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 long-term safety of AGI-003 (arverapamil) in the treatment of IBS-D. |
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E.2.2 | Secondary objectives of the trial | |
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, and free of any cardiac contraindication to verapamil and who meet all the of the following inclusion/exclusion criteria. Inclusion Criteria: 1) Are aged 18 to 75 years, inclusive, at the time of entry into the Clin-AGI003-003 study. 2) Have completed the Clin-AGI003-003 study. 3) Provide signed written informed consent. 4) Must be willing to abstain from eating grapefruit or drinking grapefruit juice for duration of the study
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E.4 | Principal exclusion criteria |
1) Not completed the Clin-AGI003-003 study. 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 less than 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 (eg, 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 either 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 they have had a pre-screening colonoscopy to eliminate any other diseases of the gastrointestinal tract that might explain the symptoms). 6) Abnormal screening lab tests assessed as clinically significant by the Investigator, 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) Greater than one episode of vomiting per week within a month prior to screening 11) Acute diverticulitis or a history of greater than one episode of diverticulitis 12) History of chronic colitis or acute self-limiting colitis of any etiology within 5years 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 two or more occasions within six weeks prior to study enrolment (with the exception of 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 (if measured within one month of Screening Visit) 20) Abnormal colonoscopy within the last five years (with the exception of mild benign polyps, mild diverticula, haemorrhoids) 21) Any other past or present disease likely to complicate the evaluation of the study treatment, e.g. significant cardiovascular, renal or liver disease, or malignancy 22) Pregnancy or lactation. Women of childbearing potential must maintain effective contraception 23) Use of drugs judged by the Investigator to be the cause of the current episode of symptoms 24) Evidence of formal psychiatric illness, apart from depression (not major), which is controlled by antidepressants 25) On tricyclic antidepressants (TCA) or serotonin selective reuptake inhibitors (SSRI) dose that has not been stabilized in the patient for at least 3 months 26) Past or present alcohol or drug abuse, in the opinion of the Investigator 27) Participation in any other clinical trial within the last month. 28) Has shown previous intolerance/sensitivity to the study medication 29) Is receiving a concomitant excluded medication as per the listed drugs in Section 7.4 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety: The safety assessments will include AEs, laboratory values (hematology and chemistry), 12-lead ECG, manual blood pressure (seated and standing) and heart rate.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
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 | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
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 | 6 |
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 patient /Last Visit. Additionally if the goals of 300 patients completing the 6 months of treatment and 100 patients completing 12 months of treatment are achieved prior to the 350th patient enrolling in the study or completing the 12 month treatment, the sponsor may elect to discontinue the study at that time. |
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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 | |
E.8.9.1 | In the Member State concerned months | 19 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 19 |