A Double Blind, Randomized, Placebo-Controlled Study of CM-AT for the Treatment of Autism in Children With All Levels of Fecal Chymotrypsin (FCT)
Phase: PHASE3
Conditions: Autism
Sponsor: Curemark

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.