Clinical trial NCT02410902
Conditions: Autism
Keywords: Autism
Sponsor: Curemark
Start date: 2015-05-13; Completion date: 2017-12-22
Enrollment: 190 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether CM-AT is safe and effective in treating the core symptoms of autism in children with all levels of fecal chymotrypsin.

Detailed description:
Autism is clearly a significant cause of disability in the pediatric population. Many children with Autism exhibit impaired protein digestion which may or may not manifest in self-restricted diets. The inability to digest protein affects the availability of essential amino acids in the body. CM-AT is designed to enhance protein digestion thereby potentially restoring the pool of essential amino acids. Essential amino acids play a critical role in the expression of several genes important to neurological function and serve as precursors to key neurotransmitters such as serotonin and dopamine. CM-AT is a proprietary enzyme that is designed as a granulated powder taken three times daily.

Arms: arm 1: Active substance in single unit dose powder arm 2: Placebo powder of inactive substance
Interventions: intervention 1: CM-AT intervention 2: PLACEBO
Intervention descriptions: intervention 1: Single unit dose powder of active substance (CM-AT) administered 3 times per day for 90 days intervention 2: Single unit dose powder of non-active substance administered 3 times per day for 90 days

Protocol documents:
Prot_000.pdf: 
CUREMARK (CM-AT) 
Protocol: 00103/Autism 
NCT02410902 
NCT02410902 
IND 73,059 
CONFIDENTIAL 
Protocol ID:00103 / Autism 
A Double Blind Randomized Placebo Controlled Study of CM-AT for the 
Treatment of Autism in Children With All Levels of Fecal Chymotrypsin 
Document Date: 17 February 2017 
Upload Date: 2 May 2021  


CUREMARK (CM-AT) 
 
Amendment 5 
Protocol: 00103/Autism 
 
February 17, 2017 
 
IND 73,059 
 
CONFIDENTIAL 
 
STUDY SYNOPSIS 
Title: 
A Double Blind Randomized Placebo Controlled Study of CM-AT for the 
Treatment of Autism in Children With All Levels of Fecal Chymotrypsin 
Protocol Number: 
00103 
Development Phase: 
III 
Number of Study Centers: 
Approximately 35 clinical sites in the United States 
Number of Subjects:  
Approximately three-hundred (300) patients will be randomized 
Estimated Study Length: 
Approximately 36 months, contingent upon meeting accrual targets 
Duration of Treatment and 
Study Participation: 
12 weeks, following a 2-week blinded drug run-in period. 
Patient Population: 
The study population will consist of children, both males and females, between 3 and 
8 years of age inclusive at the time of consent, who are diagnosed with Autistic 
Disorder (AD) by DSM-IV-TR and ADI-R, and are screened by the SCQ.  
Test Product, Dose, and 
Mode of Administration: 
CM-AT (pancreatic enzyme concentrate encapsulated in hydrogenated soybean oil) 
900mg 3x daily sprinkled over food. To be taken with a meal or large snack.  
Study Methodology: 
This is a Phase III multi-center, randomized, double-blind, placebo-controlled study 
evaluating the efficacy and safety of CM-AT in pediatric patients with autism at all 
levels of fecal chymotrypsin. 
Study Design: 
In this Phase III multi-center, randomized, double-blind, placebo-controlled study, 
all study participants must have an initial ABC-I score of > 11 and a diagnosis of 
Autistic Disorder as demonstrated by the DSM-IV-TR and by the ADI-R. Subjects 
will also be screened using the SCQ and must achieve a score of > 15 to be 
considered eligible. Those subjects who qualify will be given a two week blinded 
drug run-in. Subjects will then be evaluated for compliance and re-evaluated for level 
of Irritability with the ABC-I scale. If their score on the ABC-I scale has increased 
by 30% or more or decreased by 30% or more, or is <9, they will be discontinued 
from the study.  
If all entry criteria are met, the subject will be randomized at the Visit 1/Baseline 
visit.  
Study Rationale: 
 
 
 
 
 
 
 
 
 
 
Sponsor studies have demonstrated the clinical potential of CM-AT formulations in 
treating core and non-core autism symptoms in subjects with autism ages 3-8 with 
low fecal chymotrypsin (FCT) levels when dosed at a level of 900mg 3x daily.  
This study will further quantify the changes in the target population as measured by 
standardized behavioral and quality of life tests, physiological measures, as well as 
characterize the efficacy and safety of the product. The study will further delineate 
the efficacy in a population that is biomarker negative (>12.6U/g of fecal 
chymotrypsin) who have autism.  
The data from this study will help determine safety and efficacy of CM-AT in 
pediatric patients with autism of both biomarkers positive and negative. 
 


CUREMARK (CM-AT) 
 
Amendment 5 
Protocol: 00103/Autism 
 
February 17, 2017 
 
IND 73,059 
 
CONFIDENTIAL 
 
This study will be undertaken in children whose Aberrant Behavior Checklist: 
subscale for Irritability / Agitation (ABC-I) >11 is at Screening/Enrollment. This 
number represents those who fall above approximately 0.5 std deviations from the 
mean seen in the Sponsor’s 00101 study. 
 
Safety: 
Fecal globin levels, the presence of occult blood, α1-antitrypsin, and weight loss will 
be used to monitor the safety and tolerability of CM-AT.  
• 
The presence of fecal globin may indicate bleeding in the large intestine, 
while a positive occult blood may indicate bleeding along the entire 
gastrointestinal tract.  
• 
An increase in α1-antitrypsin may signal an immunologic response of the 
colonic mucosa, leading to potential formation of colonic strictures. 
• 
Weight loss may be indicative of malabsorption.  
• 
All of the above markers may be linked due to gastrointestinal irritation, but 
have not specifically been noted thus far in the Sponsor’s experience with 
enzyme therapies.  
• 
Parental input at the standard visits, diary entries, and other assessments 
will also be used to monitor safety.  
• 
Of 468 children with autism given pancreatic enzymes in early Sponsor 
studies, and in the Phase III clinical studies (00101 & 00102), in which 180 
were initially enrolled, and 140 continued into Open-Label, the drug 
appeared to be safe and well-tolerated with no related SAE experienced in 
either study the duration of which has been greater than 288 weeks. 
Primarily, AEs appeared to be GI in nature. 
Rating Instruments: 
ABC, SRS-2 (Preschool or School Age), PedsQL Inventory – Family Impact 
Module, CGI (S), CGI (I). 
Other measures: DSM-IV, SCQ and ADI-R. 
Study Objectives: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Endpoint (outcome) measurements for treatment with CM-AT versus placebo in 
biomarker negative and positive subjects will be analyzed as described in Statistical 
Considerations. 
 
