| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Irritable bowel syndrome (not constipation predominant). |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10023003 |
|
| 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 of r-verapamil in the treatment of IBS, based on the patient’s global impression, relief of abdominal discomfort / pain and use of rescue medication. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary efficacy end-points will include:
i) The change from baseline in patient’s global severity of illness scale compared to placebo.
ii) The change from baseline in severity of gastrointestinal symptoms scale compared to placebo (bloating/distension, stool frequency, urgency, composite of all symptoms).
iii) The change from baseline in Quality of Life Assessment compared to placebo.
iv) The change from baseline in Bristol Stool Scale compared to placebo.
Daily data from the patient global impression, patient severity of illness scale, severity of gastrointestinal symptoms scale, Bristol Stool Scale and the use of rescue medication will be collected for observation purposes.
The safety of AGI 003 in doses of 20mg, 40mg and 80mg t.i.d will be evaluated by assessing adverse events, abnormal laboratory values, heart rate and the mean seated and standing diastolic blood pressure compared to placebo. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
All patients must:
1) Be aged 18-50 years
2) Have abdominal discomfort or pain on at least 8 days, which need not be consecutive within 8-14 days of the randomisation visit. A patient may be considered for randomisation at any time during the run-in period, provided they have abdominal discomfort or pain on at least 8 days.
3) Fulfil Rome II criteria (modified) for IBS i.e. in the last three months symptoms of abdominal discomfort or pain that has two out of these three features were present often (at least three weeks, at least one day a week):
a. Relieved with defecation; and/or
b. Onset associated with a change in frequency of stool; and/or
c. Onset associated with a change in form (appearance) of stool.
And
None of the following symptoms:
a. Fewer than three bowel movements a week;
b. Straining during a bowel movement.
4) Provide signed written informed consent (Attachment 2).
5) Must be able to make entries into a touch tone telephone diary on a daily basis.
6) Must be willing to abstain from taking rescue medication in the run-in phase.
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|
| E.4 | Principal exclusion criteria |
1) Any evidence of cardiovascular disease or taking of any medication active on the cardiovascular system, apart from stable low dose aspirin (< 75 mg orally/day) for prophylaxis.
2) Lactose intolerance, whose lactose intolerance symptoms are not completely or substantially relieved solely by abstaining from dairy products. (Patients with lactose intolerance on a lactose free diet who qualify otherwise, may be enrolled).
3) Celiac disease (Blood test to measure levels of antibodies (antigliadin, anti-endomysium, and antireticulin) to gluten).
4) Unexplained fever or weight loss of at least 10 pounds during the last 6 months, or any clinically significant symptoms, e.g. patients with 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).
5) Abnormal laboratory tests, positive stool cultures or abnormal proctoscopy / abdominal ultrasound which requires further investigation.
6) Presence of 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.
7) Functional dyspepsia.
8) Any severe or intolerable upper GI symptoms (i.e. early satiety, postprandial fullness, sensation of prolonged digestion, nausea).
9) Greater than one episode of vomiting per week.
10) Moderate or severe diverticulosis, in the opinion of the Investigator.
11) Acute diverticulosis or a history of greater than one episode of diverticulosis.
12) History of chronic colitis of any aetiology (e.g. ulcerative colitis, Crohn’s disease, collagen vascular disease, ischaemic colitis). A subject with a history of acute self limited colitis can be included if otherwise qualified.
13) Acute (currently active) colitis of any aetiology.
14) History of intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, faecal impaction.
15) History of laxative abuse as determined by the Investigator.
16) Moderate, severe or intolerable gastroesophageal reflux disease or heartburn symptoms.
17) Radiologic or clinical evidence of primary and metastatic gastrointestinal malignancy, stricture or obstruction of the gastrointestinal tract, paralytic ileus or intestinal atony.
18) 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).
19) History of major gastric, hepatic, pancreatic or intestinal surgery or perforation (excluding cholecystectomy, appendectomy, haemorrhoidectomy or polypectomy).
20) 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 Visit 1).
21) Antibiotic use within one month prior to Visit 1 (except for prophylactic antibiotics for such conditions as acne, cystitis, UTI’s etc. (must be on a chronic stable dose for > 3 months).
22) Abnormal colonoscopy within the last five years (with the exception of mild benign polyps, mild diverticula, haemorrhoids).
23) 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.
24) A family history of colorectal cancer - these should be properly evaluated.
25) Pregnancy or lactation. Women of childbearing potential must maintain effective contraception (See Section 5.4).
26) Use of drugs judged by the investigator to be the cause of the current episode of symptoms.
27) Evidence of formal psychiatric illness, apart from depression (not major), which is controlled by antidepressants (See Section 7.5).
28) Past or present alcohol or drug abuse, in the opinion of the Investigator.
29) Participation in any other clinical trial within the last month.
30) Has shown previous intolerance/sensitivity to the study medication.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The first primary endpoint is the difference in the percentage of responders between active and placebo based on the patient’s global impression.
The second primary endpoint is the difference in percentage of responders between active and placebo based on the patient’s relief of abdominal pain/discomfort.
The third primary endpoint is the use of rescue medication (loperamide, paracetamol) during the study compared to placebo. |
|
| 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 | No |
| 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 | Information not present in EudraCT |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
| |
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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