Clinical trial NCT04644003
Conditions: Autism Spectrum Disorder
Keywords: ASD Autism Spectrum Disorder
Sponsor: Stalicla SA
Start date: 2020-12-07; Completion date: 2022-01-28
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate safety and tolerability in a subgroup of patients with Autism Spectrum Disorder (ASD). In addition, Pharmacokinetics and Pharmacodynamics, as well as efficacy of STP1 are being explored.

Detailed description:
After obtaining written informed consent, those patients who are deemed eligible for the study, will be randomized on Day 1, in a double-blinded manner, in a 3:1ratio to receive either oral STP1 (twice daily) or placebo (twice daily). The total study duration is 6 weeks, including a screening phase of up to 2 weeks, a treatment phase of 2 weeks and a post-treatment follow-up phase of 2 weeks.

Arms: arm 1: 1 capsule and 1 tablet per intake arm 2: 1 capsule and 1 tablet per intake arm 3: 1 placebo capsule and 1 placebo tablet per intake
Interventions: intervention 1: STP1 intervention 2: Placebo
Intervention descriptions: intervention 1: STP1 is a combination of two drugs, a phosphodiesterase (PDE) inhibitor and an NKCC1 inhibitor intervention 2: Placebo medication (capsule and tablet) identical in appearance to active medication

Protocol documents:
Prot_000.pdf: 
STALICLA SA 
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Study STP1-C004 – Clinical Study Protocol, Version 6  
Page 1 of 103 
Clinical Study Protocol 
A Phase 1b, Double-Blind, Placebo-Controlled, First-in-Human 
Study to Evaluate Safety, Tolerability and Pharmacokinetics of a 
Two-Week Oral Treatment with STP1 in a Subgroup of 
Adult Patients with Autism Spectrum Disorder 
 
TEST PRODUCT:  
STP1 
STUDY NUMBER: 
STP1-C004 
IND NUMBER:  
139901 
INVESTIGATOR:  
Craig A Erickson, MD 
 
Cincinnati Children's Hospital Medical Center 
        3333 Burnet Avenue MLC 4002 
        Cincinnati, OH 45229 
 
SPONSOR:  
STALICLA SA 
            Campus Biotech Innovation Park 
                                                   Avenue de Sécheron 15, 1202  
        Geneva, Switzerland 
 
Version Number 
Edition history 
Date 
Changes requested 
by: 
1 
Original Protocol 31 August 2020 
 
2 
Amendment 1 
23 October, 2020 
FDA and STALICLA 
3 
Amendment 2 
09 December, 2020 
STALICLA 
4 
Amendment 3 
03 May 2021 
FDA and STALICLA 
5 
Amendment 4 
13 July 2021 
STALICLA 
6 
Amendment 5 
15 November 2021 
STALICLA 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the 
study are considered proprietary and may not be disclosed in whole or in part 
without the expressed, written consent of STALICLA SA, unless federal or state 
law or regulations require such disclosure. This confidential information is provided 
for the exclusive use of the investigator(s) and is subject to amendments, updates, 
edits and/or recall at any time. 




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Page 3 of 103 
 
 
 
CONTACT DETAILS 
 
Primary Sponsor Contact: 
  
Lynn Durham, MSc 
Office: +41 (0)22 545 12 41 
Mobile: +41 (0)79 799 58 08 
lynn.durham@stalicla.com 
STALICLA 
Campus Biotech Innovation Park 
Avenue de Sécheron 15 
1202 Geneva 
Switzerland 
  
 
Medical Contact*: 
From the CRO  
 
Sergio Delgado, MD  
 
Medical Monitor  
Cincinnati Children’s Hospital Medical Center (CCHMC) 
3779 Vineyard Woods Dr. 
Cincinnati, OH 45255, USA 
Mobile: +1 (513) 309-9633 
Office: +1 (513) 636-8101 
Sergio.Delgado@cchmc.org  
 
* Nominated individual to be contacted in case of a serious adverse event. 
 
Baltazar Gomez-Mancilla, MD PhD 
Chief Medical Officer 
Office:  +41 (0)22 545 12 42 
Mobile:  +41 (0)79 483 34 75 
baltazar.gomez-mancilla@stalicla.com 
STALICLA 
Campus Biotech Innovation Park 
Avenue de Sécheron 15 
1202 Geneva 
Switzerland 
 
 


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INVESTIGATOR, STUDY PERSONNEL AND SITE OF STUDY 
 
This will be a single-center study. 
 
Principal Investigator: 
Craig A. Erickson, M.D. 
Director of Research, Division of Child & Adolescent Psychiatry and The Kelly O'Leary 
Center for Autism Spectrum Disorders 
Cincinnati Children's Hospital Medical Center 
University of Cincinnati College of Medicine- Affiliated 
3333 Burnet Avenue MLC 4002 
Cincinnati, OH 45229 - USA 
Email: craig.erickson@cchmc.org  
Clinic: +1 513-636-6553 
Research: +1 513-636-1150 
 
 
 


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Protocol Amendment 5 Summary of Changes (15 November 
2021) 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page, protocol approval 
page, footers, protocol 
amendment summary of 
changes. 
 
Updated the protocol version, 
and date. 
To reflect the new version and 
date of the protocol.  
Cover page, Signature page, 
Section 
INVESTIGATOR, 
STUDY 
PERSONNEL 
AND 
SITE OF STUDY  
 
Contact details of the Stalicla 
Chief Medical Officer added 
and signature page as well. 
To provide information about 
the Medically Qualified Stalicla 
staff  
SYNOPSIS – NUMBER OF 
PATIENTS 
“…the objective to obtain 8 
patients 
completing 
each 
cohort” was replaced by “the 
objective to obtain up to 8 
patients 
completing 
each 
cohort”. 
The following was added: “As a 
minimum, 3 patients should be 
exposed to the highest dose of 
STP1”. 
 
A sample size of at least 3 
patients  exposed to the 
highest dose will provide 
sufficient information to meet 
the primary objective (safety 
and tolerability).This number 
could be increased up to 6 
patients to support secondary 
and exploratory objective. 
SYNOPSIS – SAMPLE SIZE 
«The target number of 
completers for this Phase 1b 
study is 16 ASD-Phen1 
individuals.» replaced by “The 
target number of completers 
for this Phase 1b study is up 
to 16 ASD-Phen1 individuals.» 
A sample size of at least 3 
patients  exposed to the 
highest dose will provide 
sufficient information to meet 
the primary objective (safety 
and tolerability).This number 
could be increased up to 6 
patients to support secondary 
and exploratory objective. 
 
Section 3.1.1. OVERVIEW OF 
STUDY DESIGN 
“…8 additional eligible 
patients…» replaced by “up to 
8 additional eligible patients 
...” 
A sample size of at least 3 
patients  exposed to the 
highest dose will provide 
sufficient information to meet 
the primary objective (safety 
and tolerability).This number 
could be increased up to 6 
patients to support secondary 
and exploratory objective. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.3 - METHOD OF 
TREATMENT ASSIGNMENT 
AND BLINDING 
 
“Each dose level will include 8 
patients” replaced by “Each 
dose level will include up to 8 
patients” 
A sample size of at least 3 
patients  exposed to the 
highest dose will provide 
sufficient information to meet 
the primary objective (safety 
and tolerability).This number 
could be increased up to 6 
patients to support secondary 
and exploratory objective. 
 
Section 6.1 - 
DETERMINATION OF 
SAMPLE SIZE 
“A maximum of approximately 
20 patients will be enrolled in 
this study, to ensure that 16 
patients (8 per dose level) will 
have complete dataset …” 
replaced by “A maximum of 
approximately 20 patients will 
be enrolled in this study, to 
ensure that up to 16 patients 
(up to 8 per dose level) will 
have complete dataset …” 
AND 
“Six patients on active and 2 on 
placebo per dose level (4 on 
placebo in total)...” replaced by  
“Up to six patients on active 
and up to 2 on placebo per 
dose level (maximum 4 on 
placebo in total) …”. 
A sample size of at least 3 
patients  exposed to the 
highest dose will provide 
sufficient information to meet 
the primary objective (safety 
tolerability).This number could 
be increased up to 6 patients to 
support secondary and 
exploratory objective. 
All document 
Version of the investigator’ 
brochure was removed (2020)  
This change will cover the 
updated version(s) of the 
investigator’ brochure. 
 
 
Protocol Amendment 4 Summary of Changes (13 July 2021) 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page, protocol approval 
page, footers, protocol 
amendment summary of 
changes. 
Updated the protocol version, 
and date. 
To reflect the new version and 
date of the protocol.  
Section SYNOPSIS – STUDY 
DESIGN and Section 
SYNOPSIS – SAFETY 
ASSESSMENT and Section 
3.1.1 – OVERVIEW OF 
PK data and PD data are 
removed 
The Data Safety Monitoring 
Board (DSMB) will make the 
recommendations to STALICLA 
based on the accumulated 
study data for patient safety, 




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Section # and Name 
Description of Change 
Brief Rationale 
but not the section 4.6.2. 
Section 4.6.2 - TIMING OF 
STUDY ASSESSMENTS – 
END OF STUDY (EOS) 
FOLLOW-UP VISIT 
Blood sampling for PK at any 
time  
For consistency: timing of PK 
sampling was modified in a 
previous amendment, the flow 
chart was updated accordingly 
but not the section 4.6.2. 
Section 4.7.1.1 - 
DISCONTINUATION FROM 
STP1 
“… 24 patients” replaced by 
“…16 patients” 
The number of patients was 
modified and approved in the 
protocol amendment #3 but by 
mistake the change was not 
implemented in this section 
4.7.1.1 
Section 4.7.1.2 – 
WITHDRAWAL FROM STUDY 
“…a total of 24 patients.” was 
replaced by “…a total of 16 
patients.” 
The number of patients was 
modified and approved in the 
protocol amendment #3 but by 
mistake the change was not 
implemented in this section 
4.7.1.2 
Section 9.5 – PROTOCOL 
AMENDMENTS 
“chief of translational 
development and study 
biostatistician” replaced by 
“Chief Medical Officer” 
New organization in place 
associated with a new title 
Section 11 - APPENDIX 1 
SCHEDULE OF 
ASSESSMENTS – SRS-2 
 
SRS-2 assessment at D28 
removed 
Correction of the inconsistency 
between the flowchart 
(Appendix 1) and the section 
4.6.1.8. The assessment is 
only conducted at the 
screening and D14 visits as 
described and the section 
4.6.1.8. 
 
 
 
Protocol Amendment 3 Summary of Changes (03 May 2021) 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page, protocol approval 
page, footers, protocol 
amendment summary of 
changes. 
Updated the protocol version, 
and date. 
To reflect the new title, version 
and date of the protocol.  
Contact details 
Primary Sponsor Contact 
Update the primary sponsor 
contact details. 
To reflect sponsor’s update on 
personnel.  
Protocol synopsis and 
throughout the protocol 
Change the sample size from 
12 patients per cohort to 8 
patients per cohort 
A sample size of eight patients 
is sufficient to meet the primary 
objective (safety tolerability) 


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Section # and Name 
Description of Change 
Brief Rationale 
Protocol synopsis and 
Section 4.6.2.1 SCREENING 
AND PRE-TREATMENT 
ASSESSMENTS. 
Glucose measurement has 
been included in the screening 
assessment. 
As per FDA request. 
Protocol synopsis and 
Section 4.6.1.6 
PHARMACOKINETICS 
ASSESSMENTS and Section 
4.6.2 TIMING OF STUDY 
ASSESSMENT and Section 11 
APPENDIX 1 SCHEDULE OF 
ASSESSMENT 
Changes in blood and urine 
sampling for PK to cover at 
least 3 half-lives of the IMP. 
As per FDA request. 
 
 
 
Protocol synopsis, Section 2.3 
EXPLORATORY OBJECTIVES 
and Section 3.3.3 
EXPLORATORY OUTCOME 
MEASURE and Section 4.6.1.8 
STUDY-SPECIFIC 
ASSESSMENTS and Section 
4.6.2 TIMING OF STUDY 
ASSESSMENT and Section 11 
APPENDIX 1 SCHEDULE OF 
ASSESSMENTS 
The CGI-S has been included 
within exploratory 
assessments. 
As per FDA request. 
Protocol synopsis, Section 
3.3.1 SAFETY OUTCOME 
MEASURES, Section 4.6.2 
TIMING OF STUDY 
ASSESSMENTS, Section 5.1.4 
OTHER SAFETY 
ASSESSMENTS and 
Section 11 APPENDIX 1 
SCHEDULE OF 
ASSESSMENTS  
Given the risk of ototoxicity 
with 
, hearing 
assessments will be 
performed multiple times.  
As per FDA request. 
Section 1.5.2 BENEFIT-RISK 
ASSESSMENT and Section 
4.5.1.3 MEDICATIONS TO BE 
AVOIDED WITH STP1. 
The concomitant treatment 
with CYP3A4 moderate or 
strong inhibitors is excluded.  
As per FDA request. 
Protocol synopsis and Section 
3.1.2 STOPPING RULES and 
Section 5.1.3 ADVERSE 
EVENTS OF SPECIAL 
INTEREST (IMMEDIATELY 
REPORTABLE TO THE 
SPONSOR) 
Dehydration and orthostasis 
have been included within the 
adverse events of special 
interest. 
As per FDA request. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.7.2 OTHER 
EXPLORATORY ENDPOINTS. 
All exploratory endpoints are 
now reorganized and also 
included in the screening 
process. 
For clarity and comprehension. 
Exploratory endpoints also 
performed before starting 
treatment (in the screening 
period). 
Protocol synopsis and Section 
4.2.2 INCLUSION CRITERIA 
Abstinence is not any more 
mentioned as an appropriate 
method of birth control for this 
study. 
As per FDA request 
Protocol synopsis and Section 
4.2.2. INCLUSION CRITERIA 
Requirement for at least a 6-
month seizure free period has 
been added as inclusion 
criteria 
As per FDA request 
Protocol synopsis and Section 
4.2.3. EXCLUSION CRITERIA 
Patients with an identified 
genetic cause of ASD in their 
medical record will be 
excluded from the study. 
As per FDA request 
Section 11 APPENDIX 1 
SCHEDULE OF 
ASSESSMENT 
The suicidality assessments 
(C-SSRS, C-CASA) has been 
added to the follow-up visits. 
As per FDA request 
Section 4.6.1.8 STUDY-
SPECIFIC ASSESSMENTS 
Section 11 APPENDIX 1 
SCHEDULE OF 
ASSESSMENT 
Drug accountability has been 
added to Day 7 and Day 14 
visit 
 
Typos and clarifications. 
New references have been 
added. 
Minor corrections and 
clarifications. 
 
 
Protocol Amendment 2 Summary of Changes (09 
December 2020) 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page, Protocol Approval 
Page, Footers, Protocol 
Amendment Summary of 
Changes. 
Updated the protocol version 
and date. 
To reflect the new version and 
date of the protocol.  


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Protocol synopsis and Section 
4.2.2 Inclusion criteria. 
BMI is being removed as an 
inclusion criterion. 
BMI inclusion criterion was a 
European reference. Since the 
only enrolling site is in the US, 
where participants are more 
likely to have an increased BMI, 
this criterion is not truly 
applicable for this study. 
Additionally, there are no safety 
reasons for BMI limits given the 
profile of the drugs in STP1. 
Typos and clarifications: 
 
 
• Triplicate ECG on Day 1 
(baseline) visit now clarified 
to be recorded 1 minute 
apart. 
• PK sampling points now 
include a 5-minutes window. 
• Appendix 1: Schedule of 
Assessments table now 
corrected to include 
orthostatic BP at Screening 
visit. 
Minor corrections and 
clarifications. 
 
Protocol Amendment 1 Summary of Changes (23 
October 2020) 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page, Protocol Approval 
Page, Footers, Protocol 
Amendment Summary of 
Changes. 
Updated the protocol version 
and date. 
To reflect the new version and 
date of the protocol.  
Protocol synopsis and Section 
4.2.2 Inclusion criteria 
New inclusion criteria: Before 
enrolling in the study, subjects 
intending to rely on abstinence 
as a birth control method must 
still agree to use double-barrier 
birth control methods if they 
engage in intercourse. 
As per FDA request.  
 
 
 
 
Protocol synopsis and Sections 
4.2.3 Exclusion Criteria, 4.6.1.5 
Laboratory Assessments and 
4.6.2 TIMING OF STUDY 
ASSESSMENT 
HIV-1/2 antibody and HIV-2 
antibody have been removed. 
Very low incidence of such virus 
in US population. 
Protocol synopsis and Sections 
3.1.2 STOPPING RULES and 
5.1.3 ADVERSE EVENTS OF 
SPECIAL INTEREST 
(IMMEDIATELY REPORTABLE 
New definition of 
thrombocytopenia: 
Thrombocytopenia is defined as 
meeting one or both criteria: 
As per FDA request. 


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TO THE SPONSOR) 
 
• Platelet count below 150 × 
10E9/L (or 150.000 platelets 
per microliter (mcL)) 
• Platelet count drop of ≥50% 
compared to baseline 
DATA SAFETY MONITORING 
BOARD (DSMB) 
Now it says up to 4 members 
To have enough quorum.  
Typos and clarifications: 
 
 
• Alcohol and substance 
abuse now in urine tests. 
• PK samples refer to blood 
samples (in Section 3.2.3 
RATIONALE FOR 
PHARMACOKINETIC 
SAMPLING). 
• Efficacy population. 
• Urine samples for PK 
deleted on Day 7.  
• Renumbering sections from 
page 24 onwards. 
• Update Table of contents. 
• Three references mentioned 
in the body text now also 
added to the list of 
references.  
Minor corrections and 
clarifications. 


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SYNOPSIS 
 
Study Number 
STP1-C004 
Title 
A Phase 1b, Double-Blind, Placebo-Controlled, First-in-Human Study 
to Evaluate Safety, Tolerability and Pharmacokinetics of a Two-Week 
Oral Treatment with STP1 in a Subgroup of Adult Patients with Autism 
Spectrum Disorder 
Study Phase 
1b 
Objectives 
Primary Objective: 
To determine the safety and tolerability of a 2-week twice a day (6 
hours apart) treatment with STP1 (combined oral doses of 
 
) in adult individuals with Autism Spectrum Disorder 
Phenotype 1 (ASD-Phen1). 
Secondary Objective: 
To determine the plasma pharmacokinetics of 
 
when given orally in combination, as STP1, for 2 weeks. 
Exploratory objectives:  
- To evaluate the effect of a 2-week treatment with STP1 compared 
to placebo on cognition as assessed by subtests of 
 
 the Test of 
Attentional Performance for Children (KiTAP) test battery. 
- To evaluate the effect of a 2-week treatment with STP1 compared 
to placebo on maladaptive behavior as assessed by the Aberrant 
Behavior Checklist – Community (ABC-C). 
- To evaluate the effect of a 2-week treatment with STP1 compared 
to placebo change in the context of autism as measured by the 
change in the Ohio Autism Clinical Impression Scale (OACIS) 
change.  
- To evaluate the effect of a 2-week treatment with STP1 compared 
to placebo on the Children Sleep Habit Questionnaire (CSHQ) 
scores. 
- To evaluate the effect of a 2-week treatment with STP1 compared 
to placebo on the Clinical Global Impressions-Severity (CGI-S) 
scale, as reflected by the Clinical Global Impressions-Improvement 
(CGI-I) scale. 
- To evaluate the effect of a 2-week treatment with STP1 compared 
to placebo on brain electrophysiology parameters as measured by 
electroencephalogram (EEG).  
- To evaluate the effect of a 2-week treatment with STP1 compared 
to placebo on gaze aversion and social interest by assessing eye 
tracking tasks. 
- To evaluate the effect of a 2-week treatment with STP1 compared 
to placebo on Lactate/Pyruvate ratio (L:P). 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group, 
2-dose ascending study (see Figure 2, Section 3.1.1). 
The first 8 eligible patients will be randomized and allocated to one of 
two groups with a 3:1 ratio:  






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7. If assent provided by the patient, parent or legal guardian 
willing to give written consent 
8. Patients with ASD and comorbid seizure disorder should be 
seizure-free for at least 6 months prior to screening. 
9. Before enrolling in the study, subjects must agree to use 
double-barrier birth control methods if they engage in 
intercourse. 
10. Women of childbearing potential, defined as all women 
physiologically capable of becoming pregnant, can be enrolled 
if they are using highly effective methods of contraception 
during dosing and for 1 week after discontinuation of the 
investigational drug.  
11. Sexually active males must use a condom during intercourse 
after the start of the IMP administration and for at least one 
week after stopping study medication and should not father a 
child in this period after completion of the study medication. A 
condom is required to be used also by vasectomized men in 
order to prevent delivery of the drug via seminal fluid. In 
addition, male participants should not donate sperm for the 
time period specified above. 
Exclusion Criteria 
Individuals meeting any of the following criteria will not be included in 
the trial: 
1. Patients with an identified genetic cause of ASD in their 
medical record will be excluded from the study. 
2. History of traumatic head injury, cerebrovascular disorder, 
congestive heart failure, hepatic or renal disease. 
3. Thrombocytopenia (platelet count < 100 000 mm3) within 1 
year prior to the screening visit. 
4. Diabetes (type 1 diabetes mellitus or uncontrolled type 2 
diabetes mellitus) or latent autoimmune diabetes of the adult 
(LADA). 
5. Use of prohibited medications (Section 4.5.1) or herbal 
remedies within 2 weeks prior to randomization, or 5 half-lives 
(whichever is longer). 
6. Alcohol and/or substance abuse/dependence within 12 months 
prior to screening. 
7. A significant risk for suicidal behavior, in the opinion of the 
investigator and as assessed by the Columbia Severity Rating 
Scale (C-SSRS) or the simplified version adapted from the 
Columbia Classification Algorithm for Suicide Assessment (C-
CASA). 
8. Use of antioxidant supplements and/or vitamins within 2 weeks 
prior to randomization.  
9. Initiation of, or a major change in psychological/behavioral 
intervention within 4 weeks prior to randomization.  
10. Patient with any active infection, including but not limited to the 
following: 
o Bacterial infection; or 
o Fungal infection; or  




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Endpoints 
Primary Endpoints - Safety: 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature and severity of adverse events (AEs). 
• 
Incidence, nature and severity of serious adverse events 
(SAEs).  
• 
Incidence, nature and severity of adverse events of special 
interest (AESIs). 
• 
Incidence, nature and severity of AEs leading to treatment 
discontinuation. 
• 
Changes from baseline in SBP, DBP, heart rate (HR) and 
respiratory rate. 
• 
Changes from baseline in orthostatic measurements of blood 
pressure (BP) and HR. 
• 
Changes from baseline in ECG parameters (HR, PQ, QRS, QT, 
RR and QTcF, along with information on T and U waves). 
• 
Incidence of clinically significant ECG abnormalities. 
• 
Hearing assessment. 
• 
Incidence of clinically relevant laboratory abnormalities, based 
on hematology, coagulation, blood chemistry and urinalysis 
test results: 
o Hematology: hemoglobin concentration, hematocrit 
level, erythrocytes and platelet counts, leucocytes 
differential (absolute) counts (neutrophils, eosinophils, 
lymphocytes, monocytes and basophils) 
o Coagulation: international normalized ratio (INR), 
activated partial thromboplastin time (aPTT) and 
prothrombin time (PT) 
o Blood chemistry: C-reactive protein (CRP test), 
aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase (ALT), gamma-glutamyl-transferase 
(GGT), 
total 
and 
conjugated 
bilirubin, 
alkaline 
phosphatase (ALP), albumin, creatine phosphokinase 
(CPK), creatinine, urea, total protein, total cholesterol, 
triglycerides, glucose, sodium, chloride, calcium, 
magnesium, phosphate, potassium 
o Urinalysis: protein, blood, glucose, leucocytes, nitrites, 
pH and crystals. 
• 
Incidence of value outside of the normal ranges and of clinically 
relevant blood chemistry test results for electrolytes: 
o Sodium, chloride, calcium, magnesium, phosphate, 
potassium 
Secondary Endpoints - Pharmacokinetics:  
• 
 plasma concentration will be 
evaluated at Days 1, 7, and 14 to 18. 
• 
Plasma concentrations of
and 
associated 
PK 
parameters: Area 
under 
the 
plasma 
concentration-time 
curve 
(AUC0-tau, 
AUC0-last, 
AUC0-inf), 
minimum plasma concentration prior to administration (Ctrough ),  
maximum plasma concentration (Cmax, Cmax,ss), time of 


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maximum plasma concentration (Tmax) and accumulation ratio, 
apparent plasma terminal elimination half-life (t1/2), apparent 
oral clearance and apparent volume of distribution (Vz/F). 
• 
Urine level of 
 will be assessed on 
Days 1 and 14/15. 
Exploratory Endpoints - Pharmacodynamics:  
• 
Change from baseline in subtasks from 
 and 
Cognition Battery and KiTAP test battery. 
• 
Global clinical change in the context of autism as measured by 
the change in the OACIS scale. 
• 
Change from baseline in ABC-C subscores. 
• 
Change from baseiline in the SRS2-subscores. 
• 
Change from baseline in the CSHQ scores. 
• 
Change from baseline in the CGI-S scale, reflected by the 
CGI-I scale. 
• 
Change from baseline in electrophysiology parameters as 
measured by EEG at resting state and during habituation and 
chirp tasks. 
• 
Change from baseline in eye gaze to eye regions during 
viewing of static faces and change in eye gaze to social scene 
viewing during viewing of dynamic video. 
• 
Change from baseline in Lactate/Pyruvate ratio (L:P) 
Safety Assessments 
Safety monitoring will begin when patient signs the informed consent 
form and continues through the end-of-study visit. All AEs and SAEs, 
whether reported by the patient/caregiver or noted by authorized study 
personnel, will be recorded in the patient’s medical record and on the 
appropriate AE/SAE electronic case report form (eCRF). 
As for SAEs, AESIs have to be reported to the sponsor within 24 hours 
after learning of the event.  
An SAE is any AE that meets any of the following criteria: 
- 
Fatal (i.e., the AE actually causes or leads to death). 
- 
Life-threatening (i.e., the AE, in the view of the investigator, 
places the patient at immediate risk of death). This does not 
include any AE that, had it occurred in a more severe form or 
was allowed to continue, might have caused death. 
- 
Requires or prolongs in-patient hospitalization. 
- 
Results in persistent or significant disability/incapacity (i.e., the 
AE results in substantial disruption of the patient’s ability to 
conduct normal life functions). 
- 
Congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to study drug(s). 
- 
Significant medical event in the investigator's judgment (e.g., 
may jeopardize the patient’s safety or may require 
medical/surgical intervention to prevent one of the outcomes 
listed above). 
AESI includes: 
- 
Electrolyte imbalance: hypokalemia (K+ level <3.4 mEq/L),  
hyperkalemia (>5.0 mEq/L), hyponatremia (Na+ level <135 
mEq/L), hypochloremia (Cl- level <97 mEq/L). 


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- 
Thrombocytopenia is defined as meeting one or both criteria: 
o Platelet count below 150 × 10E9/L (or 150.000 platelets 
per microliter [mcL]) 
o Platelet count drop of ≥50% compared to baseline 
- 
Drug-induced liver injury (DILI). 
- 
Dehydration and orthostasis (defined by a fall in systolic blood 
pressure overe 20 mm Hg or a fall in diastolic pressure over 10 
mm Hg within 3 minutes of standing. 
The progression from the first cohort to the second will be contingent 
upon DSMB review and agreement with the sponsor. The information 
to be reviewed will correspond to the safety and tolerability data from 
the first dose cohort (8 patients) who finish 2 weeks of treatment and 
2 weeks of follow-up. The DSMB members will be independent from 
the study team. 
Pharmacokinetic 
Assessments 
 
Blood samples will be drawn on Days 1, 7, 14, 15 and, optionally, daily 
up to Day 18, and urine will be collected on Day 1 and Day 14 to 
determine the concentrations of 
. 
The following sampling schedule will be applied: 
PK Schedulec 
Time 
Plasmaa 
Urineb 
Day 1 
0.25, 0.5, 1, 2, 4 and 6 h 
post-AM dose 
0 to 6 h post-AM 
dose 
Day 7 
Pre-AM dose 
 
Days 14 
(only AM 
dose) and 15 
Pre-AM dose and 0.25, 0.5, 
1, 2, 4, 6, 8, 10, 12, and 24 h 
post-AM dose 
0-4, 4-8 and 8-12 
h post-AM dose 
Between 
Days 16 and 
18d 
48, 72, and 96 h post-AM 
dose of Day 14 
 
a both 
will be analyzed from the same 
blood draw for each specified sampling time point 
b Urine creatinine from the urine collection will be paired with a 
serum creatinine measurement to evaluate completeness of 
collection. 
c All of these timepoints have a 5 minute window. 
d Optional 
Non-compartmental analysis (NCA) will be utilized to analyze data 
from the sampling schema. 
Plasma PK parameters such as AUC0-tau, AUC0-last, AUC0-inf, Cmax, Tmax, 
and t1/2 at Day 1 and at Day 14 for both 
. 
Ctrough and Cmax ss will be calculated at Days 7 and 14, and 
accumulation ratio will be calculated at Day 14. 
Blinding 
The study will be blinded for patients/caregivers, study personnel with 
direct interaction with the subjects and vendors, using placebo 
capsules and tablets that match the active drugs in appearance, 
labelling and packaging. The total number of capsules making up each 
dose will be identical for both STP1 dose levels and placebo. 


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Study personnel responsible for receiving the randomization lists and 
dispensing the assigned treatment will be unblinded. 
An independent DSMB will be appointed. The DSMB will be blinded to 
treatment for safety/tolerability assessments (primary outcome) and 
will advise on the start of 2nd dose level. 
Statistical Methods 
 
For this Phase 1b study, descriptive statistics will be provided for all 
endpoints by treatment group. For continuous endpoints, summary 
statistics i.e., n (number of individuals included in the analysis), mean, 
SD, median, minimum, maximum, Quartile 1, and Quartile 3 will be 
provided. For categorical endpoints, the number and frequency in 
each category will be provided.  
All subjects who have received at least one dose of the combination, 
whether prematurely withdrawn from the study or not, will be included 
in the safety analysis. 
 
SAFETY and TOLERABILITY  
The number of patients who report the following events will be 
summarized for all treated patients: 
• 
AE and treatment-related AE. 
• 
AE and treatment-related AE that led to study treatment 
discontinuation.  
• 
SAE and treatment related SA. 
• 
SAE and treatment related SAE that led to study treatment 
discontinuation. 
• 
AESIs. 
Safety and tolerability are also measured by incidence and severity of 
AEs, physical examinations, ECG, vital signs, specific laboratory 
abnormalities and change from baseline in the CSHQ scores in all 
treated patients. 
As this study will provide descriptive statistics, there will not be any 
correction for multiple primary endpoints. 
 
PHARMACOKINETICS 
The PK analysis set will include subjects with at least one sample 
collected and analyzed for plasma drug concentration. Concentration 
of each drug in plasma and urine will be listed and summarized by visit 
and nominal time. The NCA using the sampling mode of PK data and 
standard descriptive statistics for PK parameters will be calculated 
using Phoenix WinNonlin software (Certara).  
Sample size 
The target number of completers for this Phase 1b study is up to 16 
ASD-Phen1 individuals. Assuming a dropout rate of approximately 
20%, the proposed sample size is up to 20 patients to be randomized.  
This sample size should provide the first evidence of safety, tolerability 
and pharmacokinetics of STP1 in individuals with ASD-Phen1 to 
inform potential future studies.  