PRIMARY ENDPOINT MEASUREMENTS 
• 
Aberrant Behavior Checklist: subscale of Irritability/Agitation   (ABC-I) 
at FCT levels < 12.6 
 
SECONDARY ENDPOINT MEASUREMENTS 
• 
Aberrant Behavior Checklist: subscale of Lethargy/Social Withdrawal 
(ABC-L) at FCT levels < 12.6 
 
EXPLORATORY ENDPOINT MEASUREMENTS 
• 
Behavioral changes:    
o 
Aberrant Behavior Checklist: subscale of Irritability/Agitation 
(ABC-I) at FCT levels > 12.6 
o 
Aberrant Behavior Checklist: subscale of Lethargy/Social 
Withdrawal (ABC-L) at FCT levels > 12.6 
o 
Aberrant Behavior Checklist: subscale of Hyperactivity (ABC-H) 
at FCT levels < 12.6 
o 
Aberrant Behavior Checklist: subscale of Total (ABC-T) at FCT 
levels < 12.6 


CUREMARK (CM-AT) 
 
Amendment 5 
Protocol: 00103/Autism 
 
February 17, 2017 
 
IND 73,059 
 
CONFIDENTIAL 
 
o 
Aberrant Behavior Checklist: subscale of Stereotypy (ABC-S) at 
FCT levels < 12.6 
o 
Aberrant Behavior Checklist: subscale of Inappropriate Speech 
(ABC-IS) at FCT levels < 12.6 
o 
Aberrant Behavior Checklist: subscale of Irritability/Agitation 
(ABC-I) at all FCT levels 
o 
Aberrant Behavior Checklist: subscale of Lethargy/Social 
Withdrawal (ABC-L) at all FCT levels 
o 
Aberrant Behavior Checklist: subscale of Hyperactivity (ABC-H) 
at all FCT levels 
o 
Aberrant Behavior Checklist: subscale of Total (ABC-T) at all 
FCT levels 
o 
Aberrant Behavior Checklist: subscale of Stereotypy (ABC-S) at 
all FCT levels 
o 
Aberrant Behavior Checklist: subscale of Inappropriate Speech 
(ABC-IS) at all FCT levels 
o 
Pediatric Quality of Life Inventory (PedsQL) 
o 
CGI-I, CGI-S 
o 
SRS-2 
 
• 
GI health:  
o Stool Test Panel 
o Weight gain/loss 
 
SAFETY ENDPOINT MEASUREMENTS 
• 
Adverse Events 
• 
Negative change in weight, if clinically inappropriate based upon standard 
scales 
• 
Incidence and/or change in clinical laboratory results for the following: 
o 
Fecal globin / Fecal occult blood 
o 
Stool pH  
o 
Presence or continued growth of pathogens, as indicated by stool 
panel antigen/toxin tests 
o 
Elevated α1-antitrypsin levels 
o 
Change in bowel habits due to colitis 
 
Inclusion Criteria: 
1. Age between 3 and 8 years, inclusive at the time of consent 
2. If the child is 7 years of age or older, understand and sign a written assent 
form or give witnessed verbal assent, if mental capacity allows 
3. The parent or guardian of the subject must be able to understand and sign 
a written informed consent document, a waiver of assent document (in 
some cases), and be able to read English 
4. Meets the current Diagnostic and Statistical Manual for Mental Disorders 
(DSM-IV-TR) diagnostic criteria for Autistic Disorder (AD), screened by 
the SCQ and confirmed by the ADI-R.  
5. Aberrant Behavior Checklist: subscale of Irritability/Agitation (ABC-I) 
score >11.0  
 


CUREMARK (CM-AT) 
 
Amendment 5 
Protocol: 00103/Autism 
 
February 17, 2017 
 
IND 73,059 
 
CONFIDENTIAL 
 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from study 
participation: 
 
1. Patient weighing < 13kg 
2. Allergy to porcine products 
3. Previous sensitization or allergy to trypsin, pancreatin, or pancrelipase 
4. History of severe head trauma, as defined by loss of consciousness or 
hospitalization, skull fracture or stroke. 
5. Seizure within the last year prior to enrollment, or the use of seizure 
medications either at present or in the past. 
6. Diagnosed with any of the following:  
a. 
HIV-positive  
b. Cancer (regardless of remission state) 
c. 
Cerebral palsy 
d. Muscular dystrophy 
e. 
Known genetic disorder or abnormality  
f. 
Blood dyscrasia 
g. Ongoing gastrointestinal disease (e.g., Crohn’s Disease, Celiac 
Disease. Not intended to exclude gastrointestinal issues, such as 
constipation or diarrhea not associated with another GI disease 
diagnosis.) 
h. Endocrine disorder (e.g., hypothyroidism, diabetes) 
i. 
Pancreatic disease (endocrine or exocrine) 
j. 
Previous diagnosis with or hospitalization for significant co-morbid 
psychiatric conditions such as depression, bipolar or other 
psychiatric disease (Not intended to exclude ADHD, anxiety 
associated with autism or obsessive-compulsive disorder)  
k. Any diagnosis of sleep or wakefulness disorder, such as narcolepsy, 
hypo or hypersomnia. 
7. Evidence or history of severe, moderate or uncontrolled systemic disease, 
or history of metabolic disorders (e.g., amino acid deficiencies, 
hypoketosis)  
8. Any co-morbid condition which in the Investigator’s or Medical 
Director’s opinion makes it undesirable for the subject to participate in the 
trial or would jeopardize compliance with the protocol. 
9. Supplementation with any of the following within 30 days of entering the 
study: 
a. 
Any enzyme product or a product containing pancreatic/digestive 
enzymes of plant or animal origin 
b. Pancreatin, thyroid, or adrenal extracts, either synthetic, plant or 
animal-based 
c. 
Essential fatty acids, omegas, or other supplement containing these 
products (does not require a washout) 
d. Amino acids, or amino acid containing products 
e. 
Any secretin product including transdermal, oral, or injectable 
f. 
Vitamin B12/folate either oral or injectable (Allowable as part of a 
multivitamin.  Folate not to exceed 400 mcg, B12 not to exceed 12 
mcg). No injectables allowed of either. 


CUREMARK (CM-AT) 
 
Amendment 5 
Protocol: 00103/Autism 
 
February 17, 2017 
 
IND 73,059 
 
CONFIDENTIAL 
 
g. Chelating agents / chelation therapy 
h. Any other investigational drug or therapy, oncology drug, anti-
helminthic, or anti-yeast drug 
i. 
Off-label medications 
10. Asthma, when medication (oral, inhaled, or injectable) is given on a daily 
basis or is necessary >3 times per week.  
11. Ongoing dietary restriction for allergy or other reasons except nut allergies 
(lactose-free allowable) 
12. Inability to ingest the study drug 
13. Inability to follow the prescribed dosing schedule 
14. Subjects who are likely to experience significant changes in their ongoing 
psychosocial or medical treatments for autism over the course of the trial 
(e.g., initiation of new behavioral therapy, initiation of new medication or 
alternative treatment). Minor changes in ongoing treatment (e.g., missed 
therapy sessions due to holiday/vacation; planned break in therapy due to 
school holidays) will not be considered significant. 
15. Use of any stimulant medication or other medication given for ADHD 
must be discontinued 5 days prior to entering the study (Vayarin requires a 
30-day washout) 
16. Subjects taking an SSRI must be on a stable dose for a minimum of 30 
days prior to entering the study. 
17. History of premature birth < 35 weeks gestation 
18. Prior history of stroke in utero, or other intrauterine insult 
 
Additional Inclusion Criteria 
at Visit 1/Baseline for 
Randomization:  
The subject must meet the following additional inclusion criteria upon returning for 
Visit 1/Baseline in order to be randomized: 
1. The subject must have demonstrated IP compliance that is >50% during 
the 2-week blinded drug run-in period 
2. Upon retest at Visit 1/Baseline, the subject’s score on the ABC-I must have 
increased or decreased by less than 30%, and also must be >9 
3. Subjects must continue to meet all inclusion/exclusion criteria 
 
