E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Diverticulitis is inflammation of small pouches (diverticula) that can form in the walls of the large intestine |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10013538 |
E.1.2 | Term | Diverticulitis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
-To compare the efficacy and tolerability of two doses mesalazine granules (1.5 g and 3 g 5-ASA/d) vs. placebo for the prevention of recurrence of diverticulitis
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E.2.2 | Secondary objectives of the trial |
-To study safety and tolerability in the form of adverse events and laboratory parameters
-To assess patients´quality of life |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent
2. Man or woman between 30 and 80 years of age
3. Diagnosis of left-sided uncomplicated diverticular disease confirmed by computed tomography
4. Presence of at least one diverticulum of the left colon
5. Most recent attack of left-sided uncomplicated diverticulitis responding to antibiotics and/or dietary modification within the last 6 months (Response: normalization of clinical and biochemical parameters)
6. Most recent attack of left-sided uncomplicated diverticulitis documented by medical records
7. 3 or more of the following symptoms reported since the most recent attack:
- left lower quadrant pain
- fever (higher than 38 °C, ear measurement preferred)
- altered bowel habit (diarrhea, constipation, passage of mucus, or urgency)
- systemic upset (nausea, lethargy)
8. CRP > ULN or leucocytosis (> 10 000/mm³) at the start of the most recent attack
9. Women of child-bearing potential have to apply during the entire duration of the study a highly effective method of birth control, which is defined as those which result in a low failure rate (i.e., less than 1% per year) when used constantly and correctly such as implants, injectables, combined oral contraceptive method, some IUDs, sexual abstinence or vasectomised partner. The investigator is responsible for determining whether the patient has adequate birth control for study participation. |
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E.4 | Principal exclusion criteria |
1. Chronic inflammatory bowel disease (such as Crohn’s disease, ulcerative colitis)
2. Complicated diverticular disease (diverticulitis with associated abscess, fistula, obstruction or perforation); diverticular abscess to be excluded by computed tomography
3. Right-sided diverticulitis
4. Previous colonic surgery (except appendectomy, haemorrhoidectomy, and endoscopic removal of polyps)
5. Presence of symptomatic organic disease of the gastrointestinal tract (with the exception of non-bleeding hemorrhoids or hiatal hernia)
6. Active colorectal cancer or a history of colorectal cancer
7. Active malignancy other than colorectal cancer or treatment with anticancer drugs during the last 5 years. Patients with a history of cancer other than colorectal cancer and at least five years of uneventful follow up and no signs of recurrence may be eligible.
8. Hemorrhagic diathesis
9. Active peptic ulcer disease, local intestinal infection
10. Asthma if careful medical monitoring is not ensured
11. Abnormal hepatic function or liver cirrhosis (ALT, AST or AP >= 2 x ULN)
12. Abnormal renal function (Cystatin C, creatinine > ULN)
13. Severe co-morbidity and/or immobility
14. 5-aminosalicylic acid (5-ASA, mesalazine) containing drugs, glucocorticosteroids, opioid analgesics, laxatives, antidiarrheals, immunosuppressants, or non-steroidal anti-inflammatory drug (NSAIDs; as permanent treatment) within the last 2 weeks before inclusion; acetylsalicylic acid (<= 100 mg/day) or paracetamol, inhaled or nasal steroids allowed
15. Baseline stool positive for organisms causing bowel disease
16. Known intolerance/hypersensitivity/resistance to study drug or drugs of similar chemical structure or pharmacological profile
17. Doubt about the patient’s cooperation, e.g. because of addiction to alcohol or drugs
18. Existing or intended pregnancy or breast-feeding
19. Participation in another clinical trial within the last 30 days, simultaneous participation in another clinical trial, or previous participation in this trial
20. For patients in need of a CT-scan as part of the protocol, any condition that may increase the risk of conducting the required CT-scan with contrast media. Such conditions include but are not limited to hyperthyroidism, hypersensitivity to CT-scan contrast media, congestive heart failure (NYHA III/IV), and diabetes requiring medication that cannot be safely stopped for the CT-scan |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Proportion of recurrence-free patients at 48 weeks;
- Proportion of recurrence-free patients at 96 weeks:
Recurrence of diverticulitis, defined as CRP > ULN or leucocytosis (> 10 000/mm³) and recurrence of diverticulitis-like symptoms (left lower quadrant pain, fever) and confirmation by computed tomography |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 48 weeks and 96 weeks of treatment of 300 patients will be evaluated in the first stage, 420 patients in the second stage, total 720 patients.
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E.5.2 | Secondary end point(s) |
• Proportion of patients with recurrence,
• Time in study,
• Time to recurrence,
• Time to recurrence or discontinuation,
• Subgroup analysis for number of episodes of diverticulitis in the previous year,
• Subgroup analysis for prompt vs de¬layed start of treatment after attack,
• Subgroup analysis for inflammatory markers increased vs not increased at baseline,
• Subgroup analysis by number/location of diverticula,
• Subgroup analysis for concomitant treatment with statins vs no statins,
• Course of ESR,
• Course of CRP,
• Course of leucocytosis,
• Occurrence of diverticulitis-associated fever,
• Number of days with left lower quadrant pain,
• Number of days with stools of solid consistency,
• Number of days with stools of soft or solid consistency,
• Number of days with diarrhea (> 3 stools per day),
• Number of days with stools of watery consistency,
• Average frequency of stools per week,
• Amount of used spasmolytics,
• Amount of used analgesics,
• Worsening of symptoms, e.g., use of antibiotics, hospitalization for underlying disease, surgery,
• Quality of life,
• Health assessment,
• Assessment of efficacy by investigator and patient.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary and safety parameters will be evaluated for exploratory purposes in the same manner like the primary endpoints. |
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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 | Yes |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 | No |
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 |
Australia |
Belgium |
Finland |
Germany |
Greece |
Spain |
Sweden |
Switzerland |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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The study end is defined as "last patient out" (LPO) |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |