Clinical trial NCT04483479
Conditions: Parkinson Disease Constipation
Sponsor: Enterin Inc.
Start date: 2020-07-30; Completion date: 2022-02-17
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will be conducted as an open-label safety follow-on to a multi-center, double-blind, randomized study. All subjects who participated in the randomized study will be offered participation in this unblinded, single-arm, safety study. Approximately 50 subjects will be entered into the study and ENT-01 will be administered daily in escalating doses followed by a fixed dose for 12 weeks. Each subject will participate for approximately 20 weeks; dosing duration will be approximately 14 weeks.

Detailed description:
The study will be conducted on an out-patient or in-patient basis with visits performed at the screening visit, at 6 and 12 weeks, and at the end of the 6th week of the wash-out period (end of study).

The dose escalation period will last up to 20 days, the fixed dose period will last 12 weeks, and the wash-out period will last 6 weeks.

Subjects will begin dosing at the same dose level they were stratified to in the ENT-01-030 randomized study (i.e., starting at either 3 tablets or 6 tablets,) and escalate up to a pro-kinetic dose or a maximum dose of 250mg.

Arms: arm 1: Orally Administered ENT-01 25mg Tablet Once Daily (Dose dependent on ENT-01-030 dose level stratification)
Interventions: intervention 1: Active Investigational Treatment ENT-01
Intervention descriptions: intervention 1: ENT-01 will be administered in tablet form, once daily in escalating doses followed by a fixed-dose for 12 weeks.

Protocol documents:
Prot_SAP_001.pdf: 
  
 
Protocol ENT-01-2b-20-02 
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A Multicenter, Non-Randomized, Open-Label Study to 
Evaluate the Safety and Efficacy of Orally Administered 
ENT-01 in Improving Constipation and Neurologic 
Symptoms in Patients with Parkinson’s disease and 
Constipation over a 14-week Period. 
Clinical Trial Protocol 
Name of product 
ENT-01 
Phase 
Phase 2b Follow-on Safety “Roll-over” study 
Trial Protocol Number 
ENT-01-2b-20-02 
IND Number 
130770 
Sponsor 
Enterin, Inc. 
2005 Market St. Suite 3125 
Philadelphia, PA 19103 
Protocol Chair 
Denise Barbut, MD, FRCP 
Co-Founder, President and CMO 
Email: d.barbut@enterininc.com 
Office: 215-634-9243 
Cell: 917-975-1377 
Protocol Contact 
Shari Thomas, M/Biotech 
Senior Director of Clinical Operations  
Email: s.thomas@enterininc.com 
Office: 215-999-2818 
Clinical Trial Protocol Version / Date 
Version 3.0 / June 30th, 2020 
Protocol Amendment Number / Date 
NA 
 
 
 


  
 
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CONFIDENTIALITY STATEMENT 
This study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices 
as defined in Title 21 of the US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well 
as ICH GCP consolidated guidelines (E6) and applicable regulatory requirements. 
This document is confidential and proprietary to Enterin, Inc. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disseminated or disclosed without prior written approval of 
Enterin, Inc., except that this document may be disclosed in any medium to appropriate clinical 
investigators, Institutional Review Boards, and others directly involved in the clinical investigation 
that is the subject of this information under the condition that they keep the information strictly 
confidential. 
 
 


  
 
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CLINICAL TRIAL PROTOCOL SIGNATURE PAGE 
 
Authored by: 
Signature 
 
 
 
 
 
 
 
 
 
 
 
Date of Signature 
 
 
 
 
 
 
 
 
 
 
 
(DD/MMM/YY) 
 
Name 
Denise Barbut, MD. FRCP.  
Title 
President and Chief Medical Officer 
Email 
d.barbut@enterininc.com 
Telephone 
(917) 975-1377 
 
 
 


  
 
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Investigator Agreement 
I have read this protocol “A Multicenter, Non-Randomized, Open-Label Study to Evaluate the 
Safety and Efficacy of Orally Administered ENT-01 in Improving Constipation and Neurologic 
Symptoms in Patients with Parkinson’s disease and Constipation over a 14-week Period,” and any 
auxiliary materials related to Study ENT-01-2b-20-02, and agree to the following: 
1. To conduct the study as described in the protocol, protocol amendment, and any auxiliary 
materials 
2. To protect the rights, safety, and welfare of the participants in the study 
3. To provide oversight to all personnel to whom study activities have been delegated 
4. To maintain control all investigational product (IP) provided by the Sponsor and to maintain 
records of the disposition of those products 
5. To conduct the study in accordance with the protocol amendment and all applicable local 
and national regulations, including, but not limited to, the International Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice (GCP), and the standards set 
forth by the ethical principles that have their origin in the Declaration of Helsinki, GCPs as 
indicated in Food and Drug Administration (FDA), ICH E6 (R2) and ICH E3 
6. To obtain approval for the protocol, protocol amendment, and all written materials provided 
to participants prior to initiating the study at my site 
7. To obtain informed consent from all participants enrolled at my study site prior to initiating 
any study-specific procedures or administrating IP to participants 
8. To maintain accurate records of each patient’s participation. 
 
 
Investigator’s Signature  
 
Date 
 
 
 
 


  
 
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STUDY SYNOPSIS 
Study Title 
A Multicenter, Non-Randomized, Open-Label Study to Evaluate the 
Safety and Efficacy of Orally Administered ENT-01 in Improving 
Constipation and Neurological Symptoms in Patients with Parkinson’s 
disease and Constipation over a 14-week Period. 
Protocol Number 
ENT-01-2b-20-02 
Study Phase  
Phase 2b Follow-on study.   
Methodology 
This study will be conducted as an open-label safety follow-on to a 
multi-center, double-blind, randomized study. Dosing duration will be 
approximately 14 weeks. All subjects who participated in the 
randomized study will be offered participation in this unblinded, single-
arm, safety study. ENT-01 will be administered daily in escalating 
doses followed by a fixed-dose for 12 weeks. The study will be 
conducted on an out-patient or in-patient basis with visits performed at 
the screening visit, at 6 and 12 weeks, and at the end of the 6th week of 
the wash-out period (end of study).    
Study Duration 
Each subject will participate for approximately 20 weeks: the dose 
escalation period lasting up to 20 days, the fixed dose period lasting 12 
weeks, and the wash-out period lasting 6 weeks. 
Study Centers 
This is a multi-center trial with approximately 20 sites. 
Objectives 
The purpose of this study is to evaluate the long-term safety and 
efficacy of orally administered ENT-01 in subjects with Parkinson’s 
disease and constipation. 
 Primary Safety Objective: 
To determine the safety and tolerability of orally administered 
ENT-01 for up to 14 weeks in subjects with Parkinson’s disease-
related constipation. 
 Primary Efficacy Objectives: 
To determine the efficacy of repeated oral doses of ENT-01 in 
improving constipation in subjects with Parkinson’s disease. 
Secondary Efficacy Objectives: 
To determine the effect of repeated oral doses of ENT-01 on motor 
and non-motor symptoms such as cognition and psychosis in subjects 
with Parkinson’s disease.  


  
 
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Number of Subjects 
Approximately 50 subjects will be entered into the study 
Study Description 
Open-Label, Multicenter study of daily oral doses of ENT-01 for up to 
14 weeks 
Study Population 
Parkinson’s disease with constipation 
Study Drug 
Administration 
Oral 
Inclusion/Exclusion 
Criteria 
The study population is defined as subjects who meet the following 
criteria: 
Inclusion Criteria: 
1. All subjects who participated in the randomized study ENT-
01-030 (KARMET Stage 2 Extension subjects) and who 
completed the dosing period. 
2. Subjects aged 30-90 years at the time of screening for the 
ENT-01-030 study, both genders. 
3. Subjects must provide informed consent and be willing and 
able to comply with study procedures. 
4. Subjects must be able to read, understand, and accurately 
record data into the diary to guarantee full participation in the 
study. 
5. Female subjects must have negative serum or urine 
pregnancy tests and must not be lactating. For females able to 
bear children, a hormonal (i.e., oral, implantable, or 
injectable) and single-barrier method, or a double-barrier 
method of birth control must be used throughout the study. A 
vasectomized partner will be allowed as one in conjunction 
with another single-barrier method. 
6. Female subjects unable to bear children must have this 
documented in the CRF (i.e., tubal ligation, hysterectomy, or 
postmenopausal [defined as a minimum of one year since the 
last menstrual period]). Post-menopausal status will be 
confirmed by follicle stimulating hormone (FSH) in women 
less than 60 years of age 
 
 


  
 
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Exclusion Criteria 
1. Unable or unwilling to provide informed consent or to 
comply with study procedures. 
2. Unable to withdraw proton pump inhibitors. 
3. Unable or unwilling to withdraw from laxatives, opiates, 
clonazepam, or any medications which may cause 
constipation 2 weeks prior to the dose adjustment period and 
throughout the rest of the study. 
4. Diagnosis of secondary constipation beyond that of 
Parkinson’s disease. 
5. A compromised gastrointestinal system which includes:  
• Structural, metabolic, or functional GI diseases or 
disorders. 
• Acute GI illness within 2 weeks of the screening visit. 
• History of major GI surgery within 30 days of the 
screening 
visit 
(a 
history 
of 
cholecystectomy, 
polypectomy, hernia repair or appendicectomy are not 
exclusionary as long as they were performed more than 30 
days before the screening visit). 
6. Neurological disorder other than Parkinson’s disease that in 
the opinion of the investigator might interfere with the 
conduct of the study. 
7. On 
treatment 
with 
intra-jejunal 
dopamine 
or 
carbidopa/levodopa (i.e. Duopa). 
8. Subjects starting a new Parkinson’s disease medication or 
modifying an existing medication within 2 weeks prior to 
enrollment. 
9. Unable to maintain a stable diet regimen. 
10. Subjects with a cognitive impairment that preclude them from 
understanding the informed consent. 
11. Subjects placed under legal guardianship. 
12. History of excessive alcohol use or substance abuse. 
13. Any clinically significant abnormalities on screening 
laboratories or physical examination requiring further 
evaluation or treatment. 


  
 
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14. Females who are pregnant or breastfeeding 
15. Subject or caregiver unable to administer daily oral dosing of 
study drug. 
16. Participation in a non-Enterin investigational drug trial within 
the month prior to dosing in the present study. 
17. Any other reason, which in the opinion of the investigator 
would confound proper interpretation of the study. 
Study Product, Dose, 
Route, Regimen 
ENT-01 will be administered in tablet form, once daily, on an empty 
stomach, first thing in the morning, with 8 oz of water. No food intake 
will be allowed for 60 minutes after taking medication. The tablets 
will be 25mg each. Subjects will begin dosing at the same dose level 
they were stratified to in the ENT-01-030 randomized study (i.e., 
starting at either 3 tablets or 6 tablets,) and escalate up to a pro-kinetic 
dose or a maximum dose of 250mg.  
Study Endpoints 
Safety Endpoints: 
Adverse events as evaluated with subject report, vital signs, chemical 
chemistry and electrocardiograms (EKG).  
Tolerability Endpoints: 
• Recurrent vomiting defined as 3-5 episodes of vomiting within 
24 hours.  
• Recurrent diarrhea defined as 7 episodes of diarrhea within 
24 hours for 2 consecutive days.  
• Dizziness defined as lightheadedness or fainting on rising from 
lying to sitting or standing and severe enough to require non-
urgent medical intervention within 24 hours. 
Primary Efficacy Endpoint: 
• Change from baseline in weekly CSBM rate during the 12 weeks 
of treatment over baseline. 
Secondary Efficacy Endpoints: 
• Change from baseline in the MDS-UPDRS score at the end of 
the 12-week fixed dose period. 
• Change from baseline in cognition as assessed by the MMSE at 
the 12-week fixed dose period. 