 


CUREMARK (CM-AT) 
 
Amendment 5 
Protocol: 00103/Autism 
 
February 17, 2017 
 
IND 73,059 
 
CONFIDENTIAL 
 
 
Statistical 
Considerations: 
 
The sample size is based on (a) the primary efficacy variable of the change from 
baseline to week 12 for the Aberrant Behavior Checklist (ABC) subscale for 
Irritability; (b) the primary analysis set of low-level fecal chymotrypsin  (FCT) ≤ 
12.6 Units/gram randomized subjects; and (c) a 1:1 randomization scheme.  
Assuming a mean ± standard deviation decrease in ABC Irritability from baseline to 
week 12 of 3.7 ± 7 for CM-AT and 0.6 ± 5 for Placebo, a sample size of 82 evaluable 
low-level subjects per treatment group yields 90% power to declare a statistically 
significant difference between treatments at a two-sided 0.05 level of significance.  
Assuming 15% premature withdrawal, 97 low-level subjects will be randomized.  In 
order to achieve 97 randomized low- level subjects per group, a total of 162 subjects 
per group will be randomized (based on previous data indicating 60% of autistic 
children are low-level).     
Primary analyses (assessing CM-AT vs. Placebo difference) on change from baseline 
to week 12 will be estimated from a Mixed Model Repeated Measures (MMRM) across 
all visits assuming the unstructured within-subject correlation structure. Included in the 
model will be the main effects of randomized treatment group, visit, baseline ABC 
irritability, study center and the treatment-by-visit interaction effect.  Analyses with and 
without imputation for missing data will be performed. 
If statistical significance, in favor of CM-AT, is shown on the primary efficacy 
endpoint in the primary analysis set of low-level randomized patients (FCT ≤ 12.6 
Units/gram), the study will be considered to be a success statistically. The secondary 
efficacy variable is change from baseline to week 12 in ABC Lethargy/ Social 
Withdrawal (ABC-L) of low-level randomized patients (FCT ≤ 12.6 Units/gram). 
As an exploratory analysis, the MMRM analyses will be repeated on the ABC-I and 
ABC-L for the non-low-level FCT randomized patients (FCT > 12.6 Units/gram) 
As an additional exploratory analysis, the above MMRM analyses will be repeated on 
the ABC-I and ABC-L on all randomized patients in a similar manner as for the low-
level randomized patients. 
For safety, fecal globin levels, the presence of occult blood, α1-antitrypsin, and weight 
loss will be used to monitor the safety and tolerability of CM-AT.  These safety 
measures will be presented descriptively by treatment group.  No formal statistical 
comparisons will be carried out. 
 
  

SAP_001.pdf: 
CUREMARK (CM-AT) 
 
 
SAP: 00103/Autism 
 
 
 
 
 
 
 
NCT02410902 
 
 
NCT02410902 
IND 73,059 
 
CONFIDENTIAL 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol ID:00103 / Autism 
 
 
A Double Blind Randomized Placebo Controlled Study of CM-AT for the 
Treatment of Autism in Children With All Levels of Fecal Chymotrypsin 
 
 
 
Document Date: 27 December 2017 
Upload Date: 2 May 2021  
 




Curemark, LLC 
 
December 27, 2017 
Protocol No. 00103 Autism 
 
Statistical Analysis Plan                                                                                                                  Final 2.0 
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TABLE OF CONTENTS 
1.  Study Objectives ........................................................................................................ 3 
2.  Study Design .............................................................................................................. 3 
3.  Study Analysis Sets ................................................................................................... 4 
4.  Test product, Dose and Mode of Administration ....................................................... 6 
5.  Demographics, Other Baseline Characteristics (other than efficacy and safety 
variables), Study Drug Compliance ........................................................................... 6 
6.  Efficacy Variables ...................................................................................................... 7 
7.  Safety Parameters ....................................................................................................... 9 
8.  Statistical Methodology ........................................................................................... 10 
9.  Interim Efficacy Analysis ........................................................................................ 18 
10.  Software ................................................................................................................. 19 
Scoring of the Aberrant Behavior Checklist (ABC) ..................................................... 20 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.  Study Objectives 
To examine children with autism at all levels of fecal chymotrypsin using the 
Aberrant Behavior Checklist.  
 
Endpoint (outcome) measurements to determine efficacy of treatment with CM-
AT versus placebo for changes in the Aberrant Behavior Checklist subscale for 
Irritability/Agitation (ABC-I) between Baseline (defined as score at Screening 
Part 1 for efficacy assessments; in the event a subject has more than one 
Screening Part 1 value, the value to be used will be the last value of the variable 
measured prior to start of randomized treatment) and Week 12 visit and changes 
in the Aberrant Behavior Checklist subscale for Lethargy/Social Withdrawal 
(ABC-L) between Baseline and Week 12 of treatment. 
 
To continue to monitor the safety of CM-AT in this population of children. 
 
2.  Study Design 
This is a Phase III, multi-center, randomized, double-blind, placebo-controlled 
study of approximately 300 subjects diagnosed with autism from approximately 
35 clinical sites in the United States. Subjects will be between 3 and 8 years of 
age (inclusive) at the time of consent. All study participants must have an initial 
ABC-I score > 11 and a diagnosis of Autistic Disorder as demonstrated by the 
Diagnostic and Statistical Manual for Mental Disorders IV Text Revision (DSM-
IV-TR) and by the Autistic Diagnostic Interview – Revised (ADI-R). Subjects 
will also be screened using the Social Communication Questionnaire (SCQ) and 
must achieve a score > 15 to be considered eligible.  
 
After initial screening criteria are met, including the diagnosis of Autistic 
Disorder as demonstrated on the DSM-IV-TR, SCQ and ADI-R, the study 
participants will be administered the ABC. If their ABC-I score is greater than or 
equal to 11 (≥ 11) they can be enrolled and given a two-week initial blinded 
placebo run-in. At the end of the run-in, subjects will be evaluated and 
randomized if all inclusion criteria are satisfied.  
 
The compliance and inclusion criteria required for randomization are: 1) subjects 
must take the study drug on the prescribed regimen and 2) continue to meet 
inclusion criteria. At the Visit 1 Visit, they will be reevaluated for their level of 
Irritability/Agitation with the ABC-I scale. If a subject’s score on the ABC-I scale 
has increased or decreased by 30% or more, or is <9 on the retest, they will be 
discontinued from the study and not randomized. Qualified subjects can be 
randomized into the study if they meet all inclusion/exclusion criteria.  
 
After enrolling in the study at a clinical site, subjects ultimately randomized to 
treatment will receive study drug or placebo three times daily with food for a 


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Protocol No. 00103 Autism 
 
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period of 12 weeks. Parents will keep a missed dose log. Subjects will be seen at 
Week 2, 4, 6, 8, 10, and 12, post-randomization. Standardized measures of 
behavior, health, and quality of life will be utilized. In addition, measures of 
overall health including growth and weight will be obtained. 
 
Subjects will be randomized in a 1:1 ratio to CM-AT or Placebo (both biomarker 
negative (>12.6 U/g) and positive (≤12.6 U/g) will be included). Randomization 
will be based upon study drug vs placebo. 
 
