during 8 hours following study 
medication intake (Visit 3) 
 and  
 
After 12 weeks of daily dosing, during 8 hours following study 
medication intake (Visit 5) 
 On each occasion, 7 blood samples (1 pre-dose and 6 post-dose time 
points at 0.5, 1, 1.5, 2, 4, and 8 hours) will be collected; (3 ml per 
sample; 21 ml per visit).  
Safety Evaluations 
 Physical examination, vital signs including body temperature, ECG, 
pulse oximetry, laboratory assessments such as complete blood cell 
counts (CBC), comprehensive metabolic panel (CMP), liver 
ultrasound, urine analysis and AE collection 
Efficacy 
Feasibility 
Evaluations 
 Hospital-based pulmonary function tests by standard spirometry: 
Forced Vital Capacity (FVC), Slow Vital Capacity (SVC), Forced 
Expiratory Volume (FEV1), Peak Expiratory Flow (PEF), 
Maximum Inspiratory Mouth Pressures (MIP), Maximum 
Expiratory Mouth Pressures (MEP), Peak Cough Flow (PCF) and 
Sniff Nasal Inspiratory Pressure (SNIP). 
 Home-based pulmonary function tests using a child-compatible 
hand-held device (ASMA-1): PEF and FEV1  
 Hospital-based hand-held myometry: elbow flexion, elbow 
extension, knee flexion, knee extension, myotools/Moviplate 

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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 Hospital-based goniometry: knee extension/flexion contracture, 
elbow flexion contracture, ankle dorsiflexion 
 Hospital-based Timed tests: 2 minute walk and 10 meter walk 
 Hospital-based motor function scales: North Star, MFM 32, 
Performance Upper Limb (PUL) scale, Jebsen Hand Function Test 
 Hospital-based functional Tests: ACTIVLIM, Egen Klassification 
(EK2) 
 Muscle imaging (muscle ultrasound and muscle MRI) 
Study Procedures 
16-20 CMD patients (8-10 COL6-RD and 8-10 LAMA2-RD) whose 
weight, age, and FVC likely meet the inclusion/exclusion criteria will be 
notified of the study. Patients may be identified using known data from 
the annual Congenital Muscular Dystrophy natural history study (CMD 
Comparative Outcome Measure Study- CMD COM) at the NIH or 
through the CMDIR. Trial flyers will be distributed through an outreach 
organization Cure CMD as well as through other community contacts. 
Patients who have learned of the trial by any means, including 
clinicaltrials.gov and flyer distribution, may contact the investigators 
directly and be considered for screening. 
A pre-screening call will be scheduled to confirm interest to participate 
and to give verbal assent for release of medical records data within the 
NIH in order to confirm eligibility. Preliminary determination of 
eligibility at the pre-screening evaluation will include: patient age, 
patient disease type, current weight in kilograms, recent hospitalization 
history, any known/ planned upcoming surgical interventions, 
pulmonary function test data (specifically forced vital capacity), medical 
history (list of current additional known medical diagnoses), and list of 
current medications. Upon identifying a confirmed cohort of at least 8-
10 COL6-RD and 8-10 LAMA2-RD patients, each patient will be 
assigned a de-identified number.  
 
Two participant variables: CMD subtype and current weight (in 
kilograms) will be sent to the RAE. Patients will be stratified by disease 
type and weight and will be similarly represented. For each strata, one 
patient will be assigned from each strata to each dose-escalating group 
(cohort), so that the cohorts will have similar representation of disease 
type and weight, to ensure comparable PK, safety, tolerability and 
efficacy feasibility assessment data. In the event of a patient drop out, 
study investigators will replace the patient with another from the same 
stratum. Patients who discontinue study drug or express intent to 
withdraw will be asked to return for a final safety follow-up visit prior 
to withdrawal. Furthermore, patients who are withdrawn due to safety 
reasons (e.g. AE, SAE) will be followed up with safety calls and may be 
requested to return for study visits for safety assessments to be 
performed as necessary.  Thus, using this procedure, approximately 20 
CMD patients will be assigned to one of three dose-escalating cohorts 

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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of 4 patients, 4 patients, and 8-12 patients in order to obtain a total of 16 
to 20 patients completing the study. Each cohort will receive one of three 
doses of omigapil daily for 12 weeks.  
 
Patients will have the possibility to perform the screening and baseline 
visits combined or within a period of less than 6 days in order to allow 
for the laboratory results to be available to confirm patient eligibility. 
Up to 7 study visits will be required: Screening; Visit 1 - 
Baseline/initiation of run-in phase; Visit 2 - Week 4/ initiation of 
omigapil dosing; Visit 3 - Week 8 after 4 weeks of omigapil dosing; 
Visit 4 – Week 12 after 8 weeks of active treatment; Visit 5 – Week 16 
after 12 weeks of omigapil dosing; Visit 6 – Week 24, Follow-Up visit, 
8 weeks after stopping the drug.  
 
