A Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Study to Evaluate the Safety and Efficacy of S-297995 for the Treatment of Opioid-Induced Bowel Dysfunction in Subjects With Chronic Pain
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Enrollment
- 72
- Locations
- 1
- Primary Endpoint
- Number of Participants With Adverse Events
Study Overview
Brief Summary
The primary objective of the study is to evaluate the safety of single doses of oral naldemedine in adults physically dependent on opioids.
Detailed Description
A single dose of naldemedine or matching placebo will be administered orally to each cohort of 12 participants (9 treatments, 3 placebos) in the morning of Day 15 under fasted conditions. The first cohort will receive a 0.1 mg dose. Cohorts will continue to be enrolled at the next higher dose level until the highest dose level (3 mg) has been achieved or until the study is discontinued due to adverse events or Clinical Opioid Withdrawal Score of >8. A 0.03 mg dose will also be tested. A 0.01 mg dose will be tested if 4 or more subjects experience 1 or more bowel movements within the 24 hour period post dose in the 0.03 mg dosing cohort.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Understand and sign an informed consent form
- •Males will agree to use an approved double-barrier method of contraception from Day 1 until 1 month after study completion
- •Subject tests negative on urine drug test unless the subject has a prescription for the drug(s) that test positive
Exclusion Criteria
- •Subjects under opioid therapy for cancer-related pain or for the management of drug addiction
- •Fecal incontinence, irritable bowel syndrome, inflammatory bowel disease, or other active medical disorders associated with diarrhea, intermittent loose stools, or constipation
- •Subjects who have participated in any other investigational drug study within 30 days prior to Day 1
- •Prior exposure to S-297995
Arms & Interventions
Cohort 1
In this cohort 9 participants received one 0.1 mg naldemedine tablet and 3 participants received matching placebo administered on Day 15 under fasted conditions.
Intervention: Naldemedine (Drug)
Cohort 1
In this cohort 9 participants received one 0.1 mg naldemedine tablet and 3 participants received matching placebo administered on Day 15 under fasted conditions.
Intervention: Placebo (Drug)
Cohort 2
In this cohort 9 participants received a single dose of 0.3 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions.
Intervention: Naldemedine (Drug)
Cohort 2
In this cohort 9 participants received a single dose of 0.3 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions.
Intervention: Placebo (Drug)
Cohort 3
In this cohort 9 participants received a single dose of 1 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions.
Intervention: Naldemedine (Drug)
Cohort 3
In this cohort 9 participants received a single dose of 1 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions.
Intervention: Placebo (Drug)
Cohort 4
In this cohort 9 participants received a single dose of 3 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions.
Intervention: Naldemedine (Drug)
Cohort 4
In this cohort 9 participants received a single dose of 3 mg naldemedine tablets and 3 participants received matching placebo tablets administered on Day 15 under fasted conditions.
Intervention: Placebo (Drug)
Cohort 5
In this cohort 9 participants received a single dose of 0.03 mg naldemedine oral solution and 3 participants received matching placebo oral solution administered on Day 15 under fasted conditions.
Intervention: Naldemedine (Drug)
Cohort 5
In this cohort 9 participants received a single dose of 0.03 mg naldemedine oral solution and 3 participants received matching placebo oral solution administered on Day 15 under fasted conditions.
Intervention: Placebo (Drug)
Cohort 6
In this cohort 9 participants received a single dose of 0.01 mg naldemedine oral solution and 3 participants received matching placebo oral solution administered on Day 15 under fasted conditions.
Intervention: Naldemedine (Drug)
Cohort 6
In this cohort 9 participants received a single dose of 0.01 mg naldemedine oral solution and 3 participants received matching placebo oral solution administered on Day 15 under fasted conditions.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Number of Participants With Adverse Events
Time Frame: From the first dose of study drug on Day 15 up to Day 24.
Severity of adverse events (AEs) was graded according to the following definitions: * Mild: The subject experiences awareness of symptoms but these are easily tolerated or managed without specific treatment * Moderate: The subject experiences discomfort enough to cause interference with usual activity, and/or the condition requires specific treatment * Severe: The subject is incapacitated with inability to work or do usual activity, and/or the event requires significant treatment measures. The relationship of the event to the study drug was determined by the investigator. A serious adverse event (SAE) is defined as any AE occurring at any dose that resulted in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.
Secondary Outcomes
- Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day(Baseline and 48 hours post-dose)
- Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day(Baseline (Day 1 to Day 15) and Day 15 to Day 17 (0 to 48 hours post-dose))
- Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day(Baseline and 24 hours post-dose)
- Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day(Baseline (Day 1 to Day 15) and Day 15 to 16 (0 to 24 hours post-dose))
- Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day(Baseline and 24 hours post-dose)
- Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day(Baseline and 48 hours post-dose)
- Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day(Baseline and 24 hours post-dose)
- Change From Baseline in the Number of Bowel Movements With No Straining Per Day(Baseline, 24 hours post-dose and 48 hours post-dose)
- Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995(Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.)
- Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995(Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.)
- Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995(Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.)
- Time to First Complete Spontaneous Bowel Movement(From first dose on Day 15 through Day 17)
- Change From Baseline in BM Consistency(Baseline, 24 hours post-dose and 48 hours post-dose)
- Change From Baseline in Number of Rescue Medications Used Per Day(Baseline, 24 hours post-dose and 48 hours post-dose)
- Time to First Spontaneous Bowel Movement(From first dose on Day 15 through Day 17)
- Time to First Bowel Movement(From first dose on Day 15 through Day 17)
- Change From Baseline in Abdominal Bloating(Baseline, 24 hours post-dose and 48 hours post-dose)
- Change From Baseline in Abdominal Discomfort(Baseline, 24 hours post-dose and 48 hours post-dose)
- Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study(The COWS assessments were performed at Screening, on Day 14, Day 15 (pre-dose and 1, 2, 3, 4, 5, 6 and 8 hours post-dose, and at unscheduled times as signs or symptoms indicate), on Days 16 and 17, and on Day 24/End of Study.)
- Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995(Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.)
- Change From Baseline in Straining During Bowel Movements(Baseline, 24 hours post-dose and 48 hours post-dose)
- Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day(Baseline and 48 hours post-dose)
- Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995(Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.)
- Change From Baseline in Number of False Start Bowel Movements Per Day(Baseline, 24 hours post-dose and 48 hours post-dose)
- Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study(The WOWS assessment was performed at Screening, Day 14, Day 15 at pre-dose , and 24 and 48 hours post-dose and at the Follow-up/End of Study visit (Day 24).)