Clinical trial NCT01805024
Conditions: Congenital Muscular Dystrophy
Sponsor: Santhera Pharmaceuticals
Start date: 2014-12-01; Completion date: 2018-01-29
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to establish the pharmacokinetic profile of omigapil in paediatric and adolescent patients with CMD and to evaluate the safety and tolerability of omigapil.

Funding source - FDA OOPD

Detailed description:

Arms: arm 1: Omigapil treatment oral administration once per day after breakfast Cohort 1 Cohort 1 0.02 mg/kg/day Cohort 2 0.08 mg/kg/day Cohort 3a 0.04 mg/kg/day Cohort 3b 0.06 mg/kg/day
Interventions: intervention 1: Omigapil
Intervention descriptions: intervention 1: Cohort 1 0.02 mg/kg/day Cohort 2 0.08 mg/kg/day Cohort 3a 0.04 mg/kg/day Cohort 3b 0.06 mg/kg/day

Protocol documents:
Prot_000.pdf: 
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 
 
 
28 
 
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 
 
 
29 
 
 
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. 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study analysing 
Pharmacokinetics at three dose Levels in Children and Adolescents with Assessment of 
Safety and Tolerability of Omigapil 
(CALLISTO) 
 
 
Study code: SNT-I-015 
 
Phase I study 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 


 
Statistical Analysis Plan 
            Page 2 (18) 
 
Sponsor: Santhera Pharmaceuticals 
Final 1.0 
29AUG18 
Study: CALLISTO 
 
 
 
 
Signatures: 
 
 
Statistical Analysis Plan was prepared by: 
 
 
 
Sofia Männikkö 
Study Statistician, Oy 4Pharma Ltd. 
Date 
 
 
 
Statistical Analysis Plan was reviewed/approved by: 
 
 
 
Senior Statistician 
Date 
 
 
 
Responsible person from the Sponsor 
Date 
 
 
 
Principal Investigator 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
            Page 3 (18) 
 
Sponsor: Santhera Pharmaceuticals 
Final 1.0 
29AUG18 
Study: CALLISTO 
 
 
 
Table of Contents 
 
1 
Abbreviations................................................................................................................................. 4 
2 
Introduction ................................................................................................................................... 5 
3 
Study objectives ............................................................................................................................. 5 
4 
Design and type of the study ......................................................................................................... 5 
5 
Sample size considerations ............................................................................................................ 5 
6 
Analysis sets .................................................................................................................................. 6 
6.1 
Intention-to-treat (ITT) dataset ............................................................................................... 6 
6.2 
Pharmacokinetic (PK) dataset ................................................................................................. 6 
6.3 
Safety dataset .......................................................................................................................... 6 
7 
Disposition of patients ................................................................................................................... 6 
8 
Demographic and other baseline characteristics ........................................................................... 6 
9 
Concomitant medication/treatment................................................................................................ 7 
10 
Extent of exposure and compliance ........................................................................................... 7 
11 
Pharmacokinetics ....................................................................................................................... 7 
12 
Analysis of safety and tolerability .............................................................................................. 7 
12.1 
Adverse events ................................................................................................................. 7 
12.2 
Laboratory safety variables .............................................................................................. 7 
12.3 
Other safety variables ....................................................................................................... 8 
13 
Disease relevant clinical assessments ........................................................................................ 8 
13.1 
Respiratory function testing (hospital spirometry)........................................................... 8 
13.2 
Respiratory function testing (handheld ASMA-1 device) .............................................. 11 
13.3 
Muscle strength and motor function testing ................................................................... 12 
14 
Deviations from the analyses planned in the study protocol .................................................... 14 
15 
Execution of statistical analyses ............................................................................................... 14 
16 
Hardware and software ............................................................................................................. 14 
17 
References ................................................................................................................................ 14 
18 
Appendices ............................................................................................................................... 15 
18.1 
Table and figure plan (section 14 in the Study report) ................................................... 15 
18.2 
Data listing plan (section 16 in the Study report) ........................................................... 18 
 


 
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1 
Abbreviations 
AE 
 
Adverse Event 
AESI               Adverse Event of Special Interest 
ATC  
Anatomical Therapeutic Chemical 
AUC  
Area Under the Curve 
BMI 
 