  
 
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• Change from baseline in psychosis as assessed by the SAPS-PD 
score at the 12-week fixed dose period. 
Statistical 
Considerations 
Study Populations: 
• Safety Population:  All enrolled subjects who have received at 
least 1 dose of study drug.  
• Fixed Dose Population:  The Fixed Dose Population will include 
all subjects who are in Safety Population who enter the Fixed 
Dose period of the study.  
• Efficacy Evaluable Population: All subjects in the ITT 
Population who complete the study with no major protocol 
violations.  
Analysis Methods: 
Descriptive summary statistics will be presented for the safety and 
tolerability endpoints overall. Continuous variables will be 
summarized using the number of observations, mean, standard 
deviation, median, minimum, and maximum. Categorical variables 
will be summarized using frequency counts and percentages. 
Primary Efficacy Endpoint Analysis: 
The primary efficacy endpoint is the change from KARMET Stage 2 
baseline in the weekly CSBM rate during 12 Weeks of the Treatment 
Period. The primary efficacy endpoint analysis is a Mixed Model 
Repeated Measures (MMRM) analysis.  
Sample Size Justification:  
To assess tolerability and safety, a sample size of 50 patients yields 
92% probability that an AE with an underlying rate of 5% will occur 
in at least one of these patients. 
Initial Date 
July 2020 
Completion Date 
December 2021 
 
 
 
 


  
 
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Table of Contents 
STUDY SYNOPSIS .................................................................................................................................... 5 
ABBREVIATIONS ................................................................................................................................... 12 
1. 
BACKGROUND ............................................................................................................................... 14 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................................. 21 
2.1. 
PRIMARY SAFETY OBJECTIVE ............................................................................................. 21 
2.2. 
PRIMARY EFFICACY OBJECTIVE AND ENDPOINTS ............................................................... 22 
2.3. 
SECONDARY EFFICACY OBJECTIVES AND ENDPOINTS ........................................................ 22 
3. 
STUDY DESCRIPTION .................................................................................................................. 23 
3.1. 
PRE-SCREENING PLANNING ................................................................................................. 25 
3.2. 
VISIT 1: SCREENING AND DOSE ESCALATION PERIOD (DAY -20 TO DAY 1) ....................... 26 
3.3. 
VISIT 2: BEGINNING OF FIXED DOSE PERIOD (DAY 1, +3 DAYS)......................................... 29 
3.4. 
VISIT 3: 6TH WEEK OF FDP (DAY 43, +/- 3 DAYS) ............................................................... 30 
3.5. 
VISIT 4: 12TH WEEK OF FDP, START OF WOP, ET (DAY 85, +/- 3 DAYS) ........................... 31 
3.6. 
VISIT 5: END OF 6-WEEK WASH-OUT PERIOD/END OF STUDY (DAY 127, +/- 3 DAYS) ........ 32 
4. 
STUDY POPULATION ................................................................................................................... 33 
5. 
SELECTION CRITERIA ................................................................................................................ 34 
6. 
DISCONTINUATION CRITERIA AND EARLY TERMINATION PROCEDURES ............. 36 
7. 
CONCOMITANT AND PROHIBITED MEDICATIONS AND THERAPIES ......................... 37 
8. 
MATERIALS .................................................................................................................................... 38 
8.1. 
STUDY DRUG ....................................................................................................................... 38 
8.2. 
PACKAGING AND LABELING ................................................................................................ 38 
8.3. 
STORAGE, DISPENSING AND RECONCILIATION OF STUDY DRUG AND IDENTITY OF 
INVESTIGATIONAL PRODUCTS ............................................................................................. 38 
9. 
WARNINGS AND PRECAUTIONS .............................................................................................. 40 
10. STUDY PROCEDURES .................................................................................................................. 41 
10.1. 
OBSERVATIONS AND MEASUREMENTS ................................................................................ 41 
10.2. 
INSTRUCTIONS TO SUBJECTS ............................................................................................... 41 
10.3. 
CTCAE DEFINITIONS OF DOSE LIMITING ADVERSE EVENTS ............................................. 41 
10.4. 
CRITERIA FOR DOSE LIMITING TOXICITY (DLT) ENDPOINTS: ............................................ 42 
10.5. 
PRE-EXISTING MEDICAL CONDITIONS ................................................................................ 42 
10.6. 
TREATMENT EMERGENT ADVERSE EVENTS ........................................................................ 42 
10.7. 
LABORATORY ABNORMALITIES .......................................................................................... 42 
10.8. 
ADVERSE EVENT ASSESSMENT AND RECORDING ............................................................... 43 
10.9. 
REPORTING REQUIREMENTS ................................................................................................ 45 
10.10. SERIOUS ADVERSE EVENTS ................................................................................................. 45 
10.11. NOTIFICATION OF SERIOUS ADVERSE EVENTS ................................................................... 46 
10.12. REPORTING A SERIOUS ADVERSE EVENT ............................................................................ 47 
10.13. DEPARTURE FROM PROTOCOL FOR EMERGENCY OR ADVERSE EVENT .............................. 48 


  
 
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10.14. SAFETY MONITORING .......................................................................................................... 48 
10.15. STOPPING RULES ................................................................................................................. 48 
10.16. FOLLOW-UP AND FINAL REPORTS ....................................................................................... 49 
10.17. REGULATORY ASPECTS ....................................................................................................... 49 
11. DATA MANAGEMENT AND STATISTICS ................................................................................ 50 
11.1. 
POPULATIONS FOR ANALYSES ............................................................................................. 50 
11.2. 
ANALYSIS METHODS ........................................................................................................... 50 
11.3. 
SAFETY ANALYSES .............................................................................................................. 50 
11.4. 
TOLERABILITY ANALYSES ................................................................................................... 52 
11.5. 
EFFICACY ANALYSES .......................................................................................................... 52 
11.6. 
HANDLING OF MISSING DATA ............................................................................................. 52 
11.7. 
SAMPLE SIZE/POWER CONSIDERATIONS ............................................................................. 52 
12. ESTIMATED DURATION OF THE STUDY ............................................................................... 53 
13. ADMINISTRATIVE PROCEDURES AND ETHICAL CONSIDERATIONS .......................... 54 
13.1. 
SUBJECT INFORMATION AND INFORMED CONSENT ............................................................. 54 
13.2. 
STUDY MONITORING ........................................................................................................... 54 
13.3. 
AUDITS AND INSPECTIONS ................................................................................................... 55 
13.4. 
ETHICS COMMITTEE REVIEW .............................................................................................. 55 
13.5. 
STANDARDS ......................................................................................................................... 55 
13.6. 
CONFIDENTIALITY ............................................................................................................... 56 
13.7. 
PROTOCOL ADHERENCE ...................................................................................................... 56 
13.8. 
AMENDMENTS TO THE PROTOCOL ....................................................................................... 57 
13.9. 
PROTOCOL DEVIATIONS ...................................................................................................... 57 
13.10. STUDY TERMINATION .......................................................................................................... 57 
13.11. INSPECTION OF RECORDS .................................................................................................... 58 
13.12. DATA MANAGEMENT .......................................................................................................... 58 
13.13. LIABILITY AND INSURANCE ................................................................................................. 58 
13.14. RETENTION OF RECORDS ..................................................................................................... 58 
13.15. DATA QUALITY ASSURANCE ............................................................................................... 59 
14. USE OF INFORMATION ............................................................................................................... 60 
15. REFERENCES .................................................................................................................................. 61 
APPENDIX 1: LABORATORY TESTS ................................................................................................ 65 
APPENDIX 2: SCHEDULE OF EVENTS ............................................................................................. 66 
 
Tables and Figures 
Figure 1: Illustration of Study Visits ..........................................................................................23 
Table 1: Identification of Investigational Product ....................................................................39 
Table 2: NCI CTCAE v. 4.03 Definitions for DLT Adverse Events ........................................41 
Table 3: Adverse Event Grading Terms ....................................................................................44 
Table 4: Adverse Event Relatedness Terms ..............................................................................44 


  
 
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ABBREVIATIONS 
ADL 
Activity of Daily Living 
AE 
Adverse Event 
αS 
Alpha-synuclein 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
COMT 
Catechol-O-methyltransferase 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSBM 
Complete Spontaneous Bowel Movement 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEP 
Dose Escalation Period 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety and Monitoring Board 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EKG 
Electrocardiogram 
ENS 
Enteric Nervous System 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FDP 
Fixed Dose Period 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HDPE 
High Density Polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IPAN 
Intrinsic Primary Afferent Neurons 
IRB 
Internal Review Board 
ITT 
Intention to Treat 
MedRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 


  
 
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MMSE 
Mini Mental State Examination 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NOAEL 
No Observable Adverse Effect Level 
PD 
Parkinson’s Disease 
RBD 
REM Behavior Disorder 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAPS-PD 
Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis 
SD 
Standard Deviation 
SNRI 
Serotonin Norepinephrine Reuptake Inhibitor 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TEAE 
Treatment Emergent Adverse Event 
MDS-
UPDRS 
International Parkinson and Movement Disorder Society - sponsored revision of the 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 
UPT 
Urine Pregnancy Test 
WOP 
Wash Out Period 
 
 
 


  
 
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1. 
BACKGROUND 
Parkinson’s disease is a progressive neurodegenerative disorder caused by accumulation of the 
protein alpha-synuclein (αS) within the enteric nervous system (ENS), autonomic nerves and brain 
(Braak).  The diagnosis of Parkinson’s disease requires the presence of motor symptoms such as 
rigidity, bradykinesia and tremor (Hughes), although non-motor symptoms such as constipation 
(Ondo, Lin), disturbances in sleep architecture (Ondo, Gjerstad), depression (Aarsland), cognitive 
dysfunction (Auyeung) and hallucinations (Friedman, Diedirich) represent significant therapeutic 
challenges (Zahodne). While the motor symptoms are the result of dysfunction of dopaminergic 
neuronal circuits largely involving the substantia nigra and basal ganglia, non-motor symptoms 
largely result from impaired function of non-dopaminergic neural pathways. A strategy that targets 
neurotoxic aggregates of αS in the gastrointestinal tract represents a novel approach to the 
treatment of Parkinson’s disease that may restore the function of the enteric nerve cells and prevent 
retrograde trafficking to the brain. Such actions could potentially benefit both dopaminergic and 
non-dopaminergic circuits and slow the progression of the disease in addition to restoring normal 
gastrointestinal function. 
In 2003, Braak proposed that Parkinson’s disease begins with the formation of toxic αS aggregates 
within the ENS and manifests clinically as constipation in a majority of people years before the 
onset of motor symptoms (Braak et al., 2006). We have recently reported that αS is induced in the 
ENS in response to viral, bacterial and fungal infections (Stolzenberg, et al., 2017) and that 
excessive intraneuronal  accumulation of αS promotes formation of  toxic aggregates (Perni et al., 
2017).  As a result of the normal trafficking of αS aggregates from the ENS to the central nervous 
system (CNS) via afferent nerves such as the vagus (Greene, 2014; Visanji et al., 2014), neurotoxic 
aggregates accumulate progressively within the brainstem and more rostral structures. Inhibiting 
αS aggregation in the ENS may reduce the continuing Parkinson’s disease process in both the ENS 
and CNS (Phillips, et al., 2008).  
ENT-01 is administered orally and acts locally on the ENS. The active ion of ENT-01, squalamine, 
an aminosterol originally isolated from the dogfish shark, has been shown to reverse 
gastrointestinal dysmotility in several mouse models of PD (West et al, manuscript in preparation). 
In addition, ENT-01 has been shown to inhibit the formation of aggregates of αS both in vitro, and 
in a C. elegans model of PD in vivo. In the C. elegans model in which the animal has been 
engineered to express human α-synuclein in its muscles, orally administered squalamine inhibits 
formation of membrane disruptive intracellular aggregates and produced a complete reversal of 
muscle paralysis (Perni et al., 2017).  
Squalamine is a small molecule, originally discovered in the liver of the dogfish shark, where it is 
delivered following a meal via the biliary tract into the intestine (Moore et al., 1993). When 


  
 
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squalamine is applied to the isolated colon and/or jejunum of a mouse, the compound stimulates 
organized peristaltic waves (Kunze et al, manuscript in preparation). This effect occurs through 
direct stimulation by squalamine of the intrinsic primary afferent neurons (IPANS) which are the 
most abundant type of neuron within the ENS. The IPANs, in turn, excite the ganglia of the 
myenteric plexus, and promote propulsive peristalsis. In addition, intense electrical signals are 
directed to the brainstem via the vagus following exposure of the ENS to squalamine which persist 
for some time. Of relevance to this clinical study, squalamine reverses the impaired motility of the 
colon from aged animals engineered to express a Parkinson’s disease phenotype.  
Furthermore, in a recent study, squalamine has been shown to prevent the formation of toxic alpha-
synuclein aggregates (Perni et al., 2017). The molecule accomplishes this as a consequence of its 
mechanism of action and the mechanism by which alpha-synuclein aggregates to form toxic 
polymers. Squalamine enters a neuron and binds to the negatively charged phospholipids that are 
present on the cytoplasmic face of the neuron’s plasma membrane, effectively neutralizing the 
negative charge of the membrane surface. Alpha-synuclein normally binds to the cytoplasmic face 
of the membrane via the positive charge on its N-terminus. Thus, when squalamine binds to the 
cytoplasmic face of the plasma membrane it displaces alpha-synuclein into the cytoplasm. As the 
concentration of alpha-synuclein on the membrane decreases, the likelihood that monomers will 
aggregate into higher order polymers decreases, thus reducing the rate of formation of aggregates 
and thereby rescuing neurons from certain death. At the same time, squalamine excites the neuron 
by displacing certain ion channels and transporters from the membrane. Thus, squalamine both 
excites the neurons of the ENS and protects them from alpha-synuclein induced cytotoxicity.  
In a Phase 2a (RASMET) study involving 50 patients with Parkinson’s disease and constipation, 
we assessed the safety of orally administered ENT-01, and the effect on bowel function and 
neurologic symptoms of PD. In addition, we identified a dose of ENT-01 that normalizes bowel 
function in each patient. The study achieved the objectives of identifying safety and 
pharmacodynamic responses and demonstrated that directly targeting αS pharmacologically can 
achieve beneficial GI, autonomic and CNS responses.  
The effective dose ranged between 75mg and 250mg, with 82.4% of patients responding within 
this range. This dose correlated positively with constipation severity at baseline consistent with 
the hypothesis that gastrointestinal dysmotility in PD results from the progressive accumulation of 
αS in the ENS, and that ENT-01 can restore neuronal function by displacing αS and stimulating 
enteric neurons. These results demonstrate that the ENS in PD is not irreversibly damaged and can 
be restored to normal function.  
Several exploratory endpoints were incorporated into the trial to evaluate the impact of ENT-01 
on neurologic symptoms associated with PD. The MDS-UPDRS score, a global assessment of 