Patient management will be the same for all three Cohorts.   
 At Screening, which should take place no more than 4 weeks prior 
to Baseline/Visit 1, written informed consent/assent will be obtained 
and the eligibility of the patient will be assessed. For further details 
on procedures that will be done at this visit, see Section 4.3.3. 
 At Visit 1/ Baseline (or Screening/Baseline if the visits are combined 
or within 6 days of each other to allow for all information to confirm 
eligibility to be available such as laboratory results) patients will 
undergo the safety evaluations and efficacy feasibility assessment 
tests if the patient is capable of performing them.Patients will be 
dispensed a 4-weeks supply of vehicle (Humco Cherry Syrup) and 
given an appointment for Visit 2 (Day 1 of omigapil dosing). AEs 
will be collected during this run-in period for comparative purposes. 
To assist with AE capture and dosing compliance, patients and/or 
their caregivers will be asked to maintain a diary card (See Appendix 
H) throughout the study period. This will be reviewed at each visit. 
For further details on procedures that will be done at this visit, see 
Section 4.3.4. 
 At Visit 2/ Week 4, patients will repeat the safety evaluations. The 
first dose of omigapil will be given during this visit and PK sampling 
will also be initiated. 
o Blood samples for PK will be taken pre-dose and at 0.5, 1, 1.5, 
2, 4, and 8 hours post-dose.  
o Vital signs and oxygen saturation using a pulse oximeter will be 
monitored throughout the day and patients monitored for 
treatment emergent adverse events. 
o Patients will be dispensed sufficient omigapil for 4 weeks of 
omigapil dosing.   
 Interim Calls: A safety follow-up call will be made in weeks 5, 6 and 
7 (after approximately 1, 2 and 3 weeks of starting omigapil dosing) 
to elicit reporting of any treatment emergent adverse events. 

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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 At Visit 3/ Week 8 (after 4 weeks of omigapil dosing) an identical 
visit to Visit 2 with safety assessments and full PK sampling will be 
performed. 
 Interim Calls: A safety follow-up call will be made in weeks 9, 10 
and 11 (after approximately 5, 6 and 7 weeks of starting omigapil 
dosing) to elicit reporting of any treatment emergent adverse events. 
 
 DSMB Review: 
o After the first patient of each cohort has completed Visit 2, the 
PK samples collected at visit 2 will be sent to the laboratory for 
analysis. At that point, all available data from the PK analysis, 
safety and tolerability for the first patient of each cohort will be 
provided to the DSMB to ensure that the PK data reflects the 
expected PK profile and no major safety concerns are detected. 
The DSMB will make a recommendation on the continuation of 
the cohort at the planned dose. 
o Thereafter, as soon as the last patient in the cohort has had their 
Visit 3, the site will send all PK blood samples from all the 
patients dosed to the laboratory for analysis. 
o Data from the PK analyses, safety and tolerability from Baseline 
to Visit 3 will be provided to the DSMB for review once all 
necessary data is available. Based on this review the DSMB will 
make a recommendation (including any dose adjustments) on the 
initiation of the next cohort.  
o At subsequent meetings, the DSMB will be provided with all 
safety data from the completed and on-going cohort(s) in addition 
to PK data from the cohort under review. Patients in the cohort 
under review will continue their treatment uninterrupted during 
DSMB review unless Stopping Rules are invoked. 
 
 At Visit 4/ Week 12 Safety evaluations and efficacy feasibility 
assessments (as capable) will be conducted. PK sampling will not be 
done.   
 Interim Calls: A safety follow-up call will be made in weeks 13, 14 
and 15 (after approximately 9, 10 and 11 weeks of starting omigapil 
dosing) to elicit reporting of any treatment emergent adverse events. 
 At Visit 5/ Week 16 the patient will attend a half day hospital visit to 
do efficacy feasibility assessments (as capable) before returning to 
the clinic the next morning to do PK sampling as described for Visit 
2.   
 In Week 20 (approximately 4 weeks post omigapil dosing) the site 
will make a safety follow-up call. 
 At Visit 6/ Week 24 (8 weeks after study drug discontinuation) the 
patient will attend a final visit to the site (Visit 6) for a safety 
evaluation and efficacy feasibility assessment testing (as capable).  

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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Random 
Assignment 
Method 
This is an open-label, sequential group, ascending, multiple dose study 
in which Cohort 1 will complete at least the first 4 weeks of active 
treatment before Cohort 2 can be initiated; and in which Cohort 2 will 
complete the first 4 weeks of active treatment before Cohort 3 can be 
initiated.  Stratification methodology will be described in the Random 
Assignment Specification Guidelines. A random assignment expert 
(RAE) will be designated to perform the random assignment and will be 
trained on the Random Assignment Guidelines. The RAE will hold a 
master’s degree in statistics or be a pharmacist. 
 