Body Mass Index 
CMD  
Congenital Muscular Dystrophy 
COL6-RD 
Collagen 6-related dystrophies and myopathies 
CRM  
Continual Reassessment Method 
CV 
 
Coefficient of Variation 
EK2 
 
Egen Klassification 2  
FEV1  
Forced Expiratory Volume during first second of the forced breath 
FVC  
Forced Vital Capacity 
HHM  
Hand held myometry 
IFR 
 
Inspiratory Flow Reserve 
ITT 
 
Intention to Treat 
JHFT   
Jebsen Hand Function Test 
LAMA2-RD Laminin Alpha 2-related dystrophy 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEP  
Maximum Expiratory Pressure 
MFM   
Motor Function Measure 
MIP 
 
Maximum Inspiratory Pressure 
PCF 
 
Peak Cough Flow 
PEF 
 
Peak Expiratory Flow 
PK 
 
Pharmacokinetic 
PP 
 
Per Protocol 
PT 
 
Preferred Term 
PUL   
Performance Upper Limb 
QTcF  
QT corrected for HR using Fridericia’s method 
QTcB  
QT corrected for HR using Bazett’s method 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SD 
 
Standard Deviation 
SOC  
System Organ Class 


 
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SVC  
Slow Vital Capacity 
TEAE  
Treatment Emergent Adverse Event 
 
2 
Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analyses to be conducted for study 
SNT-I-015, an exploratory phase I study of omigapil. The statistical methods were prospectively 
planned in the study protocol. This SAP was written during the study conduct and the authors and 
reviewers of the SAP had access to the study data. This SAP serves as documentation of statistical 
methods used to derive the endpoints and summarize the study data. 
3 
Study objectives 
The study objectives were defined in the study protocol. The primary objective of the study is to 
establish the pharmacokinetic (PK) profile of omigapil in a range of doses in paediatric and 
adolescent patients with Congenital Muscular Dystrophy (CMD). The secondary objective is to 
evaluate the safety and tolerability of omigapil at a range of doses in paediatric and adolescent 
patients. The tertiary objective is to establish the feasibility of conducting disease-relevant clinical 
assessments in paediatric and adolescent patients with CMD to aid in the design of future studies. 
4 
Design and type of the study 
Study SNT-I-015 is a phase I, open-label, sequential group, ascending oral dose, continual 
reassessment method (CRM) based model, PK, cohort study with patients randomly assigned to one 
of the three dose cohorts.  
Dose levels were to be defined based on the following rules. Four subjects were to be treated at 0.02 
mg/kg (level 1) daily for 12 weeks. In case of no toxicity, dose escalation would occur after every 4 
subjects until one or more patients exceed the target AUC0-24h range. When exceeding the target 
range, subsequent dose levels were to be determined from the observed PK. Subsequent patients 
were to 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). As a result, 4 dose levels of 
omigapil were used for the randomized groups in the following order, along the study, (0.02 mg/kg, 
0.08 mg/kg, 0.04 mg/kg, 0.06 mg/kg). 
Patients were stratified by disease type (Laminin Alpha 2-related dystrophy [LAMA2-RD] or 
Collagen 6-related dystrophies and myopathies [COL6-RD]) and weight and will be similarly 
represented. One patient was to be assigned from each stratum 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. 
5 
Sample size considerations 
A total of 16-20 evaluable patients were planned to be accrued using a CRM-type dose 
escalation/reduction design with the possibility to interpolate between pre-specified doses. The 
proposed dosing schedule adapts from a CRM-like algorithm called SAVOR (Cheung, Elkind, 
2010) that aims to identify a dose exceeding AUC0-24h of 33 ng h/ml with a probability of 10% or 
less. The upper end of the AUC0-24h of 3-33 ng h/ml was targeted because animal modelling in 


