Constipation, Parkinson's Disease
Conditions
Keywords
non-motor symptoms
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.
Interventions
DRUGENT-01
Daily dosing with ENT-01. ENT-01 is an orally administered proprietary substance formulated as a small 25mg coated tablet. Dosing will range from 25-200mg, and the dose will be taken upon awakening on an empty stomach with 8oz water simultaneous to dopamine.
OTHERPlacebo
Daily dosing with a placebo
Sponsors
Enterin Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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.
Eligibility
Sex/Gender
ALL
Age
30 Years to 86 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events. | Through study completion, up to 11 weeks | Specific treatment related events of recurrent vomiting, recurrent diarrhea, abdominal pain, and hypotension will be assessed with respect to grade and frequency of occurrence. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Bowel Movements | Through study completion, up to 11 weeks | The frequency of spontaneous bowel movements will be assessed at each dose across the study population and compared to baseline measures. |
Countries
United States
Participant flow
Pre-assignment details
50 subjects signed informed consent. 6 were screen failed during the run-in period and were not eligible to continue into the dose escalation period.
Participants by arm
| Arm | Count |
|---|---|
| Stage 1 Sentinel group to establish safe and tolerable dose of ENT-01
Patients will begin with a dose level of 25 mg taken daily. Patients will dose escalated until they reach a maximum dose level of 200 mg daily or experience a dose limiting toxicity. | 10 |
| ENT-01 ENT-01: Daily dosing with ENT-01.
Patients will begin with a dose level of 75 mg taken daily. Patients will dose escalated until they reach a maximum dose level of 175 mg daily, experience a dose limiting toxicity or have a complete spontaneous bowel movement | 26 |
| Placebo Comparator Placebo to be taken by mouth every day upon awakening
Placebo: Daily dosing with a placebo | 8 |
| Total | 44 |
Baseline characteristics
| Characteristic | Stage 1 | ENT-01 | Placebo Comparator | Total |
|---|---|---|---|---|
| Age, Continuous | 65.5 years STANDARD_DEVIATION 4.88 | 72.6 years STANDARD_DEVIATION 7.52 | 73.1 years STANDARD_DEVIATION 7.41 | 70.4 years STANDARD_DEVIATION 3 |
| Constipation Severity- Complete Spontaneous Bowel Movement per week 0-1 per week | 4 Participants | 17 Participants | 5 Participants | 26 Participants |
| Constipation Severity- Complete Spontaneous Bowel Movement per week 1.1-2 per week | 4 Participants | 7 Participants | 2 Participants | 13 Participants |
| Constipation Severity- Complete Spontaneous Bowel Movement per week 2.1-3 per week | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 26 Participants | 7 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 10 participants | 26 participants | 8 participants | 44 participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Male | 5 Participants | 20 Participants | 5 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 26 | 0 / 8 |
| other Total, other adverse events | 10 / 10 | 26 / 26 | 8 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 26 | 0 / 8 |
Outcome results
Primary
Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events.
Specific treatment related events of recurrent vomiting, recurrent diarrhea, abdominal pain, and hypotension will be assessed with respect to grade and frequency of occurrence.
Time frame: Through study completion, up to 11 weeks
Population: Analysis completed as stage 1 and stage 2
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stage 1 | Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events. | 9 Participants |
| Stage 2: ENT-01 | Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events. | 16 Participants |
| Stage 2: Placebo Comparator | Number of Participants With Treatment-related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events. | 1 Participants |
Secondary
Frequency of Bowel Movements
The frequency of spontaneous bowel movements will be assessed at each dose across the study population and compared to baseline measures.
Time frame: Through study completion, up to 11 weeks
Population: Frequency of bowel movements was abondoned in protocol amendment date 01 Feb 2018.