In order to avoid possibility of bias being introduced whereby the patient 
demographics will not be similar across cohorts, random assignment of 
patients to 3 cohorts will take place once a minimum of 8-10 patients 
with COL6-RD and 8-10 patients with LAMA2-RD have been 
successfully pre-screened, have confirmed interest and intent to 
participate. Using the random assignment method, the entire group will 
be randomly assigned by the RAE to Cohorts 1, 2 and 3 after 
stratification using 2 patient variables: CMD subtype (COL6 or 
LAMA2) and current weight (kilograms). For each strata, the RAE will 
randomly assign one patient from each strata to each dose-escalating 
group (cohort), so that the cohorts will have similar representation of 
disease type and weight, to ensure comparable PK, safety, tolerability, 
and efficacy feasibility assessment data. Thus, using this procedure, 
approximately 20 CMD patients will be assigned to one of three dose-
escalating cohorts of 4 patients, 4 patients, or 8-12 patients in order to 
obtain a total of 16 to 20 patients completing the study. Each cohort will 
receive one of three doses of omigapil daily for 12 weeks. In the event 
of a patient drop out, study investigators will replace the patient with 
another from the same stratum. Patients who discontinue study drug or 
express intent to withdraw will be asked to return for a final safety 
follow-up visit prior to withdrawal.  Furthermore, patients who are 
withdrawn due to safety reasons (e.g. AE, SAE) will be followed up with 
safety calls and may be requested to return for study visits for safety 
assessments to be performed as necessary.  
Statistical Methods 
Random assignment and dosing will be initiated in 16-20 patients to 
obtain a total minimum of 16 patients (4+4+8) who will complete the 
pharmacokinetic sample schedule.  
 
This is a dose escalation study of omigapil in children and adolescent 
patients with CMD. It is planned that each participant will receive one 
of the 3 dose levels of omigapil (0.02 mg/kg, 0.08 mg/kg, or 0.2 mg/kg 
daily for 12 weeks).  This dose range is expected to include a dose that 
achieves patient exposure within the target  AUC0-24h  and  Cmax ranges. 
Dose determination will be based on the primary endpoint that a patient 
achieves a target AUC0-24h range (3-33 ng.h/mL). Assuming dose-

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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proportional PK, based on data from 10 mg/kg by mouth (Novartis Study 
0110073), the efficacious exposure range is expected to be in the in the 
range of 3-33 ng.h/mL (Cmax 1.5-15 ng/ml)  although based on animal 
modelling data, exposure at the upper end of this range is expected to be 
most efficacious (See Section 1.3 – Justification for dose for further 
details). The doses may be adjusted following the PK observed at the 
previous dose (see section 8.1). We aim to identify a dose under which 
the majority (90%) of patients will achieve the target AUC0-24h range.   
 
Four subjects will be treated at 0.02 mg/kg (level 1), and in case of no 
toxicity, dose escalation will occur after every 4 subjects until one or 
more patients exceed the target AUC0-24h range. When this occurs, 
subsequent dose levels will be determined from the observed PK. 
Subsequent patients will be enrolled in groups of 4 using a CRM-type 
dose escalation/reduction design with the possibility to interpolate 
between pre-specified doses (Cheung, 2011).  The proposed dose 
escalation algorithm adapts from a CRM-like algorithm called SAVOR 
that aims to identify a dose exceeding 33 ng.h/ml with 10% probability 
or less (Cheung, 2010). The upper end of the 3-33 ng.hr/ml will be 
targeted because some of the animal modelling (in  CMD-relevant 
models) showed higher efficacy at 1 mg/kg compared to 0.1 mg/kg 
(Investigator Brochure, section 4.2.4). We will plan to enroll up to 20 
patients, or when 8-12 subjects are enrolled to the dose shown to result 
in the target AUC0-24h range (which may be less than the highest dose). 
Figure 1 (Section 10.10.3) shows the operating characteristics using 
simulation of SAVOR with 20 patients with group size of 4.  Subjects 
who drop out will be replaced to meet a minimum requirement of 16 
patients who complete the current study and will be chosen based upon 
their CMD subtype and weight in kg.   
 
Patients will be stratified according to disease type and weight. 
 
There will be no placebo group and assessment of safety and tolerability 
will include analysis of relevant data from the run-in periods for all 
cohorts. 
 
Incidences of AEs/SAEs, severity and relationship of AEs/SAEs to 
study medication, and early withdrawal due to AEs/SAEs will be 
summarized using frequencies and percentages for each dose level of 
study medication and for the run-in periods. Incidences, laboratory 
abnormalities and physical examination results will be presented by visit 
for each dose level of study medication. ECG parameters will be 
summarized for each dose level using descriptive statistics. 
 Pharmacokinetic parameters Cmax, Cmin, tmax, t1/2, AUC0-t, AUC0-8h, 
AUC0-24h*, λz, and Ro (*if sufficient data are available) will be 

PI name: Carsten G. Bönnemann, MD 
 
                  Date: 01-Dec-2017 
NIH Protocol number: 15-N-0018                                                                                                                  
NIH Version: 16 
Santhera Protocol number: SNT-I-015                                                                                                                        Santhera Version: 10 
 
 
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calculated and summarized by dose level of study medication using 
descriptive statistics. 
 
 
Details of the planned analyses of the PK samples will be included in a 
separate Pharmacokinetic Analysis Plan. 
 
Details of the planned analyses of the safety and efficacy data from the 
efficacy feasibility assessments will be outlined in a separate Statistical 
Analysis Plan.