 
Subjects will be randomized to ensure 82 subjects per study arm of the low-level 
fecal chymotrypsin (FCT) children are evaluable for the primary statistical 
analysis (treatment comparison on the primary endpoint of change in ABC 
irritability from Baseline to Week 12 on the primary analysis set of children with 
FCT ≤12.6 in randomized subjects). The FCT value used in determination of 
whether the patient has FCT ≤ 12.6 is the Screening Part 1 value; if the patient has 
more than one screening FCT, the last FCT measured prior to randomization will 
be used to determine whether the patient has FCT ≤ 12.6.  It is anticipated that 
each site will enroll approximately 3 to 5 subjects per month and the study will be 
open for a period of twelve months. A power recalculation may be performed 
midway through Study Protocol 00103 to determine if sufficient numbers of 
biomarker negative children have been enrolled.  
 
 
A subject may enroll in Study Protocol 00104 Open Label Extension after 
successfully completing Week 12 of Study Protocol 00103.  The analyses of data 
collected in Study Protocol 00104 Open Label Extension will be discussed in a 
separate analysis plan. 
 
3.  Study Analysis Sets 
One-hundred sixty-two (162) subjects will be randomized per treatment arm, or 
324 subjects total.  These subjects will be randomized from approximately 35 
sites throughout the United States. Approximately 350 subjects will be enrolled 
into the placebo run-in period to ensure that 324 will be randomized. At the 
completion of the two-week placebo run-in, the subject will be assessed for 
compliance and ABC-I scores. If a subject’s score on the ABC-I scale has 
increased or decreased by 30% or more, or is <9 on the retest, they will be 
discontinued from the study and not randomized. 
 
The study population will consist of children, both males and females, between 3 
and 8 years of age inclusively at the time of consent. All study participants must 
have an initial ABC-I score of >11 and a diagnosis of Autistic Disorder as 
demonstrated by the DSM-IV-TR and by the ADI-R. Subjects will also be 
screened using the SCQ and must achieve a score of >15 to be considered 
eligible. 
 


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The following populations form the basis of the analysis sets that will be included 
in efficacy and safety analyses (not listed in order of analysis below.  For order of 
analysis see Section 6.0): 
 
Intent-to-Treat (ITT): All randomized subjects who received study drug and had 
at least one post-Baseline ABC-I assessment.  
 
Low-level FCT ITT: All randomized subjects with pathologically low levels of 
FCT (≤12.6 U/g) who received study drug and had at least one post-Baseline 
ABC-I assessment. Subjects are analyzed under the treatment to which they are 
randomized.  This is the primary analysis population for efficacy. 
 
Non-Low-Level FCT (FCT >12.6) ITT: All non-low-level (FCT >12.6 U/g) 
randomized subjects who received study drug and had at least one post-Baseline 
ABC-I assessment. Subjects are analyzed under the treatment to which they are 
randomized. This is an exploratory analysis population for efficacy. 
 
All Randomized: All randomized subjects.  This is an exploratory analysis 
population for efficacy.  Subjects are analyzed under the treatment to which they 
are randomized.  
 
Low-level FCT All Randomized Subjects: All randomized subjects with 
pathologically low levels of FCT (≤12.6 U/g). This is a population for use in a 
sensitivity analysis of efficacy. Subjects are analyzed under the treatment to 
which they are randomized. 
 
Non-Low-Level FCT (FCT >12.6) All Randomized Subjects: All non-low-level 
(FCT >12.6 U/g) randomized subjects. Subjects are analyzed under the treatment 
to which they are randomized.  This is an exploratory analysis population for 
efficacy. 
 
Per-Protocol (PP): All ITT subjects who have completed a Week 12 visit and 
have a Week 12 ABC-I score. Subjects are analyzed under the treatment to which 
they are randomized. This is an exploratory analysis population for efficacy. 
 
Low-Level FCT (FCT ≤12.6) Per Protocol (PP): All low-level (FCT ≤12.6 U/g) 
PP Subjects. Subjects are analyzed under the treatment to which they are 
randomized. This is an exploratory analysis population for efficacy. 
 
Non-Low-Level FCT (FCT >12.6) PP: All non-low-level (FCT >12.6 U/g) PP 
Subjects. Subjects are analyzed under the treatment to which they are randomized. 
This is an exploratory analysis population for efficacy. 
 
Run-in Analysis Set:  All subjects receiving at least one dose of placebo during 
the placebo-run in phase.  All subjects will be analyzed as one group. 
 


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Safety Analysis Set: All subjects receiving at least one dose of randomized 
treatment. Subjects are analyzed under the treatment received.  This is a primary 
analysis set for safety.  
 
Low-Level FCT (FCT ≤12.6) Safety Analysis Set: All Low-Level subjects (FCT 
≤12.6) receiving at least one dose of randomized treatment. Subjects are analyzed 
under the treatment received.  This is the secondary analysis set for safety. 
4.  Test product, Dose and Mode of Administration 
900mg of CM-AT (pancreatic enzyme concentrate encapsulated in hydrogenated soybean 
oil) 3x daily sprinkled over food. To be taken with a meal or large snack.  
 
5.  Demographics, Other Baseline Characteristics (other than efficacy and safety 
variables), Study Drug Compliance 
 
“Baseline” for variables other than efficacy and safety refers to the last value of the 
variable measured prior to start of randomized treatment. For efficacy and safety, 
“Baseline” is defined as the value measured at Screening Part 1, denoted as 
“Screening” below.  
 
5.1 Demographics – Baseline demographics of age, gender (male; female), 
ethnicity (Hispanic or Latino; not Hispanic or Latino), race (American 
Indian or Alaska Native; Asian; Black or African American; Native 
Hawaiian or other Pacific Islander); height (cm), weight (kg), body mass 
index (BMI).  
 
5.2 Physical examination abnormalities by body system (HEENT, Respiratory, 
Cardiovascular, Abdomen, Musculoskeletal, Central Nervous System, 
Dermatologic, General Appearance, Other) 
 
5.3 Responses to each question on Study Specific Medical History questionnaire 
 
5.4 Response to each question on Neurodevelopmental history questionnaire 
 
5.5 Responses to each question on Family History questionnaire 
 
5.6 Responses to each question on Parent Visit questionnaire 
 
5.7    Screening ABC-I score. The scoring of this subscale is given in Appendix A. 
 
5.8 Screening DSM-IV-TR total score and sub-scores (Social Interaction;   
Communication; Behavior) as described in Appendix C.  
 


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5.9 Screening 
SCQ 
total 
score 
and 
sub-scores 
(Social 
Interaction; 
Communication; Restricted, Repetitive, and Stereotyped Patterns of 
Behavior). 
 
The total score and the subscales of Reciprocal Social Interaction, 
Communication, and Restricted, Repetitive, and Stereotyped Patterns of 
Behavior domain are given in Appendix B. 
 
5.10 Screening ADI-R (Total A, Verbal Total B, Nonverbal Total B, Total C and 
Total D). These scores are determined by the rater and recorded directly on 
the questionnaire. 
 
5.11 Study Drug compliance will be assessed based upon the sachet usage.  The 
calculation for percentage of compliance is 100 times the number of sachets 
dispensed at the previous visit minus the number of sachets returned, 
divided by the days between visits times 3 (not including days after the last 
visit at which sachets were dispensed if the subject did not return after that 
last visit). Study drug compliance during the 2-week placebo run-in period 
and during the randomized double-blind treatment period will be analyzed.   
 
 
6.  Efficacy Variables 
 
The following lists the efficacy variables that will be collected on each subject and 
analyzed. Section 7 of this document provides the details of the analysis methodology.  
 