  
 
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motor and non-motor symptoms showed significant improvement. Improvement was also seen in 
the motor component. Improvements were also seen in cognitive function (MMSE scores), 
hallucinations, REM-behavior disorder (RBD) and sleep. Six of the patients enrolled had daily 
hallucinations or delusions and these improved or disappeared during treatment in five. RBD and 
total sleep time also improved progressively in a dose-dependent manner.  
Most indices related to bowel function returned to baseline value by the end of the 2-week wash-
out period while improvement in the CNS symptoms persisted. The rapid   improvement in certain 
CNS symptoms is consistent with a mechanism whereby nerve impulses initiated from the ENS 
following ENT-01 administration augment afferent neural signaling to the CNS. This may 
stimulate the clearance of αS aggregates within the afferent neurons themselves as well as the 
secondary and tertiary neurons projecting rostrally within the CNS, since it is known that neural 
stimulation is accompanied by increased neuronal autophagic activity. We speculate that after 
cessation of ENT-01 administration, the neurons of the CNS would gradually re-accumulate an αS 
burden either locally or via trafficking from αS re-aggregation within the gut.   
We are currently evaluating ENT-01 as a therapeutic to treat the constipation and neurologic 
symptoms associated with Parkinson’s disease in a randomized Phase 2b (KARMET) study. Like 
the Phase 2a study, the randomized Phase 2b study has dosing between 75mg and 250mg and a 
treatment period limited to 25 days. This safety roll-over study is for patients who have completed 
the Phase 2b study, extending the treatment period for up to 14 weeks. 
We recently completed a 19-week dog and 26-week rat study. There were no safety concerns 
specifically in relation to the GI tract.  
Study rationale: 
Constipation is a major clinical component of Parkinson’s disease and is reported to occur in 
greater than 60% of affected individuals. The pathophysiological basis of constipation in 
Parkinson’s disease is generally believed to be due to delayed transit through the colon (Edwards 
et al., 1991; Klingelhoefer and Reichmann, 2015). Several studies have demonstrated that transit 
of stool through the colon of an individual with Parkinson’s disease is about 50% that measured 
in age matched controls. As a consequence, both stool frequency and stool consistency are 
abnormal in Parkinson’s disease. For many patients, as well as those caring for these individuals, 
constipation remains a significant morbidity associated with the condition (Salat-Foix and 
Suchowersky, 2012; Sung et al., 2014).  
Few placebo-controlled clinical trials have been conducted in the Parkinson’s disease population 
to assess the efficacy of therapeutics that could be of value. Addition of fiber to the diet, although 
increasing stool volume, is reported to have no effect on colon transit time (Ondo et al., 2012; 


  
 
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Zangaglia et al., 2007). An osmotic laxative, polyethylene glycol (Macrogol) has been studied in 
a small placebo controlled clinical trial of individuals with mild constipation, and shown to provide 
benefit with respect to stool frequency and consistency (Zangaglia et al., 2007). A short term 
placebo controlled trial of Lubiprostone, a chloride channel activator which increases intestinal 
fluid secretion, was only effective in about 50% of those treated, and resulted in passage of loose 
stools/diarrhea in place of constipation (Ondo et al., 2012). Furthermore, Lubiprostone delays 
gastric emptying (Camilleri et al., 2006), a function already compromised in Parkinson’s disease.  
The pathophysiology of the gastrointestinal (GI) dysfunction in Parkinson’s disease involves 
deposition of alpha-synuclein within both the ENS as well as within the brainstem. For reasons 
that remain unknown alpha-synuclein, which is a protein normally produced in neurons, forms 
neurotoxic intracellular aggregates in Parkinson’s disease. Numerous studies suggest that the 
alpha-synuclein aggregate formation begins in the ENS of the Parkinson’s disease individual many 
years before the onset of the motor symptoms (Braak et al., 2006). As a consequence of the normal 
retrograde neuronal trafficking that occurs within the vagus nerve, toxic aggregates are transported 
from the neurons of the ENS to the dorsal motor nucleus of the vagus, and then, gradually to sites 
within the brain that are involved in physical movement and balance (Greene, 2014; Visanji et al., 
2014). Because the constipation is fundamentally of an acquired neurodegenerative nature, it 
differs, so far as we now understand, from other forms of this condition (Visanji et al., 2014). 
The mechanism of action of squalamine has been elucidated over the past decade. The molecule 
is structurally related to a bile salt, but bears a polyamine, giving it a net positive charge. It is 
produced naturally in the liver of the dogfish shark and delivered along with bile salts to small 
intestine via the bile duct. Based on studies conducted ex vivo with isolated segments of mouse 
jejunum and colon, and our knowledge of squalamine’s mechanism of action at a cellular level, 
we can understand the prokinetic effects of squalamine on intestinal motility. Once within the 
lumen of the intestine, squalamine is transported from the epithelium into the lamina propria where 
it enters neurons of the ENS, including the intrinsic primary afferent neurons, the most abundant 
neuron of the ENS (Furness et al., 1999). Once within the neuron, the positively charged 
squalamine molecule is attracted to the inner face of the plasma membrane, which has a negative 
surface charge, due to the presence of anionic phospholipids, neutralizing the negative charge 
(Zasloff et al., 2011). As a consequence, many proteins that are bound to the inner face of the 
cytoplasmic face of the plasma membrane are displaced or functionally altered, including ion 
channels and transporters (Sumioka et al., 2009; Yeung et al., 2008). By this mechanism, 
squalamine activates the firing of the IPANs, which in turn, activate the myenteric plexus, resulting 
in propulsive migrating motor complexes (MMCs), and direct electrical activity rostrally to the 
brainstem via the vagus (Kunze et al, manuscript in preparation).  


  
 
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Alpha-synuclein normally binds to membranes composed of a high proportion of anionic 
phospholipids via its positively charged N-terminus (Shi et al., 2015). When the intracellular 
concentration of alpha-synuclein increases, the concentration of alpha-synuclein molecules bound 
to the inner face of the cytoplasmic membrane increases proportionally, and as it does the 
probability that they will physically contact one another and aggregate increases. In individuals 
with Parkinson’s disease, these aggregates grow in size and eventually overwhelm the cell’s 
capacity to digest the inclusions, whereas in those without Parkinson’s disease these aggregates 
are cleared by autophagy (Recchia et al., 2004). In a recent study we show that squalamine 
effectively displaces alpha-synuclein from the surface of a negatively charged membrane surface, 
and completely prevents aggregate formation. These studies have been conducted in specialized 
in vitro systems as well as in a validated in vivo model of Parkinson’s disease, a genetically 
engineered strain of C. elegans expressing human alpha-synuclein. Oral treatment of C. elegans 
with squalamine prevents the aggregation of alpha-synuclein within the muscles of the animal and 
reverses the paralysis caused by these aggregates (Perni et al., 2017). 
Thus, squalamine has the remarkable property of stimulating peristaltic activity by directly 
activating the neurons of the ENS and via the same mechanism, inhibiting the formation of 
neurotoxic alpha-synuclein aggregates within the same neurons. In principle, squalamine could 
reverse the neurodegenerative process within the ENS of the individual with Parkinson’s disease. 
If indeed the pathophysiology of the central nervous system (CNS) component of Parkinson’s 
disease occurs as a consequence of the trafficking of alpha-synuclein aggregates from the ENS to 
the brain via the connecting nerves, then squalamine could have an impact on the disease process 
occurring within the CNS both therapeutically and prophylactically.  
A Phase 2a study involving 50 patients with Parkinson’s disease and constipation was recently 
conducted (RASMET; IND 130770, NCT03047629).  The purpose of the study was to assess the 
safety, tolerability, pharmacokinetics, and pharmacodynamics of orally administered medication 
to relieve symptoms of constipation associated with Parkinson’s disease. The study consisted of 
an 8 to 12-week Stage 1 period, and an 8 to 10-week Stage 2 period. All subjects received the 
study drug during one of the observational periods of the study. The study evaluated the safety of 
ENT-01, and its effect on bowel function and neurologic symptoms.  
In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum 
tolerated dose (MTD). The goal was to determine safety and tolerability. In Stage 2, 34 patients 
received daily doses escalating from 75 to a maximum of 250mg/day, a dose that induced change 
in bowel function or MTD, followed by a “fixed” dose for 7 days, and a 2-week washout. Primary 
efficacy endpoint was defined as increase of 1 complete spontaneous bowel movement 
(CSBM)/week, or 3 CSBM/week over 14-day baseline period. Safety was also assessed. 


  
 
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In Stage 2, 82.4% patients achieved the primary efficacy endpoint. Mean CSBM/week increased 
from 1.2 at baseline to 3.6 during fixed dose (p=1.2x10-7) (Hauser et al., 2019). Common adverse 
events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients.  No study-drug related 
serious adverse events were reported.  The only SAE was a GI bleed after medication was 
discontinued in one patient.  This patient was on aspirin, Plavix, and Motrin, and the SAE was 
considered unrelated to study medication.  There were no deaths. The only other noteworthy AE 
was dizziness 8/44 (18%).  Dizziness was graded as moderate in one patient who was receiving an 
alpha-adrenergic blocking agent (Terazosin).  This patient was withdrawn from the study and 
recovered spontaneously.  All other AEs resolved spontaneously without discontinuation of 
ENT-01.  The details of the RASMET study AEs are in the study report contained in IND 130770. 
Significant and lasting improvements were observed in total MDS-UPDRS scores (p=0.0008), the 
MDS-UPDRS-Part III scores (motor component) (p=0.0006), cognition (MMSE) (p=0.0004), 
hallucinations, sleep, and circadian rhythm (p=0.016).  Hallucinations improved in 5/6 patients. 
Systemic absorption was < 0.3%. 
The results of the study indicated that orally administered ENT-01 was safe and significantly 
improved bowel function and neurologic symptoms. Minimal systemic absorption suggests that 
improvements result from local stimulation of the ENS.  
A randomized, placebo-controlled Phase 2b study (KARMET) of orally administered ENT-01 is 
currently being conducted in patients with PD and constipation. Dosing is daily, beginning at either 
75 mg (baseline CSBM 1.0-3.0) or 150 mg (baseline CSBM 0-0.9) and escalating by 25 mg every 
3 days until pro-kinetic effect or a maximum dose of 250 mg. Total treatment duration is 25 days.  
A top-line data cut of the first 57 patients (an extension study is currently being performed) showed 
that ENT-01 achieved the primary efficacy endpoint in the treatment of constipation, with CSBM 
frequency increasing from 1.0 at baseline to 4.8 at the end of the fixed dosing period.  Six patients 
exhibited hallucinations and/or delusions at the beginning of the study.  These neurological 
symptoms disappeared or improved in 5 subjects randomized to ENT-01 but not in the 1 placebo 
patient.  The dose required for improvement or disappearance of these neurological symptoms was 
patient specific.  There were also improvements in other CNS parameters, including motor 
symptoms and memory.   
Many of the AE were confined to the GI tract and were mild to moderate. Common adverse events 
included nausea in 10/53 (18.3%), diarrhea in 4/53 (7.4%), and abdominal pain in 4/53 (7.4%). 
There were 4 SAEs, 2 hospitalizations for joint replacement (1 patient on ENT-01 and 1 on 
placebo), 1 hospitalization for cholecystectomy and 1 for diuretic induced hypokalemia with 
weakness. Two of the 6 falls in the ENT-01 group occurred during the treatment period, the other 


  
 