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TABLE OF CONTENTS 
 
SECTION 4.3 - METHOD OF TREATMENT ASSIGNMENT AND BLINDING ....................................................... 6 
SECTION 11 - APPENDIX 1 SCHEDULE OF ASSESSMENTS – SRS-2 .............................................................. 8 
1. 
INTRODUCTION ........................................................................................................................... 29 
1.1 
BACKGROUND ON THE DISEASE ................................................................................................ 29 
1.2 
STRATIFICATION AND THERAPEUTIC STRATEGIES ..................................................................... 29 
1.2.1 
CLINICAL SIGNS AND SYMPTOMS OF ASD-PHEN1 ................................................................ 30 
1.2.2 
RATIONALE FOR STP1 ........................................................................................................... 31 
1.3 
NON-CLINICAL EXPERIENCE ....................................................................................................... 32 
1.3.1 
NON-CLINICAL PHARMACOLOGY .......................................................................................... 32 
1.3.2 
NON-CLINICAL PHARMACOKINETICS AND METABOLISM ..................................................... 33 
1.3.3 
TOXICOLOGY, SAFETY PHARMACOLOGY AND GENOTOXICITY ............................................. 35 
1.4 
PREVIOUS CLINICAL EXPERIENCE ............................................................................................... 37 
1.4.1 
CLINICAL PHARMACOKINETICS ............................................................................................. 37 
1.4.2 
SAFETY AND TOLERABILITY ................................................................................................... 38 
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT ................................................................ 42 
1.5.1 
STUDY RATIONALE ................................................................................................................ 42 
1.5.2 
BENEFIT-RISK ASSESSMENT .................................................................................................. 42 
2. 
OBJECTIVES OF THE STUDY .......................................................................................................... 45 
2.1 
PRIMARY OBJECTIVE .................................................................................................................. 45 
2.2 
SECONDARY OBJECTIVE ............................................................................................................. 45 
2.3 
EXPLORATORY OBJECTIVES ....................................................................................................... 45 
3. 
INVESTIGATIONAL PLAN .............................................................................................................. 46 
3.1 
STUDY DESIGN ........................................................................................................................... 46 
3.1.1 
OVERVIEW OF STUDY DESIGN .............................................................................................. 46 
3.1.2 
STOPPING RULES .................................................................................................................. 47 
3.1.3 
DATA SAFETY MONITORING BOARD (DSMB) ....................................................................... 48 
3.1.4 
END OF STUDY ...................................................................................................................... 50 
3.2 
RATIONALE FOR STUDY DESIGN ................................................................................................ 50 
3.2.1 
RATIONALE FOR DOSAGE SELECTION AND TREATMENT DURATION .................................... 50 
3.2.2 
RATIONALE FOR STUDY POPULATION .................................................................................. 51 
3.2.3 
RATIONALE FOR PHARMACOKINETIC SAMPLING ................................................................. 51 
3.2.4 
RATIONALE FOR BIOMARKER ASSESSMENTS ....................................................................... 51 
3.3 
OUTCOME MEASURES ............................................................................................................... 52 
3.3.1 
SAFETY OUTCOME MEASURES ............................................................................................. 52 
3.3.2 
PHARMACOKINETIC OUTCOME MEASURES ......................................................................... 52 
3.3.3 
EXPLORATORY OUTCOME MEASURES .................................................................................. 53 
4. 
MATERIALS AND METHODS ......................................................................................................... 54 
4.1 
CENTER ...................................................................................................................................... 54 
4.2 
STUDY POPULATION .................................................................................................................. 54 
4.2.1 
RECRUITMENT PROCEDURES ................................................................................................ 54 
4.2.2 
INCLUSION CRITERIA ............................................................................................................. 54 
4.2.3 
EXCLUSION CRITERIA ............................................................................................................ 56 
4.3 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING ........................................................... 57 


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4.4 
INVESTIGATIONAL MEDICINAL PRODUCTS ................................................................................ 58 
4.4.1 
FORMULATION, PACKAGING AND HANDLING ..................................................................... 58 
4.4.2 
DOSAGE, ADMINISTRATION AND COMPLIANCE ................................................................... 58 
4.4.3 
INVESTIGATIONAL MEDICINAL PRODUCTS ACCOUNTABILITY .............................................. 58 
4.4.4 
POST-TRIAL ACCESS TO STP1 ................................................................................................ 59 
4.5 
CONCOMITANT THERAPIES AND FOOD ..................................................................................... 59 
4.5.1 
PROHIBITED THERAPIES ........................................................................................................ 60 
4.5.1.1 
POTENTIAL INTERACTIONS WITH 
 ................................................................... 60 
4.5.1.2 
POTENTIAL INTERACTIONS WITH
 ............................................................. 60 
4.5.1.3 
MEDICATIONS TO BE AVOIDED WITH STP1 ..................................................................... 61 
4.5.1.4 
MEDICATIONS TO BE AVOIDED IN THE STUDY POPULATION .......................................... 61 
4.5.2 
PRECAUTIONS ....................................................................................................................... 61 
4.5.3 
BEHAVIORAL AND COGNITIVE INTERVENTIONS ................................................................... 61 
4.5.4 
SPECIAL CONSIDERATIONS AND FASTING ............................................................................ 61 
4.6 
STUDY PROCEDURES ................................................................................................................. 62 
4.6.1 
DESCRIPTION OF STUDY ASSESSMENTS ............................................................................... 62 
4.6.1.1 
MEDICAL/FAMILY HISTORY AND DEMOGRAPHIC DATA .................................................. 62 
4.6.1.2 
PHYSICAL EXAMINATION ................................................................................................. 62 
4.6.1.3 
VITAL SIGNS ..................................................................................................................... 62 
4.6.1.4 
ELECTROCARDIOGRAMS .................................................................................................. 62 
4.6.1.5 
LABORATORY ASSESSMENTS ........................................................................................... 63 
4.6.1.6 
PHARMACOKINETICS ASSESSMENTS ............................................................................... 64 
4.6.1.7 
BIOMARKER SAMPLING ................................................................................................... 65 
4.6.1.8 
STUDY-SPECIFIC ASSESSMENTS ....................................................................................... 65 
4.6.2 
TIMING OF STUDY ASSESSMENTS (SEE APPENDIX 1) ............................................................ 70 
4.6.2.1 
SCREENING AND PRE-TREATMENT ASSESSMENTS .......................................................... 74 
4.6.2.2 
ASSESSMENTS DURING TREATMENT ............................................................................... 74 
4.6.2.3 
FOLLOW-UP ASSESSMENTS ............................................................................................. 75 
4.7 
PATIENT, STUDY, AND SITE DISCONTINUATION ........................................................................ 75 
4.7.1 
PATIENT DISCONTINUATION ................................................................................................ 75 
4.7.1.1 
DISCONTINUATION FROM STP1 ....................................................................................... 75 
4.7.1.2 
WITHDRAWAL FROM STUDY ........................................................................................... 75 
4.7.2 
STUDY AND SITE DISCONTINUATION .................................................................................... 75 
5. 
ASSESSMENT OF SAFETY .............................................................................................................. 77 
5.1 
SAFETY PARAMETERS AND DEFINITIONS ................................................................................... 77 
5.1.1 
ADVERSE EVENTS .................................................................................................................. 77 
5.1.2 
SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE TO THE SPONSOR) ...................... 77 
5.1.3 
ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY REPORTABLE TO THE SPONSOR) .. 78 
5.1.4 
OTHER SAFETY ASSESSMENTS .............................................................................................. 78 
5.2 
SAFETY PLAN ............................................................................................................................. 78 
5.2.1 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS .................................................................... 79 
5.2.1.1 
ABNORMAL LABORATORY FINDINGS ............................................................................... 79 
5.2.1.2 
CHANGES IN BLOOD PRESSURE ....................................................................................... 79 
5.2.1.3 
SUICIDALITY ..................................................................................................................... 79 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY PARAMETERS .................... 79 
5.3.1 
ADVERSE EVENT REPORTING PERIOD ................................................................................... 79 
5.3.2 
ELICITING ADVERSE EVENT INFORMATION .......................................................................... 80 
5.3.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS ................................................................. 80 
5.3.4 
ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS ............................................................... 80 
5.3.5 
PROCEDURE FOR RECORDING ADVERSE EVENTS ................................................................. 81 


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5.3.5.1 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS ................................................................... 81 
5.3.5.2 
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER EVENTS ..................................... 81 
5.3.5.3 
PERSISTENT OR RECURRENT ADVERSE EVENTS ............................................................... 82 
5.3.5.4 
ABNORMAL LABORATORY VALUES .................................................................................. 82 
5.3.5.5 
ABNORMAL VITAL SIGN VALUES ...................................................................................... 82 
5.3.5.6 
ABNORMAL LIVER FUNCTION TESTS ................................................................................ 83 
5.3.5.7 
DEATHS ............................................................................................................................ 83 
5.3.5.8 
PREEXISTING MEDICAL CONDITION ................................................................................. 83 
5.3.5.9 
WORSENING OF SYMPTOMS ASSOCIATED WITH ASD ..................................................... 84 
5.3.5.10 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION ................................................... 84 
5.3.5.11 
OVERDOSES ..................................................................................................................... 84 
5.3.5.12 
CAREGIVER/PARENT-REPORTED OUTCOME DATA .......................................................... 85 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO SPONSOR ........................ 85 
5.4.1 
EMERGENCY MEDICAL CONTACTS ........................................................................................ 85 
5.4.2 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS OF 
SPECIAL INTEREST ............................................................................................................................... 86 
5.4.3 
REPORTING REQUIREMENTS FOR PREGNANCIES ................................................................. 86 
5.4.3.1 
PREGNANCIES IN FEMALE PATIENTS ............................................................................... 86 
5.4.3.2 
PREGNANCIES IN FEMALE PARTNERS OF MALE STUDY SUBJECTS ................................... 86 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS .................................................................. 86 
5.5.1 
INVESTIGATOR FOLLOW-UP ................................................................................................. 86 
5.5.2 
SPONSOR FOLLOW-UP .......................................................................................................... 87 
5.6 
POST-STUDY ADVERSE EVENTS ................................................................................................. 87 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, INSTITUTIONAL REVIEW 
BOARDS, AND ETHICS COMMITTEES ....................................................................................................... 87 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................................................... 88 
6.1 
DETERMINATION OF SAMPLE SIZE ............................................................................................ 88 
6.2 
SUMMARIES OF CONDUCT OF STUDY ....................................................................................... 88 
6.3 
ANALYSIS POPULATIONS ........................................................................................................... 88 
6.3.1 
SAFETY ANALYSIS POPULATION ............................................................................................ 88 
6.3.2 
EFFICACY ANALYSIS POPULATION ........................................................................................ 88 
6.3.3 
PHARMACOKINETIC ANALYSIS POPULATION ........................................................................ 88 
6.4 
SUMMARIES OF TREATMENT GROUP COMPARABILITY ............................................................ 88 
6.4.1 
ADVERSE EVENTS .................................................................................................................. 89 
6.4.2 
CLINICAL LABORATORY TEST RESULTS .................................................................................. 89 
6.4.3 
VITAL SIGNS .......................................................................................................................... 89 
6.4.4 
ECG DATA ............................................................................................................................. 89 
6.4.5 
CONCOMITANT MEDICATIONS ............................................................................................. 89 
6.5 
EFFICACY ANALYSES .................................................................................................................. 89 
6.6 
PHARMACOKINETIC ANALYSES ................................................................................................. 89 
6.7 
EXPLORATORY ANALYSES .......................................................................................................... 90 
6.7.1 
LACTATE AND PYRUVATE BLOOD LEVELS ............................................................................. 90 
6.7.2 
OTHER EXPLORATORY ENDPOINTS ....................................................................................... 90 
7. 
DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE ................................................... 91 
7.1 
SOURCE DATA DOCUMENTATION ............................................................................................. 91 
7.2 
RETENTION OF RECORDS ........................................................................................................... 91 
8. 
ETHICAL CONSIDERATIONS .......................................................................................................... 93 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS ......................................................................... 93 


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8.2 
INFORMED CONSENT ................................................................................................................ 93 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE ......................................................... 94 
8.4 
CONFIDENTIALITY ...................................................................................................................... 94 
8.5 
FINANCIAL DISCLOSURE ............................................................................................................ 94 
9. 
STUDY DOCUMENTATION, MONITORING AND ADMINISTRATION ............................................... 95 
9.1 
STUDY DOCUMENTATION ......................................................................................................... 95 
9.2 
SITE INSPECTIONS ...................................................................................................................... 95 
9.3 
ADMINISTRATIVE STRUCTURE ................................................................................................... 95 
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ................................................. 95 
9.5 
PROTOCOL AMENDMENTS ........................................................................................................ 96 
10. 
REFERENCES ............................................................................................................................ 97 
11. 
APPENDIX 1 SCHEDULE OF ASSESSMENTS ............................................................................. 103 
 
 
LIST OF TABLES 
 
Table 1 Published Clinical Studies with Safety Data for 
 ....................... 40 
Table 2 PK sampling times .................................................................................. 65 
 
 
 
LIST OF FIGURES 
 
Figure 1 Principal Component Analysis of the Bioenergetic Profile of Untreated 
and Sulforaphane-treated Blood-derived Cells. ................................................... 33 
Figure 2 Overview of Study Design ..................................................................... 47 
 
GLOSSARY OF ABBREVIATIONS 
ABC-C 
Aberrant behavior checklist-community 
ADI-R 
Autism diagnostic interview - revised  
ADME 
Absorption, distribution, metabolism, and excretion 
ADOS-2 
Autism diagnosis observation schedule M, second edition 
AE 
Adverse event(s) 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AOI 
Areas of interest 
aPTT 
Activated partial thromboplastin time 
ASD 
Autism Spectrum Disorder 
ASD-Phen1 
ASD Phenotype 1 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-in  
 AUC extrapolated to infinity  
AUC0-last 
AUC to the last measurable concentration 
AUC0-tau 
AUC to the end of the dosing period 
AZT 
Azidothymidine 
BCRP 
Breast cancer resistance protein 


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GLOSSARY OF ABBREVIATIONS 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BPM 
beats per minute 
cAMP 
Cyclic adenosine monophosphate 
CARS 
Childhood Autism Rating Scale 
C-CASA 
Columbia Classification Algorithm for Suicide Assessment 
CDC 
Centers for Disease Control and Prevention 
CGI-I 
Clinical Global Impressions-Improvement 
CGI-S 
Clinical Global Impressions-Severity 
cGMP 
Cyclic guanosine monophosphate 
Cmax 
Maximum plasma concentration 
Cmax  ss 
Maximum plasma concentration at steady state  
Ctrough 
Minimum plasma concentration prior to administration 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CPT 
Continuous Performance Tasks 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CSHQ 
Children sleep habit questionnaire 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP450 
Cytochromes P450 
DBP 
Diastolic Blood Pressure 
DCCS 
dimensional change card sort 
DDI 
Drug-drug interaction 
DILI 
Drug-induced liver injury 
DSM-5 
Diagnostic and statistical manual of mental disorder, 5th edition 
DSMB 
Data safety monitoring board 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EEG 
Electroencephalography 
EDC 
Electronic data capture 
EF 
Executive Function 
EOS 
End-of-study 
ERP 
Event Related Potentials 
ESF 
Eligibility screening form 
FDA 
Food and Drug Administration 
FSIQ 
Full scale intellectual quotient 
GABA 
Gamma aminobutyric acid 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
HBV 
Hepatitis B Virus 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
HC 
Head cicumferance  


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GLOSSARY OF ABBREVIATIONS 
HCV 
Hepatitis C Virus 
hERG 
Human ether-a-go-go-related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
IBI 
Intensive Behavior Intervention 
IC50 
Concentration that gives half the maximum inhibition 
ICH 
International Concil on Harmonization 
ICF 
Informed consent form 
IL-1b 
Interleukin 1 beta 
IL-10 
Interleukin 10 
IMP 
Investigational medicinal product(s) 
INN 
International non-proprietary name 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
Intravenous 
KiTAP 
Test of Attentional Performance for Children 
LADA 
Latent Autoimmune Diabetes of the Adult 
LCL 
Lymphoblastoid cell line 
LC-MS/MS 
Liquid chromatography-mass spectrometry 
L:P 
Lactate-pyruvate ratio 
LPLO 
Last patient last observation 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MEDNO 
Medication number 
MOS 
Margin of safety 
NCA 
Non-compartmental analysis 
NDDs 
neurodevelopmental disorders 
NIH 
National Institute of Health 
 
 
NKCC 
Na-K-Cl cotransporter 
NOAEL 
No observed adverse effect level 
 
 
OACIS 
Ohio Clinical Impression Scale 
OACIS-C 
Ohio Clinical Impression Scale - Change 
OACIS-S 
Ohio Clinical Impression Scale - Severity 
OAT 
Organic Anion Transporter 
OATP 
Organic Anion Transporting Polypeptide 
OCT 
Organic Cation Transporter 
ORT 
oral reading recognition 
OTC 
Over the counter 
PCPS 
pattern comparison processing speed 
PD 
Pharmacodynamic 
PDE 
Phosphodiesterase 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PKA 
Protein kinase A 
PT 
Prothrombin time 


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GLOSSARY OF ABBREVIATIONS 
PR 
Pulse rate 
PV 
picture vocabulary 
qPCR 
Quantitative Polymerase Chain Reaction  
SAE 
Serious adverse event 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SB5 ABIQ 
Stanford Binet Intelligence Scales, Fifth Edition – Abbreviated Battery IQ 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SI 
Système international 
SMT 
Study management team 
SOC 
System Organ Classes 
SRS-2 
Social responsiveness scale – Version 2 
SSPR 
Social scene preference ratio 
TAP 
Tests of Attentional Performance 
TK 
toxicokinetic 
TD 
Typically developing 
Tmax 
time of maximum plasma concentration 
t½  
half-life 
ULN 
Upper limit of normal 
U.S. 
United States 
Vz/F 
Apparent volume of distribution 
WCBP 
Women patients of childbearing potential 
WHO 
World Health Organization 
 
 
 
 


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1. 
INTRODUCTION 
Further information on the scientific rationale is provided in the Investigator’s 
Brochure (STP1-IB). 
1.1 
BACKGROUND ON THE DISEASE 
Autism 
spectrum 
disorder 
(ASD) 
comprises 
a 
group 
of 
lifelong 
neurodevelopmental conditions that, according to recent estimates, affect 1.5% of 
the population in developed countries [Baxter et al, 2015]. The prevalence of ASD 
has been estimated as 1 in 59 school-aged children in the United States US 
[Christensen et al, 2016]. ASD is characterized by both core symptoms and co-
occurring conditions [Farmer et al, 2018]. Core symptoms are the fundamental 
aspects of the disorder that are required for diagnosis. According to the current 
diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition (DSM-5), [Baird, 2013]), an individual with ASD must show deficits in social 
interactions and communication, and deficits in at least 2 of the 4 subdomains of 
restricted or repetitive behaviors. Its manifestations must cause clinically 
significant impairment affecting the ability of patients to interact with others, 
especially people of their own age when referring to pediatrics. In addition to core 
symptoms, ASD is associated with a wide range of co-occurring conditions. In 
recent years, much progress has been made in understanding the prevalence and 
underlying biology of conditions co-occurring with ASD, such as seizures [Keller et 
al, 2017], sleep disorders [Deliens et al, 2015], gastrointestinal (GI) disorders 
[Hsiao, 2014; Vuong and Hsiao, 2017], psychiatric disorders (estimated to be 
around 70% of patients with ASD [Buck et al, 2014]), mitochondrial dysfunction 
[Legido et al, 2013], and immune system dysregulations [Gładysz et al, 2018]. 
Currently, there is no medicine approved for the core symptoms of ASD. The only 
approved drugs for ASD are aripiprazole (Abilify®) and risperidone (Risperdal®) to 
treat irritability associated with ASD.  
ASD symptoms and their severity vary widely across the core and co-occurring 
symptoms. Thus, each individual with ASD has his or her own unique combination 
of symptoms and levels of functioning. This may result in relatively mild challenges 
for someone on the high functioning end of the spectrum, while symptoms may be 
more severe for others interfering with everyday life or even requiring full time 
lifelong care and support. Even within syndromic (genetically well-defined) ASD, 
there is a considerable variability in the range and severity of symptoms.  
1.2 
STRATIFICATION AND THERAPEUTIC STRATEGIES 
The current version of the DSM abandoned classifications of subtypes of ASD to 
group them under one umbrella, mostly due to the lack of objective criteria to define 
these subtypes. However, ASD remains characterized by a high heterogeneity in 
its behavioral manifestations with very complex genetic underpinnings, suggesting 
the existence of subtypes of ASD. Therefore, efforts to categorize ASD are still of 
critical importance and must rely on defining a relationship between clinical 
symptoms and biological mechanisms to improve the outcome of clinical trials. 








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Comparing the bioenergetic profile of blood-derived cells from ASD-Phen1 
patients with that of blood-derived cells from TD led the identification of key 
pathophysiological features associated with ASD-Phen1 including 1) a defect in 
the balance between glycolysis and pentose phosphate pathway activity and 2) a 
lack of 
activation of the pentose phosphate pathway. Treating 
ASD-Phen1 cells with 
 led to an increase in glucose uptake, thus 
alleviating the defects in glycolysis. When related to ASD-Phen1 pathophysiology, 
the sponsor predicts that its beneficial effect will be to provide support for high-
energy demand in different cellular subtypes, including active immune cells and 
neurons.        
Figure 1 Principal Component Analysis of the Bioenergetic Profile of Untreated and 
Sulforaphane-treated Blood-derived Cells.  
 
TD=typical development ; ASD =autism spectrum disorder 
 
For further information, please refer to the STP1 Investigator’s Brochure [STP1-
IB].  
1.3.2 
NON-CLINICAL PHARMACOKINETICS AND METABOLISM 
There are no available data on the Absorption, distribution, metabolism, and 
excretion (ADME) profile of STP1 at pharmacological doses. Available 
toxicokinetic (TK) data with STP1 are completed with relevant information from the 
pharmacokinetic (PK) profile, distribution and metabolism from in vivo studies with 
individual drugs that is available in the literature. This section also summarizes in 
vitro Drug Metabolism and Pharmacokinetics (DMPK) studies that were performed 
with 
. 
STP1: 
STP1 was orally administered during 28 days in a twice a day regimen in rat and 
a once daily regimen in dog and TK profile were analyzed in both species.  




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is unlikely, but the potential for inhibition of P-gp and BCRP in vivo warrants further 
investigation. 
 
 is rapidly absorbed and rapidly cleared from plasma in rats and dogs. 
In rats, the absorption seems to be saturable. 
 is highly bound to 
proteins in plasma and shows limited distribution into tissues, with the exception 
of kidneys and liver. Cross-species metabolism and reaction phenotyping studies 
confirmed extensive metabolism of 
 by rat hepatocytes and relative 
higher metabolic stability in dogs and humans. The enzyme responsible for 
 metabolism in humans is not identified. There are no human 
disproportionate metabolites based on reaction phenotyping studies in vitro that 
compare metabolism from rat, dog and human hepatocytes. In vivo metabolism 
and excretion data from literature suggests the presence of various metabolites in 
rats, with the 3’-acid being the most abundant in pooled urine and feces samples. 
Many of the same metabolites observed in rats are also described in dog excreta, 
albeit at much lower levels. 
 is mostly excreted via the feces in rats, 
and nearly equally excreted via the urine and feces in dogs. CYP450 inhibition or 
induction are not expected. 
 is a substrate for OAT1, OAT3, Organic 
Anion Transporting Polypeptide (OATPB1) and OATPB3 and inhibits OAT3, OCT2 
and BCRP in vitro, of which, BCRP could potentially be inhibited in vivo from 
extrapolated exposure data from literature. 
For further information, please refer to the STP1 Investigator’s Brochure [STP1-
IB].  
1.3.3 
TOXICOLOGY, SAFETY PHARMACOLOGY AND GENOTOXICITY 
Toxicology studies: 
In the pivotal 4-week Good Laboratory Practice (GLP) rat toxicity study [Study 
8400256], the following treatment groups were compared to the control group: 
STP1 at 100:10 or 50:5 mg/kg twice a day 
. The main findings 
of this study were decreased body weight gain and food consumption, minor 
clinical pathology changes and high liver weight associated with centro-lobular 
hepatocyte hypertrophy. This later finding was likely an adaptive mechanism in the 
rats. Most of these findings were reversible, were clinically silent and not 
considered adverse. Thus, STP1 at 100/10 mg 
 was 
considered the no observed adverse effect level (NOAEL) in the rats. This dose 
corresponds to a 100-fold safety margin for a human dose of 10 mg twice a day of 
 and of 1 mg twice a day of 
 based on allometric scaling.  
In the pivotal 4-week GLP dog toxicity study [Study 01405001], the following once 
daily treatments were compared to the control group: STP1 at 8:0.8, 6:0.6 and 
3/0.3 mg/kg/day 
. The primary findings were emesis, 
decreased food consumption and body weight gain, suspected moderate 
dehydration and minor clinical pathology changes. Most of these findings were 
reversible. The primary target organ at necropsy was the kidney where minimal to 












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AE=adverse event; BID=twice daily; CO=crossover; DB=double-blind; GI=gastrointestinal; HV = healthy volunteers; MAD=multiple ascending dose; 
MS=multiple sclerosis; N/A=not available; NCT=National Clinical Trial number OLE=open-labeled extension; PC=placebo-controlled; PI=principal. 
investigator PK=pharmacokinetics; PD=pharmacodynamic; R=randomized; TID=three times daily; y=age. 
 








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2. 
OBJECTIVES OF THE STUDY 
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is: 
• To determine the safety and tolerability of 2-week twice a day (6 hours apart) 
treatment with STP1 (combined oral doses of 
) in adult 
patients with ASD-Phen1.  
2.2 
SECONDARY OBJECTIVE 
The secondary objective of the study is: 
• To determine the plasma PK of multiple dosing and to determine the 
concentration in the urine of 
 when given orally in 
combination, as STP1, for 2 weeks. 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are as follows: 
• To evaluate the effect of a 2-week treatment with STP1 compared to placebo 
on cognition as assessed by subtests of the 
 and the Test of Attentional Performance for Children 
(KiTAP) test battery. 
• To evaluate the effect of a 2-week treatment with STP1 compared to placebo 
on maladaptive behavior as assessed by the Aberrant Behavior Checklist–
Community (ABC-C). 
• To evaluate the effect of a 2-week treatment with STP1 compared to placebo 
change in the context of autism as measured by the change in the Ohio Autism 
Clinical Impression Scale (OACIS) change.  
• To evaluate the effect of a 2-week treatment with STP1 compared to placebo 
on the Children Sleep Habit Questionnaire (CSHQ) scores. 
• To evaluate the effect of a 2-week treatment with STP1 compared to placebo 
on the Clinical Global Impressions-Severity (CGI-S) scale, also reflected by the 
Clinical Global Impressions-Improvement (CGI-I) scale. 
• To evaluate the effect of a 2-week treatment with STP1 compared to placebo 
on brain electrophysiology parameters as measured by electroencephalogram 
(EEG). 
• To evaluate the effect of a 2-week treatment with STP1 compared to placebo 
on gaze aversion and social interest by assessing eye tracking tasks. 
• To evaluate the effect of a 2-week treatment with STP1 compared to placebo 
on Lactate/Pyruvate ratio (L:P). 
 
 


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3. 
INVESTIGATIONAL PLAN 
3.1 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, parallel-group, 2-dose 
ascending study cohort (first and second), to assess the safety, tolerability and PK of 
2-week treatment with STP1 in adult patients with ASD-Phen1.  
3.1.1 
OVERVIEW OF STUDY DESIGN 
Figure 2 gives an overview of the study design. If eligible, the first dose cohort (8 
patients) will be randomized and allocated to one of two groups with a 3:1 ratio:  
• One group will receive 
mg oral twice a day (6 hours apart) oral 
 and 
mg oral twice a day (6 hours apart) oral 
 (STP1 dose 1, N=6).  
• One group will receive matching oral placebo twice a day (6 hours apart) (N=2). 
Once the first dose cohort (8 patients) finishes the 2 weeks of STP1 treatment and the 
2 weeks of follow up, a DSMB will evaluate the safety and tolerability data to decide 
whether the dose of 
 can be increased as planned to 
 mg, or the study 
should be modified or be stopped. 
If the analysis supports the start of the next dose level, up to 8 additional eligible 
patients will be assigned to the next dose level (patients that participated in the first 
cohort maybe allowed to participate in the second if no safety concern): 
• One group will receive 
 mg oral twice a day (6 hours apart) oral 
 and 
mg oral twice a day (6 hours apart) oral 
 (STP1 dose 2, N= up to 
6).  
• One group will receive matching oral placebo twice a day (6 hours apart) (N= 
up to 2). 
For each dose cohort, the total duration of the study for each patient will be up to 6 
weeks divided as follows: 
• A screening phase of 2 weeks (from Day -14 to Day -1). 
• A double-blind treatment phase of 2 weeks (from Day 1 to Day 14). 
• A follow-up phase of 2 weeks after treatment discontinuation (from Day 15 to 
Day 28). 
 
 
 
 
 
 
 
 
 
 




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• If 2 patients at any dose level discontinue treatment due to changes in vital 
signs, ECG intervals or findings on continuous ECG monitoring no further 
patients will be enrolled at this dose level pending review by DSMB. 
The DSMB can recommend (i) for the study to continue without amendment, (ii) to 
continue the study with modifications to the protocol or (iii) to stop the study.  
The study may continue after the safety review, if the DSMB and STALICLA agree it 
is safe to proceed. 
Individual stopping rules  
If a patient experiences an AE following administration of study drug (i.e., post-
treatment) that is judged to be related to the study drug, and is graded as severe or 
SAE, no further doses of study drug will be administered. 
If a patient experiences an AE that is judged to be related to the study drug, and is 
graded as mild or moderate, the patient may receive a further dose of study drug 
following discussion with the investigator and sponsor, dependent on the nature of the 
AEs reported. Expected transient GI pain requiring 48 hours stop and not resuming 
with reinitiation of treatment is commonly observed. The number of subjects reporting 
similar AEs and reports of the same or similar AEs in a patient, will form part of the 
assessment to determine if patients should be re-challenged. 
Changes in vital signs and ECG intervals 
Patients will be discontinued if after repeated measurements, have pulse/heart 
rate, blood pressure or ECG interval measurements that fulfil one or more of the 
criteria listed below. 
Vital signs 
• Pulse/heart rate <40 or >120 beats per minute (BPM) 
• Systolic BP <90 or >180 mm Hg 
• Diastolic BP <50 or >100 mm Hg 
Laboratory tests 
• Severe hypokalemia (defined as less than 2.5 mEq/L) or persistent 
hypokalemia despite potassium supplementation 
• Thrombocytopenia is defined as meeting one or both criteria: 
o Platelet count below 150 × 10E9/L (or 150.000 platelets per microliter 
(mcL)) 
o Platelet count drop of ≥50% compared to baseline 
• Severe drug-induced liver injury (DILI).  
• 
Dehydration and orthostasis (defined by a fall in systolic blood pressure over 
20 mm Hg or a fall in diastolic pressure over 10 mm Hg within 3 minutes of 
standing.  
 
3.1.3 
DATA SAFETY MONITORING BOARD (DSMB) 
Blinded safety data will be reviewed by the sponsor on an ongoing basis throughout 
the study period. In addition, an independent group of experts (DSMB) will have a 








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disorders of the respiratory chain complex, tricarboxylic acid cycle disorders and 
pyruvate carboxylase deficiency. An L:P ratio below 10 (disproportionately elevated 
pyruvic acid) may indicate an inherited disorder of pyruvate metabolism, such as 
defects of the pyruvate dehydrogenase complex. Exploratory analysis of these 
parameters should help understanding whether the energy metabolism impairment 
observed is linked to mitochondrial activity defect. 
 
3.3 
OUTCOME MEASURES 
3.3.1 
SAFETY OUTCOME MEASURES 
The safety outcome measures for this study are as follows: 
• Incidence, nature and severity of AEs. 
• Incidence, nature and severity of SAEs. 
• Incidence, nature and severity of AESIs. 
• Incidence, nature and severity of AEs leading to treatment discontinuations. 
• Changes from baseline in systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR) and respiratory rate. 
• Changes from baseline in orthostatic measurements of BP and HR. 
• Changes from baseline in ECG parameters (HR, PQ, QRS, QT, RR and QTcF, 
along with information on T and U waves). 
• Incidence of clinically significant ECG abnormalities. 
• Hearing assessment 
• Incidence of clinically relevant laboratory abnormalities, based on hematology, 
blood chemistry and urinalysis test results: 
- 
Hematology: hemoglobin, hematocrit, erythrocytes, platelet count, 
leucocytes differential (absolute) counts (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils). 
- 
Blood 
chemistry: 
aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase (ALT), gamma-glutamyltransferase (GGT), total and 
conjugated bilirubin, alkaline phosphatase (ALP), albumin, creatine 
phosphokinase (CPK), creatinine, urea, total protein, total cholesterol, 
triglycerides, sodium, chloride, calcium, magnesium, phosphate, 
potassium, glucose.  
• Incidence of value outside of the normal ranges of blood chemistry test results 
for electrolytes: 
- 
Sodium, chloride, calcium, magnesium, phosphate, potassium 
• Urinalysis: protein, blood, glucose, leucocytes, nitrites, pH, and presence of 
crystals. 
3.3.2 
PHARMACOKINETIC OUTCOME MEASURES 
Plasma concentrations of 
 will be used and a non-
compartmental analysis (NCA) will be applied to analyze data from the sampling 


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schema. Urine concentration of 
 will be determined over a 
given period. 
Plasma PK parameters such as AUC0 tau, AUC ast, Cmax, Tmax, Ctrough, apparent oral 
clearance, apparent volume of distribution and accumulation ratio will be calculated at 
steady state for both parent drugs. If data permitted, the elimination half-life at steady 
state will be estimated. 
3.3.3 
EXPLORATORY OUTCOME MEASURES 
• Cognition, as assessed by subtasks 
 and 
the KiTAP battery test. 
• Global clinical change in the context of autism as measured by the change in 
the OACIS scale. 
• Maladaptive behavior, as assessed by the ABC-C. 
• Change from baseline in the CGI-S scale (reflected by the CGI-I scale). 
• Quality of sleep as assessed by the CSHQ. 
• Electrophysiology parameters as measured by EEG at rest and during 
habituation and chirp tasks. 
• Eye tracking. 
• Change from baseline in blood L:P. 
 