6.1 The primary efficacy variable is the change from Baseline (score at 
Screening Part 1) to Week 12 in the Aberrant Behavior Checklist (ABC) 
subscale for Irritability/Agitation (ABC-I) in Low-level FCT ITT subjects. 
The subscale item components are given in Appendix A. Only the raw 
scores will be analyzed.  
 
6.2 The secondary efficacy variable is the change from Baseline (score at 
Screening Part 1) to Week 12 for the Aberrant Behavior Checklist subscale 
for Lethargy/Social Withdrawal (ABC-L) in Low-level FCT ITT subjects. 
The scoring of this subscale is given in Appendix A. Only the raw scores 
will be analyzed.  
 
6.3 Exploratory Efficacy Variables include:  
 
• Behavioral changes from Baseline (score at Screening Part 1 unless 
otherwise specified) to Week 12 (the scoring of these subscales is 
given in Appendix A):  
 
 
 


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Aberrant Behavior Checklist 
 
FCT ≤12.6 U/g 
FCT >12.6 U/g 
FCT – All Levels 
ABC Irritability 
 
X 
X 
ABC Lethargy 
 
X 
X 
ABC Hyperactivity 
X 
X 
X 
ABC Stereotypy 
X 
X 
X 
ABC Inappropriate Speech 
X 
X 
X 
ABC Total Score 
X 
X 
X 
Additional Exploratory Endpoints 
Clinical Global Impression – 
Improvement 
X 
X 
X 
Clinical Global Impression – 
Severity (Baseline is the value 
measured at the randomization 
visit) 
X 
X 
X 
Social Responsiveness Scale 
((Baseline is the value 
measured at the randomization 
visit) 
X 
X 
X 
Pediatric Quality of Inventory 
Physical Functioning 
X 
X 
X 
Emotional Functioning 
X 
X 
X 
Social Functioning 
X 
X 
X 
Cognitive Functioning 
X 
X 
X 
Communication 
X 
X 
X 
Worry 
X 
X 
X 
Daily Activities 
X 
X 
X 
Total Score 
X 
X 
X 
 
• Gastrointestinal measures will be performed at each regularly 
scheduled visit, with abnormality status assessed at each visit and 
with change defined as the difference between Baseline (measures 
from Screening Part 1) to Week 12.  
• Weight will be assessed at each regularly scheduled visit,  
• Weight gain is defined as Post-Baseline weight ≥ Baseline weight 
(Baseline weight is the weight at Screening Part 1. If a patient has 
more than one Screening Part 1 weight, the last weight measured 
prior to randomization will be used).  
• Weight loss is defined as Post-Baseline weight ≤ Baseline weight. 


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Stool Test Panel & Weight Change 
 
FCT ≤12.6 U/g 
FCT >12.6 U/g 
FCT – All Levels 
C.Diff. Tox A&B 
X 
X 
X 
A1-Antitrypsin 
X 
X 
X 
Fecal Chymotrypsin 
X 
X 
X 
Cryptosporidum AG 
X 
X 
X 
H Pylori Ag,  
X 
X 
X 
pH Stool 
X 
X 
X 
Weight 
X 
X 
X 
 
 
7.  Safety Parameters 
7.1 Adverse Events – Incidence of treatment emergent adverse events are 
collected for each subject. A run-in emergent adverse event is defined as an 
event starting or worsening after the start of placebo run-in phase and before 
the start of double-blind treatment.  A treatment emergent adverse event 
(TEAE) is defined as an event starting or worsening on or after the start of 
double-blind treatment. Each adverse event will be coded to a MedDRA 
system organ class (SOC) and preferred term (PT). Severity, seriousness and 
relationship to study drug for each event will also be collected.  
 
7.2 A complete physical exam is conducted at the start of the placebo run-in 
phase.  Brief physical exams are conducted at the randomization visit (prior 
to randomization) and during the double-blind phase. If clinically significant 
findings are identified during the physical exam, an adverse event form will 
be completed.   
 
7.3 Stool pH is collected at Baseline (Screening Part 1) and at several Post-
Baseline visits including Week 12. The value at each visit and the change 
from Baseline at each Post-Baseline visit will be analyzed. 
 
7.4 For each subject at each visit at which Stool pH is collected, the incidence of 
abnormal outcomes for stool pH (<5.92 or >8.00), fecal globin (present) and 
fecal occult blood (present) are collected.   
 
7.5 A1-Antitrypsin in the feces from the Fecal Panel is collected at Baseline 
(Screening Part 1) and Post-Baseline.  It will be the variable for analysis 
along with the change from Baseline at each Post-Baseline visit. 
Additionally, at each time point for which α1-antitrypsin is measured, each 
subject’s incidence of A1-Antitrypsin <55 and ≥55 will be recorded. 


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7.6 Vital signs - The analysis variables are the change from Baseline (Screening 
Part 1) at each Post-Baseline at each visit for visit for weight (kg), systolic 
blood pressure (mmHg), diastolic blood pressure (mmHg) and pulse (beats 
per minute). 
 
8.  Statistical Methodology 
8.1    Sample Size 
 
Sample size is based on: 
  
§ The primary efficacy variable -   
• Change from Baseline (score at Screening Part 1) to Week 
12 for the Aberrant Behavior Checklist (ABC) subscale for 
Irritability 
 
§ The primary analysis set of Low-level FCT ITT subjects. 
 
• 1:1 randomization scheme   
 
Previously reported Sponsor data indicating that 60% of autistic children 
have pathologically low levels of FCT formed the basis for the following 
calculations. Assuming a -3.7 ± 7.0 ABC Irritability change from Baseline 
to Week 12 of for CM-AT and -0.6 ± 5.0 for Placebo, a sample size of 82 
evaluable low-level subjects per treatment group (active and placebo) yields 
90% power to declare a statistically significant difference between 
treatments at a two-sided 0.05 level of significance. To account for an 
anticipated 15% early withdrawal, 97 low-level subjects will be randomized 
per treatment group (active and placebo).  A total of 162 subjects per group 
will be randomized to achieve 97 randomized low-level subjects per group 
(active and placebo).  
 
8.2    General Statistical Issues 
 
The primary efficacy analysis set is the Low-Level FCT ITT set defined in 
Section 3.  Any efficacy analyses will be presented on other populations 
from Section 3 will be noted below.  The primary safety analysis set is the 
Low-Level FCT Safety Analysis set.  All safety analyses in the double-blind 
phase will be performed on this analysis set and, secondarily, on the entire 
Safety Analysis set defined in Section 3. 
 
For quantitative (continuous) variables summaries will include the sample 
size, mean, median, standard deviation, minimum and maximum.  For 
qualitative (i.e., categorical) variables, summaries will include the number 
and percent of subjects for each outcome.   


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Subjects may have a scheduled or unscheduled visit outside the protocol-
specified time windows for any protocol-specified visit. Windows of 
scheduled visits will be expanded to have adjacent start/stop periods so that 
all visits (scheduled or unscheduled) fall within a scheduled visit window.  
For example, efficacy data are scheduled to be collected for each subject at 
screening, Baseline (Screening Part I), Randomization visit, and at Weeks 2, 
4, 6, 8, 10 and 12 after randomization.  The Week 2 visit will be expanded 
to allow any visit from 1 – 20 days post-randomization visit to be considered 
as the Week 2 visit. The Week 4 visit will be expanded to allow any visit 
from 21 – 34 days post-randomization visit to be considered as the Week 4 
visit, etc.   
 