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4 did not. In both cases the patient had a prior history of falls.  The study is on-going, and a study 
report will be filed at the conclusion of the study.  
We recently conducted studies in the rat administered ENT-01 orally up to 80 mg/kg/day for 
26 weeks and found no significant drug-related systemic or local toxicity, establishing the NOAEL 
to be ≥ 80 mg/kg/day.  The maximum daily dose of ENT-01 to be administered in the planned trial 
is 250 mg (3.1 mg/kg), reflecting a safety margin of > 26-fold. We also conducted studies in the 
dog administered ENT-01 orally up to 20 mg/kg/day for 19 weeks and found no significant drug-
related systemic or local toxicity, establishing the NOAEL to be ≥ 20 mg/kg/day.  The maximum 
daily dose of ENT-01 to be administered in the planned trial is 250 mg (3.1 mg/kg), providing a 
safety margin of > 6-fold. 
In Stage 1 of RASMET a single oral dose of 200 mg of ENT-01 (114 mg/m2) resulted in an 
AUC 0-16hr of about 160 ng*hr/ml. At an intravenous dose of 130 mg/m2, the AUC0-24hr is estimated 
to be about 100,000 ng*hr/ml, or about 1000-fold higher, resulting in an estimate of ENT-01 oral 
bioavailability of less than 0.3%.  The MTD of intravenously administered squalamine (as judged 
over a 5-day period of continuous infusion) was estimated to be between 300-700mg/m2, where 
the corresponding AUC0-24hr was between 200,000-400,000 hr*ng/ml, respectively, representing 
plasma exposure over 1,000-fold higher than that reached following a 200 mg oral dose of ENT-01. 
Since nausea and diarrhea limit the maximal oral dose of ENT-01 to about 250 mg unintentional 
overdosing is unlikely to occur. 
The only difference between this study and both previous studies is the duration of dosing. Both 
prior studies were limited to total dosing of 25 days, whereas in this safety roll-over study, subjects 
will be dosed for 14 weeks. Those subjects who were randomized to ENT-01 during the preceding 
Phase 2b study (KARMET Stage 2 Extension subjects,) will have been dosed for an additional 
25 days, bringing the total dosing period to 18 weeks. Both the 19-week dog study and human data 
from the RASMET and KARMET studies support the safety of ENT-01 via oral administration 
up to 250 mg/day for 14 weeks. With oral bioavailability of less than 0.3%, orally administered 
ENT-01 attains systemic concentrations several hundred-fold lower than reached in the IV studies.  
In the RASMET and ongoing KARMET trials most AEs were mild, confined to the GI tract, and 
spontaneously resolved without discontinuation of ENT-01. 
Since the systemic absorption of ENT-01 in man is <0.3%, our principal safety concerns focused 
on the local toxicity to the GI tract.  No toxicity of this type has been observed to date in either the 
RASMET or the ongoing KARMET trials. Local toxicity to the GI tract will continue to be the 
focus of the proposed study. 
 
 


  
 
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2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Primary Safety Objective 
To determine the safety and tolerability of orally administered ENT-01 for approximately 
14 weeks in subjects with Parkinson’s disease-related constipation. 
Safety endpoints will include adverse events as evaluated with subject self-reporting, vital 
signs, clinical chemistry and hematology blood analyses, urinalysis, and electrocardiogram 
(EKG).  
During the dosing period, it is anticipated that no more than 2 subjects out of 50 (4.0%) 
will have an adverse event of grade 4 or 5 that is at least possibly related to ENT-01. Should 
there be more than 2 subjects with an adverse event grade 4 or 5 that is at least possibly 
related to ENT-01 in the cohort of subjects, the study will be put on an immediate clinical 
hold. Safety Monitoring processes are identified in Section 10.14.  
In addition, individual safety stopping rules will include: 
• Reaching dose-limiting tolerability (DLT) before a prokinetic effect 
• Having a non-DLT gastrointestinal adverse event > grade 3 within 24 hours of taking 
study medication that is at least possibly attributable to ENT-01 
Tolerability 
Tolerability endpoints are referred to as the DLT and will include:  
• Recurrent vomiting defined as 3-5 episodes of vomiting within 24 hours of taking 
study medication (i.e., a Grade 2 or higher AE, see Table 2). 
• Recurrent diarrhea defined as 7 episodes of diarrhea within 24 hours of taking study 
medication on 2 consecutive days (i.e., a Grade 3 or higher AE, see Table 2). 
• Dizziness defined as lightheadedness or fainting on rising from lying to sitting or 
standing that requires non-urgent medical intervention within 24 hours of taking 
study medication. (i.e., a Grade 2 or higher AE see Table 2). 
It is anticipated that all subjects will exhibit a prokinetic effect at a dose lower than DLT 
and less than or equal to 250mg. Subjects reaching DLT before a prokinetic effect will be 
treated at the highest dose at which they did not experience a DLT. 


  
 
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2.2. 
Primary Efficacy Objective and Endpoints 
The primary efficacy objective of the study is to evaluate the effect of orally administered 
ENT-01 in improving constipation in subjects with Parkinson’s disease-related 
constipation.  
Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is to determine the change from baseline in 
weekly CSBM rate during the 12 weeks of the fixed dose period. Baseline weekly CSBM 
rate will be determined during the preceding randomized study.  
2.3. 
Secondary Efficacy Objectives and Endpoints 
The Secondary Efficacy Objectives of the study are:  
• Change from baseline in the symptoms of Parkinson’s disease  
• Change from baseline in cognition 
• Change from baseline in psychosis 
Secondary Efficacy Endpoints will include the following: 
• Change from baseline in the MDS-UPDRS Parts 1-3 score at the end of the 12-week 
fixed dose period. Baseline is defined as the MDS-UPDRS score at the screening 
Visit of this roll-over study.  
• Change from baseline in cognition will be assessed by MMSE scores at the end of the 
12-week fixed dose period. Baseline is defined as the MMSE score at the screening 
Visit of this roll-over study.  
• Change from baseline in psychosis as assessed by the SAPS-PD at the end of the 
12-week fixed dose period. Baseline is defined as the SAPS-PD score at the screening 
Visit of this study.  
 
 


  
 
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3. 
STUDY DESCRIPTION 
The purpose of this Study is to obtain safety data and stool diary data out to approximately 14 
weeks (approximately 2 weeks of dose escalation plus 12 weeks of fixed dosing, see Figure 1 
below.) All subjects who participated in the randomized KARMET trial (ENT-01-030, Stage 2 
Extension subjects) and who are interested in participating in this open label safety roll-over study 
will be offered participation. Subjects from KARMET Stage 1 (non-randomized) are not eligible 
to participate in this roll-over study. There is no restriction on the time lag between the subject’s 
prior participation in ENT-01-030 and eligibility to enroll in this study, and subjects may enroll in 
this study the same day as completing the final study visit (Visit 6) of ENT-01-030. 
Figure 1: Illustration of Study Visits 
 
Approximately 50 subjects will be entered at up to 20 sites in the US, assuming 75% of patients 
randomized to ENT-01 and 50% of patients randomized to placebo choose to participate.  Each 
subject will have 5 visits to the clinic in person (under exceptional circumstances some of these 
may have to be conducted via Telemedicine): Visit 1/Screening or dosing initiation; Visit 
2/Beginning of Fixed Dose period (FDP); Visit 3/End of 6 weeks of FDP; Visit 4/End of 12 weeks 
of FDP; Visit 5/end of 6 weeks of wash out period (WOP)/End of study. It is anticipated that the 
duration of study participation for each subject will be approximately 20 weeks, as it is anticipated 
that the majority of subjects will require less than 20 days to reach their fixed dose.    
Subjects will discontinue opiates and all laxatives, bulking agents, stool softeners, suppositories, 
proton pump inhibitors, antacids, and certain antipsychotics and antidepressants from Visit 
1/Screening until Visit 4/End of 12 weeks of FDP. Where on stable doses, subjects may continue 
the use of antihistamines and anti-histaminergic agents, anti-cholinergics, COMT inhibitors, 
dopamine agonists, amantadine, and certain anti-psychotic and anti-depressant medications. (See 
Section 7 Concomitant and Prohibited Medications and Therapies.) 


  
 
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Subjects will keep daily electronic stool diaries and will record information concerning stools 
immediately after each bowel movement, including stool frequency, consistency, ease of 
evacuation, completeness, and the use of rescue medication. Site staff will monitor these entries 
regularly to ensure subjects are not at risk of becoming impacted and are using rescue medication 
appropriately. Site staff will contact subjects if the web-based questionnaires are not being 
completed on a daily basis or if there are any safety concerns. 
Each subject will be started on a pre-defined dose based upon their baseline CSBM rate during the 
randomized study, then will be able to increase their dose every 2-3 days until they reach a 
pro-kinetic dose or the maximum dose of 250mg.  This is called the Dose Escalation Period (DEP). 
After the subject documents 4 CSBMs over 5 consecutive days, the subject will fix at that dose for 
the remainder of the study.  This is called the Fixed Dose Period (FDP). At the end of the FDP 
medication will be discontinued and a 6-week wash-out period (WOP) will follow.  Daily stool e-
diary will be entered throughout the dosing period.  
Rescue medications (including oral Bisacodyl, suppositories, and enemas,) will be provided to 
subjects and will be initiated in the evening of the third day if a subject has had no bowel movement 
for three consecutive days.  
Study medication will be taken on an empty stomach first thing in the morning with 8 oz water 
and no food will be allowed for 60 minutes. Subjects prescribed levodopa should wait at least 
30 minutes between taking levodopa and study medication. Tea and coffee with/without 
milk/sugar and orange juice (without pulp) are permitted. Plain yoghurt can be added if the patient 
experiences repeated nausea.  
Symptoms of Parkinson’s disease will be assessed using the Unified Parkinson’s disease Rating 
Scale (MDS-UPDRS, Parts I-III) by certified raters and patients with fluctuations and prescribed 
levodopa will be assessed during “ON” states, approximately one hour after levodopa intake. 
Subjects who prematurely discontinue study drug for any reason will be asked to have an Early 
Termination (ET) visit within 3 days following the last study drug dose. If a subject discontinues 
study drug during a scheduled visit, then the Early Termination visit will be conducted at that time. 
(Early Termination visit assessments are the same as Visit 4.)  
 
 


  
 
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3.1. 
Pre-Screening Planning 
Subjects who wish to continue taking ENT-01 after completing the ENT-01-030 study may “roll 
over” into this study. They can do this on the same day as their final study visit (Visit 6) for 
ENT-01-030, but they are not required to do so. Keep in mind the following to help with planning 
for “roll over” subjects: 
• Informed Consent may be obtained before ENT-01-030 Visit 6 or Visit 1 of this study. Doing 
so would allow the subject to discontinue or refrain from the use of any prohibited 
medications listed in Section 7 prior to the visit, potentially allowing them to take the 
ENT-01 study medication earlier. 
• There is no limit on the amount of time between completing ENT-01-030 and being able to 
screen for this study. 
• If the subject “rolls over” within 14 days of ENT-01-030 Visit 6, then any procedures 
common to both studies do not need to be repeated. See Appendix 2: Schedule of Events and 
the individual visit descriptions below. 
• Subjects may retain their ENT-01-030 diary device for use in this study.  
• If the subject started or restarted any medications listed in Section 7 of this protocol before 
their ENT-01-030 Visit 6, they will need to discontinue them for 14 days before starting to 
take the ENT-01 study medication. This may affect the timing of Visit 2, depending on how 
long it takes them to reach a fixed dose. 
• If a subject is taking levodopa and has fluctuations but does not “roll over” on the same day 
as their ENT-01-030 Visit 6, remind them about levodopa dose timing for the MDS-UPDRS. 
 
 


  
 
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3.2. 
Visit 1: Screening and Dose Escalation Period (Day -20 to Day 1) 
Reminders 
• Once consented and eligibility is confirmed, subjects with fluctuations and 
prescribed levodopa should take their daily levodopa dose so that they are 
in an ON state when the MDS-UPDRS is administered. For most subjects, 
this would be approximately 60 minutes after taking levodopa. 
• Subjects must have discontinued and refrain from using any laxatives, 
constipation medications, and other medications as specified in Section 7 
for 14 days prior to starting ENT-01 dosing. (These “washout” days are 
not counted in the schedule, as described below.)  
 