 
 




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6. Patient willing and consenting or assenting to participate. 
7. If assent provided by the patient, parent or legal guardian willing to give written 
consent. 
8. Patients with ASD and comorbid seizure disorder should be seizure-free for at 
least 6 months prior to screening. 
9. Before enrolling in the study, subjects must agree to use double-barrier birth 
control methods if they engage in intercourse. 
10. Women of childbearing potential, defined as all women physiologically capable 
of becoming pregnant, can be enrolled if they are using highly effective methods 
of contraception during dosing and for 1 week after discontinuation of the 
investigational drug. Highly effective contraception methods include: 
- 
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy), total hysterectomy or tubal ligation at least 6 
weeks before taking the investigational drug. In case of oophorectomy 
alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment. 
- 
Male sterilization (at least 6 months prior to screening). For female 
patients on the study the vasectomized male partner should be the sole 
partner for that patient. 
- 
Use of oral (estrogen and progesterone), injected or implanted hormonal 
methods of contraception or placement of an intrauterine device (IUD) 
or intrauterine system (IUS) or other forms of hormonal contraception 
that have comparable efficacy (failure <1%), for example hormone 
vaginal ring or transdermal hormone contraception. Progesterone 
containing hormonal tablets must be associated with inhibition of 
ovulation in order to qualify as highly effective. 
- 
In case of use of oral contraception women should have been stable on 
the same pill for a minimum of 3 months before taking the investigational 
drug. If local regulations deviate from the contraception methods listed 
above and require more extensive measures to prevent pregnancy, local 
regulations apply and will be described in the informed consent form 
(ICF). 
Women are considered post-menopausal and not of childbearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g., age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before 
taking the investigational drug. In case of oophorectomy alone the reproductive 
status of the woman must be confirmed by follow up hormone level 
assessment. 
Sexually active males must use a condom during intercourse after the start of 
the IMP administration and for at least one week after stopping study 
medication and should not father a child in this period after completion of the 
study medication. A condom is required to be used also by vasectomized men 
in order to prevent delivery of the drug via seminal fluid. In addition, male 


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participants should not donate sperm for the time period specified above. 
4.2.3 
EXCLUSION CRITERIA 
Study patients who meet any of the following criteria will not be included in the study: 
1. Patients with an identified genetic cause of ASD in their medical record will be 
excluded from the study. 
2. History of traumatic head injury, cerebrovascular disorder, congestive heart 
failure, hepatic or renal disease. 
3. Thrombocytopenia (platelet count <100,000 mm3) within 1 year prior to the 
screening visit. 
4. Diabetes (type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus) or 
latent autoimmune diabetes of the adult (LADA). 
5. Use of prohibited medications (Section 4.5.1) or herbal remedies within 2 
weeks prior to randomization, or 5 half-lives (whichever is longer). 
6. Alcohol and/or substance abuse/dependence within 12 months prior to 
screening. 
7. A significant risk for suicidal behavior, in the opinion of the investigator and as 
assessed by the Columbia Severity Rating Scale (C-SSRS) or the simplified 
version adapted from the Columbia Classification Algorithm for Suicide 
Assessment (C-CASA). 
8. Use of antioxidant supplements and/or vitamins within 2 weeks prior to 
randomization.  
9. Initiation of, or a major change in psychological/behavioral intervention within 4 
weeks prior to randomization.  
10. Patient with any active infection, including but not limited to the following: 
o Bacterial infection; or 
o Fungal infection; or  
o Positive result at screening for hepatitis B virus (HBV), hepatitis C virus 
(HCV), or human immunodeficiency virus (HIV)-1 and severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). 
11. Episode of fever (i.e., ≥100.5°F or 38.0°C) or clinically significant illness without 
fever (as judged by the Investigator), within 10 days before Day 1. 
12. A SBP <80 mm Hg or a (DBP) <40 mm Hg or a drop in SBP of ≥20 mm Hg, or 
in DBP of ≥10 mm Hg, or patient experiencing lightheadedness or dizziness 
during the orthostatic recordings. 
13. Clinically relevant ECG abnormalities; QTcF (Fredericia’s correction) >450 ms 
(at screening or Day 1 pre-dose). 
14. Confirmed clinically significant abnormal laboratory test results at screening 
(lactate and pyruvate not included) other than the conditions related to ASD-
Phen1. 
15. Patients with any active clinically significant disease (i.e. gastroenterological, 
endocrinological, renal, respiratory, cardiovascular, hepatic dysfunction, 


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immunological or hematological disease) that following the judgment of the 
investigator may interfere with the conduct of the study, other than the 
conditions related to ASD-Phen1. 
16. Patients with any history of malignancy of any organ system (other than 
localized basal cell carcinoma of the skin), treated or untreated, within the past 
5 years, regardless of whether there is evidence of local recurrence or 
metastases. 
17. Pregnant (confirmed by laboratory testing) or lactating female patient. 
18. Participation in an investigational drug study within 30 days or 5 times its half-
life, whichever longer, prior to randomization. 
4.3 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Each dose level will include up to 8 patients (up to 6 subjects assigned to STP1 and 
up to 2 assigned to placebo). The list of randomized treatment assignments will be 
generated by the sponsor or its designee, distributed to the unblinded site personnel, 
and incorporated into double-blind labeling. The qualified individual responsible for 
dispensing the study drug supplies will prepare the correct medication supply required 
according to the randomization schedule. This individual will write the date dispensed 
and Patient Number on the study drug labels and on the Drug Accountability Records. 
This individual will also record the study drug batches or lot numbers received by each 
subject during the study. 
The randomized treatment assignment will be allocated from the list sequentially to 
subjects in the order in which they are enrolled. The unblinded personnel will be 
responsible for dispensing the assigned treatment.  
With the exceptions described below, the randomization list will not be available to the 
project team at STALICLA or to any blinded personnel at the study centers. 
The randomization list will be made available to the individual responsible for PK 
sample bioanalysis. The list will also be provided to the contract research organization 
(CRO) unblinded independent statisticians and programmers as needed to create 
unblinded data displays for the DSMB review(s). 
Emergency Unblinding:  
As per Health Authority reporting requirements, the sponsor will break the treatment 
code for all unexpected SAEs (see Section 5.1) that are considered by the investigator 
to be related to study drug(s). 
The PIs will receive a set of sealed treatment codes. If the identity of the test 
medication needs to be known in order to manage the patient’s condition, the 
treatment code for that patient may be broken.  
In the event of an emergency, the treatment code for an individual patient will be readily 
available to the investigator and sponsor through on-site code break envelopes, as 
well as through communication with the unblinded, independent statistician 
responsible for generating the randomization list.  
All such occurrences should be documented in the study file. Treatment codes should 
not be broken except in emergency situations and, if possible, the Chief Medical 
Officer/Clinical Trial Manager (STALICLA) should be contacted before the code is 
opened. At the final monitoring visit, the unused treatment codes will be counted and 




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(IMP), to confirm the shipment condition and content. Any damaged shipments will be 
replaced.  
The investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug 
Dispensing Log) of the IMP must be maintained. The Drug Dispensing Logs must be 
kept current and should contain the following information: 
• The identification of the Patient to whom the study drugs were dispensed (for 
example, patient initials and date of birth). 
• The date(s), quantity of the study drugs dispensed to the Caregiver. 
• The date(s) and quantity of the study drugs returned by the Caregiver. 
• All records and drug supplies must be available for inspection by the Study 
Monitor [at every monitoring visit]. 
IMP will either be disposed at the study site according to the study site’s institutional 
standard operating procedure or returned to the sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
sponsor. Local or institutional regulations may require immediate destruction of used 
investigational medicinal product for safety reasons. In these cases, it may be 
acceptable for investigational study site staff to destroy dispensed investigational 
product before a monitoring inspection provided that source document verification is 
performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned, destroyed and provided that adequate storage 
and integrity of drug has been confirmed. 
The site must obtain written authorization from the sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form. 
Written documentation of destruction must contain the following: 
• Identity (e.g., Medication number [MEDNO]) of investigational product(s) 
destroyed. 
• Quantity of investigational product(s) destroyed. 
• Date of destruction. 
• Method of destruction. 
4.4.4 
POST-TRIAL ACCESS TO STP1 
The sponsor does not intend to provide STP1 or other study interventions to patients 
after conclusion of the study or any earlier patient withdrawal.  
4.5 
CONCOMITANT THERAPIES AND FOOD  
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-
counter (OTC) drugs, approved dietary and herbal supplements, nutritional 
supplements and any non-medication interventions (e.g., individual psychotherapy, 
cognitive behavioral therapy, smoking cessation therapy, and rehabilitative therapy) 
used by a patient from screening until the follow-up visit. All concomitant therapies 
taken within 30 days of the screening visit should be reported to the investigator and 
recorded on the Concomitant Medications electronic Case Report Form (eCRF). 
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4.5.1.3 
MEDICATIONS TO BE AVOIDED WITH STP1 
• 
BCRP substrates: both 
 are inhibitors of the BRCP 
transporter. Although BCRP inhibition by each individual drug might not be of 
clinical relevance at the dose level used, it is difficult to predict the effect of both 
drugs administered together on the BRCP transporter activity. Therefore, drugs 
that are substrates of BCRP will be prohibited during this clinical trial. The list 
includes [Mao and Unadkat, 2015]: 
• 
Anthracenes: mitoxantrone, bisantrene and aza-anthrapyrazole. 
• 
Camptothecin derivates: topotecan, SN-38, irinotecan and diflomotecan. 
• 
Polyglutamates: methotrexate, methotrexate-Glu2 and methotrexate-
Glu3. 
• 
Nucleoside analogs: azidothymidine (AZT), AZT 5′-monophosphate and 
lamivudine (3TC). 
• 
Other drugs: prazosin, indolocarbazole, flavopiridol, canertinib, imatinib 
mesylate, gefitinib, nilotinib, glyburide, cimetidine, sulfasalazine, 
nitrofurantoin, rosuvastatin and pantoprazole.  
• 
The concomitant treatment with CYP3A4 moderate or strong inhibitors 
is excluded. Medicines that are potent CYP3A4 inhibitors include (but 
are not limited to) clarithromycin, diltiazem, erythromycin, itraconazole, 
ketoconazole, ritonavir, telithromycin, and verapamil. Grapefruit juice is 
also a strong CYP3A4 inhibitor. 
4.5.1.4 
MEDICATIONS TO BE AVOIDED IN THE STUDY POPULATION 
• 
Potent 
 activators: potent 
 activators such as sulforaphane should be 
avoided in ASD-Phen1 subpopulation as it is predicted that it would increase 
the patient ASD symptoms. 
4.5.2 
PRECAUTIONS 
Consumption of food and beverages containing caffeine or methylxanthines (e.g., 
coffee, tea, cola, chocolate) is permitted during the study but meals served at the clinic 
should not contain caffeine or methylxanthines. 
Vitamin/mineral supplements and occasional use of paracetamol (up to 1,000 mg/day) 
are allowed up until 24 hours before dosing. 
Because of a theoretical DDI with 
 i.e., risk or severity of bleeding can be 
increased secondary to thrombocytopenia, Non-steroidal anti-inflammatory drugs, 
acetylsalicylic acid and other drugs that might have an impact on coagulation 
parameters should be used with caution during this clinical trial. 
4.5.3 
BEHAVIORAL AND COGNITIVE INTERVENTIONS  
Behavioral or cognition-oriented interventions should not be changed or initiated 
during the study. Similarly, initiation of new medication or other treatments intended to 
improve cognition is not permitted. 
4.5.4 
SPECIAL CONSIDERATIONS AND FASTING 
Subjects will be required to refrain from intense physical exercise within 72 hours 
before the screening visit and throughout the study and should inform the investigator 
of any event which could interfere with the conduct or interpretation of the study. 




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ECG machine equipped with computer-based interval measurements should be used 
for each patient. The conditions of the post-dose recordings should be as close as 
possible to pre-dose time points; this includes but is not limited to food intake, activity 
level, stressors and room temperature. To minimize variability, the ECG will be 
recorded in triplicate at baseline (recorded 1 minute apart) and it is important that 
patients be in a resting position for at least 10 minutes prior to each ECG evaluation. 
Body position should be consistently maintained for each ECG evaluation to prevent 
changes in HR. Environmental distractions (e.g., television, radio, conversation) 
should be avoided during the pre-ECG resting period and during ECG recording. 
ECGs should be performed prior to meals and any scheduled vital sign measurements 
and blood draws. In some cases, it may be appropriate to repeat abnormal ECGs to 
rule out improper lead placement as contributing to the ECG abnormality. 
For safety monitoring purposes, the investigator or designee must review, sign and 
date all ECG tracings. Paper or electronic copies will be kept as part of the patient’s 
permanent study file at the site.  
ECG characteristics, including heart rate, QRS duration and HR, and QT intervals will 
be recorded on the eCRF. QTcF (Fredericia’s correction) and RR will be recorded on 
the eCRF. Changes in T-wave and U-wave morphology and overall ECG interpretation 
will be documented on the eCRF. T-wave information will be captured as normal or 
abnormal, U-wave information will be captured in two categories: absent/normal or 
abnormal. 
4.6.1.5 
LABORATORY ASSESSMENTS 
Normal ranges for the study laboratory parameters must be supplied to the sponsor 
before the study starts. Laboratory safety tests shall be collected at time-points 
specified in the Schedule of Assessments (Appendix 1). 
Additional blood or urine samples may be taken at the discretion of the investigator if 
the results of any test fall outside the reference ranges, or clinical symptoms 
necessitate additional testing to monitor patient’s safety. Where the clinical 
significance of abnormal laboratory results is considered uncertain, screening 
laboratory tests may be repeated before randomization to confirm eligibility. If there is 
an alternative explanation for a positive urine or blood test for drugs of abuse, e.g., 
previous occasional intake of a medication or food-containing for example, codeine, 
benzodiazepines or opiates, the test could be repeated to confirm washout. 
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the local or central laboratory. 
When a fasted state is required, subjects have to be fasted for at least 4 hours. 
Blood samples for the following laboratory tests will be sent to the local laboratory(ies) 
for analysis.  
• Hematology (5 mL per sample): hemoglobin, hematocrit, erythrocytes, platelet 
count, leucocytes differential (absolute) counts (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils). 


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• Blood chemistry (5 mL per sample): C-reactive protein (CRP test), AST, ALT, 
GGT, total and conjugated bilirubin, alkaline phosphatase (ALP), lactate, 
pyruvate, albumin, creatine phosphokinase (CPK), creatinine, urea, total 
protein, total cholesterol, triglycerides, sodium, chloride, calcium, magnesium, 
phosphate, potassium, glucose. 
• Coagulation (2 mL per sample): international normalized ratio (INR), activated 
partial thromboplastin time (aPTT), prothrombin test (PT). 
• Viral serology (2 mL per sample):  
• 
HIV (specific tests HIV-1 antibody).  
• 
Hepatitis B surface antigen (HBsAg).  
• 
Total hepatitis B core antibody (HBcAb).  
• 
Hepatitis C virus (HCV) antibody.  
To test for ongoing infection to the SARS-CoV-2, the Food and Drug Adminiastration 
(FDA)’s approved biosamples (nasal swab, saliva) will be collected and quantitative 
Polymerase Chain Reaction (qPCR) test will be performed on this sample.  
Urine samples will be used for analyses of protein, blood, glucose, leucocytes, nitrites, 
pH and presence of crystals. A urine pregnancy test will also be done for female 
patients. 
Urine tests for barbiturates, benzodiazepines, amphetamines (including ecstasy), 
opiates (including methadone), cocaine, and cannabinoids will also be done. It will be 
performed at the site’s local laboratory. 
An alcohol test in urine will be performed at the screening visit and at the discretion of 
the investigator for the subsequent visits. 
4.6.1.6 
PHARMACOKINETICS ASSESSMENTS 
Blood samples (2 samples of 2 mL) for determination of plasma concentration of 
 (and metabolite if appropriate) and 
 will be collected as specified 
in Appendix 1 and Table 2. 
 
 


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Table 2 PK sampling times  
Plasma and urine concentration of 
 will be measured by a 
specific and validated liquid chromatography-mass spectrometry (LC-MS/MS) 
method.  
The actual dosing time of the preceding dose before each study visit (ie, time of PM 
dosing for Day 6 and Day 13) will be captured in the subject’s medication diary (see 
Section 4.6.1.8) and in the relevant page of the eCRF. The actual time of the PK blood 
sampling needs to be precisely entered into the corresponding eCRF section. 
4.6.1.7 
BIOMARKER SAMPLING 
- 
Lactate to pyruvate ratio (L:P) 
Blood levels of lactate and pyruvate will be measured as an exploratory tool to further 
characterize the specificity of the ASD-Phen1 subpopulation, and as a potential 
biomarker of STP1 activity (lactate and pyruvate are part of the laboratory 
assessments list in Section 4.6.1.5). Whole blood lactate to pyruvate ratio (L:P) will be 
used to assess the mitochondrial function as detailed in Section 3.2.4. 
4.6.1.8 
STUDY-SPECIFIC ASSESSMENTS 
- 
Stanford Binet Intelligence Scales, Fifth Edition – Abbreviated Battery IQ 
(SB5 ABIQ) 
The Stanford–Binet Intelligence Scales (or more commonly the Stanford–Binet) is an 
individually administered cognitive ability and intelligence test that is used to diagnose 
developmental or intellectual deficiencies in young children. The ABIQ consists of two 
routing subtests from the full battery (Full Scale IQ – FSIQ). This abbreviated battery 
is based on Nonverbal Fluid Reasoning (Object Series/Matrices) and Verbal 
Knowledge (Vocabulary) [Janzen et al, 2004]. The test measures five weighted 
factors: knowledge, quantitative reasoning, visual-spatial processing, working memory 
and fluid reasoning [Nicolas et al, 2013]. It takes approximately 15 to 30 minutes to 
administer and will be administered at baseline only (screening). 
- 
Aberrant Behavior Checklist – Second Edition – Community (ABC-C) 
The Aberrant Behavior Checklist-Community, ABC-C, [Aman et al., 1985; Kaat et al, 
2014] is a 58-item, parent or caregiver-rated questionnaire rating scale that measures 
PK Schedu ec 
T me 
P asmaa 
Ur neb 
Day 1 
0.25, 0.5, 1, 2, 4 and, 6h post-AM dose 
0-6 h post-AM dose 
Day 7 
Pre-AM dose 
 
Days 
14 
(on y AM dose) 
and 15 
Pre-AM dose and 0.25, 0.5, 1, 2, 4, 6, 8, 
10, 12 and 24 h post-AM dose 
0-4, 4-8 and 8-12 h post-AM dose 
Between Days 
16 and 18d 
48, 72 and 96 h post-AM dose of 
Day 14 
 
a both 
 be ana yzed from the same b ood draw for each spec f ed samp ng t me 
po nt 
b ur ne creat n ne from the ur ne co ect on w  be pa red w th a serum creat n ne measurement to eva uate 
comp eteness of co ect on 
c a  these t mepo nts have a 5 m nutes w ndow 
d Opt ona  


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the severity of a range of problem behaviors commonly observed in individuals with 
intellectual and developmental disabilities, across 5 domains: irritability, agitation and 
crying; lethargy/social withdrawal; stereotypic behavior; hyperactivity/noncompliance; 
and inappropriate speech. Behaviors are rated on a 4-point scale from 0 to 3, with 
higher scores indicating more severity of the behavior specified. It will provide 
information about the range and severity of maladaptive behaviors in ASD-Phen1 
patients. The ABC-C should take approximately 15 minutes to be completed and will 
be administered at baseline (screening) and at D14 and D28. 
- 
Social Responsiveness Scale, 2nd Edition (SRS-2) 
The Social Responsiveness Scale™, Second Edition, or SRS-2, identifies social 
impairment associated with ASD and quantifies its severity. It is a 65-item 
parent/caregiver rating scale used to assess the severity of social impairment within 
patients with ASD. Social awareness, social motivation and restricted interests and 
repetitive behavior are the domains explored by the scale [Constantino et al, 2013]. 
Standardized scores are derived (total score and 5 subscores). It is sensitive enough 
to detect even subtle symptoms but specific enough to differentiate clinical groups, the 
SRS-2 can be used to monitor symptoms throughout the life span. It allows to assess 
social impairment in natural settings—teachers, parents and others are asked to rate 
symptoms that they have noticed over time at home, in the classroom or elsewhere. 
Raters evaluate symptoms using a quantitative scale representing a range of severity. 
In addition to a total score reflecting severity of social deficits in the autism spectrum, 
five treatment subscale scores are provided: social awareness, social cognition, social 
communication, social motivation and restricted interests and repetitive behavior (for 
details see https://www.parinc.com/Products/Pkey/426). The questionnaire should 
take approximately 20 minutes to be completed and will be administered at baseline 
(screening) and Day 14 visits.  
- 
Ohio Autism Clinical Impression Scale – Severity (OACIS severity) and 
Improvement (OACIS change) 
The Ohio Autism Clinical Impressions Scale (OACIS) is an autism-specific clinical 
global impression scale, used as an outcome measures in psychopharmacology 
clinical trials. The OACIS is composed of two scales: the OACIS-Severity scale 
(OACIS-S), which measures global severity of illness at a given point in time as well 
as scores for 9 anchors: social interactions; aberrant/abnormal behaviors; 
repetitive/ritualistic behaviors; verbal communication; non-verbal communication; 
hyperactivity/inattention; anxiety/fears; sensory sensitivities; restricted and narrow 
interests. The OACIS improvement scale (OACIS-C), which measures change from 
the baseline state at following visits. The OACIS-C rating scale permits a global 
evaluation by the clinician of the subject’s improvement over time. The OACIS-S is a 
7-point scale ranging from 1 (no symptoms) to 7 (very severe). The OACIS-C is a 
seven-point scale, ranging from 1 (very much improved) to 7 (very much worse). The 
OACIS-S will be administered at baseline (screening) and Day 14 and the OACIS-C 
will be administered at the end of the study treatment only (D14). 
A single clinician will rate the OACIS for each subject. In addition, the clinician must 
be blinded for side effects since potential diuretic effect of 
 may unblind 
the clinician. It is highly recommended that the clinician who will complete the OACIS 
is not involved in any other cognitive assessments or should complete the OACIS 
before any other interviews or cognitive testing. 




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project [prior to medication initiation], this patient's condition is: 1=very much improved 
since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no 
change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 
7=very much worse since the initiation of treatment.” 
- 
Clinical Global Impressions-Severity (CGI-S) Scale  
The CGI-S score is often obtained, by researchers conducting psychopharmacology 
trials, at the baseline (initiation) visit and serves as a good basis for making this 
assessment. An illness severity rating is made on a scale of 1 to 7, with 1 being “normal 
not at all mentally ill” and 7 being “among the most extremely ill patients”. 
Subsequently, the patient's condition on the study drug (or placebo) is compared to 
the patient's condition before the initiation of the study drug (or placebo) (baseline) via 
additional CGI-S ratings or the CGI-I item.  
- 
EEG 
Acquisition: Human recordings are acquired through 128-channel Phillips/EGI 
HydroCel nets with a Phillips/EGI Netamp 400 Amplifier (EGI, Eugene, OR). Data are 
recorded using Phillips/EGI Netstation acquisition software at a sampling rate of 1,000 
Hz with saline based net electrodes (impedance under 10 KΩ). Systematic behavioral 
interventions have been developed by the site including social stories, visual 
schedules and demo nets/parent training to optimize successful data collection from 
our target population. In our experience, >95% of adults with ASD tolerate the 
procedure and provide usable EEG data following the implementation of these 
preparation/training procedures. EEG studies are conducted in sound attenuated and 
electrically shielded private rooms dedicated for EEG/ERP studies. Acoustic and 
tactile stimuli are generated using MATLAB (MathWorks, Natick, MA) and presented 
using Presentation 17 software (Neurobehavioral Systems, Berkeley, CA). Sound 
delivery is synchronized with the EEG recording using a Presentation 17 generated 
TTL pulse to mark the onset of each stimulus. During experimental neurophysiological 
procedures, when appropriate, subjects sit while watching a silent video (i.e., cartoon 
movie). The silent video will be standardized across all patients and used to facilitate 
cooperation in ASD. 
1. Resting State: Continuous data will be recorded for 4 minutes eyes open and 4 
minutes eyes closed (dependent on patient cooperation).  
2. Auditory Chirp: Auditory “chirp” stimuli will be delivered at 65 dB SPL through 
standardized headphones with a 1,000-Hz carrier tone amplitude modulated (AM) by 
a chirp sinusoid linearly increasing in frequency from 0 to 100 Hz over 2,000 ms. Two 
hundred stimuli will be separated by a 1.5 to 2 second inter-trial interval, for 12.5 
minutes of testing.  
EEG will be recorded before and after morning dosing on Day 1 and after dosing on 
Day 14 and Day 28. 
- 
Eye Tracking 
Eye tracking data will be collected using a Tobii (Stockholm, Sweden) T120 infrared 
binocular eye tracker sampling at a rate of 120 Hz to record X and Y coordinates of 
eye position and pupil diameter along with gaze duration. The paradigms will be run 
on an integrated 17-inch flat-panel monitor (1,280 × 1,024 pixels resolution) running 
Tobii Studio (Version 3.0, Tobii Technology, Sweden).  


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Paradigm 1. Social scene preference ratio 
Rectangular areas of interest (AOIs) will be created around both the social 
scene and geometric pattern videos. Social scene preference ratio (SSPR) will 
be calculated by dividing the time spent viewing the social scene videos by the 
total time spent viewing the social scene or geometric pattern videos (Eq. 1). 
Only the silent side-by-side video paradigm will be used in this analysis as audio 
from the social scene video was found to have a significant impact on selective 
preference towards the coinciding video. 
Eq. 1: SSPR = Viewing TimeSocial Scenes 
     Viewing TimeTotal 
Paradigm 2. Emotional faces 
Stimuli will consist of 12 colored photographs of adult human faces (equal 
numbers of males and females) from the NimStim Face Stimulus Set 
[Tottenham et al, 2009], each showing a calm, happy, or fearful facial 
expression. Each emotional face will be presented on the screen for 5 s. Prior 
to presenting the emotional faces, a scrambled version of the face image will 
be presented for 1 s. Similar to Farzin et al, [2009, 2011], each face and 
corresponding scrambled image will be matched on mean luminance, and 
equivalence will be confirmed using a photometer (Minolta, LS-100, Osaka, 
Japan). Face images will subtend a 12.12° by 17.19° region (the size of an 
actual human face) when viewed from a distance of 60 cm and will be presented 
on a standard 50% gray background (RGB: 128, 128, 128). 
- 
Children Sleep Habit Questionnaire (CHSQ) 
The Children Sleep Habits Questionnaire (CSHQ) is a retrospective, 45-item parent 
questionnaire that has been used in a number of studies to examine sleep behavior in 
young children. The CSHQ includes items relating to a number of key sleep domains 
that encompass the major presenting clinical sleep complaints in this age group: 
bedtime behavior and sleep onset; sleep duration; anxiety around sleep; behavior 
occurring during sleep and night wakings; sleep-disordered breathing; parasomnias; 
and morning waking/daytime sleepiness. Parents are asked to recall sleep behaviors 
occurring over a “typical” recent week. Items are rated on a three-point scale: “usually” 
if the sleep behavior occurred five to seven times/week; “sometimes” for two to four 
times/week; and “rarely” for zero to one time/week. Some items were reversed in order 
to consistently make a higher score indicative of more disturbed sleep [Owens et al, 
2000]. The abbreviated version of this questionnaire includes 22 items assessing 
sleep habits and possible difficulties with sleep [Owens et al, 2000]. Unless noted, 
“always” refers to something occurring every night, “usually” if it occurs 5 or 6 times a 
week, “sometimes” if it occurs 2 to 4 times a week, “rarely” if it occurs once a week 
and “never” if it occurs less than once a week. Since the questionnaire is designed for 
children, the questionnaire will be answered by the parent/caregiver whenever 
possible. It should take approximately 5 to 10 minutes to be completed. 
- 
Clinical Assessment of Suicidality 
The assessment of suicidality will be collected for all patients at all visits using the 
Columbia Suicide Severity Rating Scale (C-SSRS) or the Columbia Classification 
Algorithm for Suicide Assessment (C-CASA). 


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• Columbia Severity Rating Scale (C-SSRS): The Columbia Suicide Severity 
Rating Scale, or C-SSRS, is a suicidal ideation and behavior rating scale 
created by researchers at Columbia University, University of Pennsylvania, 
University of Pittsburgh and New York University to evaluate suicide risk. It rates 
an individual's degree of suicidal ideation on a scale, ranging from "wish to be 
dead" to "active suicidal ideation with specific plan and intent and behaviors". 
Questions are phrased for use in an interview format, but the C-SSRS may be 
completed as a self-report measure if necessary. The scale identifies specific 
behaviors which may be indicative of an individual's intent to complete suicide. 
An individual exhibiting even a single behavior identified by the scale was 8 to 
10 
times 
more 
likely 
to 
complete 
suicide 
(for 
details 
see 
https://cssrs.columbia.edu/).  
• Simplified version adapted from the Columbia Classification Algorithm for 
Suicide Assessment (C-CASA). The C-CASA is a classification system that 
utilizes definitions of suicidality derived from empirical findings on the 
phenomenology of suicidality and identified predictive and risk factors. The 
criteria for a suicide attempt include both self-injurious behavior and suicidal 
intent (at least some intention to commit suicide). Intent to die portends a risk 
for future suicide and repeated attempts and can be reliably obtained. Inclusion 
of intent in the definition of suicide allows a distinction between those who self-
injure in an attempt to die and those who self-injure for purely other non-suicidal 
reasons (e.g., to manage affect). The C-CASA has eight categories that 
distinguish suicidal events from non-suicidal events and indeterminate or 
potentially suicidal events [Posner et al, 2007]. 
• Suicidal Ideation: Has the patient wished he/she were dead or wished they 
could go to sleep and not wake up? 
• Suicidal Behavior: Has the patient made a suicide attempt? Has the patient 
done anything to harm himself or herself? 
• Self-injurious Behavior: Has the patient engaged in non-suicidal self-injurious 
behavior? 
• If the investigator determines that any of these questions can be asked directly 
to the subject based on the subject’s ability to understand and to react to the 
questions, then those questions should be directed to the subject. If the answer 
is “yes” to any of these 3 questions, then the investigator will further evaluate 
the suicidal risk of the patient. 
- 
Subject Medication Diary 
All enrolled (i.e., randomized patients) will be asked to maintain a “Subject Medication 
Diary”. This template diary will be provided during the Baseline/Randomization visit to 
keep track of the daily doses and of the timing of study medications. Patients will be 
asked to bring this diary along with the study medication bottles to the Day 7 and Day 
14 study visits to assess for compliance and drug accountability. If this is not done at 
the Day 14 visit for any reason, this can also be completed at Day 28 visit. 
4.6.2 
TIMING OF STUDY ASSESSMENTS (SEE APPENDIX 1) 
The patients willing to participate in the study will only be included when all screening 
examination procedures have demonstrated that all inclusion criteria and none of the 


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exclusion criteria apply. The patients will be assigned a patient number within the 
study.  
Screening (Visit 1, Day -14 to Day -1) 
During the screening visit the following assessments will be performed: 
• Informed consent to be obtained from the patient, parent or legal guardian . 
• Eligibility criteria including all inclusion and exclusion criteria. 
• Demographics 
. 
• Medical history: including all clinically significant diseases, prior medical 
interventions (e.g., vaccines, surgeries) or smoking/substance use history. All 
medication (e.g., prescription drugs, OTC drugs, herbal/homeopathic 
remedies, nutritional supplements) used by the patient within 4 weeks leading 
up to the screening visit will be collected.  
• Physical examination: a general physical examination will be performed. 
• Vital signs: including temperature, HR, respiratory rate, orthostatic SBP and 
DBP. 
• ECG-12 lead.  
• Serology: HIV (specific tests HIV-1 antibody), Hepatitis B (HBsAg, HBsAb) and 
hepatitis C virus (HCV) antibody. 
• Pregnancy test (urine) in females. 
• SARS-Cov-2 test (nasal swab, saliva).  
• Substance abuse history, and test urine 
• Blood sampling for hematology, chemistry, and coagulation. 
• Urine sampling for urinalysis. 
• Alcohol (urine test). 
• Suicidality assessment. 
• ABC-C test. 
• SRS-2 test. 
• SB5 ABIQ test. 
• OACIS-severity assessment. 
• NIH toolbox assessment. 
• KiTAP assessment. 
• CSHQ assessment. 
• CGI-S assessment. 
• AEs 
 
• Previous and concomitant treatments. 
 