 
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CMD-relevant models showed higher efficacy at 1 mg/kg compared to 0.1 mg/kg. By enrolling up 
to 20 patients, 8-12 subjects were to be assigned to the dose predicted to result in the target AUC0-
24h range (which may be less than the highest dose).  
6 
Analysis sets 
6.1 
Intention-to-treat (ITT) dataset 
The ITT dataset will include all enrolled patients who received at least one dose of the study 
medication and completed at least one post-baseline assessment. The ITT dataset will be used for all 
analyses related to disease relevant clinical assessments. 
6.2 
Pharmacokinetic (PK) dataset 
The PK dataset will include all enrolled patients who received at least one dose of the study 
medication and completed at least one PK assessment. However, a review of dosing information 
will be performed by the investigator to consider excluding data in any period or on any day where 
a subject was judged to have received <80 % or >120% of the scheduled dose of the investigational 
product. Plasma concentration data will be excluded if concentrations are extremely low relative to 
other subjects’ data; in these cases plasma concentrations will be excluded from all or part of the 
profile, as appropriate. The PK dataset will be used for all PK analyses. 
6.3 
Safety dataset 
The Safety dataset will include all enrolled patients who received at least one dose of study 
medication. Safety dataset will be used for all the safety analyses. 
7 
Disposition of patients 
The number of patients enrolled into the study at screening, the number of patients who failed the 
screening and the reasons for screening failures will be summarized. The number of patients 
entering and completing the study will be summarized by dose level and overall. Also, the number 
of patients who discontinued prematurely, the reasons for premature discontinuations and 
replacement information will be summarized by dose level and overall. The disposition data will 
also be presented in a listing format. 
8 
Demographic and other baseline characteristics 
All demographic and other baseline characteristics (age, height, weight, body mass index [BMI], 
gender, ethnicity, race, child-bearing potential, ambulatory status, disease type (LAMA2-RD or 
COL6-RD), time since CMD diagnosis and use of respiratory aid [Bi-Pap]) will be listed by dose 
level and summarized with descriptive statistics by dose level. The physical examination findings, 
medical history and pregnancy test results will be listed by dose level.  
Age will be calculated using month of birth and month of baseline (screening) visit as difference in 
months between baseline and time of birth divided by 12. Height will be estimated from ulna length 
by using the following formulas (Gauld, 2003, 2004): 
Height (male, age <20) = ((4.605* ulna length [cm]) + (1.308 * age [years]) + 28.003 


 
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Height (female, age < 20) = ((4.459* ulna length [cm]) + (1.315 * age [years]) + 31.485. 
Height and weight will also be presented as percentages of normal growth at the age of the patient 
(Clinical Growth Charts, U.S. National Center for Health Statistics). 
9 
Concomitant medication/treatment 
Concomitant medication and treatments are coded to WHO drug dictionary version September 
2017, and will be listed by dose level, including the Preferred term and ATC classification levels 1 
and 4.  
10 Extent of exposure and compliance 
The extent of exposure will be summarized based on the duration of study treatment (days). The 
duration of study treatment will be listed and summarized with descriptive statistics by dose level.  
Compliance will be evaluated as percentage of the daily doses taken (calculated from the estimated 
volume withdrawn from the bottle and daily dosing volumes) since previous visit. Patients with 
compliance of 80-120% are considered as compliant. The compliance (as %) will be listed by dose 
level. In addition, the proportion of compliant patients will be tabulated by dose level. 
11 Pharmacokinetics 
The analysis of the PK parameters is described in a separate PK Analysis Plan (Appendix 18.3).  
12 Analysis of safety and tolerability 
12.1 
Adverse events 
All recorded adverse events (AEs) will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA version 20.1). All treatment emergent AEs (TEAEs), i.e. events 
starting or worsening during study treatment or follow-up will be listed by dose level and tabulated 
by dose level, system organ class (SOC) and preferred term (PT). Both patient and event counts will 
be included in the tabulations. In addition, tabulations by severity and causality will be provided. 
Serious TEAEs (SAEs) and TEAEs leading to discontinuation of study treatment will be 
summarized as data listings. The AEs occurring during the run-in period will be listed separately.  
Adverse events of special interest (AESI) will be summarized by dose level, SOC and PT. Also a 
listing with PFT information from all visits during the study will be presented together with the AE 
information for subjects experiencing AESI. The following preferred term will be considered as 
AESI: Pulmonary function test decreased.  
12.2 
Laboratory safety variables 
All laboratory data will be listed by dose level. In addition, descriptive statistics of routinely 
measured laboratory safety variables at each visit will be computed. Both the absolute values and 
changes from baseline will be summarized by dose level. Frequencies of out-of-range values (low, 
normal or high) and clinically significant values defined by the investigator will be summarized by 
dose level and visit as shift tables.  