Perform the assessments and procedures as listed in Appendix 2: Schedule of Events: 
• Informed consent 
• Inclusion/Exclusion Criteria 
• Demographics/Medical History 
• Complete Physical Exam 
• Weight (Height from ENT-01-030 will be used, so it is not required to be recorded) 
• Orthostatic Vital Signs: Vital signs will include supine blood pressure and heart rate, sitting 
or standing blood pressure and heart rate, respiratory rate, and body temperature.  Supine 
measurements will be taken after the subject has been in the supine position for at least 5 
minutes.  Sitting or standing measurements will be taken within 5 minutes of the subject 
sitting or standing from the supine position. 
• 12-lead EKG 
• Labs (chemistry, hematology, and urinalysis): as defined in Appendix 1: Laboratory Tests. 
• Pregnancy Testing – For women of child-bearing potential, this is done on-site with the urine 
pregnancy kit (UPT) provided.  If the on-site UPT is positive, then a serum pregnancy test 
will be done.  For post-menopausal women less than 60 years of age, a serum FSH will be 
done at the screening visit only. 
• Instruct subject to refrain from using or discontinue the use of any laxatives, constipation 
medications, and other medications as specified in Section 7 for 14 days prior to starting 
ENT-01 dosing. Determine the date ENT-01 dosing should begin and provide to the subject. 
(Although Visit 1 is listed as Day -20, that is more of a rough estimate for schedule planning. 
Most subjects should get to their fixed dose before 20 days; at that point Day 1 for that 
subject is set and their remaining visits are scheduled based on Day 1.) 


  
 
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• Dispense Rescue Medication and instruct on use: Subjects will be provided with rescue 
medications (including oral Bisacodyl, suppositories, and enemas,) and instructed on their 
use.  Subjects will use rescue medications per investigator instructions to ensure adequate 
BMs every 3 days. 
• Dispense ENT-01 with instructions regarding starting dose and escalation regimen. 
• Educate subject with respect to stool diary daily entries. 
• Assess for Adverse Events 
• Review Prior and Concomitant Medications/Therapies 
• MDS-UPDRS – Only Parts I, II, and III of the scale will be rated, assessed by personnel 
certified in the MDS-UPDRS. Subjects with fluctuations and prescribed levodopa should be 
assessed when in an ON state. Non-fluctuating subjects and subjects not on levodopa can be 
assessed at any point during the visit. 
• SAPS-PD  
• MMSE 
The SAPS-PD is repeated at every visit only if the SAPS-PD score is > 0 at screening. 
The purpose of the dose escalation is to achieve a pro-kinetic dose. The prokinetic dose is the dose 
that results in a CSBM on at least 4 of 5 consecutive dosing days. Starting dose will be determined 
by the baseline weekly CSBM rate as determined during the randomized study. Dose will be 
escalated by one tablet (25mg) every 2 or 3 days until a pro-kinetic dose or the maximum dose is 
reached. If repeated diarrhea occurs at a given dose, the dose will be reduced by one tablet (25mg).  
Care will be given to ensure that patients take rescue medication as instructed during this period. 
Subjects will self-administer the study medication at home; either starting the following morning 
or on the date instructed. (The day the subject starts taking study medication is considered 
Day -20.)  
• Subjects with baseline CSBM of 0-0.9 at the beginning of the randomized study will begin 
treatment at 150 mg of ENT-01.   
• Subjects with baseline CSBMs of 1.0-3.0 at the beginning of the randomized study will begin 
treatment at 75 mg of ENT-01.  
The dose will be taken upon awakening on an empty stomach along with 8 oz. of water. Subjects 
prescribed levodopa should wait at least 30 minutes between taking levodopa and study 
medication. The subject will be instructed to not eat for at least 60 minutes after study drug 
administration. Tea, coffee with/without milk/sugar and orange juice (without pulp) are permitted. 
Plain yoghurt can be added if the patient experiences repeated nausea. Dosing will be increased 
every 2-3 days until a pro-kinetic dose or the maximum dose is reached. If the subject has not 


  
 
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produced a CSBM within 24 hours of on at least 4 of 5 consecutive days, then they will increase 
their daily dose by 1 tablet (by 25 mg). This incremental dosing will continue until the subject: 
• reaches the prokinetic dose (the dose producing a CSBM within 24 hours on at least 4 of 
5 consecutive days). The subject then remains on that dose until Visit 4; 
• reaches the maximum dose of 10 tablets (250mg for active treatment); or,  
• reaches the dose limiting tolerability (DLT). 
If the subject has 7 or more discrete episodes of diarrhea separated by 30 minutes or more within 
24 hours at any dose on 2 consecutive days, the dose will be reduced by 25mg and fixed at that 
dose (assuming the diarrhea abates at the lower dose).  
Should a prokinetic response not occur at the maximum allowed number of tablets (10 tablets or 
250mg), subjects will continue to take 10 tablets throughout the Fixed Dose period. 
Site staff will review subject diary entries daily and contact subjects as needed to ensure subject 
safety, compliance with study and dosing instructions, and to determine the subject’s individual 
fixed dose level. The day that a subject “fixes” their dose for the first time (as determined by site 
staff) is considered Day 1 for the purposes of scheduling subsequent study visits. 
 
 


  
 
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3.3. 
Visit 2: Beginning of Fixed Dose Period (Day 1, +3 days) 
This visit is to be done within 3 days from dose fixing. Perform the assessments and procedures 
as listed in Appendix 2: Schedule of Events: 
• Brief Physical Exam (review of body systems as indicated) 
• Weight 
• Orthostatic Vital Signs: Vital signs will include supine blood pressure and heart rate, sitting 
or standing blood pressure and heart rate, respiratory rate, and body temperature.  Supine 
measurements will be taken after the subject has been in the supine position for at least 5 
minutes.  Sitting or standing measurements will be taken within 5 minutes of the subject 
sitting or standing from the supine position.   
• 12-lead EKG 
• Labs (chemistry, hematology, urinalysis, pregnancy): as defined in Appendix 1: Laboratory 
Tests. 
• IP Collection and Accountability 
• Dispense Rescue Medication, as needed. Subjects continue appropriate use of rescue 
medication, ensuring adequate bowel movements every 3 days. 
• Dispense ENT-01 for 6 weeks of dosing with instructions regarding dosing. 
• Re-educate subject with respect to stool diary daily entries. 
• Assess for Adverse Events (new, ongoing, since last visit, etc.) 
• Review Concomitant Medications/Therapies (current, since last visit, etc.) 
• MDS-UPDRS – Only Parts I, II, and III of the scale will be rated, assessed by personnel 
certified in the MDS-UPDRS. Subjects with fluctuations and prescribed levodopa should be 
assessed when in an ON state. Non-fluctuating subjects and subjects not on levodopa can be 
assessed at any point during the visit. 
• SAPS-PD (for subjects who scored > 0 on the SAPS-PD at screening.) 
 
 


  
 
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3.4. 
Visit 3: 6th week of FDP (Day 43, +/- 3 days) 
Perform the assessments and procedures as listed in Appendix 2: Schedule of Events: 
• Brief Physical Exam (review of body systems as indicated) 
• Weight 
• Orthostatic Vital Signs: Vital signs will include supine blood pressure and heart rate, sitting 
or standing blood pressure and heart rate, respiratory rate, and body temperature.  Supine 
measurements will be taken after the subject has been in the supine position for at least 5 
minutes.  Sitting or standing measurements will be taken within 5 minutes of the subject 
sitting or standing from the supine position.   
• 12-lead EKG 
• Labs (chemistry, hematology, urinalysis, pregnancy): as defined in Appendix 1: Laboratory 
Tests. 
• IP Collection and Accountability 
• Dispense Rescue Medication, as needed. Subjects continue appropriate use of rescue 
medication, ensuring adequate bowel movements every 3 days. 
• Dispense ENT-01 for 6 weeks of dosing with instructions regarding dosing. 
• Re-educate subject with respect to stool diary daily entries. 
• Assess for Adverse Events (new, ongoing, since last visit, etc.) 
• Review Concomitant Medications/Therapies (current, since last visit, etc.) 
• MDS-UPDRS – Only Parts I, II, and III of the scale will be rated, assessed by personnel 
certified in the MDS-UPDRS. Subjects with fluctuations and prescribed levodopa should be 
assessed when in an ON state. Non-fluctuating subjects and subjects not on levodopa can be 
assessed at any point during the visit. 
• SAPS-PD (subjects who scored > 0 on the SAPS-PD at screening) 
 
 


  
 
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3.5. 
Visit 4: 12th week of FDP, Start of WOP, ET (Day 85, +/- 3 days) 
Perform the assessments and procedures as listed in Appendix 2: Schedule of Events: 
• Brief Physical Exam (review of body systems as indicated) 
• Weight 
• Orthostatic Vital Signs: Vital signs will include supine blood pressure and heart rate, sitting 
or standing blood pressure and heart rate, respiratory rate, and body temperature.  Supine 
measurements will be taken after the subject has been in the supine position for at least 5 
minutes.  Sitting or standing measurements will be taken within 5 minutes of the subject 
sitting or standing from the supine position.   
• 12-lead EKG 
• Labs (chemistry, hematology, urinalysis, pregnancy): as defined in Appendix 1: Laboratory 
Tests. 
• IP Collection and Accountability  
• Reinstate all discontinued medications, antacids, proton pump inhibitors and laxatives. 
• Dispense Rescue Medication, as needed. Subjects continue appropriate use of rescue 
medication, ensuring adequate bowel movements every 3 days. 
• Re-educate subject with respect to stool diary daily entries. 
• Assess for Adverse Events (new, ongoing, since last visit, etc.) 
• Review Concomitant Medications/Therapies (current, since last visit, etc.) 
• MDS-UPDRS – Only Parts I, II, and III of the scale will be rated, assessed by personnel 
certified in the MDS-UPDRS. Subjects with fluctuations and prescribed levodopa should be 
assessed when in an ON state. Non-fluctuating subjects and subjects not on levodopa can be 
assessed at any point during the visit. 
• SAPS-PD (for subjects who scored > 0 on the SAPS-PD at screening.) 
• MMSE 
 
 


  
 
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3.6. 
Visit 5: End of 6-week Wash-out Period/End of study (Day 127, +/- 3 days) 
Perform the assessments and procedures as listed in Appendix 2: Schedule of Events: 
• Brief Physical Exam (review of body systems as indicated) 
• Weight 
• Orthostatic Vital Signs: Vital signs will include supine blood pressure and heart rate, sitting 
or standing blood pressure and heart rate, respiratory rate, and body temperature.  Supine 
measurements will be taken after the subject has been in the supine position for at least 5 
minutes.  Sitting or standing measurements will be taken within 5 minutes of the subject 
sitting or standing from the supine position.   
• 12-lead EKG 
• Labs (chemistry, hematology, urinalysis, pregnancy): as defined in Appendix 1: Laboratory 
Tests. 
• Assess for Adverse Events (new, ongoing, since last visit, etc.) 
• Review Concomitant Medications/Therapies (current, since last visit, etc.) 
• MDS-UPDRS – Only Parts I, II, and III of the scale will be rated, assessed by personnel 
certified in the MDS-UPDRS. Subjects with fluctuations and prescribed levodopa should be 
assessed when in an ON state. Non-fluctuating subjects and subjects not on levodopa can be 
assessed at any point during the visit. 
• SAPS-PD (for subjects who scored > 0 on the SAPS-PD at screening.) 
• Collect eDiary device. 
 
 


  
 
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4. 
STUDY POPULATION 
Subjects will have participated in Stage 2 of the randomized, double-blinded KARMET study 
ENT-01-030. All subjects who complete the treatment period in that study will be offered 
participation in this safety roll-over study. 
Number of Subjects  
Approximately 50 subjects will be included, and approximately 40 will complete all visits, 
assuming a 20% early termination rate. 
 
 


  
 
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5. 
SELECTION CRITERIA 
Subjects will be screened according to the inclusion/exclusion criteria below.  
Inclusion Criteria  
1. All subjects who participated in the randomized study ENT-01-030 (KARMET Stage 2 
Extension subjects) and who completed the dosing period. 
2. Subjects aged 30-90 years at the time of screening for the ENT-01-030 study, both genders. 
3. Subjects must provide informed consent and be willing and able to comply with study 
procedures. 
4. Subjects must be able to read, understand, and accurately record data into the diary to 
guarantee full participation in the study. 
5. Female subjects must have negative serum or urine pregnancy tests and must not be lactating. 
For females able to bear children, a hormonal (i.e., oral, implantable, or injectable) and 
single-barrier method, or a double-barrier method of birth control must be used throughout 
the study. A vasectomized partner will be allowed as one in conjunction with another single-
barrier method. 
6. Female subjects unable to bear children must have this documented in the CRF (i.e., tubal 
ligation, hysterectomy, or postmenopausal [defined as a minimum of one year since the last 
menstrual period]). Post-menopausal status will be confirmed by follicle stimulating 
hormone (FSH) in women less than 60 years of age. 
Exclusion Criteria 
1. Unable or unwilling to provide informed consent or to comply with study procedures. 
2. Unable to withdraw proton pump inhibitors. 
3. Unable or unwilling to withdraw from laxatives, opiates, clonazepam, or any medications 
which may cause constipation 2 weeks prior to the dose adjustment period and throughout 
the rest of the study. 
4. Diagnosis of secondary constipation beyond that of Parkinson’s disease. 
5. A compromised gastrointestinal system which includes: 
• Structural, metabolic, or functional GI diseases or disorders. 
• Acute GI illness within 2 weeks of the screening visit. 
• History of major GI surgery within 30 days of the screening visit (a history of 
cholecystectomy, polypectomy, hernia repair or appendicectomy are not exclusionary as 
long as they were performed more than 30 days before the screening visit). 
6. Neurological disorder other than Parkinson’s disease that in the opinion of the investigator 
might interfere with the conduct of the study. 


