Tolerability, Safety, and Feasibility of Naloxegol in Patients With Cancer and OIC (Opioid Induced Constipation)

Study Overview
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Brief Summary
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The purpose of this study is to determine if naloxegol can be used in the treatment of opioid-induced constipation in patients with cancer and pain. This phase 4 study consists of a two week randomized double blind period followed by a two week open-label period.

Official Title
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A Study to Assess the Tolerability, Safety, and Feasibility of Naloxegol in Patients With Cancer and Opioid-Induced Constipation

Conditions
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Cancer, Constipation, Pain

Intervention / Treatment
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* Drug: Naloxegol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 or older: Women of child bearing potential must have a negative urine pregnancy test during the Screening/Opioid Induced Constipation (OIC) Confirmation/Baseline period, a history of no sexual activity or consistent use of an effective birth control method for at least 12 weeks prior to the study, and agreement that no sexual activity or the method of birth control will be continued during the study and for a period of 8 weeks after it ends; male patients who are sexually active must agree to use a barrier method of contraception (condom with spermicide) from the first dose of Investigational Product until 12 weeks after their last dose Able to follow instructions in English, give informed consent and to answer patient reported outcomes (PRO) questions by himself/herself; the patient will provide written informed consent before initiation of any study-related procedures Active cancer of any type with an investigator-estimated life expectancy ≥ 8 weeks and a Palliative Performance Status scale score ≥ 30% Patients receiving concurrent chemotherapy must have received and recovered from a minimum of 1 cycle of the current chemotherapy regimen upon consenting to the study and be considered stable in the opinion of the investigator Chronic cancer-related pain, defined as pain for a minimum of ≥2 weeks which on review by the investigator, can be attributed to the neoplasm or its treatment Daily treatment with an opioid drug which is taken at a dose equal to or greater than 20 mg morphine or its equivalent for at least one week, with no expectation of a decrease greater than 25% or an increase greater than 100% during the study period. Patients may or may not be on a stable laxative regimen, defined as daily use at a stable dose for >7 days; if the patient is taking a stable dose, he or she must be willing to remain on that regimen for the 7 day confirmation period without titration or adjustments. History of constipation, defined through history and through participation in the Screening/OIC Confirmation/Baseline period: Patient history must include 2 or more of the following during defecations occurring in the two weeks prior to screening: <3 spontaneous bowel movements per week hard/lumpy stools (Bristol Stool Scale Type 1 or 2) in more than 25% of defecations sensation of incomplete evacuation in more than 25% of defecations sensation of anorectal obstruction in more than 25% of defecations Straining during more than 25% of defecations Note: (spontaneous bowel movements (SBMs) are defined as not using a laxative if not already taking daily laxatives, or if taking daily laxatives, not using an additional laxative). Confirmation during the 7-day OIC confirmation period must include at least 2 or more of the following symptoms: <3 SBMs per week hard/lumpy stools (Bristol Stool Scale Type 1 or 2) in more than 25% of defecations sensation of incomplete evacuation in more than 25% of defecations sensation of anorectal obstruction in more than 25% of defecations Straining during more than 25% of defecations Exclusion Criteria: Cancer-related/medical comorbidity-related Patients with a past or current history of intra-abdominal neoplasm AND clinical findings that, on review by the investigator, may increase the risk of bowel perforation An active condition associated with clinically significant brain pathology, including known brain metastases, meningeal metastases, past traumatic brain injury, multiple sclerosis, uncontrolled epilepsy with signs or symptoms of compromised blood brain barrier Patients expected to undergo a first course of a chemotherapy regimen during the study period, patients who received a vinca alkaloid within 2 months, patients who have any history of vinca-associated GI autonomic neuropathy and/or constipation, or patients receiving a chemotherapy regimen including a VEGF-inhibitor (e.g., bevacizumab, sorafenib). Requiring radiation therapy between the diaphragm and pelvis 2 weeks prior to Visit 1 (screening) and/or during the study Any other significant and/or progressive condition (medical, neurological, psychiatric or metabolic) or symptom that could increase the risk of participation in the study or affect the interpretation of study data as determined by the investigator (e.g., uncontrolled hypothyroidism, inadequately