 
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12.3 
Other safety variables 
ECG results (Heart rate, PR, QRS, RR, QT, QTcF and QTcB times) will be listed by dose level and 
summarized with descriptive statistics by dose level using absolute values and changes from 
baseline to post-baseline pre-dose values. Moreover, the changes within each visit from pre to post-
dose will be summarized. The ECG interpretation (Normal, Abnormal but not clinically significant 
or Abnormal and clinically significant) and abnormal QTcF and QTcB results (values >500 ms or 
changes of >30 ms and of > 60 ms) will be listed by dose level and summarized by visit, time point 
and dose level as shift tables. The QTcF and QTcB times will be calculated based on the following 
formulas:  
QTcF = QT / RR1/3 
QTcB = QT / RR1/2, 
where RR = 60 / HR. 
Vital signs results (ulna length, height based on ulna length, weight, saturation of peripheral 
oxygen, blood pressure, heart rate, respiratory rate, body temperature, ability to stand, ambulatory 
status) will be listed by dose level and summarized descriptively by visit, time point and dose level. 
Absolute values, changes from baseline to post-baseline pre-dose values and within visit changes 
from pre- to post-dose values will be presented in the summaries. 
Liver abdominal ultrasound results (liver span, echogenicity, presence of cysts and tumours, bile 
duct dilatation, gallbladder filled, presence of stones and portal vein dilatation) will be listed by 
dose level and summarized descriptively by dose level and visit. For the last visit, information on 
changes in the ultrasound from baseline will be listed.  
13 Disease relevant clinical assessments 
All disease relevant clinical assessment variables will be summarized as data listings by dose level. 
In addition, descriptive statistics/ frequency tables will be included when appropriate. Both absolute 
values and changes from baseline (if feasible) will be presented. The descriptive statistics/ 
frequency tables will be broken down by visit. Relevant background status (age of the patient, 
ambulatory status and type of disease) and AUC0-24h information from PK analysis of plasma 
concentrations vs time profiles of omigapil will be included in the listings. 
13.1 
Respiratory function testing (hospital spirometry) 
Respiratory function tests will be presented as non-normalized values and as percentages of 
predicted values for Peak Expiratory Flow (PEF), Forced Vital Capacity (FVC), Forced Expiratory 
Volume during first second of the forced breath (FEV1), Maximum Expiratory Pressure (MEP) and 
Maximum Inspiratory Pressure (MIP).  The equations presented in table 13.1.1 will be used for 
calculation of the percent predicted values. For the equations presented by race, the Caucasian 
equation will be used also for the Asian subjects. Due to loss of ambulation/ loss of ability to stand, 
the height will be estimated from the ulna length for all subjects. Age and height used in the 
equations will always be the age at the time of the measurement and calculated using month of birth 
and month of assessment date as time difference in months divided by 12. 
 
 
 
 


 
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Table 13.1.1 Percent predicted equations for respiratory function tests 
Value 
(Reference) 
Formula 
PEF%p 
 
(Hankinson, 1999) 
Caucasian 
Male (age < 20 years):  PEF/((-0.5962–(0.12357*age)) + (0.013135* 
(age^2))+((0.00024962*(height^2))*1))/60*100 
Female (age < 18 years): PEF/((-3.6181+(0.60644*age))-(0.016846* 
(age^2))+((0.00018623*(height^2))*1))/60*100 
 
Black or African-American 
 
Male (age < 20 years):  PEF/((-0.2684–(0.28016*age))+(0.018202*(age^2)) 
+((0.00027333*(height^2))*1))/60*100 
Female (age < 18 years): PEF/((-1.2398+(0.16375*age))+ 
((0.00019746*(height^2))*1))/60*100 
 
FVC%p 
 
(Hankinson 1999) 
Caucasian 
Male (age < 20 years): FVC*100/((-0.2584-( 0.20415*age))+(0.010133* 
(age^2))+((0.00018642*(height^2))*1)) 
 
