Evaluation of the Efficacy and Safety of ADL5945 Once Daily for the Treatment of Opioid-induced Constipation in Adults Taking Opioid Therapy for Chronic Noncancer Pain

ID: NCT01275755
Status: Completed
Phase: Phase 2
Start Date: January 01, 2011
First Submitted: January 11, 2011
Last Updated: January 05, 2016
Results: Available
Success Rate: 97%
Sponsors & Collaborators: Cubist Pharmaceuticals LLC
Location: United States
Conditions: Constipation
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Study Description

Brief Summary

Morphine and related opioid analgesics are known to slow gastrointestinal (GI) motility and reduce intestinal secretion through their binding to μ opioid receptors (MORs) within the GI tract. The most common symptoms associated with the effects of opioids are constipation and nausea and/or vomiting. Moreover, constipation is a common and distressing side effect of long-term opioid therapy.

The primary objective of this study was to compare ADL5945 once daily, a MOR antagonist, with placebo in the treatment of opioid-induced constipation (OIC) in adults taking long-term opioid therapy for chronic noncancer pain.

Detailed Description

Condition or disease Intervention/treatment Phase

Constipation

Drug: Placebo
Other Names
Drug: ADL5945 0.25 mg
Other Names
Phase 2

Tracking Information

First Submitted DateJanuary 11, 2011
Last Update Posted DateJanuary 05, 2016
Start DateJanuary 01, 2011
Actual Completion DateAugust 01, 2011
Primary Completion DateAugust 01, 2011
Results First Submitted DateApril 21, 2015
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment [Time Frame: Baseline, Weeks 1 through 4 of treatment]

    An SBM was defined as a bowel movement (BM) with no laxative use in the previous 24 hours. Each weekly SBM average was calculated as follows: (7 × number of SBMs) / (number of days with nonmissing data). The overall SBM rate for the 4-week double-blind treatment period was calculated as follows: (the average of the first week + the average of the second week + the average of the third week + the average of the fourth week) / 4.

Original Primary Outcome Measures

  • Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment

    An SBM was defined as a bowel movement (BM) with no laxative use in the previous 24 hours. Each weekly SBM average was calculated as follows: (7 × number of SBMs) / (number of days with nonmissing data). The overall SBM rate for the 4-week double-blind treatment period was calculated as follows: (the average of the first week + the average of the second week + the average of the third week + the average of the fourth week) / 4.

Current Secondary Outcome Measures

Not Available

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleEvaluation of the Efficacy and Safety of ADL5945 Once Daily for the Treatment of Opioid-induced Constipation in Adults Taking Opioid Therapy for Chronic Noncancer Pain
Official TitleA Randomized, Double-blind, Placebo-controlled, Phase 2 Study to Evaluate the Efficacy and Safety of ADL5945 Once Daily for the Treatment of Opioid-induced Constipation in Adults Taking Opioid Therapy for Chronic Noncancer Pain
Brief Summary

Morphine and related opioid analgesics are known to slow gastrointestinal (GI) motility and reduce intestinal secretion through their binding to μ opioid receptors (MORs) within the GI tract. The most common symptoms associated with the effects of opioids are constipation and nausea and/or vomiting. Moreover, constipation is a common and distressing side effect of long-term opioid therapy.

The primary objective of this study was to compare ADL5945 once daily, a MOR antagonist, with placebo in the treatment of opioid-induced constipation (OIC) in adults taking long-term opioid therapy for chronic noncancer pain.

Detailed Description

Study TypeInterventional
Study PhasePhase 2
Estimated Enrollment
81
Allocation
Randomized
Interventional Model
Parallel Assignment
Masking
Quadruple
Primary Purpose
Treatment
Conditions
Constipation
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Placebo

Other Names
Drug: ADL5945 0.25 mg

Other Names
Study Groups/Cohorts
Placebo
Each participant received 1 placebo capsule orally every day (QD) during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week).

ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-milligrams (mg) ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.