Treatment period 
The treatment period consists of 3 visits (Days 1, 7 and 14). After screening 
assessments, the enrolment and treatment period will be started. Patients meeting all 
inclusion and none of the exclusion criteria will be enrolled.  
Patients will then receive the study medication, orally, twice daily (6 hours apart) for 
14 days. The patient will be closely observed during and after the administration of the 
study medication. The following procedures and assessments will be performed during 
and after the treatment: Please refer to the Schedule of Assessment (Appendix 1). 
 


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Visit 2 (Day 1) 
During the Day 1 visit, defined as the first day of the study drug administration, the 
following assessments will be performed: 
• Randomization. 
• Physical examination: a general physical examination will be performed. 
• Vital signs: including temperature, HR, respiratory rate, SBP and DBP. 
• Orthostatic BP assessment. 
• ECG-12 lead. 
• Substance abuse history, and test (urine) 
• Hearing assessment. 
• Administration of the study medication. 
• Study medication supply. 
• Blood and urine sampling for PK. 
• Suicidality assessment. 
• 
 
• KiTAP assessment. 
• Eye tracking assessment (pre- and post-dose). 
• EEG (pre- and post-dose). 
• CSHQ assessment. 
• AEs. 
• 
Previous and concomitant treatments. 
Visit 3 (Day 7) 
• Physical examination: a general physical examination will be performed. 
• Vital signs: including temperature, HR, respiratory rate, SBP and DBP. 
• Orthostatic BP assessment. 
• ECG-12 lead. 
• Blood sampling for hematology, chemistry and coagulation 
. 
• Urine sampling for urinalysis. 
• Administration of the study medication. 
• Blood sampling for PK at pre-AM dose. 
• Suicidality assessment. 
• Hearing assessment. 
• AEs. 
• 
Previous and concomitant treatments. 
Visit 4 (Day 14) 
• Physical examination: a general physical examination will be performed. 
• Vital signs: including temperature, HR, respiratory rate, SBP and DBP. 
• Orthostatic BP assessment. 
• ECG-12 lead. 
• Blood sampling for hematology, chemistry, and coagulation. 
• Urine sampling for urinalysis. 
• Administration of the study medication. 
• Blood and urine sampling for PK  
• Suicidality assessment. 
• ABC-C test. 


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• SRS-2 test. 
• OACIS-severity assessment. 
• OACIS-change assessment. 
• 
 
• KiTAP assessment. 
• Eye tracking assessment. 
• EEG. 
• CSHQ assessment. 
• CGI-I assessment. 
• CGI-S assessment. 
• Hearing assessment. 
• AEs. 
• Previous and concomitant treatments. 
Visit 4 (Day 15) and optional visit 5/6/7 (Day 16/17/18) (adults) 
Patients will be given the option to have their follow-up PK sampling visit between 
Day 16 and Day 18.  
• Blood sampling for PK. 
• Urine sampling for PK (visit 4 [Day 15] only). 
• Suicidality assessment. 
• AEs. 
• 
Previous and concomitant treatments. 
End-of-study (EOS) follow-up visit (visit 8, Day 28) 
The following assessments will be performed for each patient on Day 28, at the end 
of the follow-up: 
• Physical examination: a general physical examination will be performed. 
• Vital signs: including temperature, HR, respiratory rate, SBP and DBP. 
• Orthostatic BP assessment. 
• ECG-12 lead. 
• Pregnancy test (urine) in females. 
• Blood sampling for hematology, chemistry, and coagulation. 
• Urine sampling for urinalysis. 
• Blood sampling for PK at any time. 
• Suicidality assessment. 
• ABC-C test. 
• SRS-2 test 
• 
 
• KiTAP assessment.  
• Eye tracking assessment. 
• EEG. 
• CSHQ assessment. 
• CGI-I assessment. 
• CGI-S assessment. 
• Hearing assessment. 
• AEs. 
• Previous and concomitant treatments. 


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At visit days when multiple assessments involving the patient coincide, the following 
sequence should be followed: 
• Vital signs and ECG recordings. 
• Fasting laboratory samplings (and PK sampling where applicable). 
• Break. 
• EEG and eye tracking recordings (on Day 1 only). 
• Break, snack and dose administration. 
• Cognitive assessment. 
• EEG and eye tracking recordings. 
The cognitive testing should be performed at a similar time of day and in the same 
sequence across all study visits. Breaks can be allowed between the cognitive tasks 
if deemed necessary by the clinician/rater. 
4.6.2.1 
SCREENING AND PRE-TREATMENT ASSESSMENTS 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Informed Consent Forms 
(ICFs) for enrolled patient and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that patients meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or 
record reasons for screening failure. 
An Eligibility Screening Form (ESF) documenting the investigator’s assessment of 
each screened patient with regard to the protocol’s inclusion and exclusion criteria is 
to be completed by the investigator and kept at the investigational site. Where the 
clinical significance of an abnormal screening test result (e.g., laboratory test) is 
considered uncertain, the test should be repeated to confirm the result. 
Subjects who participated in the observational study [STP1-C003, NCT04273087] will 
not have to redo the ASD-Phen1 semi-structured interview form. Data from the STP1-
C003 study will be transferred or entered into this study database.  
An abbreviated rescreening may be allowed under circumstances where the patient is 
screen-passed but could not be randomized within the 2-week screening window due 
to a study halt, logistical, personal or technical reasons. At no time should the duration 
between the original screening visit and the abbreviated rescreening visit exceed 2 
months, otherwise a full screening visit will be required. The abbreviated rescreening 
will include the following: a written informed consent, updated medical history, physical 
examination, drugs of abuse, pregnancy test (females only), alcohol urine test, 
laboratory safety, coagulation, viral serology, urinalysis, and inclusion/exclusion 
criteria. 
4.6.2.2 
ASSESSMENTS DURING TREATMENT 
All assessments must be performed according to the Schedule of Assessments 
(Appendix 1). Under no circumstances will patients who enroll in this study and have 
completed treatment as specified, be permitted to be allocated a new randomization 
number and re-enroll in the study within the same cohort. 


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4.6.2.3 
FOLLOW-UP ASSESSMENTS 
Patients who complete the Day 15 study visit or discontinue from the study early, will 
be asked to return to the clinic on Day 28 (±2 days) for the follow-up visit. After the 
study completion, AEs should be followed as outlined in Section 5.6. 
4.7 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.7.1 
PATIENT DISCONTINUATION 
The investigator has the right to discontinue a patient from STP1 or withdraw a patient 
from the study at any time. In addition, patients have the right to voluntarily withdraw 
from the study at any time for any reason. Reasons for discontinuation of STP1 or 
withdrawal from the study may include, but are not limited to, the following: 
• Patient withdrawal of consent at any time. 
• Any medical condition that the investigator or sponsor determines may 
jeopardize the patient’s safety if he or she continues in the study. 
• Investigator or sponsor determines it is in the best interest of the patient. 
• Patient non-compliance. 
Patients who fulfill the criteria described in the Stopping Rules section (as defined in 
Section 3.1.2) should be discontinued from the study. 
4.7.1.1 
DISCONTINUATION FROM STP1 
Patient must discontinue STP1 if they experience any of the following: 
• Pregnancy. 
• Patient unable to continue to comply with study requirements. 
• Unblinding of a patient. 
Patients who discontinue STP1 prematurely will be asked to return to the clinic for a 
follow-up visit (see Section 4.6.2.4). The primary reason for premature STP1 
discontinuation should be documented on the appropriate eCRF page. Patients who 
discontinue STP1 prematurely may be replaced to achieve a total of 16 patients. 
4.7.1.2 
WITHDRAWAL FROM STUDY 
Every effort should be made to obtain information on patients who withdraw from the 
study. The sponsor or a designee should follow up by telephone or electronic mail. 
The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. The Study Monitor should include reviewing of subject withdrawals 
as part of the monitoring visit scope and Monitoring Plan. 
Patients will not be followed for any reason after consent has been withdrawn. 
Patients who withdraw consent may be replaced to achieve a total of 16 patients. 
4.7.2 
STUDY AND SITE DISCONTINUATION 
The sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
• The incidence or severity of AE in this or other studies indicates a potential 
health hazard to patients. 
• Patient enrollment is unsatisfactory. 
• Important new information becomes available that may be relevant to the 
subject’s consent. 


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The sponsor will notify the investigator and Health Authorities if the study is placed on 
hold, or if the sponsor decides to discontinue the study or development program. 
The sponsor has the right to replace a site at any time. Reasons for replacing a site 
may include, but are not limited to, the following: 
• Excessively slow recruitment. 
• Poor protocol adherence. 
• Inaccurate or incomplete data recording. 
• Non-compliance with the International Council for Harmonisation (ICH) 
guideline for Good Clinical Practice (GCP). 
 
 


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5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording the incidence, nature and 
severity of AEs, including SAEs and AEIs; measurement of protocol-specified safety 
laboratory assessments; and measurement of protocol-specified vital signs, ECGs 
and other protocol-specified tests described in Section 5.1.4. 
Certain types of events require immediate reporting to the sponsor, as outlined in 
Section 5.4. 
5.1.1 
ADVERSE EVENTS 
According to the ICH guideline for GCP, an AE is any untoward medical occurrence 
in a clinical investigation subject administered a pharmaceutical product, regardless 
of causal attribution. An AE can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
• Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition). 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG) that is 
associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug(s). 
• AEs that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies). 
5.1.2 
SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE TO THE 
SPONSOR) 
An SAE is any AE that meets any of the following criteria: 
• Fatal (i.e., the AE actually causes or leads to death). 
• Life-threatening (i.e., the AE, in the view of the investigator, places the patient 
at immediate risk of death). This does not include any AE that, had it occurred 
in a more severe form or was allowed to continue, might have caused death. 
• Requires or prolongs in-patient hospitalization (see Section 5.3.5.10). 
• Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
• Congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug(s). 
• Significant medical event in the investigator’s judgment (e.g., may jeopardize 
the patient’s safety or may require medical/surgical intervention to prevent one 
of the outcomes listed above). 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity 
of an AE (rated as mild, moderate or severe, or according to a pre-defined grading 
criterion; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings). 


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Severity and seriousness need to be independently assessed for each AE recorded 
on the eCRF. 
SAEs are required to be reported by the investigator to the sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.1.3 
ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY 
REPORTABLE TO THE SPONSOR) 
AESIs are required to be reported by the investigator to the sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). AESIs for this study include the following: 
• Electrolyte imbalance: hypokalemia (K+ level <3.4 mEq/L), hyperkalemia 
(>5.0 mEq/L), hyponatremia (Na+ level <135 mEq/L), hypochloremia (Cl- level 
<97 mEq/L) 
• Thrombocytopenia is defined as meeting one or both criteria: 
o Platelet count below 150 × 10E9/L (or 150.000 platelets per microliter 
(mcL)) 
o Platelet count drop of ≥50% compared to baseline 
• Drug-induced liver injury (DILI) 
• 
Dehydration and orthostasis (defined by a fall in systolic blood pressure over 
20 mm Hg or a fall in diastolic pressure over 10 mm Hg within 3 minutes of 
standing.  
5.1.4 
OTHER SAFETY ASSESSMENTS 
Additional safety data will be obtained on the following: 
• Changes from baseline in SBP, DBP, HR and respiratory rate. 
• Changes from baseline in orthostatic measurements of BP and HR 
• Changes from baseline in ECG parameters (HR, PQ, QRS, QT, RR and QTcF, 
along with information on T and U waves) 
• Incidence of clinically significant ECG abnormalities 
• Hearing assessment 
• 
Incidence of laboratory abnormalities, based on hematology, blood chemistry, 
coagulation and urinalysis test results, as described in Section 4.6.1.5. 
5.2 
SAFETY PLAN 
The Safety Plan considers observations made in non-clinical investigations including 
GLP toxicology studies in rats and dogs and the observations made in clinical trials. 
Hypothetical considerations are included in the interpretation of non-clinical and 
clinical data. 
The safety monitoring and the frequency of the scheduled visits are described in 
Appendix 1. All safety data will be reviewed throughout the study by the sponsor in a 
treatment-blinded manner. However, the DSMB will review the blinded safety and 
tolerability data obtained from the first dose cohort (8 patients) who finish the 2 weeks 
of treatment and the 2 weeks of follow-up. The following sections specify some of the 
monitoring measures that will be taken to maximize the patient’s safety in this study. 


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5.2.1 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
5.2.1.1 
ABNORMAL LABORATORY FINDINGS 
Laboratory abnormalities reported with 
 included hyperuricemia (18.4%) 
and electrolytes imbalance (e.g., hypochloremia for 14.9% or hypokalemia for 14.7%). 
Hypokalemia was also observed in a 
 dose-dependent manner in the 
BUMEA trial [NCT01078714; Lemonnier et al, 2017]. In the current study, laboratory 
assessment will be done every week during the treatment period and at the end of the 
follow-up period. If hypokalemia is observed, potassium supplements should be 
administered, and patients should be advised to eat potassium-rich foods.  
5.2.1.2 
CHANGES IN BLOOD PRESSURE 
As a potent loop diuretic compound, 
 is as an anti-hypertensive drug. 
Hypotension and dizziness have been reported in approximately 1% of the patients 
taking 
 [
 
]. In this study, assessment of BP, including 
orthostatic BP, will be performed at each study visit. If considered needed, 
symptomatic treatment should follow standard of care. Additional assessments of vital 
signs might be considered by the investigator. 
5.2.1.3 
SUICIDALITY 
Clinical data does not point to any suicidality liability of 
. 
However, monitoring for suicidality is mandatory in clinical trials of CNS-active 
molecules and will be implemented as outlined in Section 4.6.1.8 and Appendix 1. The 
Investigator is asked to assess individually appropriate next steps in case a suicidality 
alert arises. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.1.1 for 
definition) are recorded on the AE eCRF page and reported to the sponsor in 
accordance with instructions provided in this section and in Sections 5.4 through 
Section 5.6. 
For each AE recorded on the AE eCRF page, the investigator will make an 
assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
ADVERSE EVENT REPORTING PERIOD 
Investigators will seek information on AEs at each patient contact. All AEs, whether 
reported by the patient or the caregiver or noted by study personnel, will be recorded 
in the patient’s medical record. AEs will then be reported on the AE eCRF page as 
follows: 
After informed consent has been obtained but prior to initiation of study drug(s), only 
SAEs caused by a protocol-mandated intervention should be reported (e.g., SAE 
related to invasive procedures such as biopsies). 
After initiation of study drug(s), all AEs, regardless of relationship to study drug(s), 
will be reported until the follow-up visit (i.e., 2 weeks after the last dose of study 
drug[s]). 


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At the end of the 2-week follow-up period, investigators should report any deaths, 
SAEs, or other AEs of concern that are believed to be related to prior treatment with 
study drug(s) (see Section 5.6). 
5.3.2 
ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for eliciting 
AE information at all patient evaluation time-points. Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
5.3.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
Table 3 provides guidance for assessing AE severity. 
Table 3 Adverse Event Severity Grading Scale  
Severity 
Description 
Mild 
 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. Discomfort noticed, but no 
disruption of normal daily activity.  
Moderate 
 
A type of AE that is usually alleviated with specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of 
harm to the research subject. Discomfort sufficient to reduce or 
affect normal daily activity. 
Severe 
A type of AE that interrupts usual activities of daily living, significantly 
affects clinical status, may require intensive therapeutic intervention, 
or is incapacitating with inability to work or to perform normal daily 
activity. 
The term “severe” does not necessarily equate to “serious”. 
Note: Regardless of severity, some events may also meet seriousness criteria. Refer 
to definition of a serious adverse event (see Section 5.1.2). 
5.3.4 
ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS 
Investigators should use their knowledge of the patient, the circumstances 
surrounding the event and an evaluation of any potential alternative causes to 
determine whether or not an AE is considered to be related to the study drug(s), 
indicating "yes" or "no" accordingly as per below definitions:  
• Related: The AE is known to occur with the study intervention, there is a 
reasonable possibility that the study intervention caused the AE or there is a 
temporal relationship between the study intervention and event. Reasonable 
possibility means that there is evidence to suggest a causal relationship 
between the study intervention and the AE. 
 
• Not related: There is not a reasonable possibility that the administration of the 
study intervention caused the event, there is no temporal relationship between 
the study intervention and event onset or an alternate etiology has been 
established. 
 


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The following guidance should be taken into consideration: 
• Temporal relationship of event onset to the initiation of study drug(s). 
• Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug(s), or reintroduction of study drug(s) (where 
applicable). 
• Known association of the event with the study drug(s) or with similar treatments. 
• Known association of the event with the disease under study. 
• Presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event. 
• Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event. 
For patient receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
PROCEDURE FOR RECORDING ADVERSE EVENTS 
Investigator(s) should use correct medical terminology/concepts when recording AEs 
on the AE eCRF page. Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the AE eCRF page. 
5.3.5.1 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
A diagnosis (if known) should be recorded on the AE eCRF page rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, each individual event should be recorded on the AE eCRF page. If 
a diagnosis is subsequently established, all previously reported AEs based on signs 
and symptoms should be nullified and replaced by one AE report based on the single 
diagnosis, with a starting date that corresponds to the starting date of the first symptom 
of the eventual diagnosis. 
5.3.5.2 
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER EVENTS 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent 
events on the AE eCRF page. For example: 
• If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the eCRF. 
• If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF. 
• If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
• If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
All AEs should be recorded separately on the AE eCRF page if it is unclear as to 
whether the events are associated. 


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5.3.5.3 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points. Such events should only be recorded once on the AE eCRF 
page. The initial severity of the event should be recorded, and the severity should be 
updated to reflect the most extreme severity any time the event worsens. If the event 
becomes serious, the AE eCRF page should be updated to reflect this. 
A recurrent AE is one that resolves between patient evaluation time-points and 
subsequently recurs. Each recurrence of an AE should be recorded separately on the 
AE eCRF page. 
5.3.5.4 
ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be 
reported as an AE if it meets any of the following criteria: 
• Accompanied by clinical symptoms. 
• Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
• Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy. 
• Clinically significant in the investigator’s judgment. 
It is the investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
ALP and bilirubin 5 times the upper limit of normal (ULN) associated with cholecystitis), 
only the diagnosis (i.e., cholecystitis) should be recorded on the AE eCRF page. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the AE eCRF page, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., 
"elevated potassium", as opposed to "abnormal potassium"). If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, 
the clinical term should be recorded as the AE. For example, a serum potassium level 
of 7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the AE eCRF page, unless the etiology changes. 
The initial severity of the event should be recorded, and the severity or seriousness 
should be updated any time the event worsens. 
5.3.5.5 
ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an AE. A vital sign result should be 
reported as an AE if it meets any of the following criteria: 
• Accompanied by clinical symptoms. 
• Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
• Results in a medical intervention or a change in concomitant therapy. 
• Clinically significant in the investigator’s judgment. 


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It is the investigator’s responsibility to review all vital sign findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated vital sign 
abnormality should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., 
high BP), only the diagnosis (i.e., hypertension) should be recorded on the AE eCRF 
page. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the AE eCRF page, unless the etiology changes. 
The initial severity of the event should be recorded, and the severity or seriousness 
should be updated any time the event worsens. 
5.3.5.6 
ABNORMAL LIVER FUNCTION TESTS 
The finding of elevated liver tests, like: 
• ALT and/or AST >3xULN or 
• ALP >1.5xULN or 
• TBL to >2xULN or 
• AT >3xULN accompanied by elevated TBL >2xULN and not primarily 
cholestatic: ATx / ALPx <2 (Hy’s Law case definition) or 
• Elevation of AT in temporal association with nausea, vomiting, anorexia, 
abdominal pain, or fatigue, or 
• Possibly liver-related deaths and liver-related treatment discontinuations. 
is considered to be an indicator of severe liver injury.  
5.3.5.7 
DEATHS 
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.3.1), regardless of relationship to study drug, must be recorded on the AE eCRF 
page and immediately reported to the sponsor (see Section 5.4). 
Death should be considered an outcome and not a distinct event. The event or 
condition that caused or contributed to the fatal outcome should be recorded as the 
single medical concept on the AE eCRF page. Generally, only one such event should 
be reported. The term “sudden death” should only be used for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within one hour of the onset of acute symptoms or, 
in the case of an unwitnessed death, within 24 hours after the patient was last seen 
alive and stable. If the cause of death is unknown and cannot be ascertained at the 
time of reporting, “unexplained death” should be recorded on the AE eCRF page. If 
the cause of death later becomes available (e.g., after autopsy), “unexplained death” 
should be replaced by the established cause of death. 
5.3.5.8 
PREEXISTING MEDICAL CONDITION 
A preexisting medical condition is one that is present at the screening visit. Such 
conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF page. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity or character of the condition worsens during the study. When recording such 


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events on the AE eCRF page, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”). 
5.3.5.9 
WORSENING OF SYMPTOMS ASSOCIATED WITH ASD 
Worsening of symptoms associated with ASD should be recorded as an AE if judged 
by the investigator to have unexpectedly worsened in severity or frequency or changed 
in nature at any time during the study. When recording an unanticipated worsening of 
symptoms associated with ASD on the AE eCRF page, it is important to convey the 
concept that the condition has changed by including applicable specific descriptors 
(e.g., exacerbation of repetitive behaviors or worsening of verbal communication). 
A worsening of symptoms of ASD does not generally constitute a reason for 
withdrawal of the subject from the study. This must be discussed with and agreed to 
by the medical monitor/sponsor and should be recorded in the treatment section of the 
AE eCRF form. 
5.3.5.10 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as a SAE (per the definition of SAE in Section 5.1.2), except 
as outlined below. 
The following hospitalization scenarios are not considered to be SAEs: 
• Planned hospitalization required by the protocol. 
• Hospitalization for a preexisting condition, provided that all of the following 
criteria are met: 
- 
The patient has not suffered an AE. 
- 
Prolonged hospitalization due to psychosocial issues such as lack of 
home care facilities, caregiver issues, transport issues, etc. 
The following hospitalization scenarios are not considered to be SAEs, but should be 
reported as AEs instead: 
• Hospitalization for an AE that would ordinarily have been treated in an out-
patient setting had an out-patient clinic been available. 
A hospitalization of the patient does not necessarily constitute a reason for withdrawal 
of the patient from the study (for instance, a short hospitalization for psychosocial 
reasons may be acceptable). Each case should be discussed with the medical 
monitor/sponsor. It should be determined if the patient can continue the study 
medication while hospitalized. In case study medication cannot be continued while the 
patient is hospitalized, it should be determined whether the hospitalization is of such 
duration that a continuation in the study after discharge can be justified. The decision 
should be recorded in the eCRF. 
5.3.5.11 
OVERDOSES 
Study drug(s) overdose is the accidental or intentional use of the drug in an amount 
higher than the dose being studied. An overdose or incorrect administration of study 
drug(s) is not an AE unless it results in untoward medical effects. 
Any study drug(s) overdose or incorrect administration of study drug(s) should be 
noted on the Study Drug Administration eCRF page. 


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All AEs associated with an overdose or incorrect administration of study drug(s) should 
be recorded on the AE eCRF page. If the associated AE fulfills serious criteria, the 
event should be reported to the sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
Appropriate supportive treatment should be initiated according to the individual's 
clinical signs and symptoms and in accordance with best medical practices. In case of 
 overdosage, for instance, treatment may consist of electrolyte 
supplementation and/or replacement of fluid and electrolyte losses by careful 
monitoring of the urine and electrolyte output and serum electrolyte levels.  
5.3.5.12 
CAREGIVER/PARENT-REPORTED OUTCOME DATA 
In this trial, caregiver/parent questionnaires are administered. AE reports will not be 
derived from these questionnaires. However, if any responses suggestive of a 
possible AE are identified during site review of questionnaires, site staff will alert the 
investigator, who will determine if the criteria for an AE have been met and will 
document the outcome of this assessment in the patient’s medical record per site 
practice. If the event meets the criteria for an AE, it will be reported on the AE eCRF 
page. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the sponsor immediately; under no circumstances should reporting 
take place more than 24 hours after the investigator learns of the event. The following 
is a list of events that the investigator must report to the sponsor or designee within 
24 hours after learning of the event, regardless of relationship to study drug(s): 
• SAEs 
• AESIs 
• Pregnancies 
The investigator must report new significant follow-up information for these events to 
the sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
• New signs or symptoms or a change in the diagnosis. 
• Significant new diagnostic test results. 
• Change in causality based on new information. 
• Change in the event’s outcome, including recovery. 
• Additional narrative information on the clinical course of the event. 
Investigators must also comply with local requirements for reporting SAE to the local 
Health Authority and IRB. 
5.4.1 
EMERGENCY MEDICAL CONTACTS 
To ensure the safety of study patients, access to the medical monitors is available 24 
hours a day 7 days a week. Medical monitors contact details are listed in the “Protocol 
Administrative and Contact Information & List of investigators”. 


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5.4.2 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS 
AND ADVERSE EVENTS OF SPECIAL INTEREST 
For reports of SAEs and AESIs (see Sections 5.1.2 and 5.1.3), investigators should 
record all case details that can be gathered on the SAE Reporting Form and forward 
this form to the sponsor and independent medical monitor and follow the safety 
reporting process as instructed in the Safety Management Plan, within 24 hours to:  
 
 
Phone 
email 
SAE Reporting Line 
+1 513-309-9633 
or 
+1 513-858-2989 
 (ext. 304 or 320) 
STP1Safety@statkingclinical.com 
 
5.4.3 
REPORTING REQUIREMENTS FOR PREGNANCIES 
5.4.3.1 
PREGNANCIES IN FEMALE PATIENTS 
Women patients of childbearing potential (WCBP) will be instructed to immediately 
inform the investigator if they become pregnant during the study or within 2 weeks 
after the last dose of study drug(s). A Clinical Trial Pregnancy Reporting Form should 
be completed by the investigator and submitted to the sponsor within 24 hours after 
learning of the pregnancy. Pregnancy should not be recorded on the AE eCRF page. 
The investigator should discontinue study drug(s) and counsel the patient/caregiver, 
discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring 
of the patient should continue until conclusion of the pregnancy. 
5.4.3.2 
PREGNANCIES IN FEMALE PARTNERS OF MALE STUDY SUBJECTS 
Male patients will be instructed through the ICF to immediately inform the investigator 
if their partner becomes pregnant during the study or within 2 weeks after the last dose 
of study drug(s). A Clinical Trial Pregnancy Reporting Form should be completed by 
the investigator and submitted to the sponsor within 24 hours after learning of the 
pregnancy. Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male study subject exposed to study 
drug(s). The pregnant partner will need to sign an Authorization For Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. 
Once the authorization has been signed, the investigator will update the Clinical Trial 
Pregnancy Reporting Form with additional information on the course and outcome of 
the pregnancy. An investigator who is contacted by a male study subject or his 
pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
INVESTIGATOR FOLLOW-UP 
The investigator should follow each AE until the event has resolved to baseline grade 
or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-u, or the patient withdraws consent. Every effort should be made to follow all 
SAEs considered to be related to study drug(s) or trial-related procedures until a final 
outcome can be reported. 


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During the study period, resolution of AEs (with dates) should be documented on the 
AE eCRF page and in the patient’s medical record to facilitate source data verification. 
If, after follow-up, return to baseline status or stabilization cannot be established, an 
explanation should be recorded on the AE eCRF page. 
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 5.4.3. 
5.5.2 
SPONSOR FOLLOW-UP 
For SAEs, AESIs, and pregnancies, the sponsor or a designee may follow-up by 
telephone, electronic mail, and/or a monitoring visit to obtain additional case details 
and outcome information (e.g., from hospital discharge summaries or consultant 
reports) in order to perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
The investigator is not required to actively monitor patients for AEs after the end of the 
AE reporting period (defined as 2 weeks after the last dose of the study drug). 
If the investigator becomes aware of any other SAEs occurring after the end of the AE 
reporting period, if the event is believed to be related to prior study drug treatment, the 
event should be reported directly to the sponsor or its designee, either by scanning 
and emailing the SAE Reporting Form using the email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The sponsor will promptly evaluate all SAEs and AESIs against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
investigators, IRB and applicable Health Authorities based on applicable legislation. 
To determine reporting requirements for single AE cases, the sponsor will assess the 
expectedness of these events using the STP1 Investigator’s Brochure [STP1-IB]. 
The sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of 
causality and seriousness, with allowance for upgrading by the sponsor as needed. 
 
 


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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
The primary objective of this study is to evaluate the safety and tolerability profile of 2 
dose levels of STP1 in patients with ASD-Phen1. A maximum of approximately 20 
patients will be enrolled in this study, to ensure that up to 16 patients (up to 8 per dose 
level) will have complete dataset after 2 weeks of treatment and 2 weeks of follow-up. 
They will be randomized with a 3:1 ratio to one of the 2 groups (active/placebo) for 
each dose level. 
Up to six patients on active and up to 2 on placebo per dose level (maximum 4 on 
placebo in total) was considered sufficient for the primary objective. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
To determine whether the integrity of the study was maintained, listing/summary of 
data referring to the general conduct of the study (such as enrollment, protocol 
violations, use of prohibited co-medication, treatment code break) will be generated. 
6.3 
ANALYSIS POPULATIONS 
6.3.1 
SAFETY ANALYSIS POPULATION 
All patients who have received at least one administration of the study treatments, 
whether prematurely withdrawn from the study or not, will be included in the safety 
analysis. For the safety analysis population, data will be analyzed according to the 
treatment actually taken. 
6.3.2 
EFFICACY ANALYSIS POPULATION 
This study has not been designed for efficacy analysis, but exploratory endpoints will 
be analyzed to look at early efficacy and/or to allow selection of relevant endpoints for 
a Phase 2 study. The efficacy population will consist of all randomized patients who 
meet the inclusion/exclusion criteria, received full course of the study drug as per 
randomization, have completed the main relevant visits and without any major protocol 
violations which would render the data unreliable. 
6.3.3 
PHARMACOKINETIC ANALYSIS POPULATION 
All patients who have received at least one administration of the study treatments and 
with at least one sample collected and analyzed for plasma drug concentration, 
whether prematurely withdrawn from the study or not, will be included in the PK 
analysis. 
6.4 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographics, baseline characteristics and all baseline laboratory values will be 
summarized descriptively by treatment using frequency tables and summary statistics 
as appropriate. Placebo data will be pooled from the 2 dose groups. 
All safety analysis will be based on the safety analysis population. 
As appropriate, listings, summary tables and graphs will be provided for safety and 
tolerability assessments, including: 
• Incidence of AEs (overall, by intensity and by relationship to study medications). 
• Incidence of SAEs. 
• Incidence of AESIs. 
• Incidence of discontinuations due to AEs. 