Female (age < 18 years): FVC*100/((-1.2082+(0.05916*age)) 
+((0.00014815*(height^2))*1)) 
 
Black or African American 
Male (age < 20 years): FVC*100/((-0.4971-(0.15497*age))+ 
(0.007701*(age^2))+((0.00016643*(height^2))*1)) 
 
Female (age < 18 years): FVC*100/((-0.6166-(0.04687*age))+ 
(0.003602*(age^2))+ (0.00013606*(height^2))*1)) 
 
 
MEP%p (age < 18) 
 
(Domenech-Clar, 
2003) 
Male:  MEP*100/(7.619+(7.806*age)+(0.004*height*weight)) 
Female:  MEP*100/(17.066+(7.220*age)) 
 
MIP%p 
 
(Domenech-Clar, 
2003) 
Male:   -MIP*100/(–27.020–(4.132*age)–(0.003*height*weight)) 
Female:   -MIP*100/(–33.854–(1.814*age)–(0.004*height*weight)) 
FEV1%p 
 
(Hankinson 1999) 
Caucasian 
Male (age < 20 years): FEV1*100/((-0.7453-(0.04106*age))+ 
(0.004477*(age^2 ))+((0.00014098*(height^2))*1)) 


 
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Value 
(Reference) 
Formula 
 
Female (age < 18 years): FEV1*100/((-0.8710+(0.06537*age))+ 
((0.00011496*(height^2))*1)) 
 
Black or African American 
Male (age < 20 years): FEV1*100/((-0.7048-(0.05711*age))+ 
(0.004316*(age^2))+((0.00013194*(height^2))*1)) 
 
Female (age < 18 years): FEV1*100/((-0.9630+(0.05799*age))+ 
((0.00010846*(height^2))*1)) 
 
The highest respiratory function test value at each visit will be used in the calculations.  
Percent predicted values for PCF will be counted by using the 50th percentiles by age presented in 
table 12.1.2 (Bianchi, 2008) with the following formula: PCF%p = PCF*100/ 50th percentile for the 
age. Age used in defining the percentiles will be the age at the time of the measurement and 
calculated with precision using month of birth and month of assessment date. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 13.1.2 Percentile values of peak cough flows (liters/min) by gender and age (Bianchi 2008) 
 
Additionally, Slow Vital Capacity (SVC) will be evaluated as non-normalized values and 
Inspiratory Flow Reserve (IFR) both as a fraction and as absolute based on the following formulas:  
IFR, fraction (%) = (1 – (V’I, max (t)/ V’I, max (FVC)) *100 
IFR, absolute = V’I, max (FVC) – V’I, max (t). 
The best values on the CRF, i.e. the lowest V’I, max (t) and the highest V’I, max (FVC) will be 
used in the calculations.  
For all respiratory parameters, information of use of respiratory aid (Bi-Pap) will be given in the 
data listings.  
13.2 
Respiratory function testing (handheld ASMA-1 device) 
PEF and FEV1 will be presented as non-normalized values and as percent predicted (see equations 
in 12.1.1). Information of use of respiratory aid (Bi-Pap) will be given in the data listings.  


