Clinical trial NCT03781791: Orally Administered ENT-01 for Parkinson's Disease-Related Constipation (KARMET)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Constipation
Parkinson Disease
Lead sponsor: Enterin Inc.
Sponsor class: INDUSTRY
First posted: 2018-12-20
Enrollment: 151
Sex: ALL
Minimum age (years): 30
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The Number of Participants Who Experience Treatment Related Adverse Events-Safety Endpoint
timeFrame: Through Study treatment up to 10 weeks
measure: The Number of Participants Who Experience Dose Limiting Toxicity Adverse Events
timeFrame: Through Study treatment Dosing Period up to 10 weeks
measure: Change in Baseline Weekly CSBM-Primary Efficacy Endpoint
timeFrame: 25 day treatment period, part of which is at a fixed dose.
Secondary outcomes:
Other outcomes:
Locations:
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Little Rock
country: United States
facility: Clinical Trials, Inc.
state: Arkansas
city: Fountain Valley
country: United States
facility: The Parkinson's and Movement Disorder Institute
state: California
city: Fresno
country: United States
facility: Neuro Pain Medical Center
state: California
city: Oxnard
country: United States
facility: Pacific Neuroscience Medical Group
state: California
city: Pasadena
country: United States
facility: SC3 Research - Pasadena
state: California
city: Santa Clarita
country: United States
facility: Trial Connections - Care Access Research, Santa Clarita
state: California
city: Englewood
country: United States
facility: Rocky Mountain Movement Disorders Center
state: Colorado
city: Fairfield
country: United States
facility: Associated Neurologist of Southern CT
state: Connecticut
city: Norwich
country: United States
facility: Care Access Research, Norwich
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Miami
country: United States
facility: Elias Research - Floridian Research Institute
state: Florida
city: Miami
country: United States
facility: Elias Research - Allied Biomedical Research Institute
state: Florida
city: Miami
country: United States
facility: Pharmax Research of South Florida
state: Florida
city: Port Charlotte
country: United States
facility: MEDSOL Clinical Research
state: Florida
city: Port Charlotte
country: United States
facility: Parkinson's Disease Treatment Center of SWFL
state: Florida
city: Sarasota
country: United States
facility: Intercoastal Medical Group
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: West Palm Beach
country: United States
facility: Palm Beach Neurology and Premier Research Institute
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Anderson
country: United States
facility: BTC Network - Community Clinical Research Center
state: Indiana
city: Alexandria
country: United States
facility: Interspond - The Neuromedical Clinic of Central Louisiana
state: Louisiana
city: Baton Rouge
country: United States
facility: The NeuroMedical Center, P.C.
state: Louisiana
city: Elkridge
country: United States
facility: Parkinson's and Movement Disorders Center of Maryland
state: Maryland
city: West Bloomfield
country: United States
facility: Henry Ford West Bloomfield Hospital
state: Michigan
city: Lincoln
country: United States
facility: Neurology Associates Clinical Research
state: Nebraska
city: Las Vegas
country: United States
facility: Interspond - Neurology Center of Las Vegas
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Toms River
country: United States
facility: Evolution Research Group - Neuroscience Research Institution
state: New Jersey
city: Toms River
country: United States
facility: Neuroscience Researc Institute of NJ
state: New Jersey
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Raleigh
country: United States
facility: Raleigh Neurology Associates
state: North Carolina
city: Wake Forest
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Centerville
country: United States
facility: Dayton Center for Neurological Disorders
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Dayton
country: United States
facility: Elias Research - Neurology Diagnostics Research
state: Ohio
city: Toledo
country: United States
facility: University of Toledo Medical Center
state: Ohio
city: Tulsa
country: United States
facility: The Movement Disorder Clinic of Oklahoma
state: Oklahoma
city: Hershey
country: United States
facility: Penn State University
state: Pennsylvania
city: Greer
country: United States
facility: Interspond - Premier Neurology
state: South Carolina
city: Indian Land
country: United States
facility: Interspond - Metrolina Neurological Associates
state: South Carolina
city: Bedford
country: United States
facility: North Texas Movement Disorders Institute
state: Texas
city: Dallas
country: United States
facility: BTC Network - Neurological Associates of North Texas
state: Texas
city: Houston
country: United States
facility: Clinical Trial Network
state: Texas
city: Norfolk
country: United States
facility: Sentara Neuroscience Institute
state: Virginia
city: Kirkland
country: United States
facility: Evergreen Health - Booth Gardner Parkinson's Care Center
state: Washington
city: Huntington
country: United States
facility: University Physicians & Surgeons, Inc. dba Marshall Health
state: West Virginia
Study officials:
affiliation: Enterin Inc.
name: Michael Zasloff, MD PhD
role: STUDY_CHAIR
affiliation: Enterin Inc.
name: Denise Barbut, MD, FRCP
role: STUDY_DIRECTOR
References:
citation: 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.