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• Incidence of laboratory abnormalities (including hematology, clinical chemistry, 
coagulation and urinalysis parameters). 
• Incidence of BP abnormalities. 
• Incidence of ECG abnormalities as well ECG changes as compared to baseline 
measurements. 
Further details on the safety parameters are given in Section 5.1. Safety data will be 
summarized using descriptive statistics using the safety analysis population, which will 
include all patients treated. Additional safety analyses may be performed as stated in 
the Statistical Analysis Plan (SAP) for the study. 
6.4.1 
ADVERSE EVENTS 
The original terms recorded on the eCRF by the investigator for AEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized 
according to the MedDRA System Organ Classes (SOC) and preferred terms within 
SOC. 
AEs will be summarized by mapped term and appropriate thesaurus level. 
6.4.2 
CLINICAL LABORATORY TEST RESULTS 
All clinical laboratory data will be stored on the database in the units in which they 
were reported. Patient listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing. 
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges. 
6.4.3 
VITAL SIGNS 
Vital signs data will be presented by individual listings with flagging of values outside 
the normal ranges. In addition, tabular summaries will be used as appropriate. 
6.4.4 
ECG DATA 
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges. In addition, tabular summaries will be used as appropriate. 
6.4.5 
CONCOMITANT MEDICATIONS 
The original terms recorded on the patients’ eCRF by the investigator for concomitant 
medications will coded using World Health Organization (WHO) Drug dictionary. 
Concomitant medications will be presented in summary tables and listings. 
6.5 
EFFICACY ANALYSES 
This study has not been designed for efficacy analysis, but exploratory endpoints will 
be analyzed to look at early efficacy and/or allow selection of relevant endpoint for a 
phase II study. 
6.6 
PHARMACOKINETIC ANALYSES 
Individual plasma and urine concentrations of 
 will be listed. 
NCA using Phoenix 64, Build 8.0.0.3176 (or later), WinNonlin will be used to analyze 
the dose-concentration-time data of 
. As far as possible, 
individual pharmacokinetic parameters will be estimated and the influence of various 
covariates (such as body weight) on these parameters will be investigated in an 


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exploratory way. When applicable, the following secondary PK parameters will be 
derived from the model for each individual included in the PK analysis and will be 
presented descriptively: AUC0 tau, AUC0 ast, Cmax, Tmax, Ctrough, t1/2, apparent oral 
clearance and apparent volume of distribution (Vz/F) and accumulation ratio. 
6.7 
EXPLORATORY ANALYSES 
6.7.1 
LACTATE AND PYRUVATE BLOOD LEVELS 
Individual and mean blood levels (including change from baseline) of lactate, pyruvate, 
and L:P ratio will be presented by listings and descriptive summary statistics, by 
treatment group. 
6.7.2 
OTHER EXPLORATORY ENDPOINTS 
Individual and mean data (including change from baseline) will be presented as listings 
and descriptive summary statistics, by treatment group. Graphical displays may be 
added where applicable.  
• Change from baseline in subtask scores of 
 
and KiTAP test battery. 
• Global clinical change in the context of autism as measured by the change in 
the OACIS scale. 
• Change from baseline in the ABC-C sub-scores. 
• Change from baseline in the SRS-2 subscores. 
• Change from baseline in the CSHQ. 
• Change from baseline in eye tracking. 
• Change from baseline in selected EEG parameters at resting state and during 
habituation and chirp tasks. 
• Change from baseline in the CGI-S (reflected by the CGI-I) scale. 
 
 


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7. 
DATA COLLECTION, MANAGEMENT AND QUALITY 
ASSURANCE 
7.1 
SOURCE DATA DOCUMENTATION 
Where applicable, the data will be transcribed by the study center from the paper 
source documents into the eCRF.  
A CRO identified by the sponsor will be responsible for data management of this study, 
including quality checking of the data. Sites will be responsible for data entry into the 
Electronic Data Capture (EDC) system. A comprehensive validation check program 
will verify the data. Discrepancies will be generated automatically in the system at the 
point of entry or added manually for resolution by the study coordinator. Accurate and 
reliable data collection will be assured by verification and cross-checking of the eCRF 
against the investigator’s records by the study monitor (source document verification), 
and the maintenance of a study drug dispensing log by the investigator. 
The CRO will produce a Data Handling Manual and a Data Management Plan that 
describes the quality checking to be performed on the data. Data collected 
electronically will be sent to the CRO, using the CRO’s standard procedures to handle 
and process the electronic transfer of these data. Before study initiation, data to be 
entered directly into the eCRF (i.e., no prior written or electronic record of the data) 
and considered source data must be defined in the Study Monitoring Plan. When 
clinical observations are entered directly into an investigational site’s computerized 
medical record system (i.e., in lieu of original hardcopy records), the electronic record 
can serve as the source document if the system has been validated in accordance 
with Health Authority requirements pertaining to computerized systems used in clinical 
research. An acceptable computerized data collection system allows preservation of 
the original entry of data. If original data are modified, the system should maintain a 
viewable audit trail that shows the original data as well as the reason for the change, 
name of the person making the change, and date of the change.  
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.2. To facilitate source data 
verification, the investigators and institutions must provide the CRO direct access to 
applicable source documents and reports for trial-related monitoring, CRO audits, and 
IRB review. The investigational site must also allow inspection by applicable Health 
Authorities. Throughout the study, the study management team (SMT) will review data 
according to the Data Handling Manual. 
For classification purposes, preferred terms will be assigned by the CRO to the original 
terms entered on the eCRF, using the most up-to-date version of the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology for AEs and diseases and 
the International Non-proprietary Name (INN) Drug Terms and Procedures Dictionary 
for treatments and surgical and medical procedures. 
System backups for data stored by the CRO and records retention for the study data 
will be consistent with the CRO’s standard procedures. 
7.2 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRF, electronic Patient Reported Outcomes data (if applicable), ICF, 


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laboratory test results and medication inventory records, must be retained by the PI 
for at least 15 years after completion or discontinuation of the study, or for the length 
of time required by relevant national or local Health Authorities, whichever is longer. 
After that period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the sponsor. Written 
notification should be provided to the sponsor prior to transferring any records to 
another party or moving them to another location. 
 
 
 


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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the US or under a US Investigational New 
Drug (IND) application will comply with US Food and Drug Administration (FDA) 
regulations and applicable local, state, and federal laws.  
8.2 
INFORMED CONSENT 
The sponsor’s sample ICF (and ancillary sample ICF such as Caregiver's ICF, if 
applicable) will be provided to each site. The sponsor or its designee must review and 
approve any proposed deviations from the sponsor's sample ICF or any alternate 
consent forms proposed by the site (collectively, the “Consent Forms”) before IRB 
submission. The final IRB-approved Consent Forms must be provided to the sponsor 
or its designee for Health Authority submission purposes according to local 
requirements. 
In this study, caregiver specific information and consent may be collected, if separate 
from the legal guardian. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history 
or clinical records for each patient shall document the informed consent process and 
that written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study 
procedures or when new information becomes available that may affect the 
willingness of the patient to participate. The final revised IRB-approved Consent 
Forms must be provided to the sponsor for Health Authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or 
to a significant new information/findings addendum in accordance with applicable laws 
and IRB policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document 
the informed consent process and that written informed consent was obtained using 
the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain 
in each patient’s study file or in the site file and must be available for verification by 
study monitors at any time. 
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the US Health Insurance Portability 
and Accountability Act (HIPAA) of 1996. If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies. 


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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the patient and relevant 
supporting information must be submitted to the IRB by the PI and reviewed and 
approved by the IRB before the study is initiated. In addition, any patient recruitment 
materials must be approved by the IRB. 
The PI is responsible for providing written summaries of the status of the study to the 
IRB/ethics committee (EC) annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB. Investigators are also 
responsible for promptly informing the IRB of any protocol amendments (see Section 
9.5). 
In addition to the requirements for reporting all SAEs to the sponsor, investigators 
must comply with requirements for reporting SAE to the local Health Authority and 
IRB. Investigators may receive written IND safety reports or other safety-related 
communications from the sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB and archived in the site’s 
study file. 
8.4 
CONFIDENTIALITY 
The sponsor (or its designee) maintains confidentiality standards by coding each 
patient enrolled in the study through assignment of a unique patient identification 
number. This means that patient names are not included in data sets that are 
transmitted to any sponsor location. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the ICF (or separate authorization for use 
and disclosure of personal health information) signed by the patient, unless permitted 
or required by law. 
Medical information may be given to a patient’s personal physician or other 
appropriate medical personnel responsible for the patient’s welfare, for treatment 
purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the US FDA and other national and local Health Authorities, sponsor 
monitors, representatives, and collaborators, and the IRB for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate Health 
Authorities. Investigators are responsible for providing information on financial 
interests during the course of the study and for one year after completion of the study 
(i.e., LPLO). 


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9. 
STUDY DOCUMENTATION, MONITORING AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented, including but not limited to the protocol, protocol 
amendments, ICF and documentation of IRB and governmental approval. In addition, 
at the end of the study, the investigator will receive the patient data, which includes an 
audit trail containing a complete record of all changes to data. 
The sponsor shall also submit a Development Safety Update Report (DSUR) once a 
year to the IRB/EC and Health Authorities according to local regulatory requirements 
and timelines of each country participating in the study. 
It is the understanding of the sponsor that this protocol (and any modifications) as well 
as appropriate consent procedures and advertisements, will be reviewed and 
approved by an IRB. This board must operate in accordance with the current Federal 
Regulations. The sponsor will be sent a letter or certificate of approval prior to initiation 
of the study, and also whenever subsequent amendments/modifications are made to 
the protocol. The sponsor shall also submit an IND Annual Report to the FDA 
according to local regulatory requirements and timelines. 
9.2 
SITE INSPECTIONS 
Site visits will be conducted by the sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs. The investigator will 
permit national and local Health Authorities, sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
The sponsor of the trial is STALICLA SA. This study will be conducted using the 
services of a CRO managed by STALICLA. If needed, the CRO will manage other 
vendors required to provide services such as cardiac monitoring, event planning, 
central laboratories, scale management and cognitive testing and STALICLA will 
maintain oversight.  
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings by the 
sponsor or designated investigators. If this is foreseen, the investigator agrees to 
submit all manuscripts or abstracts to the sponsor prior to submission. All publications 
have to be approved by the sponsor. This allows the sponsor to protect proprietary 
information and to provide comments based on information from other studies that 
may not yet be available to the investigator. 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating investigator may be designated by mutual 
agreement. 


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Any formal publication of the study in which contribution of sponsor personnel 
exceeded that of conventional monitoring will be considered as a joint publication by 
the investigator and the appropriate sponsor personnel. 
Authorship will be determined by mutual agreement and in-line with International 
Committee of Medical Journal Editors authorship requirements. 
Any inventions and resulting patents, improvements, and/or know-how originating 
from the use of data from this study will become and remain the exclusive and 
unburdened property of the sponsor, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Requests from investigators to modify the protocol to ongoing studies will be 
considered only by consultation between an appropriate representative of the sponsor 
and the investigator [investigator representative(s) in the case of a multicenter trial]. 
Any substantial protocol amendments will be prepared by the sponsor and reviewed 
and approved by the Chief of Translational Development and study Biostatistician. 
All protocol modifications must be submitted to the appropriate IRB for information and 
approval in accordance with local requirements, and to Regulatory Agencies if 
required. Approval must be obtained before any changes can be implemented, except 
for changes necessary to eliminate an immediate hazard to trial patients, or when the 
change(s) involves only logistical or administrative aspects of the trial (e.g., change in 
monitor[s], change of telephone number[s]). 














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11. 
APPENDIX 1 SCHEDULE OF ASSESSMENTS 
 
PERIOD 
SCREENING 
TREATMENT PERIOD 
FOLLOW-UP VISITS 
Day 
D-14 to D-1 
Day 1 
Day 7 
Day 14 
Day 15-18e 
Day 28 
Visit Window 
 
 
+/-1 
+/-1 
+/-1 
+/-2 
Assessments 
  
  
  
  
  
  
Informed Consent 
x 
  
  
  
  
  
Eligibility 
x 
  
  
  
  
  
Randomization 
  
x 
  
  
  
  
Demography 
x 
  
  
  
  
  
Medical History 
x 
  
  
  
  
  
Physical Examination 
x 
 x 
 x 
x  
  
x 
Vital Signs  
x 
xa 
x 
xa 
  
x 
Orthostatic BP  
x 
xa 
x 
xa 
  
x 
ECG-12 Lead  
x 
xa 
x 
xa 
  
x 
Hearing Assessment 
 
x 
x 
x  
 
x 
Serology 
x 
  
  
  
  
  
Pregnancy Test (urine)b 
x 
  
  
  
  
x 
SARS-Cov-2 Test (nasal swab, saliva) 
x 
 
 
 
 
 
Substance Abuse (urine test)  
x 
x 
  
  
  
  
Blood Chemistry 
x 
  
x 
x 
  
x 
Hematology 
x 
  
x 
x 
  
x 
Coagulation 
x 
  
x 
x 
  
x 
Urinalysis 
x 
  
x 
x 
  
x 
Alcohol (urine test) 
x 
 
 
 
 
 
Administration of Study Medicationc 
  
x 
x 
x 
  
  
Study medication supply 
  
x 
 
  
  
  
Drug Accountability 
 
 
x 
x 
 
xf 
Blood PK Sampled 
  
x 
x 
x 
x 
 
Urine PK Sampled 
  
x 
 
x 
 
  
Suicidality (C-SSRS, C-CASA) 
x 
x 
x 
x 
 x 
x 
ABC-C 
x 
  
  
x 
  
x 
SRS-2 
x 
  
  
 x 
  
  
SB5 ABIQ 
x 
  
  
  
  
  
OACIS-Severity 
 x 
 
  
x 
  
  
OACIS-Change 
  
  
  
x 
  
  
 
 x 
x 
  
x 
  
x 
KiTAP 
x 
x 
 
x 
 
x 
Eye Tracking 
 
x 
 
x 
 
x 
EEG 
  
x 
  
x 
  
x  
CSHQ 
 x 
x 
  
x 
  
x 
CGI-I 
 
 
  
x 
  
x 
CGI-S 
x 
 
 
x 
  
x 
Adverse Events 
x 
x 
x 
x 
x 
x 
Previous and Concomitant 
Treatments 
x 
x 
x 
x 
x 
x 
 
a 
To be performed pre-dose and between 4 and 5 hours post-dose as specified in the protocol. 
b 
Females only. 
c 
Patients will receive their AM and PM dose of study drug during the Day 1, Day 7 and Day 14 visits to allow for proper PK sampling.   
d 
PK samples will be collected as described in the PK assessment section. A 5 minutes window for each timepoint is allowed 
e 
Day 16 to Day 18 are optional 
f 
If not done at Day 14 visit 
 

SAP_001.pdf: 
Statistical Analysis Plan (SAP)
Study No. STP1-C004
A Phase 1b, Double-Blind, Placebo-Controlled, First-in-Human
Study to Evaluate Safety, Tolerability and Pharmacokinetics of
a Two-Week Oral Treatment with STP1 in a Subgroup of
Adult Patients with Autism Spectrum Disorder
Version 1.1
17 February 2022
Prepared for
STALICLA SA
Campus Biotech Innovation Park
Avenue de Secheron 15, 1202
Genève Switzerland
Prepared by
STATKING Clinical Services
759 Wessel Drive
Fairfield, OH 45014
513-858-2989
www.statkingclinical.com


Statistical Analysis Plan
STP1-C004
Approval Page
By entering into this Statistical Analysis Plan (SAP), the parties acknowledge
and agree that this SAP shall be incorporated into and subject to the terms of
the Master Services Agreement (MSA). Any changes requested by Client to this
SAP shall be subject to Section I.C of the MSA requiring a mutually agreed upon
“Change Order” prior to any modification of the procedures set forth herein.
I agree to the format and content of this document.
Approved by:
______________________________________
Baltazar Gomez-Mancilla, MD, PhD
Chief Medical Officer
STALICLA SA
Campus Biotech Innovation Park
Avenue de Secheron 15, 1202
Genève Switzerland
Authored by:
_________________________________________
Brian Kovacic, PhD
Statistician
STATKING Clinical Services
759 Wessel Drive
Fairfield, OH 45014
513-858-2989 ext. 301
brian@statkingclinical.com
Page 2 of 121
STATKING Clinical Services
Version 1.1
STALICLA SA
February 17, 2022


Statistical Analysis Plan
STP1-C004
Approved by (internal review):
_________________________________________
Lori Christman, PhD
Statistician
STATKING Clinical Services
759 Wessel Drive
Fairfield, OH 45014
513-858-2989 ext. 317
lori@statkingclinical.com
Approved by:
_________________________________________
Mark Tetrick, DVM, PhD
Clinical Trial Manager
STATKING Clinical Services
759 Wessel Drive
Fairfield, OH 45014
513-858-2989 ext. 320
mtetrick@statkingclinical.com
Page 3 of 121
STATKING Clinical Services
Version 1.1
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Revision History
Version 1.0 to 1.1
x SAP updated based on the latest version of the protocol (v6.0)
x Added the cognition crystallized composite results to the in-text
description of the NIH Toolbox analysis and to the corresponding table
and listing shells in the appendix.
x Updated Section 6.2 to state that the eye tracking data will not be
included in the final study database.
Page 4 of 121
STATKING Clinical Services
Version 1.1
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Table of Contents
1.0 SYNOPSIS OF STUDY DESIGN PROCEDURES.......................................7
1.1 Design and Treatment ........................................................................................................................ 7
1.2 Study Procedures ................................................................................................................................ 8
1.3 Sample Size.........................................................................................................................................12
2.0 DATA ANALYSIS CONSIDERATIONS.....................................................12
2.1 Types of Analyses...............................................................................................................................12
2.2 Analysis Populations..........................................................................................................................13
2.3 Missing Data Conventions.................................................................................................................13
2.4 Interim Analyses ................................................................................................................................13
2.5 Study Center Considerations in the Data Analysis .........................................................................14
2.6 Documentation and Other Considerations ......................................................................................14
3.0 ANALYSIS OF BASELINE PATIENT CHARACTERISTICS.....................14
4.0 ANALYSIS OF SAFETY............................................................................14
4.1 Description of Safety Variables ........................................................................................................14
4.2 Analysis of Safety Variables..............................................................................................................15
5.0 ANALYSIS OF PHARMACOKINETICS ....................................................18
5.1 Description of Pharmacokinetic Variables ......................................................................................18
5.2 Analysis of Pharmacokinetic Variables ...........................................................................................20
6.0 EXPLORATORY ANALYSES ...................................................................20
6.1 Description of Exploratory Variables ..............................................................................................20
6.2 Analysis of Exploratory Variables....................................................................................................21
7.0 OTHER RELEVANT DATA ANALYSES/SUMMARIES ............................22
7.1 Patient Disposition .............................................................................................................................22
Page 5 of 121
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Version 1.1
STALICLA SA
February 17, 2022


Statistical Analysis Plan
STP1-C004
7.2 Additional Assessments .....................................................................................................................23
7.3 Medical History..................................................................................................................................23
7.4 Concomitant Medication...................................................................................................................23
8.0 LIST OF ANALYSIS TABLES, FIGURES AND LISTINGS.......................24
9.0 REFERENCES...........................................................................................29
APPENDIX A – TABLES, FIGURES AND LISTING SPECIFICATIONS ........30
APPENDIX B – TABLE SHELLS ....................................................................32
Page 6 of 121
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Version 1.1
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February 17, 2022