 
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13.3 
Muscle strength and motor function testing 
13.3.1 Hand-Held Myometry (HHM) 
Knee extension, knee flexion, elbow extension and elbow flexion, measured in Newton units will be 
presented separately for right and left side. Also, total lower limb score and upper limb score as the 
sum of extension and flexion results, will be summarized. Upper limb results will also be presented 
by dominant side. Normalized values (as percentage of normal HHM) will be given for both 
extension and flexion results. For normalization, the HHM results will be scaled by weight (i.e. 
knee flexion (N)/ weight (kg)). Average normal HHM values scaled by weight presented by 
Beenakker (2001) will be used as reference for children aged 4-16. For adults the following 
formulas from NIH, previously presented by Bohannon (1997), for normalization will be used:    
Knee flexors 
No formula for adults 
Knee extensors 
(KE) %p, Female 
Dominant side: ((KE/ weight)/(465.22-84.7-(4.803*age) 
+(0.325*(4.4482216*weight))))*100 
Non-dominant side: ((KE/ weight)/(480.7-95-
(4.868*age)+(0.31*(4.4482216*weight))))*100 
Knee extensors 
(KE) %p, Male 
Dominant side: ((KE/weight)/(465.22-(4.803*age) 
+(0.325*(4.4482216*weight))))*100 
Non-dominant side: ((KE/weight)/(480.7-(4.868*age) 
+(0.31*(4.4482216*weight))))*100 
Elbow flexion (EF) 
%p, Female 
Dominant side: ((EF/weight)/(188.36-96.5-(0.61*age) 
+(0.14*(4.4482216*weight))))*100 
Non-dominant side: ((EF/weight)/(188.25-89.2-
(0.65*age)+(0.132*(4.4482216*weight))))*100 
Elbow flexion (EF) 
%p, Male 
Dominant side: ((EF/weight)/(188.36-(0.61*age) 
+(0.14*(4.4482216*weight))))*100 
Non-dominant side: ((EF/weight)/(188.25-(0.65*age) 
+(0.132*(4.4482216*weight))))*100 
Elbow extensors 
(EE) %p, Female 
Dominant side: ((EE/weight)/(156.49-73-(1.032*age) 
+(0.116*(4.4482216*weight))))*100 
Non-dominant side: ((EE/weight)/(150.37-71.5-
(1.044*age)+(0.126*(4.4482216*weight))))*100 
Elbow extensors 
Dominant side: ((EE/weight)/(156.49-(1.032*age) 


 
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(EE) %p, Male 
+(0.116*(4.4482216*weight))))*100 
Non-dominant side: ((EE/weight)/(150.37-
(1.044*age)+(0.126*(4.4482216*weight))))*100 
 
13.3.2 Goniometry 
Goniometry results include measurements of knee extension, elbow extension and ankle 
dorsiflexion, and the results are presented as grades by side (right/left). 
13.3.3 Myotools 
The Myotools results will be presented as grip strength (kg) and as key pinch (kg) for the dominant 
hand. 
13.3.4 Motor function scales 
Jebsen Hand Function Test (JHFT) will be presented as a total score (sec) separately for dominant 
and non-dominant hand. In addition, data from all subtests will be only listed (without descriptive 
statistics). For Performance Upper Limb (PUL) and North Star Ambulatory Assessment, total 
scores will be presented. Moviplate test score values will be presented separately for the dominant 
hand.  
Motor Function Measures (MFM32 or MFM20) will be presented both separately for each 
dimension (D1 Standing and Transfer, D2 Axial and Proximal Motor Function, D3 Distal Motor 
function) and as a total score, as % of highest possible scores. In MFM32 the highest possible 
scores by dimension and in total are D1: 39, D2: 36, D3: 21 and Total: 96. In MFM20 the highest 
possible scores by dimension and in total are D1: 24, D2: 24, D3: 12 and Total: 60. 
13.3.5  Timed tests 
The walking distance at 1 and 2 minutes will be presented as meters. In case the subject did not 
complete the test, the distance at the time the test was stopped will be used for the first missing 
distance value for the calculation of the descriptive statistics. In this case, the time elapsed when the 
test was stopped will be shown in the listings. 
The time to complete the 10-meter run test and the time to stand from supine will be presented as 
seconds. In case the subject did not complete the test, the time will be set as missing for the 
calculation of the descriptive statistics. 
Both timed tests will be performed only for ambulatory subjects. Other reasons for not performing 
the test will be summarized in the listings.  
13.3.6 Function scales 
The total scores of ACTIVLIM and the Egen Klassification 2 (EK2) will be presented. In addition, 
the distribution of individual scores by question will be tabulated and the individual scores listed.   


 
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14 Deviations from the analyses planned in the study protocol 
Per protocol analysis will not be conducted because the disease relevant clinical assessments are a 
tertiary objective of the study, there is no primary disease relevant clinical assessment and while a 
protocol deviation which is relevant for one organ system may not be relevant for another organ 
system, definition of a per protocol population is not feasible. Instead, relevant deviations 
potentially affecting the disease relevant clinical assessments will be discussed case by case on an 
individual patient and assessment level where appropriate. 
15 Execution of statistical analyses 
Statistical analyses will be performed by Oy 4Pharma Ltd and/or Santhera Pharmaceuticals.  
16 Hardware and software 
Statistical analysis, tables and patient data listings will be performed with SAS® version 9.3 or 
higher for Windows (SAS Institute Inc., Cary, NC, USA). 
17 
References 
Bianchi C, Baiardi P. (2008) Cough peak flows: standard values for children and adolescents. Am J 
Phys Med Rehabil.87(6):461-7. 
Bohannon RW. (1997) Reference values for Extremity Muscle Strength Obtained by Hand-Held 
Dynamometry From Adults Aged 20 to 70 Years, Arch Phys Med Rehabil Vol 78, January 1997.  
Cheung YK. Dose Finding by the Continual Reassessment Method (2011) New York: Chapman & 
Hall. 
 
