Tolerability, Safety, and Feasibility of Naloxegol in Patients With Cancer and OIC (Opioid Induced Constipation)
Condition: Cancer; Constipation; Pain
MeSH terms: Constipation; Opioid-Induced Constipation
Intervention: Naloxegol; Placebo
Intervention description: Naloxegol 25mg tablets for two weeks, followed by a two week open-label period; Placebo once daily for two weeks, followed by two week open-label period
Intervention MeSH terms: Naloxegol
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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.