Statistical Analysis Plan
STP1-C004
1.0 Synopsis of Study Design Procedures
This study is a randomized, double-blind, placebo-controlled, parallel-group, 2-
dose ascending study to assess the safety, tolerability, and pharmacokinetics
(PK) of 2-week treatment with STP1 (combined doses of ibudilast and
bumetanide) in adult patients with idiopathic Autism Spectrum Disorder
Phenotype 1 (ASD-Phen1).
The primary objective of this Phase 1b study is to assess the safety and
tolerability of 2-week oral treatment twice a day with STP1 in adult individuals
with ASD-Phen1. The secondary objective is to determine the plasma
pharmacokinetics of ibudilast and bumetanide when given orally in combination,
as STP1, for 2 weeks. Additional exploratory objectives will be assessed as
outlined in Section 6.0 of this SAP.
This SAP was written in accordance with the Clinical Study Protocol Version 6,
Amendment 5. The SAP will be revised if there are future protocol amendments
that impact the content included in this document.
1.1 Design and Treatment
The first dose cohort (8 eligible patients) will be randomized and allocated to one
of two treatment groups using a 3:1 ratio:
x
mg oral twice a day (BID) ibudilast
mg oral BID bumetanide (N=6)
x
Matching oral placebos BID (N=2)
For each dose cohort, the total duration of the study for each patient will be up to
6 weeks, divided as follows:
x
A screening phase of up to 2 weeks (from Day -14 to Day -1)
x
A double-blind treatment phase of 2 weeks (from Day 1 to Day 14)
x
A follow-up phase of 2 weeks after treatment discontinuation (from Day
15 to Day 28)
Once the first cohort (8 patients) finishes 2 weeks of treatment and 2 weeks of
follow-up, a Data Safety Monitoring Board (DSMB) will evaluate the safety data
to decide whether the dose of ibudilast can be increased as planned to 
mg, or
the study shall be modified or be stopped.
If the DSMB decision supports the start of the next dose level, up to 8 additional
eligible patients will be assigned to one of the following two treatment groups (a
minimum of 3 patients should be exposed to the highest dose of STP1):
x
mg oral BID ibudilast/ 1 mg oral BID bumetanide (up to N=6)
x
Matching oral placebos BID (up to N=2)
Patients that participated in the first dose cohort may be allowed to participate in
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the second dose cohort if there is no safety concern and after drug washout. Any
patient from Cohort 1 that is re-randomized into Cohort 2 will be counted as a
new patient in the analysis. That is, re-enrolled patients will be assigned a new
patient ID for Cohort 2, re-randomized, and have a new set of CRFs completed.
Figure 1 below summarizes an overview of the study design.
Figure 1. Overview of Study Design
2
8
6
2
8
6
For STP1 dose 2: N= up to 2 placebo and up to 6 STP1 dose 2, randomization is N= up to 8
1.2 Study Procedures
The study includes assessments at screening (Days -14 to -1), treatment period
(Days 1 to 14), and the follow-up visits (Days 16-18 (optional) and Day 28).
Screening Period (Visit 1 - Day -14 to Day -1)
Patients will be screened for study eligibility within 14 days prior to treatment
(Days -14 to -1). The following screening procedures will be performed:
•
Sign an Informed Consent Form (ICF) before any of the study related
procedures are performed
•
Eligibility criteria including all inclusion and exclusion criteria
•
Record demographics (including age, gender, height, weight, etc.)
•
Record medical history including history of substance use
•
Record previous and concomitant medications and therapies
•
Measure vital signs (temperature, heart rate (HR), and respiratory rate)
•
Orthostatic blood pressure (BP) and HR
•
Perform physical examination
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•
Perform blood laboratory tests (serology, blood chemistry, hematology,
and coagulation)
•
Perform urinalysis laboratory test
•
Perform 12-lead ECG
•
Perform urine pregnancy test for women of childbearing potential
•
Perform SARS-CoV-2 Test
•
Perform alcohol urine test/substance abuse urine test
•
Adverse event (AE) assessment and recording
•
Perform study-specific assessments: (Suicidality (Columbia Suicide
Severity Rating Scale [C-SSRS] or Columbia Classification Algorithm for
Suicide Assessment [C-CASA]), Aberrant Behavior Checklist- Second
Edition – Community (ABC-C), Social Responsiveness Scale, Second
Edition (SRS-2), and Stanford Binet Intelligence Scales, Fifth Edition-
Abbreviated Battery IQ (SB5 ABIQ), Ohio Autism Clinical Impression Scale
-Severity (OACIS-Severity), 
Test of Attentional Performance for Children (KiTAP), Children Sleep habit
Questionnaire (CSHQ), Clinical Global Impressions – Severity (CGI-S)
Scale
•
C-SSRS, OACIS- Severity, NIH-CTB, KiTAP, CSHQ and CGI-S
are collected at Screening for only those patients enrolled under
Version 4 or subsequent versions of the protocol
Treatment Period (Day 1 to Day 14)
The following procedures will be performed during the treatment period (visits
at Day 1, Day 7 & Day 14):
Visit 2 - Day 1
x
Randomization
x
Physical examination
x
Vital Signs (pre- and post-dose): including temperature, HR, respiratory
rate, and BP
x
Orthostatic BP assessment (pre- and post-dose)
x
ECG-12 lead (pre- and post-dose)
x
Substance abuse test (urine)
x
Hearing assessment (collected for only those patients enrolled under
Version 4 or subsequent versions of the protocol)
x
Administration of the study medication
x
Study medication supply
x
Blood and urine sampling for PK
x
Perform study-specific assessments: Suicidality assessment (C-SSRS or
C-CASA), OACIS-Severity, NIH-CTB, KiTAP, CSHQ, and CGI-S
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•
OACIS-Severity and CGI-S are collected for only those patients
enrolled under Version 2 or 3 of the protocol. C-SSRS is collected
for only those patients enrolled under Version 4 or subsequent
versions of the protocol.
x
Eye tracking assessment
x
EEG (pre- and post-dose)
x
Adverse Events
x
Previous and Concomitant treatments
Visit 3 - Day 7
x
Physical examination
x
Vital Signs: including temperature, HR, and respiratory rate, and BP
x
Orthostatic BP assessment
x
ECG-12 lead
x
Blood sampling for hematology, blood chemistry, and coagulation
x
Urine sampling for urinalysis
x
Administration of the study medication and drug accountability
x
Blood sampling for PK
x
Suicidality assessment (C-SSRS or C-CASA) (C-SSRS collected for only
those patients enrolled under Version 4 or subsequent versions of the
protocol)
x
Hearing assessment (collected for only those patients enrolled under
Version 4 or subsequent versions of the protocol)
x
Adverse Event
x
Previous and Concomitant treatments
Visit 4 - Day 14
x
Physical examination
x
Vital Signs: including temperature, HR, respiratory rate, and BP
x
Orthostatic BP assessment
x
ECG-12 lead
x
Blood sampling for hematology, blood chemistry, and coagulation
x
Urine sampling for urinalysis
x
Administration of the study medication and drug accountability
x
Blood and urine sampling for PK
x
Hearing assessment (collected for only those patients enrolled under
Version 4 or subsequent versions of the protocol)
x     Perform study-specific assessments: Suicidality (C-SSRS and C-CASA),
ABC-C, SRS-2, OACIS-S, Ohio Autism Clinical Impression Scale -
Improvement (OACIS – C), 
KiTAP, CSHQ, Clinical Global
Impressions – Improvement (CGI-I) Scale, and CGI-S
•
C-SSRS is collected for only those patients enrolled under Version
4 or subsequent versions of the protocol.
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x
Eye tracking assessment
x
EEG
x
Adverse Events
x
Previous and Concomitant treatments
Visit 5- Day 15 and Optional Visit 6/7/8 - Days 16/17/18
Patients enrolled under Version 2 or 3 of the protocol will have blood and urine
PK sampling done 30 hours post Day 14 AM dose (i.e., Day 15). Patients enrolled
under Version 4 or subsequent versions of the protocol will be given the option to
have their follow-up blood PK sampling visit between Day 16 and Day 18.
x
Blood and urine sampling for PK (urine sampling collected for only those
patients enrolled under Version 2 or 3 of the protocol)
x     Suicidality assessment (C-SSRS, C-CASA) (collected for only those
patients enrolled under Version 4 or subsequent versions of the protocol)
x
AEs
x
Previous and concomitant treatments
Visit 9- Day 28 - End of Study Follow-Up Visit
Patients who complete the Day 15 study visit or discontinue from the study early
will be asked to return to the clinic on Day 28 (± 2 days) for the Follow-up visit.
After study completion, AEs should be followed according to the study protocol.
The following procedures will be performed:
x
Physical examination
x
Vital Signs: including temperature, HR, respiratory rate, and BP
x
Orthostatic BP assessment
x
ECG-12 lead
x
Pregnancy Test (urine) in females
x
Blood sampling for hematology, blood chemistry, and coagulation
x
Urine sampling for urinalysis
x
Drug accountability (if not done at Day 14 visit for only those patients
enrolled under Version 4 or subsequent versions of the protocol)
x
Blood sampling for PK (collected for only those patients enrolled under
Version 2 or 3 of the protocol)
x
Perform study-specific assessments: Suicidality (C-SSRS, C-CASA),
ABC-C, SRS-2, 
, KiTAP, CSHQ, CGI-I, and CGI-S
•
C-SSRS is collected for only those patients enrolled under Version
4 or subsequent versions of the protocol. SRS-2 is collected for only
those patients enrolled under Version 2, 3, or 4 of the protocol.
x
Hearing assessment (collected for only those patients enrolled under
Version 4 or subsequent versions of the protocol)
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x
Eye tracking assessment
x
EEG
x
Adverse Events
x
Previous and Concomitant treatments
1.3 Sample Size
The target number of patients to be enrolled in this study is up to 16 individuals
with ASD-Phen1. Assuming a dropout rate of roughly 20%, the maximum sample
size of 20 patients will be enrolled in the study in order to ensure that up to 16
patients (up to 8 per dose level) will have evaluable data after 2 weeks of
treatment and 2 weeks of follow-up. They will be randomized with a 3:1 ratio to
one of the 2 groups (active/placebo) for each dose level.
Up to six patients per dose level on active and up to two on placebo per dose
level is considered sufficient for the primary objective.
1.3.1 Replacement of Study Patients
If a patient withdraws from the study after randomization but before receiving any
treatment, the next patient randomized will be assigned the same randomization
number. This will ensure that the treatment allocation within each treatment
group is preserved.
If a patient withdraws from the study after receiving any amount of treatment, the
next patient randomized will be assigned to the next available randomization
number.
2.0 Data Analysis Considerations
2.1 Types of Analyses
For this Phase 1b study, descriptive statistics will be provided for all variables by
treatment group (placebo data will be pooled from the two dose cohorts). For
continuous endpoints, summary statistics, i.e., n (number of non-missing
observations), mean, standard deviation (SD), median, minimum, and maximum
will be provided. For categorical variables, the frequency count and proportion in
each category will be summarized.
As mentioned in Section 1.2 of the SAP, some assessment time points will vary
according to which protocol amendment was in place at the time a patient was
enrolled. Data from all time points will be summarized as appropriate in
accordance with the details provided below in Section 3 – 7.
All data collected will be presented in the by-patient data listings, sorted by
patient and by time point, where appropriate.
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2.2 Analysis Populations
The following analysis populations will be defined for the study:
Safety Analysis Population: The safety population will consist of all patients
who have received at least one administration of the study treatments, whether
prematurely withdrawn from the study or not. For the safety analysis population,
data will be analyzed according to the treatment actually taken.
Pharmacokinetic (PK) Analysis Population: The PK population will consist of
all patients with at least one administration of the study treatments, and with at
least one sample collected and analyzed for plasma drug concentration, whether
prematurely withdrawn from the study or not.
Exploratory Analysis Population: The Exploratory population will consist of all
randomized patients who meet the inclusion/exclusion criteria, received full-
course of the study drug as per randomization, have completed the main relevant
visits and without any major protocol violations which would render the data
unreliable.
Analyses of safety will be performed on the Safety population, as will baseline
patient characteristics and demographics. Analysis of PK variables will be
performed on the PK population. Analyses of PD data will be performed on the
Exploratory population. Prior to the final analysis, a blinded review of the protocol
violations will be held in order to determine exclusions from the Exploratory
population.
2.2.1 Subgroup Definitions
Analyses will be presented by treatment (
mg ibudilast/
mg bumetanide, 
mg
ibudilast
mg bumetanide, or placebo (placebo data will be pooled from the two
dose cohorts)) as indicated below and shown in Appendix B.
2.3 Missing Data Conventions
No missing value imputation will be used. That is, all analyses will be based on
the observed data (i.e., complete case analysis).
2.4 Interim Analyses
An evaluation of the data by an independent DSMB will take place after 8 patients
finish 2 weeks of treatment and 2 weeks of follow-up. The primary responsibilities
of the DSMB are to:
1. Review and evaluate the accumulated study data for patient safety, study
conduct and progress, and
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2. Make recommendation to STALICLA concerning the continuation,
modification, or termination of the trial.
Refer to the separate Interim Analysis Plan (IAP) for further details on the interim
analyses.
2.5 Study Center Considerations in the Data Analysis
A study center is defined as a treatment administration site or group of treatment
administration sites under the Placebo and supervision of the same Principal
Investigator (PI). This study will be conducted as a single study center, and
therefore, study center considerations are not applicable. In case additional
site(s) is (are) added with patients enrolled, the SAP will be revised if needed.
2.6 Documentation and Other Considerations
The data analyses will be conducted using SAS® Software, version 9.4 or later.
3.0 Analysis of Baseline Patient Characteristics
Baseline and demographic characteristics will be summarized by treatment for
all patients in the Safety population. Placebo data will be pooled from the two
dose groups. Continuous variables will be displayed via summary statistics (n,
mean, median, SD, minimum, and maximum). Categorical variables will be
summarized via frequency counts and proportions.
A detailed listing of demographics data for each patient will also be provided as
shown in Appendix B.
4.0 Analysis of Safety
4.1 Description of Safety Variables
The safety variables for this study are:
x
AEs
x
Vital Signs and physical examinations
x
ECG
x
Clinical Laboratory Parameters
x
Hearing Assessment
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4.2 Analysis of Safety Variables
Adverse Events
Prior to analysis, all AEs will be recorded and classified on the basis of the
Medical Dictionary for Regulatory Activities (MedDRA®) terminology. The
number and proportion of patients with at least one AE will be summarized by
system organ class (SOC) and by preferred term (PT) within SOC for each
treatment group.
Similar tables will be provided to display the number and proportion of patients
with at least one treatment- related AE, at least one treatment-related AE that led to
study treatment discontinuation, at least one serious AE (SAE), at least one
treatment-related SAE, at least one treatment-related SAE that led to study
treatment discontinuation, at least one AE of special interest (AESI), and at least
one AESI that led to study treatment discontinuation by SOC and by PT within
SOC. For the purposes of this study, a treatment-related AE is any AE with a
relationship to study drug of ‘Related’.
In addition, tables will be constructed to summarize AEs by relationship to study
drug and by severity.
A separate AE summary table will be constructed to display the number of
patients with at least one AE, the number of patients with at least one treatment-
related AE, the number of patients with at least one treatment-related AE that led to
study treatment discontinuation, the maximum severity of AE by patient, the
highest relationship of AE to treatment, the number of patients experiencing at
least one SAE, the number of patients with at least one treatment-related SAE,
the number of patients with at least one treatment-related SAE that led to study
treatment discontinuation, the maximum severity of SAE by patient, the highest
relationship of SAE to treatment, the number of patients with at least one AESI,
the number of patients with at least one AESI that led to study treatment
discontinuation, and the number of deaths.
All AEs will be provided in data listings as shown in Appendix B. AEs having an
end date prior to signing the informed consent for this study will not be displayed in
the AE data listings.
Vital Signs
The vital signs parameters of interest include temperature, respiratory rate, and
orthostatic blood pressure and orthostatic heart rate.
Summary statistics (n, mean, median, SD, minimum, and maximum) will be
computed on the raw and change from baseline values for standard vital sign
measurements (temperature and respiratory rate) by visit and time for each
treatment. The Day 1 prior to treatment time point will serve as baseline. If there
are multiple vital signs taken at any time point, then the latest set of vital signs
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will be used for the analysis.
Additionally, summary statistics will be computed on the raw and change from
baseline values for the orthostatic vital sign measurements (BP and HR) by visit
and time for each treatment. The Day 1 prior to treatment time point will serve as
baseline. Spaghetti plots of the raw values for orthostatic diastolic BP, orthostatic
systolic BP and orthostatic HR will be displayed by patient, time point and
treatment.
All vital signs will be provided in data listings as shown in Appendix B. Vital signs
taken while standing will be included in the data listings but will not be
summarized in the tables.
Physical Examination
All physical examination results will be listed as shown in Appendix B.
ECG
The ECG parameters of interest include HR, PQ, QRS, QT, RR, and QTcF along
with information on T and U waves.
As the ECGs are performed in triplicate at Day 1 prior to treatment, the average of
the three values for each of the ECG parameters will be used as the baseline
value. Summary statistics (n, mean, median, SD, minimum, and maximum) will
be computed on the raw and change from baseline values for each parameter by
visit and time by treatment and overall. The Day 1 prior to treatment time point will
serve as baseline. Spaghetti plots of the raw values for HR and QTcF will be
displayed by patient, time point and treatment.
The ECG Interpretations for each of the three ECGs on Day 1 prior to treatment
will be used to obtain a Combined Overall ECG Interpretation. The Combined
Overall ECG Interpretation in relation to clinical significance at Day 1 prior to
treatment (i.e., baseline) will be determined as follows:
x
If at least one ECG Interpretation= ‘Abnormal – clinically significant’, then
the Combined Overall ECG Interpretation = ‘Abnormal – clinically
significant’.
x
Else if there are no readings such that ECG Interpretation = ‘Abnormal –
clinically significant’ and there is at least one ECG Interpretation =
‘Abnormal – not clinically significant’, then the Combined Overall ECG
Interpretation = ‘Abnormal – not clinically significant’.
x
Else if there are no readings such that ECG Interpretation = ‘Abnormal –
clinically significant’ or ‘‘Abnormal – not clinically significant’ and there is
at least one ECG Interpretation = ‘Normal’, then the Combined Overall
ECG Interpretation = ‘Normal’.
x
Else if all readings have a missing result for ECG Interpretation then the
Combined Overall ECG Interpretation is missing.
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Additionally, results from the ECG findings will be determined for T wave, U
wave, and ECG Interpretation regardless of clinical significance. The Combined
Overall T wave, U wave, and ECG Interpretation at Day 1 prior to treatment (i.e.
baseline) will be determined by parameter as follows:
x
If at least one ECG finding = ‘Abnormal’, then the Combined Overall
finding = ‘Abnormal’.
x
Else if there are no readings such that ECG finding = ‘Abnormal’ and there
is at least one ECG finding = ‘Normal’, then the Combined Overall finding
= ‘Normal’.
x
Else if all readings have a missing result for ECG finding then the
Combined Overall finding is missing.
Shift tables will be constructed to show the changes in ECG findings in relation to
clinical significance (e.g., normal, abnormal clinically significant (CS),
abnormal not clinically significant (NCS)) and findings (e.g., normal, abnormal)
by parameter from baseline to each visit by treatment and overall.
All ECG data will be provided in data listings as shown in Appendix B.
Laboratory Results
The laboratory tests of interest include blood chemistry, serology, hematology,
coagulation, and urinalysis results.
Summary statistics (n, mean, median, SD, minimum, and maximum) will be
computed on the raw and change from baseline values for each quantitative
laboratory parameter by visit for each treatment group and overall. The screening
time point will serve as baseline.
Spaghetti plots of the raw values for sodium, chloride, calcium, magnesium,
phosphate, potassium, and platelet count will be displayed by patient, time point
and treatment.
For those urinalysis parameters that are qualitative in nature, the number and
proportion of patients with each result for each parameter will be summarized by
visit and treatment.
Shift tables will be constructed to show the changes in laboratory results in
relation to clinical significance (e.g., normal, abnormal clinically significant (CS),
abnormal not clinically significant (NCS)) from baseline to each visit. This
analysis will be repeated for blood chemistry results for electrolytes (sodium,
chloride, calcium, magnesium, phosphate, potassium).
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A shift table for blood chemistry results for electrolytes will be constructed to
show the changes in laboratory results in relation to range of normal results (e.g.,
normal, high, low) from baseline to each visit.
The count and proportion of patients with blood chemistry results for electrolytes
outside of the normal range (low, high) for each visit will be summarized by
treatment and overall.
All laboratory results data will be provided in data listings as shown in Appendix
B.
Hearing Assessment
The patient responses to the hearing assessment for each visit will be listed as
shown in Appendix B.
5.0 Analysis of Pharmacokinetics
5.1 Description of Pharmacokinetic Variables
PK sampling will be collected from all patients for measurement of plasma and
urine concentrations of ibudilast and bumetanide.
Blood samples will be drawn on Days 1, 7, 14/15 and, optionally, between Days
16 to 18, and urine samples will be collected on Days 1 and 14 to determine
concentrations of ibudilast and bumetanide. Non-compartmental analysis (NCA)
will be utilized to analyze data from the sampling schema. See Table 1 for the
PK sample schedule.
Table 1. PK Sampling Schedule
PK Schedulec
Time
Plasmaa
Urineb
Day 1
0.25, 0.5, 1, 2, 4, and 6h post-AM dose
Day 7
Pre-AM dose
0 to 6h post-AM
dose
Day 14 (only AM
dose) and 15
Between Days 16
Pre-AM dose and 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12
and 24h post-AM dose
48, 72, and 96 h post-AM dose of Day 14
0 to 4h, 4 to 8h, and
8-12h post-AM dose
to 18d
a Both ibudilast and bumetanide will be analyzed from the same blood draw for each
specified sampling time point.
b Urine creatinine from the urine collection will be paired with a serum creatinine
measurement to evaluate completeness of collection.
c All of these timepoints have a 5-minute window.
d Optional
The following PK plasma parameters will be estimated for each patient(as far as
possible):
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PK Parameter
Cmax, Day 1
Cmax,ss
CLast
Ctrough
Tmax
t1/2
AUC0-last
AUC0-tau (6h), Day 1
AUC0-tau (6h), SS
AUC0-12h, SS
AUC0-∞
Vz/F
Cl/F
Accumulation Ratio
Definition
Maximum plasma concentration on Day 1
Maximum plasma concentration at steady state
Last measured plasma concentration following
the last administration
Minimum observed plasma concentration prior
to drug administration
Time of maximum observed plasma
concentration; if it occurs at more than one time
point, Tmax is defined as the first time point with
this value
Terminal elimination half-life, calculated as
ln(2)/λZ
Cumulative area under the plasma concentration
time curve calculated from 0 to the last
measured plasma concentration following the
last administration using the linear trapezoidal
method
Area under the plasma concentration time
curve to the end of the dosing period following
the first administration
Area under the plasma concentration time
curve to the end of the dosing period (6h)
following the last administration
Area under the plasma concentration time
curve to 12 hours post dose following the last
administration
Area under the plasma concentration time
curve extrapolated to infinity, calculated as
AUC0-last + CLast/λZ
Apparent volume of distribution
Apparent total body clearance
Ratio of accumulation of a drug, calculated by
the following equation:
ARAUC = AUC0-tau (6h), SS / AUC0-tau (6h), Day 1
and ARCmax = Cmax,ss / Cmax, Day 1
As the PK time schedules were different prior to the implementation of Version
4.0 (Amendment 3) of the clinical study protocol, the PK schedule of the first 4
patients is as follows:
Day 1
x
Blood sampling at pre-AM dose and 0.25, 0.5, 1, 2, 4, 6 h post-AM dose
x
Urine sampling at 0 to 6 h post-AM dose
Day 7
x
Blood sampling at pre-AM dose
Day 14
x
Blood sampling at pre-AM dose and 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 30
h post-AM dose
x
Urine sampling 0 to 6 h and 24 to 30 h post-AM dose
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5.2 Analysis of Pharmacokinetic Variables
Plasma and urine sample concentrations of ibudilast and bumetanide will be
summarized by treatment, visit and time point using descriptive statistics.
Individual plasma concentrations of ibudilast and bumetanide will be depicted for
each patient by treatment group using linear scale. Individual and mean plasma
concentration- time profiles will be plotted in linear and semi-logarithmic scales.
PK parameter values will be summarized by treatment group using descriptive
statistics (n, mean, SD, CV%, geometric mean, and 90% confidence interval).
Plasma PK parameters such as AUC0-tau, AUClast, Cmax, Tmax, Ctrough, apparent
oral clearance, the elimination half-life, apparent volume of distribution and
accumulation ratios will be calculated following single dose administration (as far
as possible) and at steady state for both parent drugs.
Urine parameters include the following:
x
Excretion rate by timepoint:
o Day 1, 0-6h
o Day 14, 0-4h
o Day 14, 4-8h
o Day 14, 8-12h
x
Cumulative excretion, based on Day 14 sampling over 0-12h
x
Renal clearance, based on Day 14 sampling over 0-12h
6.0 Exploratory Analyses
6.1 Description of Exploratory Variables
Exploratory variables for this study include:
x
NIH-CTB and KiTAP subtask score
x
OACIS-C
x
ABC-C subscale scores
x
SRS-2 subscale scores
x
CSHQ total score
x
Lactate and Pyruvate Blood Levels
x
Change from baseline in CGI-S, as reflected by CGI-I
x
Eye tracking
x
EEG
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6.2 Analysis of Exploratory Variables
NIH-CTB and KiTAP
Summary statistics (n, mean, median, SD, minimum, and maximum) will be
computed on the raw and change from baseline values for each subtask variable
by visit, treatment and overall. The Day 1 time point will serve as baseline.
The following results of the cognition crystallized composite will also be
summarized: uncorrected standard score, age-corrected standard score,
national percentile (age adjusted), and fully-corrected T-score.
OACIS-C
Summary statistics (n, mean, median, SD, minimum, and maximum) will be
computed on the raw score for each question will be summarized by treatment
and overall. Frequency counts and proportions will also be summarized for each
response in the assessment by treatment and for each group of responses (very
much improved or much improved; minimally improved, no change or minimally
worse; and much worse or very much worse).
ABC-C
Summary statistics (n, mean, median, SD, minimum, and maximum) will be
computed on the raw and change from baseline scores for each subscale by
visit, treatment and overall. The Screening time point will serve as baseline.
SRS-2
Summary statistics (n, mean, median, SD, minimum, and maximum) will be
computed on the raw and change from baseline scores for each subscale by
visit, treatment and overall. The Screening time point will serve as baseline.
CSHQ
The number and proportions will be summarized for each value in the
assessment by visit, question, treatment and overall. The Day 1 time point will
serve as baseline.
Lactate and Pyruvate Blood Levels
Summary statistics (n, mean, median, SD, minimum, and maximum) will be
computed on the raw and change from baseline values of lactate, pyruvate and
lactate-pyruvate ratio (L:P ratio) by treatment and overall. The Screening time
point will serve as baseline.
Spaghetti plots of the raw values for L:P ratio will be displayed by patient, time
point and treatment.
CGI-S and CGI-I
Frequency counts and proportions for each response to the CGI-S and CGI-I
assessments will be summarized by treatment and visit. Patients enrolled under
Page 21 of 121
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Statistical Analysis Plan
STP1-C004
protocol Version 3 or earlier will be summarized at the following visits: Days 1,
14 and 28. Patients enrolled under Version 4 or later will be summarized at the
following visits: Screening, Days 14 & 28. Data will be combined for overlapping
visits.
Eye Tracking and EEG
Eye tracking will not be included in the final study database. However, EEG data
will be included in the final study database.
Both the eye tracking and EEG data will not be incorporated into the analysis
datasets nor the tables, listings, and figures covered in this SAP. Analysis plans
for the eye tracking and EEG variables will be presented in a separate document.
The variables to be analyzed to assess changes from Day 1 to Day 14 are as
follows:
EEG variables:
1. Spectrum analysis
a. Alpha
b. Beta
c. Theta
d. Gamma
2. Auditory OddBall (AOB) – focusing on early components: P50, N100,
P20
Eye Tracking variables:
1. Time spent mouth and eyes
a. Region
b. Total time
7.0 Other Relevant Data Analyses/Summaries
7.1 Patient Disposition
A table will be constructed with the number of screen failures and enrolled
patients. For those patients who are screen failures, the number and proportion
for each reason for screen failure will be summarized. Of those enrolled,
frequency counts and proportion of the number of patients withdrawing from the
study before study completion and the number completing the study will be
displayed. For those patients that withdraw before completion of the study or
discontinue treatment of STP1, the number and proportion for each reason for
withdrawal will be tabulated. The table will include summary counts and
proportions by treatment and overall. A data listing of all patient completion and
withdrawal data will also be constructed.
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Statistical Analysis Plan
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7.2 Additional Assessments
Suicidality (C-SSRS, C-CASA) assessments will be performed at Screening,
throughout the treatment period and at the follow-up visits, as specified in the
protocol. The SB5 ABIQ assessment will be completed at Screening only. These
assessments will be listed for all patients in the Safety population as shown in
Appendix B.
7.3 Medical History
Prior to analysis, all medical history terms will be coded using the MedDRA
coding dictionary. The number and proportion of patients with at least one
medical history term will be summarized by system organ class (SOC) and by
preferred term (PT) within SOC for each treatment group.
A complete medical history of past and present illnesses and surgeries will be
listed as shown in Appendix B.
7.4 Concomitant Medication
All concomitant medications will be coded with the WHO Drug Dictionary. A table
will be constructed with number and proportion of patients by ATC level 4 and
preferred term.
All concomitant medications will be listed as shown in Appendix B.
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Statistical Analysis Plan
STP1-C004
8.0 List of Analysis Tables, Figures and Listings
Table
No.
Table Title
1
Patient Disposition
2
Demographics and Baseline Data Summary Statistics–
Continuous Variables (Safety Population)
3
Demographics and Baseline Data Summary Statistics–
Categorical Variables (Safety Population)
4
Summary of Adverse Events (Safety Population)
5
Number and Proportion of Patients with Adverse Events
(Safety Population)
6
Number and Proportion of Patients with Treatment-
Related Adverse Events (Safety Population)
7
Number and Proportion of Patients with Treatment-
Related Adverse Events that Led to Study Drug
Discontinuation (Safety Population)
8
Number and Proportion of Patients with Serious
Adverse Events (Safety Population)
9
Number and Proportion of Patients with Treatment-
Related Serious Adverse Events (Safety Population)
10
Number and Proportion of Patients with Treatment-
Related Serious Adverse Events that Led to Study Drug
Discontinuation (Safety Population)
11
Number and Proportion of Patients with Adverse Events
of Special Interest (Safety Population)
12
Number and Proportion of Patients with Adverse Events
of Special Interest that Led to Study Drug
Discontinuation (Safety Population)
13
Number and Proportion of Patients with Adverse Events
by Relationship to Study Drug (Safety Population)
14
Number and Proportion of Patients with Adverse Events
by Severity (Safety Population)
15
Vital Sign Parameter Summary Statistics (Safety
Population)
16
Orthostatic Vital Sign Parameter Summary Statistics
(Safety Population)
17
ECG Parameter Summary Statistics (Safety Population)
18
ECG Results Shift Table by Visit and Clinical
Significance (Safety Population)
19
ECG Results Shift Table by Visit (Safety Population)
20
Blood Chemistry Parameter Summary Statistics (Safety
Population)
21
Hematology Parameter Summary Statistics (Safety
Population)
22
Coagulation Parameter Summary Statistics (Safety
Population)
23
Quantitative Urinalysis Parameter Summary Statistics
(Safety Population)
24
Summary of Qualitative Urinalysis Results by Parameter
(Safety Population)
Included
in Final
Tables
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Shown in
Appendix
B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Statistical Analysis Plan
STP1-C004
Table
No.
Table Title
25
Blood Chemistry Results Shift Table by Visit and Clinical
Significance (Safety Population)
26
Hematology Results Shift Table by Visit and Clinical
Significance (Safety Population)
27
Coagulation Results Shift Table by Visit and Clinical
Significance (Safety Population)
28
Quantitative Urinalysis Results Shift Table by Visit and
Clinical Significance (Safety Population)
29
Blood Chemistry Results for Electrolytes Shift Table by
Visit and Clinical Significance (Safety Population)
30
Blood Chemistry Results for Electrolytes Shift Table by
Visit and Range of Normal Results (Safety Population)
31
Number and Proportion of Patients with Blood
Chemistry Results for Electrolytes Outside of Normal
Range (Safety Population)
32
Summary Statistics of Ibudilast and Bumetanide Plasma
Concentration Levels by Treatment, Visit and Time (PK
Population)
33
Summary Statistics of Ibudilast and Bumetanide Urine
Concentration Levels by Treatment, Visit and Time (PK
Population)
34
Summary Statistics of Estimated PK Plasma
Parameters for Ibudilast by Treatment (PK Population)
35
Summary Statistics of Estimated PK Plasma
Parameters for Bumetanide by Treatment (PK
Population)
36
Summary Statistics of Estimated PK Urine Parameters
for Ibudilast by Treatment (PK Population)
37
Summary Statistics of Estimated PK Urine Parameters
for Bumetanide by Treatment (PK Population)
38
NIH-CTB Summary Statistics (Exploratory Population)
39
KiTAP Summary Statistics (Exploratory Population)
40
OACIS-C Summary Statistics (Exploratory Population)
41
Summary of Responses for OACIS-C Assessment by
Question (Exploratory Population)
42
Summary of Responses for OACIS-S Assessment by
Question (Exploratory Population)
43
ABC-C Summary Statistics (Exploratory Population)
44
SRS-2 Summary Statistics (Exploratory Population)
45
Summary of Responses for CSHQ Assessment by
Question (Exploratory Population)
46
Lactate and Pyruvate Blood Level Summary Statistics
(Exploratory Population)
47
Summary of Responses for CGI-S Assessment by Visit
(Exploratory Population)
48
Summary of Responses for CGI-I Assessment by Visit
(Exploratory Population)
49
Number and Proportion of Patients with Medical History
Events (Safety Population)
Included
in Final
Tables
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Shown in
Appendix
B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Statistical Analysis Plan
STP1-C004
Table
No.
Table Title
50
Number and Proportion of Patients Taking Concomitant
Medications by ATC Level 4 and Preferred Term (Safety
Population)
Included
in Final
Tables
X
Shown in
Appendix
B
X
Listing
No.
DL1
DL2
DL3
DL4
DL5
DL6
DL7
DL8
DL9
DL10
DL11
DL12
DL13
DL14
DL15
DL16
DL17
DL18
DL19
DL20
DL21
DL22
DL23
DL24
DL25
DL26
DL27
DL28
DL29
DL30
DL31
DL32
DL33
DL34
DL35
DL36
DL37
DL38
DL39
Listing Title
Patient Disposition Data Listing
Demographics Data Listing
Adverse Events Data Listing
Vital Signs Data Listing
Baseline ECG Data Listing
ECG Data Listing
Blood Chemistry Laboratory Results Data Listing
Serology Laboratory Results Data Listing
Hematology Laboratory Results Data Listing
Coagulation Laboratory Results Data Listing
Urinalysis Laboratory Results Data Listing
Hearing Assessment Data Listing
Pharmacokinetic Blood Sample Data Listing
Pharmacokinetic Urine Sample Data Listing
Plasma Concentrations Data Listing
Urine Concentrations Data Listing
Plasma Pharmacokinetics Parameters Data Listing
Urine Pharmacokinetics Parameters Data Listing
C-SSRS Data Listing
C-CASA Data Listing
OACIS-S Data Listing
OACIS-C Data Listing
SRS-2 Data Listing
SB5 ABIQ Data Listing
NIH-CTB Data Listing
KiTAP Data Listing
ABC-C Data Listing
CSHQ Data Listing
Lactate-Pyruvate Data Listing
CGI-S/CGI-I Data Listing
Medical History Data Listing
Concomitant Medications Data Listing
Physical Exam Data Listing
Study Drug Administration Data Listing
Drug Accountability Data Listing
Urine Pregnancy Test Data Listing
Protocol Deviations Data Listing
Patients Excluded from Safety Population Data
Listing
Patients Excluded from PK Population Data Listing
Included
in Final
Listings
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Shown in
Appendix B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Statistical Analysis Plan
STP1-C004
Listing
No.
DL40
Figure
No.
FIG1
FIG2
FIG3
FIG4
FIG5
FIG6
FIG7
FIG8
FIG9
FIG10
FIG11
FIG12
FIG13
FIG14
FIG15
FIG16
FIG17
Listing Title
Patients Excluded from Exploratory Population Data
Listing
Figure Title
Orthostatic Vital Signs - Spaghetti Plot of Systolic
Blood Pressure by Patient, Time and Treatment
(Safety Population)
Orthostatic Vital Signs - Spaghetti Plot of Diastolic
Blood Pressure by Patient, Time and Treatment
(Safety Population)
Orthostatic Vital Signs - Spaghetti Plot of Heart
Rate by Patient, Time and Treatment (Safety
Population)
ECG Parameters - Spaghetti Plot of Heart Rate by
Patient, Time and Treatment (Safety Population)
ECG Parameters - Spaghetti Plot of QTcF by
Patient, Time and Treatment (Safety Population)
Blood Chemistry - Spaghetti Plot of Sodium by
Patient, Time and Treatment (Safety Population)
Blood Chemistry - Spaghetti Plot of Chloride by
Patient, Time and Treatment (Safety Population)
Blood Chemistry - Spaghetti Plot of Calcium by
Patient, Time and Treatment (Safety Population)
Blood Chemistry - Spaghetti Plot of Magnesium by
Patient, Time and Treatment (Safety Population)
Blood Chemistry - Spaghetti Plot of Phosphate by
Patient, Time and Treatment (Safety Population)
Blood Chemistry - Spaghetti Plot of Potassium by
Patient, Time and Treatment (Safety Population)
Hematology - Spaghetti Plot of Platelet Count by
Patient, Time and Treatment (Safety Population)
Biomarker - Spaghetti Plot of L:P Ratio by Patient,
Time and Treatment (Safety Population)
Patient Plasma Concentration Levels of Ibudilast for
Treatment Group = 5mg Ibudilast– Linear Scale –
Days 1-28 (PK Population)
Patient Plasma Concentration Levels of Ibudilast for
Treatment Group = 10mg Ibudilast– Linear Scale –
Days 1-28 (PK Population)
Patient Plasma Concentration Levels of Ibudilast for
Treatment Group = 5mg Ibudilast– Semi-Logarithmic
Scale – Days 1-28 (PK Population) Patient Plasma
Concentration Levels of Ibudilast for Treatment
Group = 10mg Ibudilast– Semi-Logarithmic Scale –
Days 1-28 (PK Population)
Included
in Final
Listings
X
Included
in Final
Listings
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Shown in
Appendix B
Shown in
Appendix B
X
X
X
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Statistical Analysis Plan
STP1-C004
Figure
No.
Figure Title
FIG18
Patient Plasma Concentration Levels of
Bumetanide for Treatment Group = 5mg Ibudilast–
Linear Scale – Days 1-28 (PK Population)
FIG19
Patient Plasma Concentration Levels of
Bumetanide for Treatment Group = 10mg Ibudilast–
Linear Scale – Days 1-28 (PK Population)
FIG20
Patient Plasma Concentration Levels of
Bumetanide for Treatment Group = 5mg Ibudilast–
Semi-Logarithmic Scale – Days 1-28 (PK
Population)
FIG21
Patient Plasma Concentration Levels of
Bumetanide for Treatment Group = 10mg Ibudilast–
Semi-Logarithmic Scale – Days 1-28(PK
Population)
FIG22
Mean Plasma Concentration Levels of Ibudilast for
Treatment Group = 5mg Ibudilast – Linear Scale –
Days 1-28 (PK Population)
FIG23
Mean Plasma Concentration Levels of Ibudilast for
Treatment Group = 10mg Ibudilast – Linear Scale –
Days 1-28 (PK Population)
FIG24
Mean Plasma Concentration Levels of Ibudilast for
Treatment Group = 5mg Ibudilast – Semi-
Logarithmic Scale – Days 1-28 (PK Population)
FIG25
Mean Plasma Concentration Levels of Ibudilast for
Treatment Group = 10mg Ibudilast – Semi-
Logarithmic Scale – Days 1-28 (PK Population)
FIG26
Mean Plasma Concentration Levels of Bumetanide
for Treatment Group = 5mg Ibudilast – Linear Scale
– Days 1-28 (PK Population)
FIG27
Mean Plasma Concentration Levels of Bumetanide
for Treatment Group = 10mg Ibudilast – Linear
Scale – Days 1-28 (PK Population)
FIG28
Mean Plasma Concentration Levels of Bumetanide
for Treatment Group = 5mg Ibudilast – Semi-
Logarithmic Scale – Days 1-28 (PK Population)
FIG29
Mean Plasma Concentration Levels of Bumetanide
for Treatment Group = 10mg Ibudilast – Semi-
Logarithmic Scale – Days 1-28 (PK Population)
Included
in Final
Listings
X
X
X
X
X
X
X
X
X
X
X
X
Shown in
Appendix B
X
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Statistical Analysis Plan
STP1-C004
9.0 References
Not applicable.
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Statistical Analysis Plan
STP1-C004
Appendix A – Tables, Figures and Listing Specifications
Orientation
Tables, figures, and listings will be displayed in landscape.
Margins
Margins will be 1 inch on all sides. Table, figure, and listing boundaries will not
extend into the margins.
Font
Courier New, 8 point.
Headers
The table number will be on the second line of the title area. The title area will
contain the Sponsor name, the study number, and the name of the table. The
title area will contain the page number (Page x of y) on the far right, one line
above the name of the table.
Footers
- The first line will be a solid line.
- Next will be any footnotes regarding information displayed in the table.
- Below these footnotes will be displayed “STATKING Clinical Services (month
day, year)” on the far left.
- The last line will display the name of the SAS program that generated the
table and (if applicable) the source data reference.
Table Disclaimer
The format of the mock tables shown in the appendix of this Statistical Analysis
Plan (SAP) will be the format of the deliverable tables to the extent that Word
document constructed tables can match production tables produced by SAS.
This formatting includes the content and format of the header and footer areas
of the tables. The Sponsor agrees to the format of the tables as shown in the
appendix.
Further programming charges will be applicable for changes in the format of
tables (including title statements, notes, data dependent footnotes, etc.) made
after the approval of the SAP.
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Statistical Analysis Plan
STP1-C004
Missing Values
All missing values will be displayed on the output tables/listings as blanks.
Computation Values for Study Dates
The date format to be used is dd-mmm-yyyy. Missing parts of dates are not
shown (e.g., for a missing day value, the value displayed is in mmm-yyyy
format).
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Statistical Analysis Plan
STP1-C004
Appendix B – Table Shells
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 1. Patient Disposition
STALICLA SA - Study No. STP1-C004
Screen Failures
Reason for Screen Failure
xxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxx
Enrolled
Completed
Discontinued
Reason for Patient Discontinuation
Adverse Event
Investigator Decision
Consent Withdrawn
Patient Non-compliance
Death
Other
Reason for Discontinuation from STP1
Pregnancy
Patient Non-compliance
Patient Unblinding
xxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxx
STP1- 5mg
ibudilast
(N=xxx)a
xx
xx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)a
xx
xx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)a
xx
xx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
 
(N=xxx)
xx
xx
xx
xx
xx
xx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
______________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of enrolled patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
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Page x of y
Table 2. Demographics and Baseline Data Summary Statistics – Continuous Variables
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 Variable
 Treatment Group
     n
 