Subjects may have more than one follow-up appointment that falls within a 
window for a given visit.  In such a case, the follow-up data collected 
closest to the target date the visit should have occurred (given the number of 
weeks since randomization) will be used in the analysis.  If two visits are 
equidistant from the target date of the scheduled visit, the later visit will be 
used in the analysis.   
 
Pooling of study centers (i.e., combining study centers with small numbers 
of patients) may be required prior to performing efficacy analyses that 
include Study Center as a variable in the analysis.   The following is the 
pooling algorithm that will be used (the algorithm described below is for the 
Low-Level FCT (≤12.6 U/g) analysis set; the algorithm will be repeated 
separately for every analysis set on which efficacy data will be analyzed):  
 
If one or more study centers with Low-Level FCT (≤12.6 U/g) subjects 
have fewer than 10 subjects for the given analysis population, pooling of 
study centers will be required. Pooling of small study centers will be 
implemented as follows; 
 
• Order the study centers, starting with those with the lowest 
numbers of Low-Level FCT (•12.6 U/g) subjects. 
 
• The centers will then be combined in a consecutive upward order 
unless the total number of subjects exceeds the median number of 
subjects of all sites with 10 or more subjects. 
 
• If this process does not capture all the study centers with fewer 
than 10 subjects, a second pooled study center will be created 
using the same process. 
 
• This process will be continued until all study centers with fewer 
            than 10 subjects are accounted for. 


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Again, this pooling algorithm will be repeated separately within each 
analysis population for which efficacy analyses will be run. 
 
 
Unless otherwise indicated, p-values are two-sided and statistical 
significance is declared if the two-sided p-value is ≤0.05.  There is only one 
primary efficacy endpoint and one efficacy secondary endpoint. The 
primary endpoint will be tested at the two-sided 0.05 level of significance, 
and if significant, the secondary endpoint will be tested at the two-sided 
0.05 level of significance.  All other endpoints are considered exploratory 
and there will be no adjustment for multiple comparisons across these 
exploratory endpoints. 
 
 
8.3    Subject Disposition 
 
The number and percentage of subjects in each analysis set will be 
presented.  With the exception of the Run-in Analysis Set and the All 
Randomized Analysis set, percentages will be based on the total number of 
randomized subjects who received study drug and had at least one post-
Baseline ABC-I assessment (the ITT analysis set).  For the All Randomized 
Analysis Set and the Run-in Analysis Set, no percentages will be presented; 
just the number of subjects will be presented.  Randomized subjects without 
a baseline FCT measurement will not be counted in any Low-Level FCT 
(≤12.6 U/g) or Non-Low-Level FCT analysis set (>12.6 U/g) but will be 
included in all other analysis sets in which they reside. 
 
Disposition of all subjects over the course of the double-blind portion of the 
trial will be presented for the Low-Level FCT ITT analysis set, the ITT 
analysis set, the Low-Level FCT All Randomized analysis set and the All 
Randomized analysis set. This presentation will include the number of 
subjects who completed the study through 12 weeks and the number who 
discontinued early as indicated on the End of Study Case Report Form page 
(along with the reason for study discontinuation as indicated on the same 
page).  
 
The number and percent of subjects, by treatment group and overall, who 
discontinue during the double-blind phase will be summarized by reason for 
discontinuation. Percentages are based on the total number of subjects 
randomized in the given analysis set.  The reasons for discontinuation as 
indicated on the End of Study Case Report Form page are: 
 
• Adverse Event 
• Noncompliance 
• Protocol violation 
• Withdrawal of consent 


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• Lost to follow-up 
• Investigator decision 
• Trial terminated by sponsor 
• Other 
 
- 
8.4    Demographics, Other Baseline Characteristics (other than efficacy and 
safety variables) 
 
Descriptive statistics of demographic characteristics will include:  
 
• Age, gender (male; female)  
• Ethnicity (Hispanic or Latino; not Hispanic or Latino), race 
(American Indian or Alaska Native; Asian; Black or African 
American, Native Hawaiian or other Pacific Islander)  
• Height (cm) 
• Weight (kg)  
• Body mass index (BMI) 
 
These characteristics will be summarized using the appropriate descriptive 
statistics by treatment group and overall for the Low-Level FCT ITT, the 
ITT, the Low-Level All Randomized the All Randomized analysis sets. 
 
Other Baseline characteristics listed in Section 5 will be summarized using 
the appropriate descriptive statistics by treatment group and overall for the 
Low-Level FCT ITT analysis set and for the ITT analysis set.  
 
8.5    Study Drug Usage 
 
The following analyses will be presented for the Low-Level FCT ITT 
analysis set, the ITT analysis set, the Low-Level FCT All Randomized 
analysis set and the All Randomized analysis set.  For each treatment group 
compliance will be calculated at each visit as well as for the overall study. 
 
The calculation for percentage of compliance is 100 times the number of 
sachets dispensed at the previous visit minus the number of sachets returned, 
divided by the days between visits times 3 (not including days after the last 
visit at which sachets were dispensed if the subject did not return after that 
last visit). 
 
If a subject was dispensed sachets at a given visit and then did not return to 
the study, the dispensation information at this last visit will not be used in 
the calculation of number of sachets used.  
 
Summary statistics for these variables will include the number of subjects, 
mean, standard deviation, median, minimum and maximum.   


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8.6    Efficacy Analyses 
 
The Analyses described below will be performed on every ITT, All 
Randomized and PP analysis set. The Low-Level ITT analysis will be 
considered the primary analysis set. 
 
 
8.6.1 Primary Efficacy Analysis 
 
The primary efficacy endpoint is the change from Baseline (score 
at Screening Part 1) to Week 12 visit in the ABC 
Irritability/Agitation (ABC-I) in the Low Level FCT ITT 
population as defined in Section 3. Descriptive statistics of ABC-I 
and change from Baseline ABC-I will be presented at Week 12 for 
each treatment group.  Mean change in Baseline ABC-I at Week 
12 will be compared across treatment groups using a mixed model 
repeated measures (MMRM) model with terms for treatment, study 
center, visit, and the treatment by visit interaction. The model will 
also include Baseline ABC-I score as a covariate and subject will 
be a random effect. An unstructured covariance matrix will be used 
for the within-subject correlation. Kenward-Rogers’ approximation 
will be used to estimate degrees of freedom. The SLICE option 
will be employed to examine differences across treatments at 
specific time points, with the focus being on the Week 12 change 
from Baseline. Two-sided 95% confidence intervals of the 
difference between treatment means of the primary endpoint will 
be constructed using MMRM model estimates for the mean. Tests 
of hypotheses will be two-sided and will be based on the contrasts 
between CM-AT and placebo within the MMRM model.  
 
An assessment of treatment-by-study center interaction on the 
change from Baseline (score at Screening Part 1) to Week 12 
ABC-I will be carried out using analysis of variance (ANOVA).  
Included in the ANOVA model will be main effects for treatment, 
investigative center and Baseline ABC-I and the treatment-by-
center interaction effect.  A 0.10 level of significance will be used 
to assess the interaction.  A non-significant interaction or an 
interaction significant but only quantitative in nature will support 
the pooling of results across study centers for the final analysis. 
For the PP, ITT, and All Randomized analysis sets, a treatment-by-
low-level status interaction will be assessed in a similar manner as 
the treatment-by-study center interaction. 
 