Cheung YK, Elkind MS. (2010) Stochastic approximation with virtual observations for dose-
finding on discrete levels Biometrika 97(1):109-121. 
Clinical Study Protocol, Final Protocol (01-Dec-2017), Santhera Pharmaceuticals. 
Domènech-Clar R, López-Andreu JA, Compte-Torrero L, De Diego-Damiá A, Macián-Gisbert V, 
Perpiñá-Tordera M, et al. (2003) Maximal static respiratory pressures in children and adolescents. 
Pediatr Pulmonol. 35(2):126-32. 
Gauld LM, Kappers J, Carlin JB, Robertson CF. (2003) Prediction of childhood pulmonary function 
using ulna length. Am J Respir Crit Care Med. 168(7):804-9. 
 
Gauld LM, Kappers J, Carlin JB, Robertson CF. (2004) Height prediction from ulna length. Dev 
Med Child Neurol. 46(7):475-80. 
Hankinson JL, Odencrantz JR, Fedan KB. (1999) Spirometric Reference Values from a Sample of 
the General U.S. Population. Am J Respir Crit Care Med Vol 159: 179–187. 
 
 
 


 
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18 
Appendices 
18.1 
Table and figure plan (section 14 in the Study report) 
 
14.1 Demographic data 
Table 14.1.1.1 Disposition of subjects  
Table 14.1.2.1 Demography and baseline characteristics 
Table 14.1.3.1 Analysis datasets  
Table 14.1.4.1 Medical history 
Table 14.1.5.1 Prior medication and treatments 
Table 14.1.5.2 Concomitant medication and treatments 
Table 14.1.6.1 Physical examination 
Table 14.1.7.1 Pregnancy test results 
Table 14.1.8.1 Protocol deviations 
Table 14.1.9.1 Compliance to study treatment  
 
14.2 Safety data 
14.2.1 Extent of exposure 
Table 14.2.1.1 Extent of exposure 
14.2.2 Adverse events 
Table 14.2.2.1 Summary of all adverse events 
Table 14.2.2.2 Treatment emergent adverse events by SOC and PT 
Table 14.2.2.3 Treatment emergent adverse events by PT 
Table 14.2.2.4 Treatment emergent adverse events by PT and severity 
Table 14.2.2.5 Treatment emergent adverse events by PT and causality 
Listing 14.2.2.6 Serious treatment emergent adverse events 
Listing 14.2.2.7 Treatment emergent adverse events leading to discontinuation of study treatment 
Table 14.2.2.8 Treatment emergent adverse events of special interest 
Listing 14.2.2.9 Run-in emergent adverse events 
14.2.3 Laboratory results 
Table 14.2.3.1 Descriptive statistics of laboratory results 
Table 14.2.3.2 Shift table for out of reference range laboratory values 
Table 14.2.3.3 Shift table for clinically significant values  
14.2.4 ECG results 


 
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Table 14.2.4.1 Descriptive statistics of heart rate 
Table 14.2.4.2 Descriptive statistics of PR 
Table 14.2.4.3 Descriptive statistics of QRS 
Table 14.2.4.4 Descriptive statistics of RR 
Table 14.2.4.5 Descriptive statistics of QT 
Table 14.2.4.6.1 Descriptive statistics of QTcF 
Table 14.2.4.6.2 Abnormal QTcF values  
Table 14.2.4.7.1 Descriptive statistics of QTcB 
Table 14.2.4.7.2 Abnormal QTcB values 
Table 14.2.4.8 ECG interpretation 
14.2.5 Vital signs 
Table 14.2.5.1 Descriptive statistics of ulna length, height based on ulna length and weight 
Table 14.2.5.2 Descriptive statistics of saturation of peripheral oxygen 
Table 14.2.5.3 Descriptive statistics of blood pressure, heart rate, respiratory rate and body 
temperature 
Table 14.2.5.4 Frequency distributions of being able to stand and ambulatory status 
14.2.6 Liver abdominal ultrasound results 
Table 14.2.6.1 Frequencies for findings in liver abdominal ultrasound results  
 