  
 
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7. On treatment with intra-jejunal dopamine or carbidopa/levodopa (i.e. Duopa). 
8. Subjects starting a new Parkinson’s disease medication or modifying an existing medication 
within 2 weeks prior to enrollment. 
9. Unable to maintain a stable diet regimen. 
10. Subjects with a cognitive impairment that preclude them from understanding the informed 
consent. 
11. Subjects placed under legal guardianship. 
12. History of excessive alcohol use or substance abuse. 
13. Any clinically significant abnormalities on screening laboratories or physical examination 
requiring further evaluation or treatment. 
14. Females who are pregnant or breastfeeding. 
15. Subject or caregiver unable to administer daily oral dosing of study drug. 
16. Participation in a non-Enterin investigational drug trial within the month prior to dosing in 
the present study. 
17. Any other reason, which in the opinion of the investigator would confound proper 
interpretation of the study. 
 
 


  
 
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6. 
DISCONTINUATION CRITERIA AND EARLY TERMINATION 
PROCEDURES 
Subjects may withdraw voluntarily from participation in the study at any time and for any reason. 
Subjects may also be withdrawn on the basis of the Investigator’s clinical judgment. 
This study may be terminated at the discretion of the Enterin, Inc. or of any regulatory agency for 
reasons including safety and/or efficacy.  
When a subject withdraws or is withdrawn before completing the study, the date and reason for 
withdrawal are to be documented. Subjects who withdraw or who are withdrawn prematurely are 
to attend an early discontinuation visit, at which time they will complete all Visit 4 assessments as 
outlined in Appendix 2: Schedule of Events. The subject will be asked to return in 42 ± 3 days 
(6 weeks) to the site for Visit 5 as a safety follow-up visit. 
In the event that a subject is withdrawn prematurely due to an adverse event or serious adverse 
event, the adverse event or serious adverse event will be followed until it resolves or stabilizes, or 
until it is judged by the investigator to be no longer clinically significant.  
 
 


  
 
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7. 
CONCOMITANT AND PROHIBITED MEDICATIONS AND 
THERAPIES 
Categories of medications are listed below. Enterin will provide investigative sites with detailed 
listings of specific medications. All medications shall be reviewed and approved or disapproved 
by the investigator on a case-by-case basis. 
Prohibited Medications to be discontinued at Screening (V1) and restarted during the wash-
out period (V4): 
• All oral laxatives, osmotic laxatives, pro-kinetic laxatives, stimulant laxatives, bulking 
agents, stool softeners, and suppositories, except for rescue medications used as directed 
in this protocol.  
• Antacids 
• Opiates 
• Proton pump inhibitors 
• Certain antipsychotics that worsen symptoms of Parkinson’s disease. 
• Certain antidepressants that worsen symptoms of Parkinson’s disease. 
Concomitant Medications permitted at stable doses 
• Anticholinergics 
• Antihistamines and anti-histaminergic agents 
• Catechol-O-methyltransferase COMT inhibitors 
• Certain antipsychotics 
• Certain antidepressants, including tricyclic and quadricyclic antidepressants  
• Dopamine agonists and amantadine (if on a stable dose for at least 2 weeks preceding the 
study). 
• Certain dopamine reuptake inhibitors 
• Dopamine metabolism inhibitors 
• Dopaminergic compounds 
• Selective serotonin reuptake inhibitors (SSRI) 
• Serotonin and norepinephrine reuptake inhibitors (SNRI)  
Permitted Therapies 
• Deep brain stimulation, if present for more than 6 months and at stable stimulation 
parameters. 


  
 
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8. 
MATERIALS 
8.1. 
Study Drug 
All study medication will be supplied by Enterin, Inc. as 25 mg tablets packaged in white 
opaque high-density polyethylene (HDPE) bottles with child-resistant closures. 
8.2. 
Packaging and Labeling 
Study medication will be shipped to the investigational sites in packaging. 
8.3. 
Storage, Dispensing and Reconciliation of Study Drug and Identity of 
Investigational Products 
All study medication should be stored at 20°C to 25°C (68°F to 77°F) until dispensed, at 
which time subjects may keep it at room temperature.  Storage on-site should be in a locked 
and secure location accessible only to site staff involved with this study.  A temperature 
log must be kept to document temperature which should be recorded at least once each 
working day. If the temperature is not maintained, the sponsor should be contacted. 
If a site becomes aware that study medication has not been properly handled, the sponsor 
must be contacted immediately. In such an event, study medication should not be dispensed 
to any subject until the sponsor provides further direction. 
Neither the investigator nor any study personnel will distribute any study medication to 
any person not participating in this study. The study medication will be dispensed at the 
discretion and direction of the investigator in accordance with the conditions specified in 
this protocol. It is the investigator’s responsibility to ensure that accurate records of study 
medication issuance and return are maintained. 
The sponsor is responsible for the tracking and accountability of study medication 
dispensed to sites and will inform sites how to return or destroy study medication once it 
is no longer needed at the site. 
 
 


  
 
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Table 1: Identification of Investigational Product 
Product Name 
ENT-01 
Dosage form 
Tablet 
Dosage level (mg) 
25 mg 
Route/dosage 
Oral. Doses will require 
multiple tablets:    
75 mg = 3 tablets 
100 mg = 4 tablets 
125 mg = 5 tablets 
150 mg = 6 tablets 
175 mg = 7 tablets 
200 mg = 8 tablets 
225 mg = 9 tablets 
250 mg = 10 tablets 
Dosing Instructions 
Take 60 minutes before 
breakfast with 8 oz. water 
 
 
 


  
 
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9. 
WARNINGS AND PRECAUTIONS 
Subjects will be advised to stay at home for 4-6 hours after taking the first dose of medication in 
case they need to evacuate urgently. Beyond the first dose, subjects themselves will be in a position 
to know if and when to leave the house.  
 
 


  
 
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10. STUDY PROCEDURES 
10.1. 
Observations and Measurements 
Subject informed consent must be obtained prior to conducting any study-related 
procedures. The Principal Investigator at each center will ensure that the subject is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Subjects must also be notified that they are free to discontinue from 
the study at any time. The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
All assessments and procedures will be completed according to Appendix 2: Schedule of 
Events.  
10.2. 
Instructions to Subjects 
Prior to entry into the study, subjects and their spouse/companion will be instructed about 
the use of rescue medication.  
10.3. 
CTCAE Definitions of Dose Limiting Adverse Events  
Table 2: NCI CTCAE v. 4.03 Definitions for DLT Adverse Events 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Diarrhea  
(watery stool) 
Increase of <4 
stools a day over 
baseline 
Increase of 4-6 
stools a day over 
baseline 
Increase of >7 
stools a day; 
incontinence; 
hospitalization 
indicated 
Life threatening 
complications: 
urgent intervention 
indicated 
Death 
Vomiting 
1-2 episodes per 24 
hours 
3-5 episodes per 24 
hours 
6 or more episodes 
in 24 hours; tube 
feeding, TPN or 
hospitalization 
indicated 
Life-threatening 
consequences: 
urgent intervention 
indicated 
Death 
Postural 
hypotension3 
Mild, transient 
lightheadedness or 
dizziness upon 
rising from lying or 
sitting position that 
does not interfere 
with ADL 
Moderate 
lightheadedness, 
dizziness or 
fainting upon rising 
from lying or 
sitting position that 
limits instrumental 
ADL; Non-urgent 
medical 
intervention 
indicated 
Severe 
lightheadedness, 
dizziness or 
fainting upon rising 
from lying or 
sitting position that 
limits self-care 
ADL; Medical 
intervention or 
hospitalization 
indicated 
Life-threatening 
and urgent 
intervention 
indicated 
Death 
3Definition adapted from combining CTCAE definitions for Hypotension and Dizziness 
 


  
 
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10.4. 
Criteria for Dose Limiting Toxicity (DLT) Endpoints: 
• Recurrent vomiting: 3-5 episodes of vomiting within 24 hours of taking study 
medication (Grade 2 adverse event) 
• Recurrent diarrhea: >7 episodes of diarrhea within 24 hours of taking study medication 
(Grade 3 adverse event) 
• Dizziness: Moderate lightheadedness or fainting upon rising from lying to sitting or 
standing and severe enough to require medical intervention within 24 hours of taking 
study medication (Grade 2 adverse event) or either a systolic blood pressure less than 
80mmHg or diastolic blood pressure less than 40mm Hg.  
10.5. 
Pre-Existing Medical Conditions 
All subjects enrolled in the study will have Parkinson’s disease. Specific pre-existing 
medical conditions that will be excluded are listed in subject exclusion criteria. 
10.6. 
Treatment Emergent Adverse events  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to 
the initiation of the treatments or any event already present that worsens in either intensity 
or frequency following exposure to the treatments. 
An adverse event is collected after signing the informed consent form and could be related 
or unrelated to the study drug. A TEAE is for after the subject actually takes the study drug. 
Separate summaries for adverse events that occur during treatment (summary of treatment 
emergent adverse events) and adverse events occurring during the wash-out period will be 
provided.   
10.7. 
Laboratory Abnormalities 
Clinical labs will be analyzed by a central laboratory. Labs to be drawn during the study 
include serum chemistries, a hematology panel, and urinalysis. On-site urine pregnancy 
testing is performed at each visit for women of child-bearing potential; positive tests are 
confirmed with a serum pregnancy test. For post-menopausal women less than 60 years of 
age, a serum FSH will be done at the screening visit only. Screening pregnancy tests must 
be negative prior to study entry. If any local laboratory is used, the investigator must obtain 
verification that it meets the standards for quality and consistency set by the College of 
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Clinical laboratory reports must be reviewed by a physician for out-of-range values within 
24 hours of receipt. Out-of-range values will be evaluated using the following notations: 
• NS:  Not clinically significant 
• LE:  Laboratory Error 
• PT:  Subject abnormal; relates to the subject's usual state of health 
• CS:  Clinically Significant. This value cannot be explained by any of the other flags. 
By definition a lab value flagged as "CS" must be entered on the adverse clinical laboratory 
event page in the CRF. A laboratory test flagged "CS" must be repeated as soon as possible. 
The investigator may use his/her own judgment as to whether the abnormal finding is 
sufficient reason to immediately withdraw the subject from the study. 
If a laboratory value is considered to be serious and life-threatening the subject should be 
immediately discontinued from the study and appropriate therapy started. Refer to 
Section 10.9 through Section 10.12 for the definition of a serious adverse event and related 
terms, and for details on reporting a serious adverse event. 
10.8. 
Adverse Event Assessment and Recording 
All adverse events, exacerbations of concomitant illnesses, or events known to be related 
to underlying disease processes or concomitant medications are to be recorded on the CRF 
throughout the study. (Procedures such as surgery should not be recorded as adverse events. 
However, the medical condition for which the procedure was performed should be reported 
if it meets the definition of adverse event.) If a pre-existing condition worsens on study, 
the date on which the exacerbation began should be recorded. Onset dates for study 
treatment-related adverse events must be on or after the date of initial study treatment use. 
The need to record an adverse event on the CRF is not dependent on whether the adverse 
event is associated with the use of the study medication. In order to avoid vague, ambiguous 
or colloquial expressions, the adverse event should be recorded in standard medical 
terminology. 
Adverse event recording will include the date of onset, severity, duration, whether or not 
the study medication was discontinued, or its dosage changed because of the event, the 
treatment given and the outcome. The investigator must also assess whether the event was 
related to the study medication, concurrent drug therapy, underlying disease, a combination 
of these factors, or if it is unknown. Subjects with an adverse event should be carefully 
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The investigator will use the National Cancer Institute (NCI) definitions to grade the 
severity of the event. There is a distinction between the severity and the seriousness of an 
adverse event. Severe is a measurement of intensity, thus a severe reaction is not 
necessarily a serious adverse event. For example, a headache may be severe in intensity, 
but would not be serious unless it met one of the criteria for serious adverse events listed 
previously. 
Table 3: Adverse Event Grading Terms 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2:  Moderate; minimal, local, or non-invasive intervention indicated; limiting 
age-appropriate ADL 
Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4:  Life-threatening consequences; urgent intervention indicated. 
Grade 5:  Death 
 
The relationship or association of the study medication in causing or contributing to the 
adverse event will be characterized as defined below: 
Table 4: Adverse Event Relatedness Terms 
Not related:  Evidence indicates no plausible direct relationship to the study medication. 
Remote:  
Suggests other conditions are reasonably likely to account for the event 
including concurrent illness, progression or expression of the disease state, 
or reaction to concurrent medication. 
Possible:  
Suggests that the association of the event with the study medication is 
unknown; however, the adverse event is not reasonably supported by other 
conditions. 
Probable:  
Suggests that a reasonable temporal sequence of the event with medication 
administration exists and, based upon the investigator's clinical experience, 
the association of the event with study medication seems likely. 
Definite:  
Suggests that based upon the investigator’s experience, the association of 
the event with the study medication seems very certain.  
 