Study Arms
Experimental ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-milligrams (mg) ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.
Drug : Placebo

Experimental ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-milligrams (mg) ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.
Drug : ADL5945 0.25 mg

Placebo Comparator Placebo
Each participant received 1 placebo capsule orally every day (QD) during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week).
Drug : Placebo

Arm Intervention/Treatment
Experimental ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-milligrams (mg) ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.
Drug : Placebo
Experimental ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-milligrams (mg) ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.
Drug : ADL5945 0.25 mg
Placebo Comparator Placebo
Each participant received 1 placebo capsule orally every day (QD) during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week).
Drug : Placebo

Recruitment Information

Recruitment Status:Completed
Enrollment81
Completion DateAugust 01, 2011
Eligibility Criteria: Key Inclusion Criteria
- be a man or woman aged 18 to 75 years, inclusive, at the time of screening
- have a body weight ≥45 kilograms (kg) and a body mass index (BMI) ≤40 kilograms per square meter (kg/m^2)
- be taking a stable daily dose of opioids of ≥30-milligrams (mg) morphine-equivalent total -daily dose for chronic noncancer pain for ≥30 days before screening
- have opioid-induced constipation (OIC) by history. Additionally, based on the data collected during the 1-week screening period, participants must have <3 spontaneous bowel movements (SBMs) per week and have experienced ≥1 other bowel movement (BM) symptom (that is, straining to pass a stool, lumpy hard stools or small pellets, or sense of incomplete evacuation after passing a stool) for ≥25% of the total BMs
- be willing to discontinue use of all laxatives and stool softeners during the study period except as allowed by the protocol
Key
Exclusion Criteria
- be pregnant, lactating, or planning to become pregnant during the study
- have aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen, or serum creatinine results ≥2 times the upper limit of normal
- have a recent history of myocardial infarction (MI) or unstable angina
- have an active malignancy of any type
- be taking opioids primarily for fibromyalgia
- be taking methadone as a maintenance medication (participants taking methadone for pain may be enrolled)
- be taking intrathecal opioids for the management of pain
- be taking tramadol, tapentadol, or any mixed agonist/antagonist opioid analgesics as the sole opioid for analgesia
- be taking any μ-opioid receptors (MOR) antagonist, including opioids in combination with naloxone, naltrexone, or methylnaltrexone bromide
- be taking medical marijuana
- have gastrointestinal (GI) or pelvic disorders known to affect bowel transit, produce GI obstruction, or contribute to bowel dysfunction
- have taken antispasmodics, antidiarrheals, or prokinetics within 7 days before the start of the screening week
- be taking nonopioid medications known to cause constipation
- be taking antidiarrheals and have an incidence or a history of intermittent diarrhea or loose stools
- be unwilling to abstain from grapefruit and grapefruit-containing products
- have a history of alcoholism or illicit drug dependence or abuse within 5 years before screening
- have positive results on a urine drug screen (excluding opioids) that indicate illicit drug use
GenderAll
Age18 Years to 75 Years
Accepts Healthy VolunteersNo
Contacts
Not Available
Listed Location Countries
United States

Administrative Information

NCT Number:NCT01275755
Other Study ID Numbers
2402-002
45CL243
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Cubist Pharmaceuticals LLC
Collaborators
Not Available
Investigators
Not Available

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Not Available

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Not Available

Reporting Groups

TitleDescription
Placebo
Each participant received 1 placebo capsule orally every day (QD) during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week).
ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-milligrams (mg) ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.