14.3 Disease relevant clinical assessments 
14.3.1 Respiratory function tests 
Table 14.3.1.1 Descriptive statistics respiratory function tests 
Figure 14.3.1.2 Individual line plots by cohort for respiratory function tests 
14.3.2 ASMA-1 results 
Table 14.3.2.1 Descriptive statistics of ASMA-1 results 
Figure 14.3.2.2 Individual line plots by cohort for ASMA-1 results 
14.3.3 Muscle strength and motor function testing 
Table 14.3.3.1 Descriptive statistics of Hand-Held Myometry 
Table 14.3.3.2 Descriptive statistics of Goniometry results 
Table 14.3.3.3 Descriptive statistics of Myogrip results 
Table 14.3.3.4 Descriptive statistics of Jebsen Hand Function Test  
Table 14.3.3.5 Descriptive statistics of Performance Upper limb assessment 
Table 14.3.3.6 Descriptive statistics of North Star Ambulatory Assessment 
Table 14.3.3.7 Descriptive statistics of Moviplate test score 


 
Statistical Analysis Plan 
            Page 17 (18) 
 
Sponsor: Santhera Pharmaceuticals 
Final 1.0 
29AUG18 
Study: CALLISTO 
 
Table 14.3.3.8 Descriptive statistics of Motor Function Measure 
14.3.4 Timed tests 
Table 14.3.4.1 Descriptive statistics of 2 min walking test distances 
Table 14.3.4.2 Descriptive statistics of 10 m run test results 
14.3.5 Function scores 
Table 14.3.5.1 Descriptive statistics of ACTIVLIM results 
Table 14.3.5.2 Descriptive statistics of Egen Klassification 2 results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
            Page 18 (18) 
 
Sponsor: Santhera Pharmaceuticals 
Final 1.0 
29AUG18 
Study: CALLISTO 
 
18.2 
Data listing plan (section 16 in the Study report) 
16.2.1 Demographic listings 
Listing 16.2.1.1 Inclusion criteria 
Listing 16.2.1.2 Exclusion criteria 
Listing 16.2.1.3 Medical history 
Listing 16.2.1.4 Concomitant medication 
Listing 16.2.1.5 Informed consent / Demographic data / Reproductive status  
Listing 16.2.1.6 Protocol deviations 
Listing 16.2.1.7 Visit dates 
Listing 16.2.1.8 End of study information 
Listing 16.2.1.9 Populations 
Listing 18.2.1.10 Physical examination 
 
16.2.2 Compliance and/or Drug concentration data 
Listing 16.2.2.1 Dispensing of study medication and dosing  
Listing 16.2.2.2 Date of first dose of study medication 
Listing 16.2.2.3 Collection of medicine and compliance 
 
16.2.3 Individual efficacy response data 
Listing 16.2.3.1 Office spirometry 
Listing 16.2.3.2 ASMA-1 
Listing 16.2.3.3 Muscle strength 
Listing 16.2.3.4 Motor function  
Listing 16.2.3.5 Timed tests 
Listing 16.2.3.6 Functional tests 
Listing 16.2.3.7 Muscle imaging 
 
16.2.4 Safety data listings 
Listing 16.2.4.1 Adverse events 
Listing 18.2.4.2 Vital signs  
Listing 18.2.4.3 ECG 
16.2.5 Listing of individual laboratory measurements by subject 
Listing 16.2.5.1 Lab data listings: Pharmacokinetics 
Listing 16.2.5.2 Lab data listings: Haematology 
Listing 16.2.5.3 Lab data listings: Biochemistry 
Listing 16.2.5.4 Lab data listings: Urine analysis 
Listing 16.2.5.5 Lab data listings: Cardiac and urinary biomarkers