Evaluation of Safety and Tolerability of ENT-01 for the Treatment of Parkinson's Disease Related Constipation

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1/2a study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of an orally-administered medication to relieve symptoms of constipation associated with Parkinson's Disease. Ten patients will be enrolled in Phase 1, and will be studied over an 8-12 week period. Forty patients will be enrolled in Phase 2, and will be studied over an 8-10 week period. All subjects will receive the study drug during one of the observational periods of the study.

Detailed Description
-----------------
Phase 1 will enroll 10 patients to assess the safety, tolerability, and pharmacokinetics of single escalating doses over a 30-60 day period. The dose-escalation period will be preceded by a 2-week run in period and followed by a 2-week wash-out period. Phase 2 follow the safe completion of Phase 1. It will enroll 40 patients and is composed of 4 periods of study: 1) a 2-week run-in period, 2) a 3-5 week escalating dose period to identify a prokinetic dose in the initial set of 10 patients, 3) a 1-week period of randomized dosing (placebo versus the previously identified pro-kinetic dose), and 4) a 2-week wash-out period. Pharmacodynamics will be assessed along with safety and tolerability. Relative outcomes will be compared within each patient and across groups for the randomized dosing period. Frequency of bowel movements and other non-motor symptoms of Parkinson's Disease will be collected over the course of both phases.

Official Title
-----------------
A Multi-Center, Single-Dose, Multiple-Dose, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Orally Administered ENT-01 for the Treatment of Parkinson's Disease Related Constipation

Conditions
-----------------
Parkinson's Disease, Constipation

Intervention / Treatment
-----------------
* Drug: ENT-01
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Parkinson's disease diagnosis confirmed by a neurologist specializing in movement disorders Insufficient criteria for a diagnosis of Irritable Bowel Syndrome Constipation for over 6 months, unresponsive to Milk of Magnesia, and requiring at least weekly treatment using an oral laxative, stool softener, bulking agent, and/or a suppository, and dissatisfaction with current treatment. Body Mass Index is 18-40 kg/m2 At least 2 of the Rome IV functional constipation criteria are met Loose stools are rarely present without the use of laxatives Patient is willing and able to sign informed consent and comply with all study procedures Patients must be able to read, understand, and accurately record data into the diary to guarantee full participation in the study Females only: Must have negative serum or urine pregnancy tests and must not be lactating If of child-bearing age: Must agree to using a hormonal (i.e., oral, implantable, or injectable) and either single- or double-barrier method of birth control throughout the study period. A vasectomized partner will be allowed as one in conjunction with another single-barrier method. If unable to have children: Must have this documented in the case report form (i.e., ubal ligation, hysterectomy, or post-menopausal [defined as a minimum of one year since last menstrual period]). Post-menopausal status will be confirmed by follicle stimulating hormone in women less than 60 years of age. Exclusion Criteria: Unable or unwilling to provide informed consent or to comply with study procedures Diagnosis of secondary constipation beyond that of PD Structural or metabolic diseases that affect the GI system Functional GI disorder Unable or unwilling to withdraw from taking the following medications 2 weeks prior to the dose-escalation period and throughout the study: Laxatives, opiates, sedatives, hypnotics, anti-histamines, protein pump inhibitors or any medications which may cause constipation History of recent major surgery (within 60 days of screening) Any clinically significant abnormalities on screening laboratories or physical examination as determined by the Investigator Neurological disorder other than PD On treatment with intra-jejunal dopamine Treatment with COMT inhibitors for fewer than 4 weeks (entacapone, tolcapone, Stalevo) Unable to maintain a stable diet regimen Patients with a cognitive impairment that preclude them from understanding the informed consent Patients placed under legal guardianship Acute GI illness within 48 hours of the baseline period History of major GI surgery (e.g. previous abdominal surgery, including cholecystectomy), except that patients with uncomplicated appendectomy are allowed ALT or AST > 1.5 X upper limit of normal (ULN) during screening Females who are pregnant or breastfeeding History of excessive alcohol use or substance abuse Patient or caregiver unable to administer daily oral dosing Participation in an investigational clinical study within the 6 months prior to dosing in the present study Any other reason, which in the opinion of the Investigator would confound proper interpretation of the study

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 86 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 is a single group; Phase 2 will begin subsequent to the safe completion of Phase 1. Phase 2 patients will undergo randomization for parallel study during one period of observation of the course of the study phase.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ENT-01<br>ENT-01 at a to-be-determined dose taken by mouth every day upon awakening. | Drug: ENT-01<br>* Daily dosing with ENT-01. ENT-01 is an orally administered proprietary substance formulated as a small 25mg coated tablet. Dosing will range from 25-200mg, and the dose will be taken upon awakening on an empty stomach with 8oz water simultaneous to dopamine.<br>|
| Placebo Comparator: Placebo Comparator<br>Placebo to be taken by mouth every day upon awakening | Other: Placebo<br>* Daily dosing with a placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events. | Specific treatment related events of recurrent vomiting, recurrent diarrhea, abdominal pain, and hypotension will be assessed with respect to grade and frequency of occurrence. | Through study completion, up to 11 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Bowel Movements | The frequency of spontaneous bowel movements will be assessed at each dose across the study population and compared to baseline measures. | Through study completion, up to 11 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
non-motor symptoms