E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Opioid-induced Constipation in Subjects with Non-malignant Chronic Pain Receiving Opioid Therapy |
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E.1.1.1 | Medical condition in easily understood language |
Opioid-induced Constipation |
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E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071128 |
E.1.2 | Term | Opioid induced constipation |
E.1.2 | System Organ Class | 100000004856 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of naldemedine compared to placebo without concomitant laxative treatment in subjects with non-malignant chronic pain receiving a stable opioid regimen and having OIC |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of naldemedine on the frequency of spontaneous bowel movements (SBMs)
To evaluate the safety and tolerability of naldemedine |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects aged 18 to 80 years inclusive at the time of informed consent
2. Subjects must have non-malignant chronic pain treated with opioids for at least 3 months and must have OIC
3. Subjects must be treated with a stable opioid regimen at a total daily dose on average of ≥ 30 mg equivalents of oral morphine sulfate for at least 1 month prior to Screening
4. Subjects must not be currently using laxatives or must be willing to discontinue laxative use (e.g., stool softener, bulking agents, gastrointestinal tract stimulants/prokinetic agents, suppositories, enemas or other medications/agents used to treat constipation) at the time of Screening and must be willing to use only the rescue laxatives provided throughout the study duration
5. Subjects must meet the following 3 criteria based on the Bowel Movement and Constipation Assessment (BMCA) Diary collected via eDiary over a 14 consecutive day qualifying period during the 28 day Screening Period:
a. No more than 4 SBMs total over the 14 consecutive day qualifying period. In addition, no more than 3 SBMs in a given week of the qualifying period.
b. Experience one or more of the following bowel symptoms in 25% or more of BMs:
1. Presence of straining
2. Lumpy or hard stools
3. Sensation of incomplete evacuation
4. Sensation of anorectal obstruction/blockage
c. Subjects must have at least 78% compliance with daily completion of eDiary entries (i.e., make 11 of 14 diary completions) during the 14 consecutive day qualification period
6. Males will be either sterile for 6 months prior to Screening (e.g., vasectomy) or agree to use an approved method of contraception (use of a condom with spermicide from the start of the Screening visit until 28 days after the last dose of IMP)
7. Females must be non-pregnant, non-lactating, and either postmenopausal (defined as cessation of regular menstrual periods for at least 1 year if ≥ 50 years old or 2 years if < 50 years old with follicle-stimulating hormone (FSH) confirmation), surgically sterile by hysterectomy, bilateral oophorectomy or agree to use a highly effective (with failure rates < 1%/year) technique of birth control from Screening visit until 28 days after the last dose of IMP, such as:
a. hormonal implants, injectables, combined oral contraceptives
b. intrauterine contraceptive devices
c. barrier method of contraception (condom or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository or condom in combination with tubal ligation)
8. Subjects who are not currently sexually active (abstinent) must agree to use one of the above-mentioned methods if they become sexually active while participating in the study
9. Females of child bearing potential must have a negative serum pregnancy test at the Screening visit and a negative urine pregnancy test at Visit 2 (Day 1), prior to dosing
10. Able to understand and willing to sign an informed consent form prior to Screening, and comply with all study procedures and requirements
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E.4 | Principal exclusion criteria |
1. Evidence of significant structural abnormalities of the gastrointestinal tract (GI)
a. history of bowel obstructions, strictures
b. history of bowel surgery such as bowel resection or bariatric surgeries
2. Evidence of active medical diseases affecting bowel transit such as ileus, uncontrolled hypothyroidism, irritable bowel syndrome (IBS), inflammatory bowel disease (ulcerative colitis, Crohn’s disease, diverticulitis), fecal incontinence
3. History or presence of pelvic disorders that may be a cause of constipation
4. Surgery (except for minor procedures) within 60 days of Screening, or planned surgery during study treatment that would influence pain or bowel function or preclude completion of the study
5. History of chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation (e.g., mechanical gastrointestinal obstruction)
6. Severe constipation that has not been appropriately managed such that the subject is at immediate risk of developing serious complications of constipation. This includes subject who have reported no bowel movements for 7 consecutive days prior to and during the Screening Period
7. Subjects who have never taken laxatives for the treatment of OIC
8. Initiation of a new bowel regimen or prokinetic agent, or significant change in diet supplement use, or exercise regimens within 28 days of the Screening visit
9. History of active treatment for cancer within the last 2 years (except for basal cell or squamous cell carcinoma of the skin that have been successfully resected or tamoxifen [Nolvadex®] and raloxifene [Evista®] when being used for prevention of breast cancer)
10. Abnormal laboratory tests at Screening:
a. >2 × upper limit of normal (ULN) for alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
b. >1.5 × ULN for total bilirubin
c. >1.5 × ULN for serum creatinine
11. Subjects with a significant comorbid medical condition(s) to the extent that study participation may not be in the subject’s best interest or that may interfere with study compliance/completion. Comorbid conditions may include cardiovascular, respiratory, hepatic, renal, endocrine dysfunction, or a history of human immunodeficiency (HIV)
12. Subjects who have significant cardiovascular (CV) risk such as presence or suspected presence of unstable coronary artery disease, myocardial infarction (MI), stroke or transient ischemic attack (TIA) within 3 months of Screening
13. Presence of any medical or psychiatric condition that, in the opinion of the Investigator, may compromise the ability of the subject to understand and comply with the study protocol or provide informed consent to participate in the study
14. Positive result for serologic test for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) or active hepatitis A virus (HAV)
15. Current use of any prohibited medication listed in Section 6.2.5 including opioid antagonists, partial agonists or mixed agonist/antagonists
16. Any history of illegal drug use in the last 2 years, documented misuse of prescribed medications or a positive urine drug screen (unless the positive drug substance has been prescribed)
17. Any allergic reaction to opioids or known or suspected hypersensitivity to naltrexone hydrochloride, methylnaltrexone bromide, naloxone hydrochloride, alvimopan or any other opioid antagonist
18. Treatment with an IMP within 2 months prior to the Screening visit
19. Prior participation in naldemedine trials |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the proportion of responders where a responder is defined as having 9 positive response weeks or more out of the 12-week Treatment Period and 3 positive response weeks out of the last 4 weeks of the 12-week Treatment Period. A positive response week will be defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week.
SBM is defined as a BM that occurs without the use of a rescue laxative medication during the 24 hours prior to the BM. However, a BM occurring within 24 hours after rescue laxative therapy will not be considered a SBM.
Any number of SBMs rated on the Bristol Stool Scale as 1 within a 2 hour period will be counted as a single SBM.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Mean change in the frequency of SBMs per week from baseline to the first four weeks of the Treatment Period
• Mean change in the frequency of SBMs per week without straining from baseline to the last two weeks of the Treatment Period
• Mean change in the frequency of SBMs per week from baseline to each two weeks of the Treatment Period
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 - Week 4
2 - Last two weeks of the Treatment Period
3 - Every two weeks |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Czech Republic |
Germany |
Poland |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last Visit Last Subject (LVLS) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |