E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of Diverticulitis |
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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 | 14.0 |
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 proportion of subjects without a 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:
• The presence of each and all of the following 3 items:
1. Abdominal pain
2. A 15% increase in white blood cell (WBC) count from Baseline
3. Bowel wall thickening (>5mm) and/or fat stranding as evidenced by spiral computerised axial tomography (CT scan)
OR
• Surgical intervention for diverticular disease.
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E.2.2 | Secondary objectives of the trial |
To compare the proportion of subjects who are CT-recurrence free up to Week 104 between each of 3 doses of SPD476 (1.2g/day QD, 2.4g/day QD, and 4.8g/day QD) and placebo QD
CT-recurrence of diverticulitis is defined as:
• A positive spiral CT scan for diverticulitis showing, at a minimum, fat stranding (with or without bowel wall thickening >5mm)
OR
• Surgical intervention for diverticular disease.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title of the Study: A follow-on, prospective outcomes sub-study to summarise healthcare resource utilisation and quality of life in subjects who withdraw study medication due to diverticulitis from SPD476-313
Primary:
To summarise healthcare resource utilisation in subjects who withdraw due to diverticulitis from the SPD476-314 study.
Recurrence of diverticulitis is defined as:
The presence of each and all of the following three items:
1. Abdominal pain
2. A 15% increase in WBC count from Baseline
3. Bowel wall thickening (>5mm) and/or fat stranding as evidenced by spiral computerised axial tomography (CT scan)
OR
Surgical intervention for diverticular disease
Secondary:
To summarise quality of life in subjects who withdraw due to recurrence of diverticulitis
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E.3 | Principal inclusion criteria |
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 6.1.
2. Male and female subjects ≥18 years of age.
3. If female of childbearing potential (FOCP), has demonstrated a negative beta HCG (human chorionic gonadotropin) serum pregnancy test, and agrees 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 a verifiable report confirming acute diverticulitis (examples include CT scan, magnetic resonance imaging (MRI) scan, ultrasound, endoscopy of the sigmoid colon, or barium enema).
5. Confirmation of diverticulosis via endoscopic evaluation of the sigmoid colon, with at least three diverticula noted. The presence of mild erythema and loss of vascularity (oedema) is acceptable, whereas frank ulceration and evidence of ischaemia is not.
6. White Blood Cell (WBC) count within central laboratory normal reference ranges.
7. Polymorphonuclear leukocyte (PMN) level within central laboratory 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 |
1. Subjects who have had an attack of diverticulitis and/or continue to exhibit signs and symptoms of diverticulitis within 6 weeks prior to and up to Baseline
2. Previous colorectal surgery, including surgical intervention for diverticular disease (with the exception of haemorrhoidectomy, colonic removal of polyps, and appendectomy)
3. Clinically relevant gross extraluminal pathology as shown by CT scan
4. Right sided diverticulosis only
5. Active peptic ulcer disease
6. History of or current presence of inflammatory bowel disease (IBD)
7. Subjects with active irritable bowel syndrome (IBS) requiring ongoing medication.
8. Active GI bleeding, except for positive faecal occult blood test (FOBT) in the stool
9. Active or recent history of endometriosis or dysmenorrhoea within 6 months prior to Baseline
10. Allergy or hypersensitivity to mesalazine (5-ASA) or aspirin
11. Subjects who are unwilling or unable to undergo a CT scan or have a known or suspected allergy to all radiologic contrast agents.
12. Subjects must not have used another investigational product within 30 days prior to Baseline
13. Within 14 days of Baseline, use of prebiotic, probiotic or 5-ASA medications, as well as drugs active at the 5HT-receptor (e.g., tegaserod, alosetron, metaclopramide) or anti-spasmodic agents
14. Any current or historical 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. Use of inhaled or nasal steroids is acceptable
17. Subjects who have conditions requiring regular and ongoing use of anti-inflammatory drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, COX 2 inhibitors, or ibuprofen. Use of aspirin (≤325mg/day) taken for cardiac prophylaxis is acceptable
18. Subjects with clinically relevant moderate or severe renal or hepatic impairment are contraindicated with mesalazine products
19. Current or relevant previous disease that could affect the colon, action, absorption, or disposition of the investigational product, or clinical or laboratory assessments.
20. Any history of malignancy, except for basal cell skin cancer, cervical carcinoma in-situ, or carcinoma in-situ in a colonoscopically removed polyp
21. Subjects with a history of alcohol or other substance abuse within the previous year
22. Females who are lactating
23. Current or relevant history of serious, severe, or unstable (acute or 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) |
To compare the proportion of subjects without a 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:
• The presence of each and all of the following 3 items:
1. Abdominal pain
2. A 15% increase in white blood cell (WBC) count from Baseline
3. Bowel wall thickening (>5mm) and/or fat stranding as evidenced by spiral computerised axial tomography (CT scan)
OR
• Surgical intervention for diverticular disease.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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. |
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E.5.2 | Secondary end point(s) |
To compare the proportion of subjects who are CT-recurrence free up to Week 104 between each of 3 doses of SPD476 (1.2g/day QD, 2.4g/day QD, and 4.8g/day QD) and placebo QD
CT-recurrence of diverticulitis is defined as:
• A positive spiral CT scan for diverticulitis showing, at a minimum, fat stranding (with or without bowel wall thickening >5mm)
OR
• Surgical intervention for diverticular disease.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The proportion of subjects who are CT-recurrence free up to Week 104 between each of 3 doses of SPD476 (1.2g/day QD, 2.4g/day QD, and 4.8g/day QD) and placebo QD. |
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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 | 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 | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Brazil |
Canada |
Finland |
Germany |
Hungary |
Italy |
Netherlands |
Romania |
South Africa |
United States |
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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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LPLV + 7 days for safety follow-up |
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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 |