controlled clinical depression, poorly controlled seizure disorder) Hemorrhagic diathesis Expected to have a surgical procedure requiring general anesthesia during the study period Other gastrointestinal disorders Medical conditions and treatments, which in the judgment of the investigator, may be associated with diarrhea, intermittent loose stools, or constipation, (e.g., active diverticular disease, peritonitis of any cause, inflammatory bowel disease, active irritable bowel syndrome, chronic idiopathic constipation). Any conditions that could affect the absorption or metabolism of the study drug (e.g., malabsorption syndrome, severe liver disease) as judged by the investigator Evidence of fecal impaction either by physical or x-ray exam Known or suspected mechanical GI obstruction Current peritoneal catheter for intra-peritoneal chemotherapy or dialysis Fecal ostomy History of fecal incontinence History of bowel surgery within 60 days of the screening period Any other potential non-opioid cause of bowel dysfunction that in opinion of investigator might be a contributor to the constipation Pain-related Receiving opioid medication on less than daily dosing schedule only Severe background pain (eg, typical average daily pain intensity rating of 8 to 10 on an 11-point NRS) refractory opioid therapy Any of the following findings or conditions between the enrollment and randomization visits: Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 x upper limit normal (ULN) and/or serum bilirubin >2 x ULN (unless elevation is due to Gilbert's syndrome) Calculated Creatinine clearance <30 ml/min A Fridericia corrected QT interval (QTcF) > 500 msec at screening, history of myocardial infarction within 6 months before randomization, symptomatic congestive heart failure despite treatment, unstable angina, or symptomatic peripheral vascular disease Active substance or alcohol use that, in the opinion of the investigator, may compromise patient's ability to comply with the study instructions Use of prohibited medications as listed in Section 5.5 Pregnancy or lactation Known history of intolerance or hypersensitivity to alvimopan, methylnaltrexone, or other peripherally acting opioid antagonists or to any other component in the tablets Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff, staff at the study site, and third-party vendors) Any receipt of an investigational medication within 30 days of screening.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo once daily for two weeks | Drug: Placebo<br>* Placebo once daily for two weeks, followed by two week open-label period<br>|
| Active Comparator: Naloxegol<br>Naloxegol 25mg tablets once daily for two weeks | Drug: Naloxegol<br>* Naloxegol 25mg tablets for two weeks, followed by a two week open-label period<br>* Other names: Movantik;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numerical Rating Scale (NRS) for Pain Change From Baseline | Change from baseline in mean daily NRS (Numerical Rating Scale) values will be calculated as the post-baseline value minus the baseline. Baseline NRS is the mean daily NRS values recorded during the Opioid Induced Constipation (OIC) Confirmation period. Numeric Rating Scale is 0-10. 0 is no pain and 10 is worst possible pain. Lower values are a better outcome and higher values are a worse outcome. Post-baseline values were calculated as the mean of NRS scores during visits 2-4. | Assessed from screening/Opioid Induced Constipation (OIC) Confirmation period through study completion, approximately 6 weeks. | 
| Daily Opioid Use Change From Baseline | Change from baseline in mean daily opioid dose will be calculated as the post-baseline value minus the baseline value. Positive changes from baseline indicate there was a need to increase the opioid dose. Baseline daily opioid dose is the mean daily opioid dose recorded during the Opioid Induced Constipation (OIC) Confirmation period. | Assessed from screening through study completion, approximately 6 weeks. | 
| Adverse Events Associated With Blood Laboratory Result Changes From Baseline | Changes from Baseline to Visit 3 (approximately Day 15) for all patients will be calculated as the post-baseline test value minus the baseline test value. | Change from Baseline at End of Double Blind Phase (Visit 3, approximately day 15) | 
| Electrocardiogram QTC Interval | Changes from Baseline to Visit 3 (approximately Day 15) for Electrocardiogram (ECG) QTC interval data will be derived by subtracting the baseline value from the final assessment data. | Change from Baseline at End of Double Blind Phase (Visit 3, approximately day 15) | 
| Electrocardiogram Heart Rate | Changes from Baseline to Visit 3 (approximately Day 15) for Electrocardiogram (ECG) heart rate data will be derived by subtracting the baseline value from the final assessment data. | Change from Baseline at End of Double Blind Phase (Visit 3, approximately day 15) | 
| Change From Baseline in Systolic Blood Pressure | Change from Baseline in systolic blood pressure at post baseline (visits 2, 3, 4) will be derived as the value at the visit minus the baseline value for the same assessment. The post-baseline values were calculated as a mean of values from visits 2 through 4. | Change from Baseline in systolic blood pressure through study completion, approximately 6 weeks. | 
