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

• ClinicalTrials.gov Identifier: NCT03047629
• Recruitment Status: Completed
• First Posted: February 9, 2017
• Last Update Posted: July 26, 2018
• Sponsor: Enterin Inc.
• Information provided by (Responsible Party): Enterin Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Parkinson's Disease; Constipation	Drug: ENT-01; Other: Placebo	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 11, 2017
• Actual Primary Completion Date: April 25, 2018
• Actual Study Completion Date: June 14, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: ENT-01; ENT-01 at a to-be-determined dose taken by mouth every day upon awakening.	Drug: ENT-01; 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.
Placebo Comparator: Placebo Comparator; Placebo to be taken by mouth every day upon awakening	Other: Placebo; Daily dosing with a placebo

Outcome Measures

Primary Outcome Measures :

1. Number of participants with treatment-related adverse events as assessed by common terminology criteria for adverse events. [ Time Frame: Through study completion, up to 11 weeks ]
   Specific treatment related events of recurrent vomiting, recurrent diarrhea, abdominal pain, and hypotension will be assessed with respect to grade and frequency of occurrence.

Secondary Outcome Measures :

1. Frequency of bowel movements [ Time Frame: Through study completion, up to 11 weeks ]
   The frequency of spontaneous bowel movements will be assessed at each dose across the study population and compared to baseline measures.

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 86 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Parkinson's disease diagnosis confirmed by a neurologist specializing in movement disorders
2. Insufficient criteria for a diagnosis of Irritable Bowel Syndrome
3. 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.
4. Body Mass Index is 18-40 kg/m2
5. At least 2 of the Rome IV functional constipation criteria are met
6. Loose stools are rarely present without the use of laxatives
7. Patient is willing and able to sign informed consent and comply with all study procedures

8. Patients must be able to read, understand, and accurately record data into the diary to guarantee full participation in the study

   Females only:

9. Must have negative serum or urine pregnancy tests and must not be lactating
10. 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.
11. 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:

1. Unable or unwilling to provide informed consent or to comply with study procedures
2. Diagnosis of secondary constipation beyond that of PD
3. Structural or metabolic diseases that affect the GI system
4. Functional GI disorder
5. 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
6. History of recent major surgery (within 60 days of screening)
7. Any clinically significant abnormalities on screening laboratories or physical examination as determined by the Investigator
8. Neurological disorder other than PD
9. On treatment with intra-jejunal dopamine
10. Treatment with COMT inhibitors for fewer than 4 weeks (entacapone, tolcapone, Stalevo)
11. Unable to maintain a stable diet regimen
12. Patients with a cognitive impairment that preclude them from understanding the informed consent
13. Patients placed under legal guardianship
14. Acute GI illness within 48 hours of the baseline period
15. History of major GI surgery (e.g. previous abdominal surgery, including cholecystectomy), except that patients with uncomplicated appendectomy are allowed
16. ALT or AST > 1.5 X upper limit of normal (ULN) during screening
17. Females who are pregnant or breastfeeding
18. History of excessive alcohol use or substance abuse
19. Patient or caregiver unable to administer daily oral dosing
20. Participation in an investigational clinical study within the 6 months prior to dosing in the present study
21. Any other reason, which in the opinion of the Investigator would confound proper interpretation of the study

Contacts and Locations

Locations

United States, California

Keck Hospital of University of Southern California

Los Angeles, California, United States, 90033

United States, Colorado

Rocky Mountain Movement Disorders Center, PC

Englewood, Colorado, United States, 80113

United States, District of Columbia

Georgetown Universtiy, Department of Neurology

Washington, District of Columbia, United States, 20007

United States, Florida

Parkinson's Disease and Movement Disorders Center of Boca Raton

Boca Raton, Florida, United States, 33486

Neuroscience Research, University of Florida Jacksonville

Jacksonville, Florida, United States, 32209

MEDSOL Clinical Research

Port Charlotte, Florida, United States, 33952

Suncoast Neuroscience Associates, Inc

Saint Petersburg, Florida, United States, 33713

Sarasota Memory Hospital Clinical Research Ctr.

Sarasota, Florida, United States, 34239

USF Health Byrd Parkinson's Disease Movement Disorders Center of Excellence

Tampa, Florida, United States, 33613

United States, Michigan

Quest Research Institute

Farmington Hills, Michigan, United States, 48334

United States, New York

Movement Disorders Division, Mt. Sinai School of Medicine

New York, New York, United States, 10029

United States, Ohio

Riverhills Healthcare, Inc.

Cincinnati, Ohio, United States, 45212

Parkinson's & Movement Disorders Center, UH Cleveland Medical Center

Cleveland, Ohio, United States, 44106

United States, Pennsylvania

Penn State Health, Department of Neurology

Hershey, Pennsylvania, United States, 17033

Thomas Jefferson University, Department of Neurology

Philadelphia, Pennsylvania, United States, 19107

Sponsors and Collaborators

Enterin Inc.

Investigators

• Study Chair: Denise Barbut, MD FRCP; Enterin Inc.
• Principal Investigator: Steven Frucht, MD; NYU Langone Health
• Principal Investigator: Robert Hauser, MD MBA; University of South Florida

More Information

• Responsible Party: Enterin Inc.
• ClinicalTrials.gov Identifier: NCT03047629
• Other Study ID Numbers: ENT-01
• First Posted: February 9, 2017
• Last Update Posted: July 26, 2018
• Last Verified: July 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: Anonymized data may be shared with other clinical researchers outside of this study that are involved in similar research at non-participating institutions.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Enterin Inc.:

non-motor symptoms

Additional relevant MeSH terms:

Parkinson Disease; Constipation; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Neurodegenerative Diseases; Signs and Symptoms, Digestive