Mean 
 Std Dev  Median  
Min 
 
Max
Age (years)
Height (cm)
Weight (kg)
BMI
Head Circumference
within First Two Years
of Age (cm)
SB5-ABIQ
STP1- 5mg ibudilast
xxx
xxx
STP1- 10mg ibudilast
xxx
xxx
Placebo
xxx
xxx
Overall
xxx
xxx
STP1- 5mg ibudilast
xxx
xxx
STP1- 10mg ibudilast
xxx
xxx
Placebo
xxx
xxx
Overall
xxx
xxx
STP1- 5mg ibudilast
xxx
xxx
STP1- 10mg ibudilast
xxx
xxx
Placebo
xxx
xxx
Overall
xxx
xxx
STP1- 5mg ibudilast
xxx
xxx
STP1- 10mg ibudilast
xxx
xxx
Placebo
xxx
xxx
Overall
xxx
xxx
STP1- 5mg ibudilast
xxx
xxx
STP1- 10mg ibudilast
xxx
xxx
Placebo
xxx
xxx
Overall
xxx
xxx
STP1- 5mg ibudilast
xxx
xxx
STP1- 10mg ibudilast
xxx
xxx
Placebo
xxx
xxx
Overall
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
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Page x of y
Table 3. Demographics and Baseline Data Summary Statistics – Categorical Variables
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Demographics
 Variable
 Category
STP1- 5mg
ibudilast
(N=xxx)a
STP1- 10mg
ibudilast
(N=xxx)a
Placebo
(N=xxx)a
Overall
(N=xxx)a
Sex
Race
Ethnicity
Male
Female
American Indian
Asian
Black
Hawaiian
White
Other
Hispanic
Not Hispanic
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
_____________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
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Page x of y
Table 4. Summary of Adverse Events
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxxx)
STP1- 5mg ibudilast
(N=xxx)a
STP1- 10mg ibudilast
(N=xxx)a
Placebo
(N=xxx)a
Overall
(N=xxx)a
Patients with at Least One Adverse Event (AE)
Patients with at Least One Treatment-Related AE
Patients with at Least One Treatment-Related AE that
Led to Study Treatment Discontinuation
Maximum AE Severity Grade
Mild
Moderate
Severe
Highest Relationship of AE to Study Drug
Not Related
Related
Patients with at Least One Serious AE (SAE)
Patients with at Least One Treatment-Related SAE
Patients with at Least One Treatment-Related SAE
that Led to Study Treatment Discontinuation
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
[Table continues on next page.]
______________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Table 4. Summary of Adverse Events
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxxx)
STP1- 5mg ibudilast
(N=xxx)a
STP1- 10mg ibudilast
(N=xxx)a
Placebo
(N=xxx)a
Overall
(N=xxx)a
Maximum SAE Severity Grade
Mild
Moderate
Severe
Highest Relationship of SAE to Study Drug
Not Related
Related
Patients with at Least One AE of Special Interest
(AESI)
Patients with at Least One AESI that Led to Study
Treatment Discontinuation
Deaths
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
______________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
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Table 5. Number and Proportion of Patients with Adverse Events
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Adverse Event Categorya:
Total Number of Adverse Events (AEs)
Patients with at Least One AE
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
____________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Table 6. Number and Proportion of Patients with Treatment-Related Adverse Events
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Adverse Event Categorya,b:
Total Number of Treatment-Related Adverse
Events (AEs)
Patients with at Least One Treatment-
Related AE
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
___________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b A treatment-related AE is any AE with a relationship to study drug of Related.
c The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Table 7. Number and Proportion of Patients with Treatment-Related Adverse Events that Led to Study Drug
Discontinuation
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Adverse Event Categorya,b:
Total Number of Treatment-Related Adverse Events
(AEs) that Led to Study Drug Discontinuation
Patients with at Least One Treatment-Related AE
that Led to Study Drug Discontinuation
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
___________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b A treatment-related AE is any AE with a relationship to study drug of Related.
c The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
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Table 8. Number and Proportion of Patients with Serious Adverse Events
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Adverse Event Categorya:
Total Number of Serious Adverse Events (SAEs)
Patients with at Least One SAE
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
____________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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STP1-C004
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Table 9. Number and Proportion of Patients with Treatment-Related Serious Adverse Events
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Adverse Event Categorya,b:
Total Number of Treatment-Related Serious
Adverse Events (SAEs)
Patients with at Least One Treatment-Related
SAE
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
___________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b A treatment-related AE is any AE with a relationship to study drug of Related.
c The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
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STP1-C004
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Table 10. Number and Proportion of Patients with Treatment-Related Serious Adverse Events that Led to
Study Drug Discontinuation
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Adverse Event Categorya,b:
Total Number of Treatment-Related Serious
Adverse Events (SAEs) that Led to Study Drug
Discontinuation
Patients with at Least One Treatment-Related SAE
that Led to Study Drug Discontinuation
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
___________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b A treatment-related AE is any AE with a relationship to study drug of Related.
c The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
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STP1-C004
Page x of y
Table 11. Number and Proportion of Patients with Adverse Events of Special Interest
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Adverse Event Categorya:
Total Number of Adverse Events of Special
Interest (AESIs)
Patients with at Least One AESI
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
____________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
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STP1-C004
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Table 12. Number and Proportion of Patients with Adverse Events of Special Interest that Led to Study
Drug Discontinuation
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Adverse Event Categorya:
Total Number of Adverse Events of Special
Interest (AESIs) that Led to Study Drug
Discontinuation
Patients with at Least One AESI that Led to
Study Drug Discontinuation
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
____________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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STP1-C004
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Table 13. Number and Proportion of Patients with Adverse Events by Relationship to Study Drug
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
STP1- 5mg ibudilast
         (N=xxx)b
STP1- 10mg ibudilast
 
(N=xxx)b
Placebo
(N=xxx)b
Adverse Event Categorya:
Not Related  
Related 
 Not Related  
Related 
 Not Related  
Related
Total Number of Adverse Events (AEs)
Patients with at Least One AE
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
____________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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STP1-C004
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Table 14. Number and Proportion of Patients with Adverse Events by Severity
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
STP1- 5mg ibudilast
(N=xxx)b
STP1- 10mg ibudilast
(N=xxx)b
Placebo
(N=xxx)b
Adverse Event Categorya:
 
Mild 
 Moderate  
Severe 
 
Mild 
 Moderate  
Severe 
 
Mild 
 Moderate  
Severe
Total Number of Adverse Events
(AEs)
Patients with at Least One AE
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
____________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version XXX.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Table 15. Vital Sign Parameter Summary Statistics
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Parameter
 Treatment 
 (units)a
Data
 
Visit 
 
Time 
 
Typeb
     n
 
Mean 
 Std Dev  Median  
Min 
 
Max
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
Baseline
xxxx
RAW
xxx
xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
Baseline
xxxx
RAW
xxx
xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
Baseline
xxxx
RAW
xxx
xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
______________________________________________________________________________________________________________________________________ a
Vital sign parameters in this table include temperature and respiratory rate.
b RAW = observed data recorded in database; CFB = change from baseline = (results at current visit) - (Baseline results).
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Table 16. Orthostatic Vital Sign Parameter Summary Statistics
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Parameter
 Treatment 
 (units)a
Data
 
Visit 
 
Time 
 
Typeb
     n
 
Mean 
 Std Dev  Median  
Min 
 
Max
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
Baseline
xxxx
RAW
xxx
xxx
xxxxxx      xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx      xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
Baseline
xxxx
RAW
xxx
xxx
xxxxxx      xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx      xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
Baseline
xxxx
RAW
xxx
xxx
xxxxxx      xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx      xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
______________________________________________________________________________________________________________________________________ a
Vital sign parameters in this table include orthostatic heart rate, orthostatic diastolic blood pressure, and orthostatic systolic
blood pressure taken in the supine position.
b RAW = observed data recorded in database; CFB = change from baseline = (results at current visit) - (Baseline results).
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Table 17. ECG Parameter Summary Statistics
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Parameter
 Treatment 
 (units)
 
Visita
Data
 
Time 
 
Typeb
     n
 
Mean 
 Std Dev  Median  
Min 
 
Max
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
Overall
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
Baseline
xxxx
RAW
xxx
xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
Baseline
xxxx
RAW
xxx
xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
Baseline
xxxx
RAW
xxx
xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
Baseline
xxxx
RAW
xxx
xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxxxxx       xxxx       RAW       xxx       xxx
xxxx       CFB       xxx       xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
xxx       xxx      xxx      xxx
_____________________________________________________________________________________________________________________________________ a
The baseline raw value for each parameter is calculated using the average of the triplicate values from the ECG performed on Day 1
pre-dose.
b Raw = observed data; CFB = change from baseline = (results at current visit) - (Baseline results).
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STP1-C004
Page x of y
Table 18. ECG Results Shift Table by Visit and Clinical Significance
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Baselinea/Visitb,c
Abnormal
Normal/
Normal/ 
Abnormal
Abnormal
Abnormal
NCS/
Abnormal
Normal/ 
Abnormal 
Abnormal
CS/          CS/       Abnormal CS/     NCS/      Abnormal        NCS/
 Treatment 
 
Visit 
 Normal 
CS
     NCS
 
Normal 
 Abnormal CS  Abnormal NCS  Normal 
CS
 Abnormal NCS
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
Overall
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
______________________________________________________________________________________________________________________________________ a
The baseline ECG result performed in triplicate is determined as outlined in section 4.2 of the SAP.
b A normal result are those results that the Principal Investigator determined to be within normal range. CS = Clinically Significant.
NCS= Not Clinically Significant.
c The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 51 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 19. ECG Results Shift Table by Visit
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Baselinea/Visitb,c
 Treatment
 Parameter  
Visit
 Normal/Normal  Normal/Abnormal  Abnormal/Normal  Abnormal/Abnormal
STP1- 5mg ibudilast
xxxxx
STP1- 10mg ibudilast
xxxxx
Placebo
xxxxx
Overall
xxxxx
xxxxxx       xxx (xxxx)
xxxxxx       xxx (xxxx)
xxxxxx       xxx (xxxx)
xxxxxx       xxx (xxxx)
xxxxxx       xxx (xxxx)
xxxxxx       xxx (xxxx)
xxxxxx       xxx (xxxx)
xxxxxx       xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
xxx (xxxx)
_____________________________________________________________________________________________________________________________________ a
The baseline ECG result performed in triplicate is determined as outlined in section 4.2 of the SAP.
b A normal result are those results that the Principal Investigator determined to be within normal range.
c The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (DDMMMYYYY)
Source Program: xxxxxxx.sas
Parameters in this table are T wave, U wave and ECG Interpretation.
Page 52 of 121
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Version 1.1
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 20. Blood Chemistry Parameter Summary Statistics
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Parameter
Data
 Treatment
 (units)
 
Visit 
 
Typea 
 
n 
 
Mean 
 Std Dev  
Median 
 Min 
 
Max
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
Overall
xxxxxxxxxxxxxx
(xxx)
xxxxxxxxxxxxxx
(xxx)
xxxxxxxxxxxxxx
(xxx)
xxxxxxxxxxxxxx
(xxx)
Baseline
RAW
xxx
xxx
xxx
xxxxxx      RAW      xxx       xxx       xxx
xxxxxx      CFB      xxx       xxx       xxx
xxxxxx      RAW      xxx       xxx       xxx
xxxxxx      CFB      xxx       xxx       xxx
Baseline
RAW
xxx
xxx
xxx
xxxxxx      RAW      xxx       xxx       xxx
xxxxxx      CFB      xxx       xxx       xxx
xxxxxx      RAW      xxx       xxx       xxx
xxxxxx      CFB      xxx       xxx       xxx
Baseline
RAW
xxx
xxx
xxx
xxxxxx      RAW      xxx       xxx       xxx
xxxxxx      CFB      xxx       xxx       xxx
xxxxxx      RAW      xxx       xxx       xxx
xxxxxx      CFB      xxx       xxx       xxx
Baseline
RAW
xxx
xxx
xxx
xxxxxx      RAW      xxx       xxx       xxx
xxxxxx      CFB      xxx       xxx       xxx
xxxxxx      RAW      xxx       xxx       xxx
xxxxxx      CFB      xxx       xxx       xxx
xxx
xxx
xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx
xxx
xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx
xxx
xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx
xxx
xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx       xxx      xxx
xxx       xxx      xxx
______________________________________________________________________________________________________________________________________ a
RAW = observed data recorded in database; CFB = change from baseline = (results at current visit) - (Baseline results).
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Table format will be repeated for Hematology, Coagulation and Urinalysis.
Page 53 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 24. Summary of Qualitative Urinalysis Results by Parameter
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
STP1- 5mg
ibudilast
 Parameter  
Visit
     Result
     (N=xxx)a
STP1- 10mg
ibudilast
(N=xxx)a
Placebo
(N=xxx)a
Overall
(N=xxx)a
xxxxx
xxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxx
xxxxxx
xxxxxx
xxxxxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
_____________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (DDMMMYYYY)
Source Program: xxxxxxx.sas
Page 54 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 25. Blood Chemistry Results Shift Table by Visit and Clinical Significance
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
         Baseline/Visita,b
Abnormal 
Abnormal
Abnormal 
Abnormal
Normal/ 
Normal/ 
Abnormal
CS/
CS/      Abnormal     NCS/
NCS/
Parameter
Normal/ 
Abnormal 
Abnormal
CS/
Abnormal 
Abnormal
NCS/
Abnormal 
Abnormal
 (units)
 Treatment 
 Visit  Normal 
CS
 
NCS 
 Normal 
CS
 
NCS 
 Normal 
CS
 
NCS
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
Overall
xxxxxxxx
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
______________________________________________________________________________________________________________________________________ a
A normal result are those results that the Principal Investigator determined to be within normal range. CS = Clinically Significant.
NCS= Not Clinically Significant.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Table format will be repeated for Hematology, Coagulation, Urinalysis, and Blood Chemistry Results for Electrolytes.
Laboratory parameters in Table 25 will exclude sodium, chloride, calcium, magnesium, phosphate, and potassium.
Laboratory parameters in Table 29 will include sodium, chloride, calcium, magnesium, phosphate, and potassium.
Page 55 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 30. Blood Chemistry Results for Electrolytes Shift Table by Visit and Range of Normal Results
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
         Baseline/Visita,b
Laboratory
Parameter
High/
High/
High/
Normal/ 
Normal/ 
Normal/
Low/
Low/
Low/
 (units)
 Treatment 
 Visit  
High 
 Normal 
 
Low 
 
High 
 Normal 
 
Low 
 
High 
 Normal 
 
Low
xxxxxxxxxx
(xxx)
xxxxxxxxxx
(xxx)
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
Overall
xxxxxxxx
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxxxxx 
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
xxx (xx)
______________________________________________________________________________________________________________________________________ a
A normal result are those results that the Principal Investigator determined to be within normal range.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Laboratory parameters include: sodium, chloride, calcium, magnesium, phosphate, and potassium.
Page 56 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 31. Number and Proportion of Patients with Blood Chemistry Results for Electrolytes Outside of
Normal Range
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
STP1- 5mg
ibudilast
Parameter (units)
     Visit
     Result
 
(N=xxx)a
STP1- 10mg
ibudilast
(N=xxx)a
Placebo
(N=xxx)a
Overall
(N=xxx)a
xxxxxxxxxx (xxx)
xxxxxxxxxx (xxx)
xxxxxx
 Low
High
xxxxxx
 Low
High
xxxxxx
 Low
High
xxxxxx
Low
High
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
_____________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (DDMMMYYYY)
Source Program: xxxxxxx.sas
Laboratory parameters include: sodium, chloride, calcium, magnesium, phosphate, and potassium.
Page 57 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 32. Summary Statistics of Ibudilast and Bumetanide Plasma Concentration Levels by Treatment, Visit
and Time
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Druga
        Treatment
 Visit  Time (hrs)  n  Mean  Std Dev  Median  Min 
 
Max
Ibudilast
Bumetanide
STP1-5mg ibudilast
xxx
xxx
STP1-10mg ibudilast
xxx
xxx
STP1-5mg ibudilast
xxx
xxx
STP1-10mg ibudilast
xxx
xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
______________________________________________________________________________________________________________________________________ a
Concentration levels measured in units of xxx.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 58 of 121
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 33. Summary Statistics of Ibudilast and Bumetanide Urine Concentration Levels by Treatment, Visit
and Time
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Druga
        Treatment
 Visit  Time (hrs)  n  Mean  Std Dev  Median  Min 
 
Max
Ibudilast
Bumetanide
STP1-5mg ibudilast
xxx
xxx
STP1-10mg ibudilast
xxx
xxx
STP1-5mg ibudilast
xxx
xxx
STP1-10mg ibudilast
xxx
xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx 
xxx       xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
xxx      xxx     xxx
______________________________________________________________________________________________________________________________________ a
Concentration levels measured in units of xxx.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 59 of 121
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 34. Summary Statistics of Estimated PK Plasma Parameters for Ibudilast by Treatment
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Part 1 of 2: STP1- 5mg ibudilast
Geometric 
Lower
Upper
 
Visit 
Parameter (units)
     n
 Mean  Std Dev  
CV% 
 
Mean 
 90% CI  90% CI
Day 1
Day 14
Overall
Cmax,Day 1(xxx/mL)
Tmax (hrs)
Ctrough (xxx /mL)
t1/2 (hrs)
AUC0-tau(6h),Day 1 (hrs* xxx/mL)
AUC0-last (hrs* xxx/mL)
Vz/F (mL)
Cl/F (mL/hrs)
Cmax,ss(xxx /mL)
Tmax (hrs)
Ctrough (xxx /mL)
t1/2 (hrs)
AUC0-tau(6h),SS (hrs* xxx/mL)
AUC0-12h,SS (hrs* xxx/mL)
AUC0-last (hrs* xxx/mL)
Vz/F (mL)
Cl/F (mL/hrs)
AUC0-∞ (hrs* xxx/mL)
ARAUC
ARCmax
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 60 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 34. Summary Statistics of Estimated PK Plasma Parameters for Ibudilast by Treatment
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Part 2 of 2: STP1- 10mg ibudilast
Geometric 
Lower
Upper
 
Visit 
Parameter (units)
     n
 Mean  Std Dev  
CV% 
 
Mean 
 90% CI  90% CI
Day 1
Day 14
Overall
Cmax,Day 1(xxx/mL)
Tmax (hrs)
Ctrough (xxx /mL)
t1/2 (hrs)
AUC0-tau(6h),Day 1 (hrs* xxx/mL)
AUC0-last (hrs* xxx/mL)
Vz/F (mL)
Cl/F (mL/hrs)
Cmax,ss(xxx /mL)
Tmax (hrs)
Ctrough (xxx /mL)
t1/2 (hrs)
AUC0-tau(6h),SS (hrs* xxx/mL)
AUC0-12h,SS (hrs* xxx/mL)
AUC0-last (hrs* xxx/mL)
Vz/F (mL)
Cl/F (mL/hrs)
AUC0-∞ (hrs* xxx/mL)
ARAUC
ARCmax
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 61 of 121
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 35. Summary Statistics of Estimated PK Plasma Parameters for Bumetanide by Treatment
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Part 1 of 2: STP1- 5mg ibudilast
Geometric 
Lower
Upper
 
Visit 
Parameter (units)
     n
 Mean  Std Dev  
CV% 
 
Mean 
 90% CI  90% CI
Day 1
Day 14
Overall
Cmax,Day 1(xxx/mL)
Tmax (hrs)
Ctrough (xxx /mL)
t1/2 (hrs)
AUC0-tau(6h),Day 1 (hrs* xxx/mL)
AUC0-last (hrs* xxx/mL)
Vz/F (mL)
Cl/F (mL/hrs)
Cmax,ss(xxx /mL)
Tmax (hrs)
Ctrough (xxx /mL)
t1/2 (hrs)
AUC0-tau(6h),SS (hrs* xxx/mL)
AUC0-12h,SS (hrs* xxx/mL)
AUC0-last (hrs* xxx/mL)
Vz/F (mL)
Cl/F (mL/hrs)
AUC0-∞ (hrs* xxx/mL)
ARAUC
ARCmax
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
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xxx
xxx
xxx
xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 62 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 35. Summary Statistics of Estimated PK Plasma Parameters for Bumetanide by Treatment
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Part 2 of 2: STP1- 10mg ibudilast
Geometric 
Lower
Upper
 
Visit 
Parameter (units)
     n
 Mean  Std Dev  
CV% 
 
Mean 
 90% CI  90% CI
Day 1
Day 14
Overall
Cmax,Day 1(xxx/mL)
Tmax (hrs)
Ctrough (xxx /mL)
t1/2 (hrs)
AUC0-tau(6h),Day 1 (hrs* xxx/mL)
AUC0-last (hrs* xxx/mL)
Vz/F (mL)
Cl/F (mL/hrs)
Cmax,ss(xxx /mL)
Tmax (hrs)
Ctrough (xxx /mL)
t1/2 (hrs)
AUC0-tau(6h),SS (hrs* xxx/mL)
AUC0-12h,SS (hrs* xxx/mL)
AUC0-last (hrs* xxx/mL)
Vz/F (mL)
Cl/F (mL/hrs)
AUC0-∞ (hrs* xxx/mL)
ARAUC
ARCmax
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
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xxx
xxx
xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 63 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 36. Summary Statistics of Estimated PK Urine Parameters for Ibudilast by Treatment
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Part 1 of 2: STP1- 5mg ibudilast
Geometric 
Lower
Upper
Visit
 
Parameter
 
n
 Mean  Std Dev  
CV% 
 
Mean 
 90% CI  90% CI
Day 1
Excretion Rate(xxx/hr), 0-6h
xxx
xxx
xxx
xxx
xxx
xxx
xxx
Day 14        Excretion Rate(xxx/hr), 0-4h      xxx      xxx      xxx       xxx        xxx        xxx        xxx
Excretion Rate(xxx/hr), 4-8h      xxx      xxx      xxx       xxx        xxx        xxx        xxx
Excretion Rate(xxx/hr), 8-12h     xxx      xxx      xxx       xxx        xxx        xxx        xxx
Cumulative Excretion (xxx)       xxx      xxx      xxx       xxx        xxx        xxx        xxx
Renal Clearance (mL/hr)        xxx      xxx      xxx       xxx        xxx        xxx        xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 64 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 36. Summary Statistics of Estimated PK Urine Parameters for Ibudilast by Treatment
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Part 2 of 2: STP1- 10mg ibudilast
Geometric 
Lower
Upper
Visit
            Parameter
 
n
 Mean  Std Dev  
CV% 
 
Mean 
 90% CI  90% CI
Day 1
Excretion Rate(xxx/hr), 0-6h
xxx
xxx
xxx
xxx
xxx
xxx
xxx
Day 14        Excretion Rate(xxx/hr), 0-4h      xxx      xxx      xxx       xxx        xxx        xxx        xxx
Excretion Rate(xxx/hr), 4-8h      xxx      xxx      xxx       xxx        xxx        xxx        xxx
Excretion Rate(xxx/hr), 8-12h     xxx      xxx      xxx       xxx        xxx        xxx        xxx
Cumulative Excretion (xxx)       xxx      xxx      xxx       xxx        xxx        xxx        xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 65 of 121
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 37. Summary Statistics of Estimated PK Urine Parameters for Bumetanide by Treatment
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Part 1 of 2: STP1- 5mg ibudilast
Geometric 
Lower
Upper
Visit
            Parameter
 
n
 Mean  Std Dev  
CV% 
 
Mean 
 90% CI  90% CI
Day 1
Excretion Rate(xxx/hr), 0-6h
xxx
xxx
xxx
xxx
xxx
xxx
xxx
Day 14        Excretion Rate(xxx/hr), 0-4h      xxx      xxx      xxx       xxx        xxx        xxx        xxx
Excretion Rate(xxx/hr), 4-8h      xxx      xxx      xxx       xxx        xxx        xxx        xxx
Excretion Rate(xxx/hr), 8-12h     xxx      xxx      xxx       xxx        xxx        xxx        xxx
Cumulative Excretion (xxx)       xxx      xxx      xxx       xxx        xxx        xxx        xxx
Renal Clearance (mL/hr)        xxx      xxx      xxx       xxx        xxx        xxx        xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 66 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 37. Summary Statistics of Estimated PK Urine Parameters for Bumetanide by Treatment
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Part 2 of 2: STP1- 10mg ibudilast
Geometric 
Lower
Upper
Visit
 
Parameter
 
n
 Mean  Std Dev  
CV% 
 
Mean 
 90% CI  90% CI
Day 1
Excretion Rate(xxx/hr), 0-6h
xxx
xxx
xxx
xxx
xxx
xxx
xxx
Day 14        Excretion Rate(xxx/hr), 0-4h      xxx      xxx      xxx       xxx        xxx        xxx        xxx
Excretion Rate(xxx/hr), 4-8h      xxx      xxx      xxx       xxx        xxx        xxx        xxx
Excretion Rate(xxx/hr), 8-12h     xxx      xxx      xxx       xxx        xxx        xxx        xxx
Cumulative Excretion (xxx)       xxx      xxx      xxx       xxx        xxx        xxx        xxx
Renal Clearance (mL/hr)        xxx      xxx      xxx       xxx        xxx        xxx        xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 67 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 38. NIH-CTB Summary Statistics
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
Neurological
Function
Data
 Treatment
     Domain
 
Visit 
 
Typea
Std
 
n 
 Mean  
Dev 
 Median  Min  
Max
STP1- 5mg ibudilast
STP1- 10mg ibudilast
Placebo
Overall
xxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxx
Baseline
RAW
xxxxxx
RAW
xxxxxx
CFB
Baseline
RAW
xxxxxx
RAW
xxxxxx
CFB
Baseline
RAW
xxxxxx
RAW
xxxxxx
CFB
Baseline
RAW
xxxxxx
RAW
xxxxxx
CFB
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
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xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
______________________________________________________________________________________________________________________________________ a
RAW = observed data recorded in database; CFB = change from baseline = (score at current visit) - (Baseline score).
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Neurological Function Domain will include the following: Picture Vocabulary Test Raw Score, Pattern Comparison
Processing Speed Test Raw Score, Flanker Inhibitory Control and Attention Test Raw Score, Dimensional Change Card Sort
Test Raw Score, Oral Reading Recognition Test Raw Score, Cognition Crystallized Composite Uncorrected Standard Score,
Cognition Crystallized Composite Age-Corrected Standard Score, Cognition Crystallized National Percentile (Age
Adjusted), and Cognition Crystallized Composite Fully-Corrected T-score.
Table format will be repeated for KiTAP.
Page 68 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 40. OACIS-C Summary Statistics
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
 Treatment
 Question
     n
 
Mean 
 
Std Dev 
 Median  
Min 
 
Max
STP1- 5mg ibudilast
STP1- 10mg ibudilast
Placebo
Overall
xxxxxxxxxxxxxx     xxx        xxx
xxxxxxxxxxxxxx     xxx        xxx
xxxxxxxxxxxxxx     xxx        xxx
xxxxxxxxxxxxxx     xxx        xxx
xxxxxxxxxxxxxx     xxx        xxx
xxxxxxxxxxxxxx     xxx        xxx
xxxxxxxxxxxxxx     xxx        xxx
xxxxxxxxxxxxxx     xxx        xxx
xxx        xxx       xxx       xxx
xxx        xxx       xxx       xxx
xxx        xxx       xxx       xxx
xxx        xxx       xxx       xxx
xxx        xxx       xxx       xxx
xxx        xxx       xxx       xxx
xxx        xxx       xxx       xxx
xxx        xxx       xxx       xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 69 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 41. Summary of Responses for OACIS-C Assessment by Question
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
Question
General Level of Autism
Social Interaction Skills
xxxxxxxxxxxxxxxxxxxxxx
Response
Very Much Improved
Much Improved
Minimally Improved
No Change
Minimally Worse
Much Worse
Very Much Worse
Very Much Improved or Much
Improved
Minimally Improved, No Change or
Minimally Worse
Much Worse or Very Much Worse
Very Much Improved
Much Improved
Minimally Improved
No Change
Minimally Worse
Much Worse
Very Much Worse
Very Much Improved or Much
Improved
Minimally Improved, No Change or
Minimally Worse
Much Worse or Very Much Worse
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
STP1- 5mg
ibudilast
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
STP1- 10mg
ibudilast
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
Placebo
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
Overall
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
______________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Exploratory population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 70 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 42. Summary of Responses for OACIS-S Assessment by Question
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
Question
xxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxx
Response
Normal
Some symptom/ behavior
Mild symptom/ behavior
Moderate symptom/ behavior
Marked symptom/ behavior
Severe symptom/ behavior
Among the Most Severe
Normal
Some symptom/ behavior
Mild symptom/ behavior
Moderate symptom/ behavior
Marked symptom/ behavior
Severe symptom/ behavior
Among the Most Severe
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
STP1- 5mg
ibudilast
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
STP1- 10mg
ibudilast
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
Placebo
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
Overall
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
______________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Exploratory population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 71 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 43. ABC-C Summary Statistics
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
Data
 Treatment 
 Subscale
 
Visit 
 Typea 
 
n 
 Mean  Std Dev  Median  
Min 
 
Max
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
Overall
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
Baseline
RAW
xxxxxx      RAW
xxxxxx      CFB
xxxxxx      RAW
xxxxxx      CFB
Baseline
RAW
xxxxxx      RAW
xxxxxx      CFB
xxxxxx      RAW
xxxxxx      CFB
Baseline
RAW
xxxxxx
RAW
xxxxxx
CFB
xxxxxx      RAW
xxxxxx      CFB
Baseline
RAW
xxxxxx
RAW
xxxxxx
CFB
xxxxxx      RAW
xxxxxx      CFB
xxx
xxx
xxx
xxx
xxx
xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
______________________________________________________________________________________________________________________________________ a
RAW = observed data recorded in database; CFB = change from baseline = (score at current visit) - (Baseline score).
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 72 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 44. SRS-2 Summary Statistics
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
Data
 Treatment 
 Subscale
 
Visit 
 Typea 
 
n 
 Mean  Std Dev  Median  
Min 
 
Max
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
Overall
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
Baseline
RAW
xxxxxx      RAW
xxxxxx      CFB
xxxxxx      RAW
xxxxxx      CFB
Baseline
RAW
xxxxxx      RAW
xxxxxx      CFB
xxxxxx      RAW
xxxxxx      CFB
Baseline
RAW
xxxxxx
RAW
xxxxxx
CFB
xxxxxx      RAW
xxxxxx      CFB
Baseline
RAW
xxxxxx
RAW
xxxxxx
CFB
xxxxxx      RAW
xxxxxx      CFB
xxx
xxx
xxx
xxx
xxx
xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx     xxx      xxx       xxx       xxx       xxx
xxx     xxx      xxx       xxx       xxx       xxx
______________________________________________________________________________________________________________________________________ a
RAW = observed data recorded in database; CFB = change from baseline = (score at current visit) - (Baseline score).
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 73 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 45. Summary of Responses for CSHQ Assessment by Question
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
Visit
Question
xxx
xxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxx
xxx
xxxxxxxxxxxxxxxxx
Response
Never
Rarely
Sometimes
Usually
Always
Never
Rarely
Sometimes
Usually
Always
xxxxxxxxxxxxxx
xxxxxxxxxxxxxx
STP1- 5mg
ibudilast
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
STP1- 10mg
ibudilast
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
Placebo
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
Overall
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
______________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Exploratory population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 74 of 121
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February 17, 2022


Statistical Analysis Plan
STP1-C004
Page x of y
Table 46. Lactate and Pyruvate Blood Level Summary Statistics
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
Data
 Treatment 
 Parameter (units)
 
Visit 
 
Typea
 
n
 
Mean 
 Std Dev  
Min 
 
Max 
 Median
STP1- 5mg
ibudilast
STP1- 10mg
ibudilast
Placebo
Overall
Lactate (xxx)
Pyruvate (xxx)
L:P Ratio (xxx)
xxxxxxxxxx (xxx)
xxxxxxxxxx (xxx)
xxxxxxxxxx (xxx)
Baseline
RAW
xxx
xxx
xxxxxx       RAW       xxx       xxx
CFB       xxx       xxx
Baseline      RAW       xxx       xxx
xxxxxx       RAW       xxx       xxx
CFB       xxx       xxx
Baseline      RAW       xxx       xxx
xxxxxx       RAW       xxx       xxx
CFB       xxx       xxx
Baseline
RAW
xxx
xxx
xxxxxx       RAW       xxx       xxx
CFB       xxx       xxx
Baseline      RAW       xxx       xxx
xxxxxx       RAW       xxx       xxx
CFB       xxx       xxx
Baseline      RAW       xxx       xxx
xxxxxx       RAW       xxx       xxx
CFB       xxx       xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx       xxx
xxx       xxx      xxx       xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx       xxx      xxx       xxx
xxx       xxx      xxx       xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
_____________________________________________________________________________________________________________________________________ a
Raw = observed data; CFB = change from baseline = (results at current visit) - (Baseline results).
STATKING Clinical Services (DDMMMYYYY)
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 47. Summary of Responses for CGI-S Assessment by Visit
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
Visit
              Response
xxx
Not Assessed
Normal, not at all ill
Borderline mentally ill
Mildly ill
Moderately ill
Markedly ill
Severely ill
Among the most extremely ill
patients
xxx
Not Assessed
Normal, not at all ill
Borderline mentally ill
Mildly ill
Moderately ill
Markedly ill
Severely ill
Among the most extremely ill
patients
STP1- 5mg
ibudilast
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
STP1- 10mg
ibudilast
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
Placebo
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
Overall
(N=xxx)a
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
______________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Exploratory population patients in the corresponding treatment group and overall.
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 48. Summary of Responses for CGI-I Assessment by Visit
STALICLA SA - Study No. STP1-C004
Exploratory Population (N=xxx)
STP1- 5mg
ibudilast
Visit
 