| Change From Baseline in Diastolic Blood Pressure | Change from Baseline in diastolic blood pressure at post baseline (visits 2, 3, 4) will be derived as the value at the visit minus the baseline value for the same assessment. The post-baseline values were calculated as a mean of values from visits 2 through 4. | Change from Baseline in diastolic blood pressure through study completion, approximately 6 weeks. | 
| Change From Baseline in Respiratory Rate | Change from Baseline in respiratory rate at post baseline (visits 2, 3, 4) will be derived as the value at the visit minus the baseline value for the same assessment. The post-baseline values were calculated as a mean of values from visits 2 through 4. | Change from Baseline in respiratory rate through study completion, approximately 6 weeks. | 
| Change From Baseline in Pulse Rate | Change from Baseline in pulse rate at post baseline (visits 2, 3, 4) will be derived as the value at the visit minus the baseline value for the same assessment. The post-baseline values were calculated as a mean of values from visits 2 through 4. | Change from Baseline in pulse rate through study completion, approximately 6 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rescue Free Bowel Movements (RFBM) Responder Rate | Daily diary data will be used to identify RFBMs. The weekly RFBM frequency within each time period will be calculated as: (Total number of RFBMs during the time period of interest/number of days) x 7. RFBM rate calculated from post baseline period. | Assessed from Baseline through Study Completion, approximately 6 weeks. | 
| Time to First Post-dose Rescue Free Laxation | Time (in hours) to first post-dose rescue free bowel movement minus first dose date and time. | First dose date to first post-dose rescue free bowel movement | 
| Bristol Stool Scale (BSS) Score | The Bristol Stool Scale classifies the type of bowel movement on a scale from 1-7, based on the appearance of stool. 1 indicates severe constipation, 2 indicates mild constipation, 3-4 indicate a normal bowel movement, 5 indicates that the patient is lacking dietary fiber, 6 indicates mild diarrhea, and 7 indicates severe diarrhea. A better score would trend toward the middle of the scale (ranges 3-4), while scores at either end of the scale correspond to worse outcomes. Bristol Stool Scale (BSS) Score calculated by the sum of daily BSS scores divided by the number of bowel movements that occurred from baseline to study completion. Change from Baseline calculated as the Baseline value minus the post-baseline value. | Assessed from baseline through Study Completion, approximately 6 weeks. | 
| Patient Assessment of Constipation Symptoms (PAC-SYM) | The PAC-SYM is divided into three subscales. Each item is scored 0-4. Items 1-4 measure abdominal symptoms (total subscale range 0-16), items 5-7 measure rectal symptoms (total subscale score 0-12), and items 8-12 measure stool symptoms (total subscale range 0-20). For each subscale, lower scores are better and higher scores are worse. The total construct score is generated by summing the scores of the subscales. This total score ranges from 0-48, with lower scores corresponding to better outcomes, and higher scores corresponding to worse outcomes. Change from baseline in mean values calculated as post-baseline value minus baseline value for each scale, and for total. Post-baseline values defined as the mean of day 15 and day 29. | day 1, day 15, day 29 | 
| Patient Assessment of Constipation Quality of Life (PAC-QOL) | The PAC-QOL is a 28-item questionnaire divided into 4 subscales. Items 1-4 measure physical discomfort (subscale range 0-16), 5-12 measure psychosocial discomfort (range 0-32), 13-23 measure worries/concerns (range 0-44), and 24-28 measure satisfaction (range 0-20). For each subscale, lower scores are better and higher scores are worse. The total score is generated by summing the scores of the subscales. This total score ranges from 0-112, with lower scores corresponding to better outcomes, and higher scores corresponding to worse outcomes. Change from baseline in mean values calculated as post-baseline value minus baseline value for each subscale, and for total. Post-baseline values defined as the mean of day 15 and day 29. | day 1, day 15, day 29 | 
| Degree of Straining Question With Each Bowel Movement | Degree of straining scale is 1 to 5 with 1 being not at all and 5 being an extreme amount. Lower scores are better and higher scores are worse. Change from baseline in mean values calculated as the post baseline value minus the baseline. Degree of Straining scale change from baseline mean scores calculated from baseline to study completion. | Assessed at baseline through Study Completion with each bowel movement, approximately 6 weeks. | 
| Complete Evacuation Question With Each Bowel Movement | Change from Baseline in mean values calculated as the post baseline value minus the baseline. The post baseline value is the percentage of days from baseline to study completion with at least one complete bowel evacuation. | Assessed at baseline through Study Completion with each bowel movement, approximately 6 weeks. |