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If statistical significance, in favor of CM-AT, is shown on the 
primary efficacy endpoint (FCT ≤12.6 U/g) in the Low-Level ITT 
analysis set, the study will be considered a success statistically.   
 
For completeness, though not of primary interest, descriptive 
statistics of ABC-I and of the change from ABC-I will be 
presented at each visit, and treatment group comparison p-values 
on mean change from Baseline ABC-I to each visit will be 
calculated from the MMRM model discussed above. 
 
Missing ABC-I Data: The primary analyses will be based on the 
MMRM model with available data discussed above. As a 
sensitivity analysis, the above analyses will be repeated where, 
first, multiple imputation using the monotone linear regression 
approach will be used to impute missing primary endpoint data at 
each visit via SAS PROC MI; included as covariates in the linear 
model will be age, sex, race, ABC Irritability measured at previous 
visits (including the randomization visit), Baseline FCT, and 
investigative center.  
 
Ten complete datasets will be created (the linear regression 
approach to multiple imputation assumes monotone missing data 
pattern; if such a pattern does not exist, then prior to each of the 10 
linear regression imputations, non-monotone missing ABC-I data 
will be imputed via the MCMC approach on ABC-I across visits to 
create a monotone missing data pattern). Once complete datasets 
are generated, the primary MMRM model will be applied to each 
of these datasets with the results will be combined into a single 
estimate of the treatment difference on the change from Baseline to 
each visit using SAS PROC MIANALYZE.  The focus is on the 
treatment difference on the change from Baseline to the Week 12 
ABC-I as the primary analysis.   
 
 
As an additional tertiary sensitivity analysis, the Last-Observation 
Carried Forward (LOCF) method will be applied prior to carrying 
out the MMRM analysis.  For subjects who prematurely withdrew, 
the last efficacy measurement obtained prior to premature 
withdrawal (even if the last measurement is the Baseline 
measurement or the measurement obtained at the randomization 
visit) will be carried forward to each visit following the withdrawal 
prior to carrying out the MMRM. 
 
8.6.2 The secondary efficacy endpoint of ABC-L will be analyzed and 
compared between treatments in a similar manner as the primary 
endpoint.  Again, the Low-Level FCT ITT analysis set is primary, 
but all ITT, All Randomized and PP analysis sets will be analyzed.    


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8.6.3 Exploratory Endpoints: 
 
For continuous exploratory endpoints, treatments will be compared 
on change from Baseline in a similar manner as the primary 
endpoint at Week 12 and each Post-Baseline visit except for 
multiple imputation and assessment of treatment-by-study center 
interaction effects.  For CGI-S, an endpoint for which there is no 
Baseline value, treatments will be compared in a similar manner as 
the primary endpoint on the CGI-S value itself (as opposed to a 
change from Baseline) without a Baseline value of the endpoint as 
a covariate.   There will be no adjustment for multiple 
comparisons. 
 
 
For dichotomous exploratory endpoints (stool test, weight 
gain/loss), no formal statistical hypothesis testing will be 
performed to compare the treatment groups on these results.  
 
 
The number and percentage of subjects experiencing the 
dichotomous endpoint will be presented for each treatment group.  
For completeness, this analysis will be repeated for each visit. 
 
 
8.7 Safety Analyses 
 
The safety analysis will be performed on the Run-in Safety Analysis Set 
(run-in phase safety data only) where specified, on the Low-Level FCT 
Safety Analysis set (for double-blind safety data) and on the entire Safety 
Analysis set (for double-blind safety data). All subjects receiving at least 
one dose of randomized treatment is the primary safety analysis set. There 
will be no imputation of missing data and there will be no adjustment for 
multiple comparisons. 
 
. 
Adverse Events – The number and percentage of subjects with TEAEs 
(Treatment Emergent Adverse Events) will be presented overall and by 
MedDRA System Organ Class (SOC) and Preferred Term (PT). Patients 
experiencing more than one occurrence of an event within a given SOC and 
PT will be counted only once within that SOC and PT, respectively. The 
analysis will be repeated for serious TEAEs, for TEAEs leading to 
premature withdrawal and for TEAEs deemed at least possibly related to 
study drug. No formal statistical hypothesis testing will be performed to 
compare the treatment groups on incidence of TEAEs.  
The number and percentage of subjects with TEAEs will be presented by 
severity of TEAE (mild/moderate/severe) within each SOC and PT. A 
subject experiencing more than one occurrence of a TEAE within an SOC or 


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PT will be categorized under the maximum severity in which the subject 
experienced the TEAE. 
 
The above will be repeated on the run-in TEAEs.  The denominator will be 
the number of patients receiving placebo in the run-in phase, and there will 
only be one group analyzed (all patients receiving placebo in the run-in 
phase).    
 
No formal statistical hypothesis testing will be performed to compare the 
treatment groups on the proportion of subjects with TEAEs. 
 
Physical exams – The number and percentage of subjects with a clinically 
significant finding on the physical exams will be presented at each Post-
Baseline double-blind visit.  No formal statistical hypothesis testing will be 
performed to compare the treatment groups on the proportion of subjects 
with clinically significant findings. 
 
Fecal Panel - For Fecal Chymotrypsin, pH and A1-Antitrypsin, descriptive 
statistics (number of subjects, mean, median, standard deviation, minimum 
and maximum) of Baseline (Screening Part I), each Post-Baseline visit and 
the change from Baseline at each Post-Baseline visit will be presented. 
Treatment groups will be compared on change from baseline at each visit 
using analysis of covariance adjusting for study center and Baseline. For 
Fecal Chymotrypsin, the number and percentage of subjects with values 
>12.6 U/g and ≤12.6 U/g at each visit will be presented.  For pH, the 
incidence rate (number and percentage of subjects) with abnormal outcomes 
will be presented at each visit.  For A1-Antitrypsin, the number and 
percentage of subjects with values <55 and ≥55 will be presented at each 
visit. Further, for fecal globin and fecal occult blood the incidence rate 
(number and percentage of subjects) with abnormal outcomes will be 
presented at each visit, where abnormal is defined as the variable being 
“present”.  No formal statistical hypothesis testing will be performed to 
compare the treatment groups on these results. 
 
Vital signs – For each of the following measurements:  weight (kg), systolic 
blood pressure (mmHg), diastolic blood pressure (mmHg) and pulse (beats 
per minute), descriptive statistics (number of subjects, mean, median, 
standard deviation, minimum and maximum) of Baseline, each Post-
Baseline visit and the change from Baseline at each Post-Baseline visit will 
be presented. No formal statistical hypothesis testing will be performed to 
compare the treatment groups on these results. 
 
Weight Loss by End of Study - The number and percentage of subjects 
losing weight by the end of the study will be tabulated for each visit for each 
treatment group.  No formal statistical hypothesis testing will be performed 


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to compare the treatment groups on the proportion of subjects with weight 
loss. 
 
9.  Interim Efficacy Analysis 
 
An Independent Statistical Group (ISG) will conduct one (1) formal interim 
efficacy analysis on the primary endpoint when at most 50% of the planned 
number of total Low-Level FCT All Randomized subjects have completed Week 
12 evaluations (the exact timing of the interim analysis will depend on enrollment 
rate; if enrollment is quicker than anticipated, the interim analysis may take place 
when <50% of the subjects have completed Week 12 evaluations). The Sponsor, 
participating clinical investigators and any personnel involved in trial conduct will 
remain blinded to study treatment. The sole purpose of the interim analysis is to 
ensure proper power of the study.  
 
