E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 10013538 |
E.1.2 | Term | Diverticulitis |
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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 proportion of subjects without recurrence of diverticulitis between 3 doses of SPD476 (1.2g/day QD, 2.4g/day QD, and 4.8g/day QD) and placebo QD at Week 104. Recurrence of diverticulitis is defined as: • Presence of each and all of the following three items: 1. Abdominal pain 2. A 15% increase in white blood cell (WBC) count from baseline and a shift to the left (1% increase in bands) 3. Bowel wall thickening (>5mm) and/or fat stranding as evidenced by spiral computerized axial tomography (CT) scan OR • Surgical intervention for diverticular disease
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E.2.2 | Secondary objectives of the trial |
• Time to recurrence of diverticulitis & presence of abdominal pain • Time to a 15% increase in WBC count from baseline and a shift to the left (1% increase in bands) • To compare the proportion of subjects without recurrence of diverticulitis between 3 doses of SPD476 and placebo QD at Weeks 26 & 52 • To compare the proportion of subjects with recurrence of complicated versus uncomplicated diverticulitis between 3 doses of SPD476 and placebo • To compare the change in C-Reactive Protein (CRP) from Baseline at all study visits between treatment groups • To compare the proportion of subjects requiring surgical intervention for diverticular disease up to 104 weeks post baseline between 3 doses of SPD476 and placebo QD • To compare Quality of Life using the EQ5D and Health Utilities Index questionnaires between treatment groups at Baseline, Weeks 16, 52 & 104 • To assess the safety and tolerability of 3 doses of SPD476 over 104 weeks. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for inclusion, each subject must meet each of the following criteria at screening, and must continue to fulfil these criteria at baseline: 1. Written, signed, and dated informed consent to participate in the study must be given by the subject, in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 and applicable regulations, before completing any study-related procedures listed in Section 6.2. 2. Male and female subjects ³18 years of age 3. Males, or non-pregnant, non-lactating females of childbearing potential (FOCP), as demonstrated by negative beta HCG (human chorionic gonadotropin) serum pregnancy test, who agree to comply with any applicable contraceptive requirements of the protocol (refer to Section 4.4) 4. At least one documented attack of acute diverticulitis in the previous 24 months that has clinically resolved without colonic resection. (Documentation must include: physical examination, laboratory analysis, and a verifiable report confirming acute diverticulitis by CT scan, MRI scan, or endoscopy.) 5. Flexible sigmoidoscopy confirmation of diverticulosis with at least three diverticula noted. Frank ulceration and evidence of ischaemia is not acceptable. The presence of mild erythema and loss of vascularity (oedema) is not exclusionary 6. WBC count within normal reference ranges 7. Polymorphonuclear leukocyte [PMN] level within normal reference ranges 8. Subject and Investigator must agree that participation in this study is in the best interest of the subject
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E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria are met at screening or at baseline: 1. History of complicated diverticular disease (peritoneal abscesses, surgical resection for diverticular stricture, active fistula disease), history of diverticular bleed or colonic stricture 2. Clinically relevant gross extraluminal pathology as shown by CT scan 3. Right sided diverticulosis only 4. Abdominal pain and abdominal tenderness upon palpation 5. Active peptic ulcer disease 6. History of or current presence of inflammatory bowel disease (IBD) or documented history of irritable bowel syndrome requiring regular monthly medication 7. Active GI bleeding, except for positive faecal occult blood test (FOBT) in the stool 8. Allergy or hypersensitivity to mesalazine (5-ASA) or aspirin 9. Subjects with asthma are excluded only if they are known to be mesalazine-sensitive 10. Allergy to radiologic contrast agents 11. Subjects must not have used another Investigational product within 30 days prior to Baseline 12. Use of antibiotic therapy within 4 weeks of Baseline 13. Use of prebiotic medication, or probiotic medication, as well as tegaserod, alosetron, laxatives, metaclopramide, domperidone, anti-spasmotic agents, and anti-diarrhoeal agents within 14 days of Baseline 14. Use of biologics (anti-TNF agents) 15. Use of immunomodulators (e.g., azathioprine, 6-mercaptopurine) within 6 weeks prior to Baseline 16. Use of systemic or rectal steroids within 6 weeks of Baseline 17. Subjects using any anti-inflammatory drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, COX-2 inhibitors, or ibuprofen on a regular basis (defined as over-the-counter NSAID use for 3 consecutive days or 7 occurrences per month, with the exception of aspirin [£325mg/day] taken for cardiac prophylaxis) 18. Subjects with clinically relevant moderate or severe renal or hepatic impairment are contraindicated with mesalazine products 19. Previous colorectal surgery (with the exception of haemorrhoidectomy, colonic removal of benign polyps, and appendectomy) 20. Current or relevant previous disease that could affect the colon, action, absorption, or disposition of the investigational product, or clinical or laboratory assessments 21. Malignancy, except for basal cell skin cancer, cervical carcinoma in-situ, or carcinoma in-situ in a colonoscopically removed polyp 22. Subjects with a history of alcohol or other substance abuse within the previous year 23. Current or relevant history of serious, severe, or unstable (acute of progressive) physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully complete the study, or any condition that presents undue risk from the study medication or procedures 24. Subjects who have previously been screened for or enrolled into this study and subsequently withdrawn
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint for this study is the proportion of subjects without a recurrence of diverticulitis at Week 104. Recurrence of diverticulitis is defined as: • Presence of each and all of the following three items: 1. Abdominal pain 2. A 15% increase in white blood cell count (WBC) from baseline and a shift to the left (1% increase in bands) 3. Bowel wall thickening and/or fat stranding as evidenced by spiral computerized axial tomography (CT) scan OR • Surgical intervention for diverticular disease
The secondary efficacy variables are: • Time to recurrence of diverticulitis • Time to presence of abdominal pain • Time to a 15% increase in white blood cell count (WBC) from baseline and a shift to the left (1% increase in bands) • To compare the proportion of subjects without recurrence of diverticulitis between 3 doses of SPD476 (1.2g/day QD, 2.4g/day QD, and 4.8g/day QD) and placebo QD at Weeks 26 and 52 • To compare the severity of recurrence of diverticulitis (complicated versus uncomplicated) between 3 doses of SPD476 (1.2g/day QD, 2.4g/day QD, and 4.8g/day QD) and placebo QD • To compare the change in CRP from Baseline at all study visits between treatment groups • To compare the proportion of subjects requiring surgical intervention for diverticular disease up to 104 weeks post baseline • To compare QoL using the EQ5D and HUI questionnaires between treatment groups at Baseline, Weeks 16, 52, and 104 • To assess the safety and tolerability of SPD476 1.2g/day QD, 2.4g/day QD, and 4.8g/day QD over 104 weeks
Tertiary Outcomes The tertiary efficacy variables are: • To compare flexible sigmoidoscopy assessments between treatment groups at Screening and End of Study visits • To compare histology of biopsy samples between treatment groups at Screening and End of Study visits
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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 | Information not present in EudraCT |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | Yes |
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 | Yes |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 | 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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |