Orally Administered ENT-01 for Parkinson's Disease-Related Constipation (KARMET)
Condition: Constipation; Parkinson Disease
MeSH terms: Parkinson Disease; Constipation
Intervention: Active Investigational Treatment ENT-01; Placebo Treatment
Intervention description: ENT-01 will be administered in tablet form, once daily.; Placebo will be administered in tablet form, once daily.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 151.0
Sex: All
Minimum age: 30 Years
Maximum age: 90 Years
Healthy volunteers: No

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.
    

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.