The ISG will calculate the conditional power for potentially achieving a 
statistically significant treatment difference at the final analysis, conditioned on 
the interim results.  The conditional power (CP) formula to be used is: 
 
 
 
 
 
 
 
where Φ is the cumulative distribution function of the standard normal 
distribution; c2 is the critical value in the final analysis =1.96 (this critical value 
corresponds to a one-sided final Type I error rate of 0.025); n2 is the planned final 
evaluable sample size per treatment group in the Low-Level FCT All Randomized 
group (=82); z1 is the test statistic based on the observed interim data (=z-test 
statistic for the treatment effect from the MMRM model); n1 is the sample size per 
group on which the interim observed rates are based (since the sample sizes may 
not exactly be equal between treatment groups at this stage despite the 1:1 
randomization, the average of the two group sample sizes will be used as an 
approximation);  σ2 is the assumption of the within-group variance (this will be 
set to the interim pooled standard deviation between the groups), Δ is the assumed 
difference in treatment means under which the conditional power is calculated. 
This will be set to the estimate based on the interim power calculation.  
 
If the conditional power is between 50% and 90%, the ISG may recommend 
increasing the final Low-Level FCT All Randomized sample size n2 in the above 
CP formula to maintain 90% conditional power, following the algorithm in Chen, 
DeMets, and Lan (2004)1. Increasing the sample size to maintain CP of 90% at a 
one-sided 0.025 level of significance only when the CP is greater than 50% does 
not inflate the Type I error, as shown in Chen, DeMets and Lan if the sample size 
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increment is less than 151.3% of the original sample size. The value of 151.3% 
corresponds to the value of 100*R=100*1.513 in Table IV of Chen, Demets and 
Lan, where R satisfies: 
 
 
 
where t is the information fraction at which the interim analysis is carried out 
(=0.5) based on the original planned final sample size, zβ is the z-critical value 
corresponding to 90% power (=1.28) and zα is the z-critical value corresponding 
to a one-sided 0.025 level of significance (or two-sided 0.05 level of significance) 
= 1.96. 
 
Again, the above assumes t=0.5; note that if t<0.5, the value of R will be revised 
accordingly.  If the Low-Level FCT All Randomized sample size is increased, the 
entire randomized sample size will be increased accordingly to ensure the 
required number of Low-Level FCT All Randomized subjects is met; enrollment 
will not be specifically focused on Low-Level FCT All Randomized subjects. 
10.  Software 
All analyses, data listings and tables will be performed/produced using SAS® 
version 9.4 or higher.   
1
                                                
1 Chen, JYH, DeMets, DL, Gordon Lan, KK, Increasing the sample size when the 
unblended interim result is promising, Statist. Med. 2004; 23:1023-1038 (DOI: 
10.1002/sim.1688) 
 


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Appendix A 
Scoring of the Aberrant Behavior Checklist (ABC) 
 
1. The subscale scores are determined by summing these results. 
 
2. Hyperactivity/Non-compliance: 
Item No.   
 
 
  1 
 
 
 
  7 
 
 
 
13 
 
 
 
15 
 
 
 
18 
 
 
 
21 
 
 
 
24 
 
 
 
28 
 
 
 
31 
 
 
 
38 
 
 
 
39 
 
 
 
44 
 
 
 
48 
 
 
 
51 
 
 
 
54 
 
 
 
56 
 
 
 
 
3. Irritability/Agitation, 
Item No.   
 
 
  2 
 
 
 
  4 
 
 
 
  8 
 
 
 
10 
 
 
 
14 
 
 
 
19 
 
 
 
25 
 
 
 
29 
 
 
 
34 
 
 
 
36 
 
 
 
41 
 
 
 
47 
 
 
 
50 
 
 
 
52 
 
 
 
57 
 
 
 
 


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            Appendix A (cont.) 
 
4. Lethargy/Social Withdrawal 
Item No.   
 
 
  3 
 
 
 
  5 
 
 
  
12 
 
 
  
16 
 
 
  
20 
 
 
  
23 
 
 
  
26 
 
 
  
30 
 
 
  
32 
 
 
  
37 
 
 
  
40 
 
 
  
42 
 
 
  
43 
 
 
  
53 
 
 
  
55 
 
 
  
58 
 
 
  
 
5. Stereotypic Behavior        
Item No.   
 
 
  6 
 
 
 
11 
 
 
  
17 
 
 
  
27 
 
 
  
35 
 
 
  
45 
 
 
  
49 
 
 
  
 
6. Inappropriate Speech        
Item No.   
 
 
  9 
 
 
 
22 
 
 
  
33 
 
 
  
46 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B 
 
Scoring of the Social Communication Questionnaire (SCQ) 
1. If Question 1 is “yes” then score items 2 through 40. If Question 1 is “no” then 
score items 8 through 40. 
2. For questions 2, 9, and 19 a response of “no” is scored as 1 and “yes” is scored as 
0. For all remaining questions a response of “yes” is scored as 1 and “no” is 
scored as 0. 
3. For the Reciprocal Social Interaction domain questions 9, 10, 19, 26-33, 36, 37, 
39, and 40 are summed. 
4. For Communication domain questions 2-6, 20-25, 34, and 35 are summed. 
5. For Restricted, Repetitive, and Stereotyped Patterns of Behavior domain 
questions 7, 8, and 11-16 are summed. 
6. The Total score is the sum of questions 2-40. 
7. There is no recommendation by the innovators of the questionnaire regarding the 
handling of missing data. For this study, it is required that at least 50% of the 
questions must be answered for each subscale before the subscale can be 
determined. The same rule will be used for the Total score. For each subscale, 
missing data for individual questions will be estimated by the average of the 
remaining questions. Similarly, for the Total score missing data for individual 
questions will be estimated by the average of the remaining question. 


Curemark, LLC 
 
December 27, 2017 
Protocol No. 00103 Autism 
 
Statistical Analysis Plan                                                                                                                  Final 2.0 
CONFIDENTIAL   
 
             Page 23 of 23 
  
Appendix C 
Scoring of the DSM-IV Diagnostic Criteria for Autism (DSM-IV-TR) 
1. For Parts A, B, and C a response of “Noted” is scored as a “1” and “Not Noted” is 
scored as “0”. 
2. The score for Part A is the sum of the four questions. 
3. The score for Part B is the sum of the four questions. 
4. The score for Part C is the sum of the four questions. 
5. The Total score is the sum of the 12 questions in Parts A, B, and C. 
6. The subject is classified as having Autism if the Total score is at least 6, the score 
for Part A is at least two and at least one for Part B and Part C, at least one of the 
three questions in Part II is checked as “abnormal”, and both questions in Part III 
are checked “Yes”. 
7. There is no recommendation by the innovators of the questionnaire regarding the 
handling of missing data. If any of the questions in Part A, B, and C are missing 
the corresponding subscales will be considered missing. Additionally, if any of 
the 12 questions in Parts A, B, and C are missing the Total score will be 
considered missing. Finally, if any of these 12 questions are missing the Autism 
assessment will be considered missing unless the criteria for Autism is satisfied 
by the questions that have been answered.