Orally Administered ENT-01 for Parkinson's Disease-Related Constipation Follow-on Safety Roll-over Study (Rollover)

Study Overview
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Brief Summary
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This study will be conducted as an open-label safety follow-on to a multi-center, double-blind, randomized study. All subjects who participated in the randomized study will be offered participation in this unblinded, single-arm, safety study. Approximately 50 subjects will be entered into the study and ENT-01 will be administered daily in escalating doses followed by a fixed dose for 12 weeks. Each subject will participate for approximately 20 weeks; dosing duration will be approximately 14 weeks.

Detailed Description
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The study will be conducted on an out-patient or in-patient basis with visits performed at the screening visit, at 6 and 12 weeks, and at the end of the 6th week of the wash-out period (end of study). The dose escalation period will last up to 20 days, the fixed dose period will last 12 weeks, and the wash-out period will last 6 weeks. Subjects will begin dosing at the same dose level they were stratified to in the ENT-01-030 randomized study (i.e., starting at either 3 tablets or 6 tablets,) and escalate up to a pro-kinetic dose or a maximum dose of 250mg.

Official Title
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A Multicenter, Non-Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Orally Administered ENT-01 in Improving Constipation and Neurologic Symptoms in Patients With Parkinson's Disease and Constipation Over a 14-week Period

Conditions
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Parkinson Disease, Constipation

Intervention / Treatment
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* Drug: Active Investigational Treatment ENT-01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects who participated in the randomized study ENT-01-030 (KARMET Stage 2 Extension subjects) and who completed the dosing period. Subjects aged 30-90 years at the time of screening for the ENT-01-030 study, both genders Subjects must provide informed consent and be willing and able to comply with study procedures. Subjects must be able to read, understand, and accurately record data into the diary to guarantee full participation in the study. 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. 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: Unable or unwilling to provide informed consent or to comply with study procedures. Unable to withdraw proton pump inhibitors. 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. Diagnosis of secondary constipation beyond that of Parkinson's disease. A compromised gastrointestinal system which includes: Structural, metabolic, or functional GI diseases or disorders. Acute GI illness within 2 weeks of the screening visit. 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). Neurological disorder other than Parkinson's disease that in the opinion of the investigator might interfere with the conduct of the study. On treatment with intra-jejunal dopamine or carbidopa/levodopa (i.e. Duopa). Subjects starting a new Parkinson's disease medication or modifying an existing medication within 2 weeks prior to enrollment. Unable to maintain a stable diet regimen. Subjects with a cognitive impairment that preclude them from understanding the informed consent. Subjects placed under legal guardianship. History of excessive alcohol use or substance abuse. Any clinically significant abnormalities on screening laboratories or physical examination requiring further evaluation or treatment. Females who are pregnant or breastfeeding. Subject or caregiver unable to administer daily oral dosing of study drug. Participation in a non-Enterin investigational drug trial within the month prior to dosing in the present study. Any other reason, which in the opinion of the investigator would confound proper interpretation of the study.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a Phase 2b, non-randomized, open-label study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Treatment<br>Orally Administered ENT-01 25mg Tablet Once Daily (Dose dependent on ENT-01-030 dose level stratification) | Drug: Active Investigational Treatment ENT-01<br>* ENT-01 will be administered in tablet form, once daily in escalating doses followed by a fixed-dose for 12 weeks.<br>* Other names: ENT-01;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment Related Adverse Events - Primary SAFETY Endpoint | The number of treatment related adverse events as evaluated with subject report, vital signs, chemical chemistry and electrocardiograms (EKG) | Through study treatment and completion up to 14 weeks | 
| Incidence of Treatment Related Recurrent Vomiting - TOLERABILITY Endpoints | The number of treatment related episodes of recurrent vomiting defined as 3-5 episodes of vomiting within 24 hours. | Through study treatment and completion up to 14 weeks | 
| Incidence of Treatment Related Recurrent Diarrhea - TOLERABILITY Endpoints | The number of treatment related episodes of recurrent diarrhea defined as 7 episodes of diarrhea within 24 hours for 2 consecutive days. | Through study treatment and completion up to 14 weeks | 
| Incidence of Treatment Related Dizziness - TOLERABILITY Endpoints | The number of treatment related episodes of dizziness defined as lightheadedness or fainting on rising from lying to sitting or standing and severe enough to require non-urgent medical intervention within 24 hours. | Through study treatment and completion up to 14 weeks | 
| Change in Baseline Weekly CSBM Rate - Primary EFFICACY Endpoint | Change from baseline in weekly CSBM rate during the 12 weeks of treatment over baseline. | Through study treatment up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MDS-UPDRS - Secondary EFFICACY Endpoints | Change from baseline in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score at the end of the 12-week fixed dose period. Score range: 0-272. Higher score indicates increased disease severity. | Through study treatment up to 12 weeks | 
| MMSE - Secondary EFFICACY Endpoints | Change from baseline in cognition as assessed by the Mini-Mental State Examination (MMSE) at the 12-week fixed dose period. Score range: 0-30. Below the score of 24, lower score indicates an increasing severity of cognitive impairment. | Through study treatment up to 12 weeks | 
| SAPS-PD - Secondary EFFICACY Endpoints | Change from baseline in psychosis as assessed by the Scale for the Assessment of Positive Symptoms for Parkinson's Disease Psychosis (SAPS-PD) score at the 12-week fixed dose period. Score range: 0-45. Higher score indicates increased presence of psychosis. | Through study treatment up to 12 weeks |