Clinical trial NCT03047629: Evaluation of Safety and Tolerability of ENT-01 for the Treatment of Parkinson's Disease Related Constipation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Parkinson's Disease
Constipation
Keywords: non-motor symptoms
Lead sponsor: Enterin Inc.
Sponsor class: INDUSTRY
First posted: 2017-02-09
Enrollment: 50
Sex: ALL
Minimum age (years): 30
Maximum age (years): 86
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events.
timeFrame: Through study completion, up to 11 weeks
Secondary outcomes:
measure: Frequency of Bowel Movements
timeFrame: Through study completion, up to 11 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Keck Hospital of University of Southern California
state: California
city: Englewood
country: United States
facility: Rocky Mountain Movement Disorders Center, PC
state: Colorado
city: Washington
country: United States
facility: Georgetown Universtiy, Department of Neurology
state: District of Columbia
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Jacksonville
country: United States
facility: Neuroscience Research, University of Florida Jacksonville
state: Florida
city: Port Charlotte
country: United States
facility: MEDSOL Clinical Research
state: Florida
city: Saint Petersburg
country: United States
facility: Suncoast Neuroscience Associates, Inc
state: Florida
city: Sarasota
country: United States
facility: Sarasota Memory Hospital Clinical Research Ctr.
state: Florida
city: Tampa
country: United States
facility: USF Health Byrd Parkinson's Disease Movement Disorders Center of Excellence
state: Florida
city: Farmington Hills
country: United States
facility: Quest Research Institute
state: Michigan
city: New York
country: United States
facility: Movement Disorders Division, Mt. Sinai School of Medicine
state: New York
city: Cincinnati
country: United States
facility: Riverhills Healthcare, Inc.
state: Ohio
city: Cleveland
country: United States
facility: Parkinson's & Movement Disorders Center, UH Cleveland Medical Center
state: Ohio
city: Hershey
country: United States
facility: Penn State Health, Department of Neurology
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University, Department of Neurology
state: Pennsylvania
Study officials:
affiliation: Enterin Inc.
name: Denise Barbut, MD FRCP
role: STUDY_CHAIR
affiliation: NYU Langone Health
name: Steven Frucht, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of South Florida
name: Robert Hauser, MD MBA
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hauser RA, Sutherland D, Madrid JA, Rol MA, Frucht S, Isaacson S, Pagan F, Maddux BN, Li G, Tse W, Walter BL, Kumar R, Kremens D, Lew MF, Ellenbogen A, Oguh O, Vasquez A, Kinney W, Lowery M, Resnick M, Huff N, Posner J, Ballman KV, Harvey BE, Camilleri M, Zasloff M, Barbut D. Targeting neurons in the gastrointestinal tract to treat Parkinson's disease. Clin Park Relat Disord. 2019 Jul 2;1:2-7. doi: 10.1016/j.prdoa.2019.06.001. eCollection 2019.