  
 
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10.9. 
Reporting Requirements 
Any adverse event, including both observed or volunteered problems, complaints, or 
symptoms that begins any time between the signing of the consent and within 30 days after 
the end of study participation are to be recorded briefly on the appropriate CRF and in 
detail in the source documents. A check list of adverse events may not be used during this 
study. 
The following are specific definitions that are relevant to meeting your reporting 
obligations and which are included in the FDA Regulations, 21 CFR Part 312.32, and 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Guidelines: 
Adverse Event: Any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. An adverse event can be any unfavorable sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the 
investigational drug, whether or not considered related to the investigational drug. 
Serious Adverse Event: An untoward event or reaction that at any dose: 
• results in death 
• is life-threatening 
• requires in-patient hospitalization 
• prolongs existing hospitalization 
• results in permanent or significant disability or incapacity 
• is a congenital anomaly/birth defect 
• requires intervention to prevent permanent impairment/damage 
Life-threatening: An event which a subject was at risk of death at the time of event. 
10.10. Serious Adverse Events 
Adverse events (AEs) and serious adverse events (SAEs) will be collected from signing of 
informed consent until the follow-up contact. Medical occurrences that began prior to the 
start of study treatment, but after obtaining informed consent were recorded on the Medical 
History/Current Medical Conditions CRF. The investigator or site staff will be responsible 
for the detection and documentation of events meeting the criteria and definition of an 
adverse event or serious adverse event, as provided in the study protocol. 


  
 
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However, any SAEs assessed as related to study participation (e.g., dosing, protocol 
mandated procedures, invasive tests, or change in existing therapy) or related to a 
concomitant medication will be recorded from the time a subject consent to participate in 
the study up to and including any follow-up contact. 
In the event of an AE or SAE, it will be the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative 
to the event and attempt to establish a diagnosis of the event based on signs, symptoms, 
and other clinical information. The diagnosis was to be documented as the adverse event 
or serious adverse event and not the individual’s signs/symptoms. Once an Investigator 
becomes aware that a SAE has occurred in a study subject, they are to report the 
information to Enterin within 24hrs and provide an assessment of causality. 
10.11. Notification of Serious Adverse Events 
Under IND regulations, 21 CFR Part 312.64, investigators must immediately report to the 
Sponsor any serious adverse event, whether or not considered drug related, including those 
listed in the protocol or investigator brochure and must include an assessment of whether 
there is a reasonable possibility that the drug caused the event. 
The Sponsor must be notified as detailed in Section 10.12, "Reporting a Serious Adverse 
Event." The Sponsor, in turn, will report all serious adverse events to regulatory agencies 
as required. In addition to the serious adverse events described in Section 10.10, other 
events that in the investigator's opinion suggest a significant hazard, contraindication, or 
precaution should be considered serious. This includes, but is not limited to, blood 
dyscrasias, endocrine disturbances, hemorrhage from any site, or severe skin disorder. 
Additional examples are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, and 
development of drug dependency or drug abuse. Hospitalization for elective surgery is not 
considered an SAE. In addition, pregnancy is not an SAE, but is reportable and must be 
reported per IND regulations and timelines, 21 CFR Part 312.64, on the SAE reporting 
form and submitted to the sponsor. 
Subjects who experience an SAE must be given appropriate examinations and treatment. 
The investigator must provide written information to the sponsor as soon as possible. 
When an investigator is in doubt when to report an event, the investigator should err on the 
side of caution and contact the Sponsor. 


  
 
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10.12. Reporting a Serious Adverse Event 
Any SAE, including death due to any cause, that occurs during this study, whether or not 
believed to be related to the study medication, must be reported immediately (within 24 
hours of knowledge of the event) by: 
1. Entering the adverse event in the appropriate section (AE page and/or SAE page) of 
the eCRF, indicating that the event is considered serious, and providing all the details 
per the eCRF completion guidelines. 
AND 
2. Completing the SAE Report Form and emailing or faxing to PAREXEL Safety 
Services.  
In the event that the site is unable to complete the SAE form or eCRF entry to report the 
event within 24 hours of their knowledge of the event, investigators may report the SAE to 
PAREXEL Safety Services over the telephone. Then the eCRF must be completed or the 
SAE Report Form must be emailed within the following 24 hours. 
Sites may obtain assistance with SAE reporting procedures or the specifics of reporting an 
event by calling PAREXEL Safety Services. 
Serious Adverse Event Reporting 
PAREXEL Safety Services 
Fax: 781-434-5957 
Phone: 781-434-5010 
NorthAmerica_Medical@parexel.com 
Specific medical questions can be addressed to the Enterin Medical Director: 
William E. Gannon, Jr., MD 
Phone: 703-447-2615 
WGannon@capcitytek.com  
The initial report should contain as much information as is available concerning the event 
in order to permit the Sponsor to file a report that satisfies regulatory requirements. Initial 
telephone reports of serious adverse events must be followed-up by completion of the 
AE/SAE eCRF or emailing the completed SAE Report Form as described above. When 
additional information is available, the investigator should provide an appropriate 
supplementary event narrative to PAREXEL Safety Services. 
All appropriate SAEs will be reported to the appropriate regulatory authorities and central 
IRB by PAREXEL Safety Services within specified timelines. A copy of all FDA 
reportable serious adverse events will be mailed to all investigators participating in ongoing 


  
 
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clinical studies with the study medication in order to permit prompt notification of the 
appropriate local IRB where required. 
10.13. Departure from Protocol for Emergency or Adverse Event 
In medical emergencies, the investigator should use medical judgment and remove the 
subject from immediate hazard. As soon as possible after removing the subject from 
hazard, the investigator must contact Enterin Inc. by telephone to permit a decision as to 
whether the subject may continue in the study. The IRB should also be notified as to the 
type of emergency and the course of action. The CRF for the subject must describe the 
departure from the protocol and state the reason. 
10.14. Safety Monitoring 
A Data Safety and Monitoring Board (DSMB) has been established to monitor the safety 
of the subjects during the study. The DSMB includes members with relevant clinical 
expertise, including a good understanding of the safety of medications for Parkinson’s 
disease.  These members include a statistician, a gastroenterologist, and a neurologist. The 
methodology and the operating procedures for the safety reviews will be developed by the 
Chairperson in collaboration with the sponsor and will be documented in the DSMB 
Charter. 
10.15. Stopping Rules 
It is anticipated that no more than 2 subjects out of 50 (4.0 %) will have an AE of Grade 4 
or Grade 5 that is at least possibly related to ENT-01 in this Study. Should there be more 
than 2 subjects with an AE grade 4 or 5 that is at least possibly related to ENT-01 in the 
cohort of subjects, the study will be put on an immediate clinical hold. Safety Monitoring 
processes are identified in Section 10.14. 
In addition, individual safety stopping criteria will include: 
• Reaching DLT before a prokinetic effect 
• Serious Adverse Event at least possibly attributable to ENT-01. 
• Having a non-DLT gastrointestinal adverse event > grade 3 within 24 hours of taking 
ENT-01 that is at least possibly attributable to ENT-01 
• A fall in systolic blood pressure to < 80 mm Hg upon rising from lying to sitting or 
standing  
• A fall in diastolic blood pressure to < 40 mm Hg upon rising from lying to sitting or 
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10.16. Follow-Up and Final Reports 
The investigator shall provide Enterin, Inc. with an accurate final report within 1 month 
after completion, termination or discontinuation of the study. The final report may not 
precede retrieval of CRFs which have not been monitored. 
10.17. Regulatory Aspects 
Neither the investigator nor Enterin Inc. shall modify this protocol without first obtaining 
concurrence of the other in writing. All changes must be submitted to the IRB. Protocol 
modifications which impact subject safety, or the validity of the study must be approved 
by the IRB and submitted to the FDA before implementation. In the case of a medical 
emergency to increase safety of subjects, a change may be made after discussion with the 
sponsor. In these instances, the IRB and FDA will be notified as soon as possible. 
 
 


  
 
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11. DATA MANAGEMENT AND STATISTICS 
11.1. 
Populations for Analyses 
The following populations will be considered for statistical analyses. 
• Safety Population:  The Safety Population will consist of all subjects who receive at 
least one dose of study drug.  
• Fixed Dose Population:  The Fixed Dose Population will include all subjects who 
are in Safety Population who enter the Fixed Dose period of the study.  
• Efficacy Evaluable Population:  The Efficacy Evaluable Population will include all 
subjects in the ITT Population who complete their Fixed Dose period with no major 
protocol violations. 
11.2. 
Analysis Methods  
General Methods 
Details of the statistical analysis methodology will be provided in a separate statistical 
analysis plan (SAP), which will be finalized prior to the interim analysis being performed.  
Continuous variables will be summarized using the number of observations, number of 
observations above the limit of quantification (if applicable), mean, standard deviation 
(SD) median, and range. Categorical variables will be summarized using frequency counts 
and percentages. 
Analysis of Subject Disposition, History, and Baseline Characteristics 
Subject disposition, including analysis population allocation, subjects enrolled, completed 
each period, discontinued, and primary reason for discontinuation, will be summarized 
using frequency and percentage. Protocol deviations will be summarized using frequency 
and percentage. Medical history data and prior and concomitant medications will be 
summarized using frequency and percentage. Subjects’ age, height, weight, and baseline 
disease characteristics will be summarized using descriptive statistics. Gender, race, and 
other categorical variables will be provided using frequency and percentage.  
11.3. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. The safety data will be 
presented in individual listings and summary tables. 


  
 
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Adverse Events 
AEs will be coded according to the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). The intensity/severity of AEs will be graded according to 
NCI-CTCAE v.4.03. 
TEAEs, AEs leading to study treatment discontinuation, AEs leading to dose interruption, 
AEs related to study medication, SAEs, and AEs leading to death will be summarized by 
system organ class, preferred term, and study period (Screening, dose escalation, Fixed 
Dose, Wash-Out).  A summary of AEs that are CTCAE Grade 3 or higher, as well as the 
most frequent preferred terms, will be provided. 
If a subject experiences the same preferred term multiple times within a period, then the 
event will be counted only once within the period and by greatest severity.  
Descriptive statistics will be used to summarize the safety data both by treatment group 
and overall. 
Clinical Laboratory Values 
All laboratory test results will be summarized by period together with the change from 
baseline. The frequency distribution for low/normal/high or normal/abnormal will be 
summarized as well. The denominators for calculating the percentages will be based on the 
number of subjects with non-missing values in the Safety Population. 
Vital Signs 
Vital sign results will be summarized by period, together with the change from baseline.  
Physical Examination 
Summaries of physical examinations will present frequency distribution of abnormal 
findings by body system and period. The denominators for calculating the percentages will 
be based on the number of subjects evaluated for a particular body system of each dose 
level in the Safety Population. 
Electrocardiogram (EKG)  
EKG findings will be classified as normal vs abnormal. The number and percentage of 
each category will be summarized using frequency table for each period. The denominators 
for calculating the percentages will be based on the number of subjects with non-missing 
values in each period. 


  
 
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11.4. 
Tolerability Analyses 
Tolerability will be measured by DLT endpoints as defined in Section 10.4. The frequency 
of occurrence for each tolerability endpoint including recurrent vomiting, recurrent 
diarrhea, abdominal pain and dizziness will be summarized by treatment group and dose 
level for the Dose Adjustment period. Percentages will be based on the number of subjects 
in each dose level in the Safety Population. 
11.5. 
Efficacy Analyses 
Primary Efficacy Endpoint Analyses 
The primary efficacy endpoint is the change from KARMET study baseline in the weekly 
CSBM rate during 12 Weeks of the Fixed Dose Period. The primary efficacy endpoint 
analysis is a Mixed Model Repeated Measures (MMRM) analysis and will be performed 
on the Safety population. Sensitivity analyses for the primary efficacy endpoint will be 
specified in the SAP.  
Secondary Efficacy Endpoint Analyses 
The following secondary efficacy endpoints will be analyzed using the same methodology 
as the primary efficacy endpoint: 
• Change from baseline in the MDS-UPDRS (Parts I-III) at the end of the Fixed Dose 
Period. 
• Change from baseline in the MMSE at the end of the Fixed Dose Period. 
• Change from baseline in the SAPS-PD at the end of the Fixed Dose Period. 
11.6. 
Handling of Missing Data  
The approaches to handling missing data will be specified in the SAP. 
11.7. 
Sample Size/Power Considerations 
To assess tolerability and safety, a sample size of 50 patients yields 92% probability that 
an AE with an underlying rate of 5% will occur in at least one of these patients.  
 