Participant Flow: Overall

PlaceboADL5945 0.25 mg
4140
Started4141
Started3940
Started4037
Completed3941
Completed3837
Completed4037
Not Completed20
Not Completed13
Not Completed00
Adverse Event02
Lost to Follow-up11
Lost to Follow-up10
Withdrawal by Subject10

Baseline Characteristics

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received at least 1 dose of study drug

Reporting Groups

TitleDescription
Placebo
Each participant received 1 placebo capsule orally QD during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week).
ADL5945 0.25mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-mg ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.
Total
Total of all reporting groups

Baseline Measures

PlaceboADL5945 0.25mgTotal
Overall Participants Analyzed
Units: Participants
Participants Analyzed
414081
414081
Age
Units: participants - Number
Participants Analyzed
414081
<=18 years000
>=65 years459
Between 18 and 65 years373572
Gender
Units: participants - Number
Participants Analyzed
414081
Female282856
Male131225

Outcome Measures

1. Primary: Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment

Measure Type
Primary
Measure Title
Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment
Measure Description
An SBM was defined as a bowel movement (BM) with no laxative use in the previous 24 hours. Each weekly SBM average was calculated as follows: (7 × number of SBMs) / (number of days with nonmissing data). The overall SBM rate for the 4-week double-blind treatment period was calculated as follows: (the average of the first week + the average of the second week + the average of the third week + the average of the fourth week) / 4.
Time Frame
Baseline, Weeks 1 through 4 of treatment

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized to study treatment and had at least 1 evaluable SBM post-dose measurement during the Double-blind Treatment Period. Last-observation-carried-forward (LOCF) was used to impute missing postbaseline values.

Reporting Groups

TitleDescription
Placebo
Each participant received 1 placebo capsule orally QD during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week).
ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-mg ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.

Outcome Measures

PlaceboADL5945 0.25 mg
Participants Analyzed
Units: Participants
4140
Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment
Units: Number of SBMs/week - Mean (Standard Error)
1.40 (0.26)2.58 (0.34)

Serious Adverse Events

Time Frame
Not Available
Additional Description
Not Available
Frequency Threshold0% (Threshold above which other adverse events are reported)

Reporting Groups

TitleDescription
Placebo
Each participant received 1 placebo capsule orally every day (QD) during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week).
ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-milligrams (mg) ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.

Serious Adverse Events

PlaceboADL5945 0.25 mg
Total, serious adverse events
No. of participants affected / at risk0/41 (0.00%)1/40 (0.00%)
Cardiac Arrest
No. of participants affected / at risk0/41 (0.00%)1/40 (0.00%)

Other Adverse Events

Time Frame
Not Available
Additional Description
Not Available
Frequency Threshold2% (Threshold above which other adverse events are reported)

Reporting Groups

TitleDescription
Placebo
Each participant received 1 placebo capsule orally every day (QD) during the Run-in Placebo Period (1 week), the Double-blind Treatment Period (4 weeks), and the Run-out Placebo Period (1 week).
ADL5945 0.25 mg
During the Run-in Placebo Period, each participant received 1 placebo capsule orally QD for 1 week. Then during the Double-blind Treatment Period, each participant received one 0.25-milligrams (mg) ADL5945 capsule orally QD for 4 weeks. Then during the Run-out Placebo Period, each participant received 1 placebo capsule orally QD for 1 week.

Other Adverse Events

PlaceboADL5945 0.25 mg
Total, other adverse events
No. of participants affected / at risk11/41 (0.00%)10/40 (0.00%)
Abdominal Pain
No. of participants affected / at risk1/41 (0.00%)2/40 (0.00%)
Abdominal Pain Upper
No. of participants affected / at risk3/41 (0.00%)2/40 (0.00%)
Diarrhea
No. of participants affected / at risk0/41 (0.00%)2/40 (0.00%)
Nausea
No. of participants affected / at risk2/41 (0.00%)0/40 (0.00%)
Vomiting
No. of participants affected / at risk1/41 (0.00%)1/40 (0.00%)
Headache
No. of participants affected / at risk2/41 (0.00%)0/40 (0.00%)
Bronchitis
No. of participants affected / at risk1/41 (0.00%)2/40 (0.00%)
Upper respiratory tract infection
No. of participants affected / at risk1/41 (0.00%)1/40 (0.00%)

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results Point of Contact

Name/TitleOrganizationPhoneEmail
Vice President, Clinical Research
Cubist Pharmaceuticals
(781) 860-8660