E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Irritable Bowel Syndrome with Diarrhea (IBS-D) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060845 |
E.1.2 | Term | Diarrhea predominant irritable bowel syndrome |
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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 |
The primary objective of this study will be to determine the efficacy and safety of AGI-003 (arverapamil) in the treatment of IBS-D during an active phase of diarrhea based on the patient’s global impression of adequate relief. |
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E.2.2 | Secondary objectives of the trial |
Change from base line of symptoms associated with IBS-D |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male or female patients, 18 to 75 years of age inclusive, meeting ROME III criteria for IBS-D, willing to abstain from taking rescue medication in the run in phase, and free of any cardiac contraindication to verapamil and who meet all the of the following inclusion/exclusion criteria. 1) Age 18-75 years inclusive 2) Fulfil ROME III criteria for IBS-D and at screening report their usual abdominal pain /discomfort score at no greater than 4 on the scale of 1-6. 3) Provide signed written informed consent 4) Must be able to make entries into a touch tone telephone diary on a daily basis 5) Must be willing to abstain from taking rescue medication in the run-in phase 6) Must be willing to abstain from eating grapefruit or drinking grapefruit juice for the treatment phase of the study If the patient meets the above criteria, then the criteria for randomization after the run-in period are the following: 1) Be compliant in the use of IVRS for at least 11 of the run-in days. 2) Has typical bowel movements on a minimum of 7 days and at least 50% of the run-in period days, e.g., 8 of 15 days reported as 5, 6 or 7 on the BSS with the IVRS. 3) Has abdominal discomfort or pain on a minimum of 7 days and at least 50% of the run-in period days, which need not be consecutive. For the days when they report on IVRS their average pain score must be 0.5-4.0 on the pain scale.
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E.4 | Principal exclusion criteria |
1) During screening the patient reports their usual abdominal pain/discomfort score is 5 or 6 on a scale of 1-6 2) Any evidence of cardiovascular disease or any other disease where treatment with verapamil is contra-indicated such as: • Severe left ventricular dysfunction • Hypotension (systolic pressure <90 mm Hg) or cardiogenic shock • Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) • Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) • Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) 3) Lactose intolerance as reported by the patient and patient is not currently abstaining from milk products or not taking lactase enzyme OTC products and for the duration of the study will not agree to continuing to abstain or will not agree to continue their OTC medication 4) Coeliac disease (diagnosed using serology or duodenal biopsy) 5) Unexplained fever or weight loss of at least 10 pounds during the last 6 months, or any clinically significant symptoms (e.g. rectal bleeding or a recent change in pattern of bowel habits, unless a pre-screening colonoscopy to eliminate any other diseases of the gastrointestinal tract might explain the symptoms) 6) Abnormal screening lab tests assessed by the Investigator as clinically significant or within 3 months of the screening visit have had a positive stool cultures or abnormal proctoscopy/abdominal ultrasound requiring further investigation 7) Presence of ongoing organic disease of the gastrointestinal tract, liver, pancreas, biliary tree (e.g. gastritis, symptomatic gallstones, duodenal ulcer, gastroenteritis, diverticulitis, or megacolon) with the exception of haemorrhoids, hiatus hernia and non-symptomatic gallstones 8) Prior gastroparesis diagnosis by a physician 9) Barrett’s and/or Grade III esophagitis 10) > 1 episode of vomiting per week within a month prior to screening 11) Acute diverticulitis or a history of greater than 1 episode of diverticulitis 12) History of chronic colitis or acute self-limiting colitis of any etiology within 5 years of the screening visit (e.g. ulcerative colitis, Crohn’s disease, collagen vascular disease, ischemic colitis, enteric infection) 13) History of intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, faecal impaction, gastric banding or bariatric surgery 14) History of laxative abuse as determined by the Investigator 15) Gastroesophageal reflux disease that is not controlled by the use of stable doses of PPIs for at least 3 months prior to the screening visit 16) Radiologic or clinical evidence of primary and metastatic gastrointestinal malignancy, stricture or obstruction of the gastrointestinal tract, paralytic ileus or intestinal atony 17) History of gastrointestinal bleeding based on clinical judgement that would interfere with the subject’s safety or with the efficacy assessments of the study, or if the subject has had gastrointestinal bleeding on 2 or more occasions within 6 weeks prior to study enrolment (except blood from haemorrhoids) 18) History of major gastric, hepatic, pancreatic or intestinal surgery or perforation (excluding cholecystectomy, appendectomy, haemorrhoidectomy or polypectomy) 19) Presence of pathogenic parasites, ova, bacteria or any occult blood in stools which in the opinion of the Investigator may be responsible for GI symptoms (measured within 1 month of Screening Visit) 20) Antibiotic use within 1 month prior to screening (except for prophylactic antibiotics for such conditions as acne, cystitis, urinary tract infections, etc). If the patient is on prophylactic antibiotics, the patient must be on a chronic stable dose for >3 months and willing to remain on a stable dose during the run-in period and throughout the study 21) Abnormal colonoscopy within the last 5 years (except mild benign polyps, mild diverticula, haemorrhoids) 22) Past or present disease likely to complicate the evaluation of the study treatment e.g. significant cardiovascular, renal or liver disease, or malignancy 23) Pregnancy or lactation. Women of childbearing potential must maintain effective contraception 24) Use of drugs judged by the investigator to be the cause of the current episode of symptoms 25) Evidence of formal psychiatric illness, apart from depression (not major), which is controlled by antidepressants 26) On tricyclic antidepressants (TCA) or serotonin selective reuptake inhibitors (SSRI) dose that has not been stabilized for at least 3 months 27) Past or present alcohol or drug abuse, in the opinion of the Investigator 28) Participation in any other clinical trial within the last month. 29) Previous intolerance/sensitivity to the study medication 30) Receiving a concomitant excluded medication as listed in Section 7.4 31) Not met the run-in criteria for randomization |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the Global Impression Treatment Response from Day 1 through Day 56. Only patients who answer ‘yes’ to the following question (defined as Global Impression) at least 50% of the days (i.e., at least 28 out of the 56 days) will be classified as a responder - “Today, do you consider that you had adequate relief from your IBS symptoms?” |
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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 | No |
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.8.3 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 of last subject. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 12 |
E.8.9.2 | In all countries concerned by the trial days | 0 |