Keywords:IBS-D , Irritable Bowel Syndrome , Diarrhea
Sub Specialty:Irritable Bowel Syndrome
This Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study was designed to evaluate the efficacy and safety of orally administered JNJ-27018966 in patients with IBS-d. The study will consist of a pretreatment phase (consisting of an up to 1-week prescreening period and an up to 3-week screening period), a 26-week double-blind treatment phase, and a 4-week blinded withdrawal period.
Approximately 1125 patients will be randomly assigned (in a 1:1:1 ratio) to 1 of 3 treatment groups as follows:
The primary objectives of this study are:
The secondary objective of this study is to further evaluate the treatment effect of JNJ-27018966 relative to placebo based on patient reports of IBS-d symptoms (abdominal pain, abdominal bloating, stool consistency, global symptom scores, adequate relief), bowel functioning, and quality of life
1. Patient is a man or woman aged 18 to 80 years, inclusive, at Prescreening.
2. Patient has a diagnosis of IBS with a subtype of diarrhea defined by the Rome III criteria as loose (mushy) or watery stools ≥25% and hard or lumpy stools <25% of bowel movements.
3. Patient has had a colonoscopy performed:
a. Within 10 years prior to Prescreening if patient is at least 50 years of age (alternatively, a sigmoidoscopy [preferably flexible], double contrast barium enema, or CT colonography within the past 5 years is acceptable [see recommendation of the American Cancer Society]).
b. Since the onset (if applicable) of any of the following alarm feature for patients of any age:
i.Patient has documented weight loss within the past 6 months;
ii. Patient has nocturnal symptoms;
iii. Patient has a familial history of first-degree relatives with colon cancer (as noted by the American Cancer Society); or
iv. Patient has blood mixed with their stool (excluding any blood from hemorrhoids).
4. Patient has an average of worst abdominal pain scores in the past 24 hours of >3.0 on a 0 to 10 scale over the week prior to randomization.
5. Patient has an average stool consistency score (BSS) of ≥5.5 and at least 5 days with a BSS score ≥5 on a 1 to 7 scale over the week prior to randomization.
6. Patient has an average daily IBS-d global symptom score of ≥2.0 on a 0 to 4 scale over the week prior to randomization.
7. Patient has completed the electronic diary on at least 6 of the 7 days during the week prior to randomization AND at least 11 of the 14 days during the 2 weeks prior to randomization. Patients have 3 weeks to meet these criteria.
8. Patient has not used any loperamide rescue medication within 14 days prior to randomization.
9. Patient is not planning to change his/her usual diet and lifestyle during the course of the study. Patients on stable doses of antidepressants (ie, for the 3 months prior to Prescreening) will be allowed to participate in the study. Medications taken for the treatment of allergies, chronic medical conditions, and migraine headaches can be taken during this study (with the exception of opioids for acute treatment of migraines). Patient must be on a stable dose of medication for chronic migraines or preventative therapy for at least 1 month at Prescreening. As needed use of benzodiazepines for anxiety is permitted during the study.
10. Patient is willing to be compliant with study procedures including completing a daily electronic diary (ie, IVRS) during the screening period and throughout the study.
11. Female patients must be:
a. postmenopausal, defined as as 52 years or older and amenorrheic for at least 2 years at Prescreening;
b. surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy);
c. abstinent (for the purposes of clinical trials conducted in the United Kingdom this is defined as true abstinence when in line with the preferred and usual lifestyle of the patient in accordance with requirements of the Medicines and Healthcare products Regulatory Agency); or
d. if sexually active, be practicing an effective method of birth control such as hormonal prescription oral contraceptives, progesterone implants or injections, contraceptive patch, intrauterine device, or male partner with a vasectomy. A double-barrier method such as condoms, diaphragms, or cervical caps with spermicidal foam, cream, or gel may be used as a method of birth control. Women using oral contraceptives must also agree to use an additional birth control method (eg, condoms).Women of childbearing potential must have a negative serum β-human chorionic gonadotropin pregnancy test at Prescreening and a negative urine pregnancy test at Baseline before the first dose of study drug is taken.
12. Patient must sign an informed consent document before the initiation of any study-related procedures indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study.
1. Patient has a diagnosis of IBS with a subtype of constipation, mixed IBS, or unsubtyped IBS by the Rome III criteria (see Appendix 6.2: Rome III Diagnostic Criteria for IBS for
a definition of IBS and subtyping by predominant stool pattern).
2. Patient has a history of inflammatory or immune-mediated GI disorders including inflammatory bowel disease (ie, Crohn’s disease, ulcerative colitis, microscopic colitis) and celiac disease.
3. Patient has a history of diverticulitis within 3 months prior to Prescreening. Patients with a history of diverticulosis are candidates for the study.
4. Patient has a history of intestinal obstruction, stricture, toxic megacolon, GI perforation, fecal impaction, gastric banding, bariatric surgery, adhesions, ischemic colitis, or impaired intestinal circulation (eg, aortoiliac disease).
5. Patient has any of the following surgical history:
a. Cholecystectomy with ANY history of post cholecystectomy biliary tract pain. Patients who had a successful cholecystectomy with no post operative biliary tract pain are candidates for the study;
b. Any abdominal surgery within the 3 months prior to Prescreening; or
c. Patient has a history of major gastric, hepatic, pancreatic, or intestinal surgery (appendectomy, hemorrhoidectomy, or polypectomy greater than 3 months post surgery are allowed). For the purposes of this study, laparoscopic surgeries without complication are considered minor and non-exclusionary, provided the condition for which the surgery was performed was not exclusionary.
6. Patient has a history of cholecystitis within 6 months before Prescreening.
7. Patient has a history of pancreatitis of any etiology.
8. Patient has a history of biliary duct disease, excluding a history of gallstones that were not in the biliary ductal system. Choledocholithiasis (ie, stones in the biliary ductal system) is considered biliary duct disease.
9. Patient has a history of Sphincter of Oddi dysfunction.
10. Patient has an elevated serum lipase >2 times the upper limit of normal at Prescreening.
11. Patient has a history within 5 years prior to Prescreening or current evidence of laxative abuse.
12. Patient has evidence of clinically significant hepatic disease as defined by alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal or total bilirubin >3 mg/dL (>51.3 mmoL/L), with the exception of Gilbert’s syndrome, at Prescreening.
13. Patient has a history of a cardiovascular event, including stroke, myocardial infarction, congestive heart failure, or transient ischemic attack within 6 months prior to Prescreening. Patients with congestive heart failure that is controlled and who have not had an acute event of worsening congestive heart failure within the past 6 months prior to Prescreening are candidates for the study.
14. Patient has an unstable renal, hepatic, metabolic, or hematologic condition.
15. Patient has a history of malignancy (except squamous and basal cell carcinomas and cervical carcinoma in situ) within 5 years before Prescreening, which includes any new diagnosis of malignancy or any treatment for or recurrence of a malignancy that was diagnosed 5 or more years prior. In order to be a candidate for the study, patient MUST be malignancy free for the past 5 years.
16. Patient has a history of human immunodeficiency virus infection.
17. Patient has a history of DSM-IV-TR–defined substance dependency, excluding nicotine and caffeine, within 2 years prior to Prescreening.
18. Patient has a history of alcohol abuse as defined by DSM-IV-TR or binge drinking as defined by the National Institutes on Alcohol Abuse and Alcoholism, or any medical treatment for alcohol-related co-morbidities, within 5 years prior to Prescreening. Recovered alcoholics who have not consumed alcohol over the 5 years prior to the Prescreening are candidates for the study.
19. Patient has a known lactose intolerance.
20. Patient has a history of a microbiologically documented lower gastrointestinal infection within 3 months prior to Prescreening
21. Patient has uncontrolled hypertension, defined as systolic blood pressure >180 mm Hg or a diastolic blood pressure >100 mm Hg at the time of randomization.
22. Patient has abnormal thyroid function test as confirmed by thyroid-stimulating hormone <0.3 mcIU/mL or ≥5 mcIU/mL at Prescreening. However, patients who are clinically euthyroid due to thyroid supplement are candidates for the study.
23. Patient has evidence of anemia as confirmed by hemoglobin <10 g/dL for women and <12 g/dL for men at Prescreening.
24. Patient has used 5HT3 antagonists (eg, alosetron) within 14 days of Prescreening.
25. Patient has used aspirin or aspirin-containing medications (>325 mg of aspirin per day) or nonsteroidal anti-inflammatory drugs, when taken specifically for the symptoms of IBS, within 14 days of randomization.
26. Patient has current (within 14 days of randomization) or expected use of any narcotic or opioid containing agents, docusate, enemas, GI preparations (including antacids containing aluminum or magnesium, antidiarrheal agents, antinausea agents, antispasmodic agents, bismuth, or prokinetic agents).
27. Patient has current (within 28 days of randomization) use of rifaximin or other antibiotics (with the exception of topical antibiotics or a 1-day course with an antibiotic). Expected use of rifaximin or other antibiotics during the course of the study that is known at the time of randomization (eg, for planned elective surgery) is also prohibited. However, a patient will be allowed to remain in the study should unplanned use of antibiotics other than rifaximin occur after the patient has been randomly assigned to study drug.
28. Patient is unable to swallow solid, oral dosage forms whole with the aid of liquid (patients may not chew, divide, dissolve, or crush the study drug).
29. Patient has known allergies or hypersensitivity to opioids. Nausea and vomiting in response to opioid treatment are not hypersensitivity reactions. Patients who have had prior mild, opioid-induced pruritus in the absence of demonstrable allergic dermatitis, angioedema, and laryngeal edema are candidates for the study.
30. Patient has received an investigational drug or used an investigational medical device within 30 days prior to randomization, or is currently enrolled in an investigational study.
31. Patient has previously received investigational drug in a study of JNJ-27018966.
32. Patient has an elective surgery planned or expects to need elective surgery at any time during the study. An elective procedure scheduled after the patient has been randomly assigned to study drug will not be considered a protocol violation.
33. Patient is pregnant or breastfeeding.
34. Patient has any condition that, in the opinion of the investigator, would compromise the well-being of the patient or the study or prevent the patient from meeting or performing study requirements.
35. Patient is an employee of the investigator or study center with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.