Response
     (N=xxx)a
STP1- 10mg
ibudilast
(N=xxx)a
Placebo
(N=xxx)a
Overall
(N=xxx)a
xxx
Not assessed
Very Much Improved
Much Improved
Minimally Improved
No change from Baseline
Minimally Worse
Much Worse
Very Much Worse
xxx
Not assessed
Very Much Improved
Much Improved
Minimally Improved
No change from Baseline
Minimally Worse
Much Worse
Very Much Worse
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
xx (xxx)
______________________________________________________________________________________________________________________________________ a
The denominator for all proportions is the number of Exploratory population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 49. Number and Proportion of Patients with Medical History Events
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Medical History Categorya:
Total Number of Medical History Events
Patients with at Least One Medical History Event
System Organ Class 1
Preferred Term 1
Preferred Term 2
System Organ Class 2
Preferred Term 1
Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)b
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
____________________________________________________________________________________________________________________________________ a
Medical history events coded with MedDRA Coding Dictionary Version XXX.
b The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
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Statistical Analysis Plan
STP1-C004
Page x of y
Table 50. Number and Proportion of Patients Taking Concomitant Medications by ATC Level 4 and Preferred
Term
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Concomitant Medication Categorya,b
Total Number of Concomitant Medications
Patients Taking at Least One Concomitant
Medication
ATC Level 4 Term
WHO Preferred Term 1
WHO Preferred Term 2
ATC Level 4 Term
WHO Preferred Term 1
WHO Preferred Term 2
STP1- 5mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
STP1- 10mg
ibudilast
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Placebo
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
Overall
(N=xxx)c
xxx
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
xxx (xxx)
______________________________________________________________________________________________________________________________________
a Concomitant medications coded with WHO Coding Dictionary xxxxxxxxxxxxx.
b Concomitant medication category will include anatomical therapeutic chemical (ATC) level 4 term followed by preferred term.
c The denominator for all proportions is the number of Safety population patients in the corresponding treatment group and overall.
STATKING Clinical Services (month day, year)
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 1. Patient Disposition Data Listing
STALICLA SA - Study No. STP1-C004
Date of
Date of
Last Visit/
If Discontinued from
Patient
Informed      Date of       Disposition 
Disposition 
Withdrawal 
If Withdrawn, Reason     STP1, Reason for
 
No. 
 Treatment  Consent  Randomization  
Status
     Date
     Date
 for Discontinuation  
Discontinuation
xxxx
xxxxxx
xxxxxx
xxxx
xxxxxx
xxxxxx
xxxx
xxxxxx
xxxxxx
xxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxx
xxxxxxxxx
xxxxxxxxx
xxxxxxxxx
xxxxxxxxx
xxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 2. Demographics Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Head
Circumference
SB5-
Informed
within First
ABIQ
Patient
Consent 
Date of
Age
Height 
Weight 
Two Years of
FSIQ
 
No. 
 Treatment  
Date 
 
Birth 
 (years)  
(cm) 
 
(kg) 
 
Age (cm)
 BMI  Gender  Ethnicity  
Race 
 
Score
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxxx
xxxxxx
xxxxxx
xxx
xxx
xxx
xxxxxx
xxxxxx
xxx
xxx
xxx
xxxxxx
xxxxxx
xxx
xxx
xxx
xxxxxx
xxxxxx
xxx
xxx
xxx
xxx
xxx 
xxxxxx
xxxxxx
xxx
xxx 
xxxxxx
xxxxxx
xxx
xxx 
xxxxxx
xxxxxx
xxx
xxx 
xxxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxx
_____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 3. Adverse Events Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Part 1 of 2
AE Start
MedDRA System Organ
Serious?
Date/              Classa/                         AE of     Relationship      (Y/N)/
Patient
Treatment
AE End
MedDRA Preferred Term/
Special
to Study
Reason
No.
 Treatment  Start Date 
Date
     CRF Verbatim Term
 Severity  Interest? 
Drug
 
Serious?
xxxxxxxxx
xxxxxxxxx
xxxxxx
xxxxxxx
xxxxxx
xxxxxxx
xxxxxxxx/
xxxxxxxx
xxxxxxxx/
xxxxxxxx
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxxx
xx/
xxxxxxxx
xx/
xxxxxxxx
_____________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version xxx.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 3. Adverse Events Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Part 2 of 2
AE Start
MedDRA System Organ
Led to Study
Date/               Classa/                                       Treatment
Patient
Treatment
AE End
MedDRA Preferred Term/
Action
Discontinuation
No. 
  Treatment  Start Date 
Date
     CRF Verbatim Term
 
Taken 
 
Outcome 
(Y/N)?
xxxxxxxxx
xxxxxxxxx
xxxxxx
xxxxxxx
xxxxxx
xxxxxxx
xxxxxxxx/
xxxxxxxx
xxxxxxxx/
xxxxxxxx
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx
xxxxx
xxxxxxxx
xxx
xxxxx
xxxxxxxx
xxx
_____________________________________________________________________________________________________________________________________ a
Adverse events coded with MedDRA Coding Dictionary Version xxx.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 4. Vital Signs Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Patient
Treatment
Visit
No.
 Treatment  Start Date  Visit  
Date 
 
Time
Patient
Positiona
Parameter
 
(Units) 
 
Result
xxxxxx        xxxx
xxxx
xxxxxx     xxxxxx     xxxxxx     xxxxxx
xxxxxx     xxxxxx     xxxxxx     xxxxxx
xxxxxx       xxxxxx(xxx)     xxxxxx
xxxxxx       xxxxxx(xxx)     xxxxxx
_____________________________________________________________________________________________________________________________________ a
Patient position will distinguish between supine blood pressure and heart rate and standing blood pressure and heart rate.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 5. Baseline ECG Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Part 1 of 2
ECG Parameters 
Patient
Date
QRS
QT
 
No. 
 Treatment  of ECG  Time  
HR 
 PQ  Duration  Interval  
RR 
 
QTcF
xxxx
xxxxxx
xxxxxx 
xxxx 
xxx 
xxx
xxxx
xxxx 
xxx 
xxx
xxxx
xxxx 
xxx 
xxx
xxxx
xxxx
xx
xxxx
xxxx
xx
xxxx
xxxx
xx
xxxx
____________________________________________________________________________________________________________________________________
The Day 1 prior to treatment (i.e., pre-dose) time point serves as baseline.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 5. Baseline ECG Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Part 2 of 2
 
ECG Results
If Abnormal,
Clinically
Patient
Date of
T
U
ECG
Significant
No.
 Treatment  
ECG
 Time  Wave  Wave  Interpretation 
(Y/N)?
 Description
xxxx
xxxxxx
xxxxxx
xxxx 
xxxx 
xxxx
xxxx 
xxxx
xxxx 
xxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxxxxxx
xxxxxxxxxxx
xxxxxxxxxxx
____________________________________________________________________________________________________________________________________
The Day 1 prior to treatment (i.e., pre-dose) time point serves as baseline.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 6. ECG Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Part 1 of 2
 
ECG Parametersa
Patient
Date of 
Pre-Dose/
QRS
QT
No.
 Treatment  Visit  
ECG 
 Post-Dose  Time  HR 
 PQ 
 Duration  Interval  RR  QTcF
xxxx
xxxxxx
xxxx
xxxxxx
xxxxx 
xxxxxxx      xxxxx
xxxxx
xxxxx 
xxxxxxx      xxxxx
xxxxx
xxxx 
xxxx 
xxxx     xxxx
xxxx 
xxxx 
xxxx     xxxx
xxxx 
xxxx 
xxxx     xxxx
xxxx 
xxxx 
xxxx     xxxx
xxxx     xx 
xxxx
xxxx     xx 
xxxx
xxxx     xx 
xxxx
xxxx     xx 
xxxx
____________________________________________________________________________________________________________________________________ 
a
ECG parameters and results for T Wave, U Wave and ECG Interpretation displayed at Baseline (i.e., Day 1 pre-dose time point) are the
average and combined overall results.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 6. ECG Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Part 2 of 2
 
ECG Resultsa
If
Abnormal,
Clinically
Patient
Date of 
Pre-Dose/
ECG
Significant
No.
 Treatment  
Visit 
ECG
 Post-Dose  Time  T Wave  U Wave  Interpretation  
(Y/N)?
 Description
xxxx
xxxxxx
xxxx
xxxxxx
xxxxx
xxxxxxx
xxxxx
xxxxxxx
xxxxx      xxxx     xxxx       xxxx           xxx
xxxxx      xxxx     xxxx       xxxx           xxx
xxxxx      xxxx     xxxx       xxxx           xxx
xxxxx      xxxx     xxxx       xxxx           xxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxxxxxx
xxxxxxxxxxx
xxxxxxxxxxx
xxxxxxxxxxx
____________________________________________________________________________________________________________________________________
a ECG parameters and results for T Wave, U Wave, and ECG Interpretation displayed at Baseline (i.e., Day 1 pre-dose time point) are the
average and combined overall results.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Data Listing 7. Blood Chemistry Laboratory Results Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 
Normal Range
Patient
Date of
No.
 Treatment  
Visit 
 Visit  Parameter (units)  Result  
Low 
 
High 
 Normal/High/Lowa
Page x of y
Normal/Abnormal CS/
Abnormal NCSb
xxxx
xxxxxx
xxxx
xxxxxx
xxxxxx 
xxxxxx
xxxxxx 
xxxxxx
xxxxxxxxxx (xxx)
xxx
xxx
xxx
xxxxx
xxxxxxxxxx (xxx)
xxx
xxx
xxx
xxxxx
xxxxxxxxxx
xxxxxxxxxx
______________________________________________________________________________________________________________________________________ a
Indicates whether the results of the parameter indicated were within the normal range, lower than the normal range, or higher than the
normal range.
b Indicates whether the results of the parameter indicated were Normal, Abnormal Clinically Significant (CS), and Abnormal Not
Clinically Significant (NCS).
STATKING Clinical Services (month day, year)
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 8. Serology Laboratory Results Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Patient
Date of
No.
 Treatment  
Visit 
 Visit  Parameter (units) 
Result
xxxx
xxxxxx
xxxx
xxxxxx
xxxxxx 
xxxxxx
xxxxxx 
xxxxxx
xxxxxxxxxx (xxx)
xxx
xxxxxxxxxx (xxx)
xxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Data Listing 9. Hematology Laboratory Results Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 
Normal Range
Date of
 Patient No.  Treatment 
 
Visit 
 
Visit 
 
Parameter (units) 
 Result  
Low 
 
High
Page x of y
Normal/High/Lowa
xxxx
xxxxxx
xxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxx
xxxxxxxxxx (xxx)
xxxxxxxxxx (xxx)
xxx
xxx
xxx
xxxxx
xxx
xxx
xxx
xxxxx
______________________________________________________________________________________________________________________________________ a
Indicates whether the results of the parameter indicated were within the normal range, lower than the normal range, or higher than the
normal range.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Listing format repeats for Coagulation and Urinalysis.
Page 91 of 121
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 12. Hearing Assessment Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Date of 
Any changes in hearing
If yes, explain
 Patient No.  Treatment 
 
Visit 
 
Visit 
since last visit?
xxxx
xxxxxx
xxxx
xxxxxx
xxxxxx
xxxxxx
xxx
xxxxxx
xxxxxx
xxx
xxxxxxxxxxx
xxxxxxxxxxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 13. Pharmacokinetic Blood Sample Data Listing
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Dose
Blood Draw
Reason
Time of
Time of
Time of
Patient
Date/     Completed       Not         Time       Blood       Plasma
Aliquot
No.
 Treatment  Visit  
Time 
 
(Y/N)
 Completed  
Point 
 
Sample 
 Extraction  
Freezing
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxx/
xxxxx
xxxx
xxxxx/
xxxxx
xxx
xxxxxxxxx
xxx
xxxxxxxxx
xxxxxxxx
xxxx
xxxx
xxxx
xxxxxxxx
xxxx
xxxx
xxxx
xxxxxxxx
xxxx
xxxx
xxxx
xxxxxxxx
xxxx
xxxx
xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 14. Pharmacokinetic Urine Sample Data Listing
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Urine
Dose
Collection
Reason
Time of
Urine
Time of
Patient
Date/     Completed       Not         Time       Urine       Volume
Aliquot
No.
 Treatment  Visit  
Time 
 
(Y/N)
 completed  
Point 
 
Sample 
(mL)
 
Freezing
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxx/
xxxxx
xxxx
xxxxx/
xxxxx
xxx
xxxxxxxxx
xxx
xxxxxxxxx
xxxxxxxx
xxxx
xxxx
xxxx
xxxxxxxx
xxxx
xxxx
xxxx
xxxxxxxx
xxxx
xxxx
xxxx
xxxxxxxx
xxxx
xxxx
xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 15. Plasma Concentrations Data Listing
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Ibudilast Plasma 
Bumetanide Plasma
Patient
Time
Sample
Concentration
Concentration
No.
 Treatment  Visit  
Point 
 Collected(Y/N)?  Sample Date/ Time 
(units)
        (units)
xxxx
xxxxxx
xxxx
xxxxxx
xxxx 
xxxxxxxx
xxxx
xxxxxxxx
xxxx
xxxx 
xxxxxxxx
xxxx
xxxxxxxx
xxxx
xxxx/xxxx
xxxx/xxxx
xxxx/xxxx
xxxx/xxxx
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 16. Urine Concentrations Data Listing
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Patient
Time
Sample
Sample
Ibudilast Urine
Bumetanide Urine
No.
 Treatment  Visit  Interval  Collected(Y/N)?  
Date/Time 
 Concentration (units)  Concentration (units)
xxxx
xxxxxx
xxxx
xxxxxx
xxxx 
xxxxxxxx
xxxx
xxxxxxxx
xxxx
xxxx 
xxxxxxxx
xxxx
xxxxxxxx
xxxx
xxxx/xxxx
xxxx/xxxx
xxxx/xxxx
xxxx/xxxx
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
xxxxxxx (xxx)
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 17. Plasma Pharmacokinetics Parameters Data Listing
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Patient
No.
 Treatment  
Visit 
 
Drug 
 
Parameter (units) 
 
Value
xxxxx
xxxx
xxxxx
xxxx
xxxxx
xxxx
xxxxx
xxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
xxxxxxxxxxxx(xxx)
xxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 18. Urine Pharmacokinetics Parameters Data Listing
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
Patient
No.
 Treatment  
Visit 
 
Drug 
 
Parameter (units) 
Value
xxxxx
xxxx
xxxxx
xxxx
xxxxx
xxxx
xxxxx
xxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxx
xxxxx
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xxx
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xxx
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xxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 19. C-SSRS Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 
Patient No. 
 Treatment  Visit  
Date 
Question
 Response
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
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xxxx
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____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 20. C-CASA Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 
Patient No. 
 Treatment  Visit  
Date 
Question
 Response
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
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xxxx
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xxxx
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xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 21. OACIS-S Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 
Patient No. 
 Treatment  Visit  
Date 
Question
     Response
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxx
xxxxxxxxxxxxxx
xxxx
xxxxxxxxxxxxxx
xxxx
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xxxx
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xxxx
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STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 22. OACIS-C Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 
Patient No. 
 Treatment  Visit  
Date 
Question
 Response
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxx
General Level of Autism          xxxx
Social Interaction Skills         xxxx
Aberrant/Abnormal Behavior         xxxx
Repetitive and Ritual Behaviors      xxxx
Verbal Communication Skills        xxxx
Nonverbal Communication Skills       xxxx
Hyperactivity and Inattention       xxxx
Anxiety and Fears             xxxx
Sensory Sensitivities           xxxx
Restricted and Narrow Interests      xxxx
General Level of Autism          xxxx
Social Interaction Skills         xxxx
Aberrant/Abnormal Behavior         xxxx
Repetitive and Ritual Behaviors      xxxx
Verbal Communication Skills        xxxx
Nonverbal Communication Skills       xxxx
Hyperactivity and Inattention       xxxx
Anxiety and Fears             xxxx
Sensory Sensitivities           xxxx
Restricted and Narrow Interests      xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
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Data Listing 23. SRS-2 Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Global
Social
Social
Social
Social
 Patient No.  Treatment  Visit  
Date 
 
Time 
 
Score
 Awareness  Cognition  Communication  Motivation  Mannerisms
xxxx
xxxxxx
xxxx
xxxxxx
xxxxxx 
xxxxxx     xxxxxx       xxxx
xxxxxx 
xxxxxx     xxxxxx       xxxx
xxxxxx 
xxxxxx     xxxxxx       xxxx
xxxxxx 
xxxxxx     xxxxxx       xxxx
xxxx         xxxx           xxxx
xxxx         xxxx           xxxx
xxxx         xxxx           xxxx
xxxx         xxxx           xxxx
xxxx          xxxx
xxxx          xxxx
xxxx          xxxx
xxxx          xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 24. SB5 ABIQ Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Abbreviated
IQ Test Performed with
 
Patient No. 
 Treatment 
Date
     IQ Test
 
Last 2 years? (Y/N) 
 FSIQ Score
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 25. NIH-CTB Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Neurological
 
Patient No. 
 Treatment  Visit  
Date 
 Function Domain 
Score
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxxxxxxxxxxxx
xxxx
xxxxxxxxxxxxxx
xxxx
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xxxx
xxxxxxxxxxxxxx
xxxx
xxxxxxxxxxxxxx
xxxx
xxxxxxxxxxxxxx
xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Neurological Function Domain will include the following: Picture Vocabulary Test Raw Score, Pattern Comparison
Processing Speed Test Raw Score, Flanker Inhibitory Control and Attention Test Raw Score, Dimensional Change Card Sort
Test Raw Score, Oral Reading Recognition Test Raw Score, Cognition Crystallized Composite Uncorrected Standard Score,
Cognition Crystallized Composite Age-Corrected Standard Score, Cognition Crystallized National Percentile (Age
Adjusted), and Cognition Crystallized Composite Fully-Corrected T-score.
Listing format repeats for KiTAP.
Page 105 of 121
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 27. ABC-C Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Subscales
Social
Stereotypic
Hyperactive/
Inappropriate
 
Patient No. 
 Treatment  Visit  
Date 
 
Time 
 Irritability  Withdrawal  
Behavior 
 Noncompliance 
Speech
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 28. CSHQ Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 
Patient No. 
 Treatment  Visit  
Date 
Category
        Question
     Response
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
xxxx
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xxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 29. Lactate-Pyruvate Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Date of
Lactate
Pyruvate
L:P
 Patient No.  Treatment  
Visit 
 
Visit
 
(units) 
 
(units) 
 
Ratio
xxxx        xxxxxx
xxxx        xxxxxx
xxxxxxxx
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xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 30. CGI-S/CGI-I Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
 Patient No.  Treatment  
Visit 
 Date of Visit  Severity of Illness  Global Improvement
xxxx        xxxxxx 
xxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxxx
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 31. Medical History Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
MedDRA System Organ Classa/
Patient
MedDRA Preferred Term/
Ongoing?
No.
 Treatment 
CRF Verbatim Term
 Start Date  End Date  
(Y/N)
xxxxxx
xxxxxxx
xxxxxx
xxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxx
xxxxxxx
xxx
______________________________________________________________________________________________________________________________________ a
Medical history terms coded with MedDRA Coding Dictionary Version xxx.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 32. Concomitant Medications Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
WHO Preferred Terma/
Verbatim Drug Name/
Patient
Indication/
Dose
Start
Stop
Ongoing?
 
No. 
 
Treatment 
ATC Level 4 Term
 (units)  Frequency  
Date 
 
Date 
 Route  Indication  
(Y/N)
xxxxxxxx
xxxxxxxx
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/     (xxx)
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/     (xxx)
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxx
xxxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx 
xxxxx
xxxxxxx 
xxxxx
xxxxxxx
xxxxx
xxxxxxx
xxxxx
______________________________________________________________________________________________________________________________________ a
Concomitant medication coded with WHO Coding Dictionary xxxxxxxxx.
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 33. Physical Exam Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
If Abnormal,
Patient
Date
Clinically
 
No. 
 Treatment  Visit  Conducted  
Body System 
 
Result
 Significant (Y/N)? 
Abnormality
xxxx
xxxxxx 
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
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xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 34. Study Drug Administration Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Morning Dose
Reason Morning
Patient
Administered
Dose Not
Date Morning Dose 
Time Morning Dose
 
No. 
 Treatment  Visit 
(Y/N)?
     Administered
 
Administered 
Administered
xxxx      xxxxxx     xxxx        xxx
xxxx        xxx
xxxx      xxxxxx     xxxx        xxx
xxxx        xxx
xxxxxxxxxxxxx
xxxxxxxxxxxxx
xxxxxxxxxxxxx
xxxxxxxxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 113 of 121
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 35. Drug Accountability Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Did Patient
Take Study
Study Drug 
Date Study 
Number of 
Study Drug 
Date Study 
Number of 
Medication
Patient
Dispensed
Drug
Pills
Returned
Drug
Pills
as Directed 
If No, Please
 
No. 
 Treatment  Visit  Kit Number  Dispensed  Dispensed  Kit Number  
Returned 
 
Returned 
 
(Y/N)? 
Specify
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxxxx
xxxx
xxxxxxx
xxxx
xxxx
xxxxxxx
xxxx
xxxxxxx
xxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx         xxx
xxxxxxx         xxx
xxxxxxx         xxx
xxxxxxx         xxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Page 114 of 121
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 36. Urine Pregnancy Test Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Reason
Date and Time
Result of
Pregnancy Test
Pregnancy Test
Pregnancy Test 
of Pregnancy
Pregnancy
 Patient No.  Treatment 
Visit
 Required? (Y/N)  Performed? (Y/N)  Not Performed 
Test
      Test
xxxx         xxxxxx         xxxxxx           xxxxxx
xxxxxx           xxxxxx
xxxx         xxxxxx         xxxxxx           xxxxxx
xxxxxx           xxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
xxxxxxxxxx
xxxxxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 37. Protocol Deviations Data Listing
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Patient
Date of
Deviation Major or
No.
     Treatment
     Deviation
 
Deviation Description 
Minor
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxxx
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxx
xxxxxxxxxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
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Statistical Analysis Plan
STP1-C004
Page x of y
Data Listing 38. Patients Excluded from Safety Population Data Listing
STALICLA SA - Study No. STP1-C004
All Patients (N=xxx)
Patient No.
     Treatment
      Reason for Exclusion
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxxx
xxxx
xxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxxxxxxxxxx
______________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Data listing will be repeated for the PK and Exploratory populations.
Page 117 of 121
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Screening
Day 1 Pre-Dose
Day 1 Post-Dose
Day 7
Day 14 Pre-Dose
Day 14 Post-Dose
a
D y 28
Screening
Day 1 Pre-Dose
Day 1 Post-Dose
Day 7
Day 14 Pre-Dose
Day 14 Post-Dose
Day 28
Screening
Day 1 Pre-Dose
Day 1 Post-Dose
Day 7
Day 14 Pre-Dose
Day 14 Post-Dose
Day 28
Systolic Blood Pressure (mmHg)
Statistical Analysis Plan
STP1-C004
Page x of y
Figure 1. Orthostatic Vital Signs - Spaghetti Plot of Systolic Blood Pressure by Patient, Time and
Treatment
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
Treatment = Placebo
Treatment = STP1-10 mg
Treatment = STP1-5 mg
140
130
120
110
100
90
Visit
Patient ID
10
13
16
17
8
12
18
2
5
6
1
3
4
7
9
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Figure format will be repeated for Orthostatic Vital Signs – Diastolic Blood Pressure (Figure 2), Orthostatic Vital
Signs – Heart Rate (Figure 3), ECG Parameters – Heart Rate (Figure 4), and ECG Parameters – QTcF (Figure 5).
Note: the axis values and labels will vary depending on the figure generated and the data in the database. Patient ID’s
will be displayed as in the study database.
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Statistical Analysis Plan
STP1-C004
Page x of y
Figure 6. Blood Chemistry - Spaghetti Plot of Sodium by Patient, Time and Treatment
STALICLA SA - Study No. STP1-C004
Safety Population (N=xxx)
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Figure format will be repeated for Figure format will be repeated for Blood Chemistry – Chloride (Figure 7), Blood
Chemistry – Calcium (Figure 8), Blood Chemistry – Magnesium (Figure 9), Blood Chemistry – Phosphate (Figure 10), Blood
Chemistry – Potassium (Figure 11), Hematology – Platelet Count (Figure 12), and Biomarker – L:P Ratio (Figure 13). Note:
the axis values and labels will vary depending on the figure generated and the data in the database. Patient ID’s will
be displayed as in the study database.
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Concentration (units)
Statistical Analysis Plan
STP1-C004
Page x of y
Figure 14. Patient Plasma Concentration Levels of Ibudilast for Treatment Group = 5mg Ibudilast– Linear
Scale – Days 1-28
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
250
200
150
100
50
0
0
50
100
150
200
250
300
350
400
450
500
550
600
650
Time in Hours (Actual)
Patient ID
10
11
12
15
18
19
3
4
9
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Figure format will be repeated for the 10mg ibudilast treatment group for ibudilast concentration levels, for the 5mg
and 10mg ibudilast treatment groups for bumetanide concentration levels. These figures will be repeated in the semi-
logarithmic scale for each combination of treatment group and study drug concentration level.
Note: the axis values and labels in the figure may vary. Patient ID’s will be displayed as in the study database.
Page 120 of 121
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Day 1 Pre-AM Dose
Day 1 0.25h
Day 1 0.5h
Day 1 1h
Day 1 2h
Day 1 4h
Day 1 6h
Day 7 Pre-AM Dose
Day 14 Pre-AM Dose
Day 14 0.25h
Day 14 1h
Day 14 2h
Day 14 4h
Day 14 6h
Day 14 8h
Day 14 10h
Day 14 24h
Day 14 30h
Day 16
Day 17
Day 18
Day 28
Concentration (units)
Statistical Analysis Plan
STP1-C004
Page x of y
Figure 22. Mean Plasma Concentration Levels of Ibudilast for Treatment Group = 5mg Ibudilast – Linear
Scale – Days 1-28
STALICLA SA - Study No. STP1-C004
PK Population (N=xxx)
200
150
100
50
0
Time in Hours (Planned)
Treatment
STP1-5mg
____________________________________________________________________________________________________________________________________
STATKING Clinical Services (month day, year)
Source Program: xxxxxxx.sas
Figure format will be repeated for the 10mg ibudilast treatment group for ibudilast concentration levels, for the 5mg
and 10mg ibudilast treatment groups for bumetanide concentration levels. These figures will be repeated in the semi-
logarithmic scale for each combination of treatment group and study drug concentration level. 
Note:
the axis values and labels in the figure may vary.
Page 121 of 121
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February 17, 2022


Certificate Of Completion
Envelope Id: 8C4D2141974A4A22BCBAF80DF8665E44
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Time Zone: (UTC-05:00) Eastern Time (US & Canada)                                                                                  mtetrick@statkingclinical.com
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Signature ID:
D32195A3-119A-4616-B959-EFE41655886B
Using IP Address: 74.219.206.115
Timestamp
Sent: February 18, 2022 | 08:57
Resent: February 18, 2022 | 10:08
Viewed: February 18, 2022 | 10:08
Signed: February 18, 2022 | 10:09
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab):
I approve this document
Electronic Record and Signature Disclosure:
Accepted: February 18, 2022 | 10:08
ID: 4adae6cc-21f4-4b6a-9455-3cc8b9262a35
Mark Tetrick
mtetrick@statkingclinical.com
Clinical Trial Manager
Statking Consulting, Inc.
Security Level: Email, Account Authentication
(Required)
Signature Adoption: Uploaded Signature Image
Signature ID:
FF75403B-BD93-466E-ABA9-DFBDFE59F935
Using IP Address: 216.196.246.214
Sent: February 18, 2022 | 08:57
Viewed: February 18, 2022 | 08:57
Signed: February 18, 2022 | 08:58
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab):
I approve this document
Electronic Record and Signature Disclosure:
Not Offered via DocuSign
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Timestamps
February 18, 2022 | 08:57
February 18, 2022 | 08:57
February 18, 2022 | 08:58
February 18, 2022 | 10:09
Timestamps
Electronic Record and Signature Disclosure


Electronic Record and Signature Disclosure created on: June 29, 2020 | 16:44
Parties agreed to: Baltazar Gomez-Mancilla, Brian Kovacic, Lori Christman
ELECTRONIC RECORD AND SIGNATURE DISCLOSURE
From time to time, Statking Consulting, Inc. (we, us or Company) may be required by law to
provide to you certain written notices or disclosures. Described below are the terms and
conditions for providing to you such notices and disclosures electronically through the DocuSign
system. Please read the information below carefully and thoroughly, and if you can access this
information electronically to your satisfaction and agree to this Electronic Record and Signature
Disclosure (ERSD), please confirm your agreement by selecting the check-box next to ‘I agree to
use electronic records and signatures’ before clicking ‘CONTINUE’ within the DocuSign
system.
Getting paper copies
At any time, you may request from us a paper copy of any record provided or made available
electronically to you by us. You will have the ability to download and print documents we send
to you through the DocuSign system during and immediately after the signing session and, if you
elect to create a DocuSign account, you may access the documents for a limited period of time
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to
send you paper copies of any such documents from our office to you, you will be charged a
$0.00 per-page fee. You may request delivery of such paper copies from us by following the
procedure described below.
Withdrawing your consent
If you decide to receive notices and disclosures from us electronically, you may at any time
change your mind and tell us that thereafter you want to receive required notices and disclosures
only in paper format. How you must inform us of your decision to receive future notices and
disclosure in paper format and withdraw your consent to receive notices and disclosures
electronically is described below.
Consequences of changing your mind
If you elect to receive required notices and disclosures only in paper format, it will slow the
speed at which we can complete certain steps in transactions with you and delivering services to
you because we will need first to send the required notices or disclosures to you in paper format,
and then wait until we receive back from you your acknowledgment of your receipt of such
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to
receive required notices and consents electronically from us or to sign electronically documents
from us.
All notices and disclosures will be sent to you electronically


Unless you tell us otherwise in accordance with the procedures described herein, we will provide
electronically to you through the DocuSign system all required notices, disclosures,
authorizations, acknowledgements, and other documents that are required to be provided or made
available to you during the course of our relationship with you. To reduce the chance of you
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required
notices and disclosures to you by the same method and to the same address that you have given
us. Thus, you can receive all the disclosures and notices electronically or in paper format through
the paper mail delivery system. If you do not agree with this process, please let us know as
described below. Please also see the paragraph immediately above that describes the
consequences of your electing not to receive delivery of the notices and disclosures
electronically from us.
How to contact Statking Consulting, Inc.:
You may contact us to let us know of your changes as to how we may contact you electronically,
to request paper copies of certain information from us, and to withdraw your prior consent to
receive notices and disclosures electronically as follows:
To contact us by email send messages to: mtetrick@statkingclinical.com
To advise Statking Consulting, Inc. of your new email address
To let us know of a change in your email address where we should send notices and disclosures
electronically to you, you must send an email message to us at mtetrick@statkingclinical.com
and in the body of such request you must state: your previous email address, your new email
address. We do not require any other information from you to change your email address.
If you created a DocuSign account, you may update it with your new email address through your
account preferences.
To request paper copies from Statking Consulting, Inc.
To request delivery from us of paper copies of the notices and disclosures previously provided
by us to you electronically, you must send us an email to mtetrick@statkingclinical.com and in
the body of such request you must state your email address, full name, mailing address, and
telephone number. We will bill you for any fees at that time, if any.
To withdraw your consent with Statking Consulting, Inc.
To inform us that you no longer wish to receive future notices and disclosures in electronic
format you may:


i. decline to sign a document from within your signing session, and on the subsequent page,
select the check-box indicating you wish to withdraw your consent, or you may;
ii. send us an email to mtetrick@statkingclinical.com and in the body of such request you must
state your email, full name, mailing address, and telephone number. We do not need any other
information from you to withdraw consent.. The consequences of your withdrawing consent for
online documents will be that transactions may take a longer time to process..
Required hardware and software
The minimum system requirements for using the DocuSign system may change over time. The
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.
Acknowledging your access and consent to receive and sign documents electronically
To confirm to us that you can access this information electronically, which will be similar to
other electronic notices and disclosures that we will provide to you, please confirm that you have
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for
your future reference and access; or (ii) that you are able to email this ERSD to an email address
where you will be able to print on paper or save it for your future reference and access. Further,
if you consent to receiving notices and disclosures exclusively in electronic format as described
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before
clicking ‘CONTINUE’ within the DocuSign system.
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm
that:
x
You can access and read this Electronic Record and Signature Disclosure; and
x
You can print on paper this Electronic Record and Signature Disclosure, or save or send
this Electronic Record and Disclosure to a location where you can print it, for future
reference and access; and
x
Until or unless you notify Statking Consulting, Inc. as described above, you consent to
receive exclusively through electronic means all notices, disclosures, authorizations,
acknowledgements, and other documents that are required to be provided or made
available to you by Statking Consulting, Inc. during the course of your relationship with
Statking Consulting, Inc..