Orally Administered ENT-01 for Parkinson's Disease-Related Constipation (KARMET) (KARMET)

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate Safety, Tolerability and Efficacy of Orally Administered ENT-01 for the Treatment of Parkinson's Disease-Related Constipation (KARMET)

This study will be conducted as a multi-center, randomized, double-blind, placebo-controlled study. Approximately 72 patients will be randomized 3:1 to treatment or placebo, with approximately 54 patients allocated to receive the active investigational product and approximately 18 patients allocated to receive placebo.

- Study Update-

Amendment 3 - In this amendment, an additional 80 patients (approximately) will be randomized 1:1 to treatment or placebo (double-blind) with approximately 40 subjects allocated to each group.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease; Constipation
• Intervention / Treatment: Drug: Active Investigational Treatment ENT-01; Drug: Placebo Treatment

Detailed Description

The study will be conducted on an out-patient basis. Each patient will have 6 visits to the clinic: a screening visit, a randomization visit, 3 follow up visits, and 1 end of study visit.

Patient randomization will be stratified based upon the baseline weekly complete spontaneous bowel movement rate (CSBM) established during the screening period. Patients will be allowed to adjust their dosing, based upon protocol specifications. Rescue medications will be provided to all patients to ensure they move their bowels on a regular basis.

Patients will also be asked to participate in up to 2 sub-studies: a pk study and/or a stool microbiome study. The first 20 patients to consent to the pk study will have additional blood samples taken at randomization and at 2 follow up visits. The first 20 patients to consent to the stool microbiome study will provide stool samples at randomization and at 2 follow up visits.

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Sun City, Arizona, United States, 85351
      • Banner Sun Health Research Institute
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Clinical Trials, Inc.
  • California
    • Fountain Valley, California, United States, 92708
      • The Parkinson's and Movement Disorder Institute
    • Fresno, California, United States, 93710
      • Neuro Pain Medical Center
    • Oxnard, California, United States, 93030
      • Pacific Neuroscience Medical Group
    • Pasadena, California, United States, 91105
      • SC3 Research - Pasadena
    • Santa Clarita, California, United States, 91321
      • Trial Connections - Care Access Research, Santa Clarita
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Rocky Mountain Movement Disorders Center
  • Connecticut
    • Fairfield, Connecticut, United States, 06824
      • Associated Neurologist of Southern CT
    • Norwich, Connecticut, United States, 06360
      • Care Access Research, Norwich
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital
  • Florida
    • Atlantis, Florida, United States, 33462
      • JEM Research Institute
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease and Movement Disorders Center of Boca Raton
    • Miami, Florida, United States, 33145
      • Elias Research - Floridian Research Institute
    • Miami, Florida, United States, 33155
      • Elias Research - Allied Biomedical Research Institute
    • Miami, Florida, United States, 33175
      • Pharmax Research of South Florida
    • Port Charlotte, Florida, United States, 33980
      • Parkinson's Disease Treatment Center of SWFL
    • Port Charlotte, Florida, United States, 33952
      • MEDSOL Clinical Research
    • Sarasota, Florida, United States, 34239
      • Intercoastal Medical Group
    • Tampa, Florida, United States, 33603
      • University of South Florida
    • West Palm Beach, Florida, United States, 33407
      • Palm Beach Neurology and Premier Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Atlanta Center for Medical Research
  • Indiana
    • Anderson, Indiana, United States, 46011
      • BTC Network - Community Clinical Research Center
  • Louisiana
    • Alexandria, Louisiana, United States, 71301
      • Interspond - The Neuromedical Clinic of Central Louisiana
    • Baton Rouge, Louisiana, United States, 70810
      • The NeuroMedical Center, P.C.
  • Maryland
    • Elkridge, Maryland, United States, 21075
      • Parkinson's and Movement Disorders Center of Maryland
  • Michigan
    • West Bloomfield, Michigan, United States, 48322
      • Henry Ford West Bloomfield Hospital
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Neurology Associates Clinical Research
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Interspond - Neurology Center of Las Vegas
  • New Hampshire
    • Lebanon, New Hampshire, United States, 13756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Evolution Research Group - Neuroscience Research Institution
    • Toms River, New Jersey, United States, 08755
      • Neuroscience Researc Institute of NJ
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Raleigh Neurology Associates
    • Wake Forest, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center
  • Ohio
    • Centerville, Ohio, United States, 45459
      • Dayton center for neurological disorders
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44095
      • Cleveland Clinic
    • Dayton, Ohio, United States, 45459
      • Elias Research - Neurology Diagnostics Research
    • Toledo, Ohio, United States, 43614
      • University of Toledo Medical Center
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • The Movement Disorder Clinic of Oklahoma
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State University
  • South Carolina
    • Greer, South Carolina, United States, 29650
      • Interspond - Premier Neurology
    • Indian Land, South Carolina, United States, 29707
      • Interspond - Metrolina Neurological Associates
  • Texas
    • Bedford, Texas, United States, 76021
      • North Texas Movement Disorders Institute
    • Dallas, Texas, United States, 75218
      • BTC Network - Neurological Associates of North Texas
    • Houston, Texas, United States, 77074
      • Clinical Trial Network
  • Virginia
    • Norfolk, Virginia, United States, 23456
      • Sentara Neuroscience Institute
  • Washington
    • Kirkland, Washington, United States, 98034
      • Evergreen Health - Booth Gardner Parkinson's Care Center
  • West Virginia
    • Huntington, West Virginia, United States, 25701
      • University Physicians & Surgeons, Inc. dba Marshall Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects aged 30-90 years, both genders
2. Subjects must provide written informed consent and be willing and able to comply with study procedures.
3. Subjects must be diagnosed with Parkinson's Disease defined as the presence of at least three of the following cardinal features, in the absence of alternative explanations or atypical features: rest tremor, rigidity, bradykinesia and/or akinesia, postural and gait abnormalities.
4. There are insufficient criteria for Irritable Bowel Syndrome (IBS)
5. Constipation which has been present for over 6 months and is unresponsive to first line, typically over the counter treatments such as Milk of Magnesia (1g), Miralax (17g in 8 ounces of water) or the equivalent at least once weekly with an inconsistent response over a 6-week period or the subject is dissatisfied with first line treatments.
6. Body mass index (BMI) of 18-40 kg/m2

7. Subjects must fulfill Rome IV criteria for functional constipation which includes 2 or more of the following:

   1. Straining during at least 25% of defecations
   2. Lumpy or hard stools in at least 25% of defecations
   3. Sensation of incomplete evacuation for at least 25% of defecations
   4. Sensation of anorectal obstruction/blockage for at least 25% of defecations
   5. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor)
8. Self-report of fewer than 3 complete spontaneous bowel movements per week
9. Loose stools are rarely present without the use of laxatives
10. Subjects must be able to read, understand, and accurately record data into the diary to guarantee full participation in the study.
11. 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.
12. 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. Diagnosis of secondary constipation beyond that of Parkinson's Disease
3. Review of Screening Diaries indicates fewer than 11 days of diary completion and/or 3 or more complete spontaneous bowel movements (CSBM) per week based upon the average CSBM rate reported during the Screening Period