 


  
 
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12. ESTIMATED DURATION OF THE STUDY 
This study has an estimated maximum duration of up to 20 weeks for each subject, as it is 
anticipated that the majority of subjects will require less than 20 days to reach their fixed dose. 
The study duration from the first subject in (FPFV) to the last subject out (LPLV) is expected to 
be approximately 17 months. 
 
 


  
 
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13. ADMINISTRATIVE PROCEDURES AND ETHICAL 
CONSIDERATIONS 
13.1. 
Subject Information and Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risk and benefit 
of the study. Subjects must also be notified that they are free to discontinue from the study 
at any time. The subject should be given the opportunity to ask questions and allowed time 
to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any 
study procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form. 
A copy of the signed Informed Consent Form must be given to the subject. 
13.2. 
Study Monitoring 
During the study, a Clinical Research Associate (CRA) from Enterin, Inc. will have regular 
contacts with the investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability 
checks are being performed 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (e.g. clinic charts). 
• Record and report any protocol deviations not previously sent to Enterin, Inc. 
• Confirm adverse events and serious adverse events have been properly documented 
on eCRFs and confirm any serious adverse events have been forwarded to Enterin, 
Inc. and those serious adverse events that met criteria for reporting have been 
forwarded to the IRB. 
The CRA will be available between visits if the investigator(s) or other staff needs 
information or advice. 


  
 
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13.3. 
Audits and Inspections 
Authorized representatives of Enterin, Inc., a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an Enterin, Inc. 
audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP) guidelines of the International Conference on Harmonization (ICH), and 
any applicable regulatory requirements. The investigator should contact Enterin, Inc. 
immediately if contacted by a regulatory agency about an inspection. 
13.4. 
Ethics Committee Review 
The final study protocol, including the final version of the Informed Consent Form, must 
be approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
investigator must submit written approval to Enterin, Inc. before he or she can enroll any 
subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment 
to the protocol in accordance with local requirements. In addition, the IRB or IEC must 
approve all advertising used to recruit subjects for the study. The protocol must be re-
approved by the IRB or IEC upon receipt of amendments and annually, as local regulations 
require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the 
investigational product. Enterin, Inc. will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB or IEC according to local regulations and guidelines. 
13.5. 
Standards 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory 
requirements and Enterin, Inc.’s policy on Bioethics. 


  
 
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13.6. 
Confidentiality 
Any research information obtained about the subject in this study will be kept confidential. 
A subject will not be identified by name, only by his/her initials. The subject’s name or 
any identifying information will not appear in any reports published as a result of this study. 
However, information obtained from individual subject’s participation in the study may be 
disclosed with his/her consent to the health care providers for the purpose of obtaining 
appropriate medical care. The subject’s medical records/charts, tests with his/her name on 
them may be made available to the appropriate contract research organization (CRO), 
Enterin, Inc., its potential eventual partners, and any other regulatory authorities. This is 
for the purpose of verifying information obtained for this study. Confidentiality will be 
maintained throughout the study within the limits of the law. 
A subject’s name will not be given to anyone except the researchers conducting the study, 
who have pledged an oath of confidentiality. All identifying information will be kept 
behind locked doors, under the supervision of the study Investigator and will not be 
transferred outside of the investigator site. 
A subject may take away his/her permission to collect, use and share information about 
him/her at any time. If this situation occurs, the subject will not be able to remain in the 
study. No new information that identifies the subject will be gathered after that date. 
However, the information about the subject that has already been gathered and transferred 
may still be used and given to others as described above in order to preserve the scientific 
integrity and quality of the study. 
13.7. 
Protocol Adherence 
The site will maintain records of study treatment delivered to the study site; the inventory 
at the site; the distribution to and use by each subject; and the return of materials to Enterin, 
Inc. for storage or disposal. These records should include dates, quantities, batch/serial 
numbers, expiration dates, in-clinic temperature log, and unique code numbers assigned to 
the product and study subjects. 
At each visit after initiation of treatment, site staff will record compliance of subjects with 
their assigned regimen. Subjects will be instructed to return their unused/partially 
used/empty bottles for inspection at each study visit. Subjects are to be reminded of the 
importance of compliance with their assigned regimen, with an emphasis on taking their 
study drug on schedule and maintaining the prescribed interval between doses. 


  
 
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Investigator will maintain records that document adequately that the subjects were 
provided with the correct study drug and will reconcile the products received from the drug 
dispensing center. Investigational product will not be returned to Enterin, Inc. until 
accountability has been fully monitored. 
Medication containers must be returned at each visit, as compliance will be assessed by 
tablet counts. Noncompliance is defined as taking less than 80% or more than 120% of 
study drug during any out-patient evaluation period (visit to visit). Discontinuation for 
noncompliance is at the Investigator’s discretion and is to be noted in the eCRF. 
13.8. 
Amendments to the Protocol 
Modifications to the protocol are only possible by approved protocol amendments 
authorized by the Enterin, Inc. All protocol amendments will be approved by the 
appropriate regulatory authorities as well as each institutional review board prior to 
implementation. The Investigator must not implement any deviations from, or changes to 
the protocol, except where it is necessary to eliminate an immediate hazard to the study 
subject. 
13.9. 
Protocol Deviations 
The protocol must be read thoroughly, and the instructions followed exactly. Enterin, Inc. 
will not grant waivers for protocol deviations. Any deviation to the protocol has to be 
reported as soon as possible to Clinical Research Associate/designee. The governing 
reporting guidelines for protocol deviations must be adhered to by the Investigator. 
13.10. Study Termination 
This study may be prematurely terminated, if in the opinion of the Investigator or Enterin 
Inc., there is sufficient reasonable cause. Written notification documenting the reason for 
study termination will be provided to the Investigator or EnterinInc.by the terminating 
party. Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects. 
• Failure to enroll subjects at an acceptable rate. 
• Insufficient adherence to protocol requirements. 
• Insufficient complete and/or evaluable data. 
• Plans to modify, suspend, or discontinue the development of ENT-01. 
Should the study be closed prematurely, all study materials must be returned to Enterin Inc. 


  
 
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13.11. Inspection of Records 
Enterin, Inc. will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
13.12. Data Management 
All data relating to study procedures will be entered on to eCRFs provided by Enterin, Inc. 
All forms must be completed electronically. All requested information must be entered in 
the eCRF. Sites will be trained on the eCRF Completion Guidelines which provide 
instructions on how to enter the required data in the Electronic Data Capture (EDC) system. 
Enterin, Inc. will provide the study sites with access and training to the Electronic Data 
Capture system. 
eCRFs will be completed for each subject. It is the Investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data entered in each subject’s eCRF. 
Source documentation supporting the eCRF data should indicate the subject’s participation 
in the study and document the dates and details of study procedures, adverse events, and 
subject status. 
The Investigator, or designee, should complete the eCRF as soon as possible after 
information is collected, preferably on the same day that a subject is seen for an 
examination, treatment, or any other study procedure. The information collected from the 
daily sleep and stool diaries will be entered on an on-going basis. Any outstanding entries 
must be entered immediately after the final examination. An explanation should be given 
for all missing data. 
13.13. Liability and Insurance 
Enterin, Inc. has subscribed to an insurance policy covering, in its terms and conditions, its 
legal liability for certain injuries to participating persons arising out of this research 
performed strictly in accordance with the scientific protocol as well as with applicable law 
and professional standards. 
13.14. Retention of Records 
Study records and source documents must be preserved for the longer of (i) two (2) years 
following completion of the study; or (ii) two (2) years following the termination or 
withdrawal of the Investigational New Drug application under which this study was 


  
 
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conducted; or (iii) the period required by local, state, and federal laws, regulations and 
FDA Guidance. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited 
to, the Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 
164 (the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy 
Regulation). The Investigator shall ensure that study subjects authorize the use and 
disclosure of protected health information in accordance with HIPAA Privacy Regulation 
and in a form satisfactory to Enterin, Inc. 
13.15. Data Quality Assurance 
As per GCP guidelines, Enterin, Inc. or designee will be responsible for implementing and 
maintaining quality assurance and quality control systems for this study. 
Participating sites, the study database, and study documentation including subject medical 
records may be subject to a quality assurance audit during the course of the study. In 
addition, inspections may be conducted by regulatory bodies at their discretion. 
If sites receive a request for an inspection or written or oral inquiries regarding any aspect 
of institution’s or Investigator’s activities related to this study from a regulatory authority, 
the Investigator must immediately notify Enterin, Inc. of the request. Following this 
inspection and/or audit, the Investigator must notify Enterin, Inc. of any violation or 
deficiency noted by the regulatory authority. 
 
 


  
 
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14. USE OF INFORMATION 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will be 
agreed between the Institution and Enterin, Inc. or their designee. With respect to such rights, 
Enterin, Inc. or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by Investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, Investigators will be required to assign all such inventions directly to Enterin, Inc. or 
its designee, as will be set forth in the clinical study agreement. 
 
 


  
 
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Zasloff M, Adams AP, Beckerman B, Campbell A, Han Z et al. Squalamine as a broad-
spectrum systemic antiviral agent with therapeutic potential. Proceedings of the National 
Academy of Sciences of the United States of America. 2011;108:15978-15983. 
 
 


  
 
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APPENDIX 1: LABORATORY TESTS 
Hematology 
Serum Chemistry 
Urinalysis 
White Blood Cell (WBC) Count 
Red Blood Cell (RBC) Count 
Hemoglobin (Hb) 
Hematocrit (Hct) 
Mean Corpuscular Volume (MCV) 
Red Blood Cell Distribution Width (RDW) 
Platelet Count  
Differential - absolute and percent of: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Albumin 
Alanine Aminotransferase (ALT) 
Alkaline Phosphatase (ALP) 
Aspartate Aminotransferase (AST) 
Blood Urea Nitrogen (BUN)/Creatinine 
Ratio 
Calcium 
Carbon Dioxide  
Chloride  
Creatinine  
Glucose  
Potassium  
Sodium  
Total Bilirubin 
Total Protein  
Urea Nitrogen  
Lactate Dehydrogenase (LDH) 
Creatine Kinase, Total 
 
Appearance 
pH 
Protein 
Glucose 
Ketone Bodies 
Indicators of Blood and 
WBCs 
Specific Gravity 
Urobilinogen 
 
Pregnancy tests 
For women of child-bearing potential, this is done on-site with the urine pregnancy kit (UPT) provided.  
If the on-site UPT is positive, then a serum pregnancy test will be done.  For post-menopausal women 
less than 60 years of age, a serum FSH will be done at the screening visit only. 
 
 
 
 


  
 
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APPENDIX 2: SCHEDULE OF EVENTS 
 
Period Name 
Dose 
Escalation 
(DEP) 
Fixed Dose 
(FDP) 
Wash-Out 
(WOP) 
Period Duration 
Up to 20 
days 
12 weeks 
6 weeks 
Visit Number 
V1 
V2 
V3 
V4 
V5 
Study Day 
Day -20 to 1 
Day 1 
Day 43 
Day 85 
Day 127 
Visit Window 
N/A 
+ 3 days 
± 3 days 
± 3 days 
± 3 days 
Informed Consent 
X 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
Orthostatic Vitals 
X 
X 
X 
X 
X 
EKG 
X 
X 
X 
X 
X 
Labs 
X 
X 
X 
X 
X 
Urine 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
X 
X 
X 
X 
Discontinue Laxatives 
X 
 
 
 
 
Restart Laxatives 
 
 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
Medications Review 
X 
X 
X 
X 
X 
MDS-UPDRS  
(Parts I-III) 
X 
X 
X 
X 
X 
SAPS-PD 
X 
X* 
X* 
X* 
X* 
MMSE 
X 
 
 
X 
 
Stool Diary Review 
X 
X 
X 
X 
X** 
Rescue Medications 
X 
X 
X 
X 
 
Investigational Product 
X 
X 
X 
X*** 
 
* Conduct SAPS-PD only if greater than 0 at Visit 1. 
** Collect Stool Diary device at V5 and do not return it to subject. 
*** Investigational Product accountability only at V4; do not dispense.