4. A compromised gastrointestinal system which includes:

   1. Structural, metabolic, or functional GI diseases or disorders
   2. Acute GI illness within 2 weeks of the screening visit
   3. 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)
5. 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.
6. Unable or unwilling to withdraw from proton pump inhibitors and antacids at the end of the screening period.
7. Unable or unwilling to withdraw from pimavanserin during the study.
8. Any clinically significant abnormalities on screening laboratories or physical examination requiring further evaluation or treatment.
9. Neurological disorder other than Parkinson's Disease that in the opinion of the investigator might interfere with the conduct of the study.
10. On treatment with intra-jejunal dopamine or carbidopa/levodopa (i.e. Duopa).
11. Subjects starting a new Parkinson's Disease medication or modifying an existing medication within 2 weeks prior to enrollment.
12. Unable to maintain a stable diet regimen.
13. Subjects with a cognitive impairment that preclude them from understanding the informed consent.
14. Subjects placed under legal guardianship.
15. Females who are pregnant or breastfeeding.
16. History of excessive alcohol use or substance abuse.
17. Participation in an investigational drug trial within the month prior to dosing in the present study.
18. Any other reason, which, in the opinion of the investigator, would confound proper interpretation of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Treatment; ENT-01 tablet will be taken once daily by mouth.	Drug: Active Investigational Treatment ENT-01; ENT-01 will be administered in tablet form, once daily.; Other Names: ENT-01
Placebo Comparator: Placebo Treatment; Placebo tablet will be taken once daily by mouth.	Drug: Placebo Treatment; Placebo will be administered in tablet form, once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants Who Experience Treatment Related Adverse Events-Safety Endpoint	The number of treatment related adverse events as reported and assessed by NCI CTCAE v.4.3.	Through Study treatment up to 10 weeks
The Number of Participants Who Experience Dose Limiting Toxicity Adverse Events	The number of participants who experience dose limiting toxicity adverse events as reported and assessed by NCI CTCAE v.4.3. Per protocol, dose limiting toxicity adverse events are vomiting, diarrhea, abdominal pain and dizziness.	Through Study treatment Dosing Period up to 10 weeks
Change in Baseline Weekly CSBM-Primary Efficacy Endpoint	Change from participant's weekly CSBM baseline rate during treatment fixed Dose period. The fixed dose period begins on the first day or the subject's highest dose at which the subject did not experience a dose limiting toxicity (nausea, vomiting, diarrhea or dizziness) The fixed dose period will not be a specific time period for all subjects since each subject will start the fixed dose period based on their tolerability to ENT-01 dosing.	25 day treatment period, part of which is at a fixed dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in participant constipation severity from baseline-Secondary Efficacy Endpoints	Participant reported change from baseline as assessed according to Bristol Stool rating scale (0-5) of increasing severity of ease of bowel evacuation.	Through Study Treatment Dosing Period up to 10 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in baseline stool Microbiome - Exploratory Outcome	Collection of participant baseline intestinal microbiome condition as observed in stool to on treatment related effect of ENT-01 on stool microbiome	Through Study Treatment Dosing Period and Completion up to 24 weeks

Collaborators and Investigators

• Sponsor: Enterin Inc.
• Investigators: Study Director: Denise Barbut, MD, FRCP, Enterin Inc.; Study Chair: Michael Zasloff, MD PhD, Enterin Inc.

Publications and helpful links

General Publications

• Camilleri M, Subramanian T, Pagan F, Isaacson S, Gil R, Hauser RA, Feldman M, Goldstein M, Kumar R, Truong D, Chhabria N, Walter BL, Eskenazi J, Riesenberg R, Burdick D, Tse W, Molho E, Robottom B, Bhatia P, Kadimi S, Klos K, Shprecher D, Marquez-Mendoza O, Hidalgo G, Grill S, Li G, Mandell H, Hughes M, Stephenson S, Vandersluis J, Pfeffer M, Duker A, Shivkumar V, Kinney W, MacDougall J, Zasloff M, Barbut D. Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial. Ann Intern Med. 2022 Dec;175(12):1666-1674. doi: 10.7326/M22-1438. Epub 2022 Nov 8. Erratum In: Ann Intern Med. 2023 Jan;176(1):144.

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2018
• Primary Completion (Actual): December 14, 2021
• Study Completion (Actual): December 14, 2021

Study Registration Dates

• First Submitted: November 27, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 20, 2018

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Digestive; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Constipation
• Other Study ID Numbers: ENT-01-030

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No