E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Active, Chronic, Antibiotic Refractory Primary Idiopathic Pouchitis |
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E.1.1.1 | Medical condition in easily understood language |
Active, Chronic, Primary Idiopathic Pouchitis which cannot be treated efficiently with antibiotics |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036463 |
E.1.2 | Term | Pouchitis |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the effect of alicaforsen enema on endoscopic healing and symptoms associated with pouchitis in those subjects with active antibiotic refractory pouchitis |
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E.2.2 | Secondary objectives of the trial |
1. To determine the ability of alicaforsen enema to improve the clinical symptoms associated with antibiotic refractory pouchitis
2. To determine the effect of alicaforsen enema on health related quality of life.
3. To evaluate duration of effect following cessation of therapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent;
2. Male or female subjects, ≥ 18 years of age who have undergone an IPAA for UC
3. History of pouchitis
Documented evidence of active pouchitis, based on endoscopy, symptoms and histopathology, as follows:
4. Endoscopic score ≥2 on the endoscopic component of a modified MAYO score (where friability is scored as ≥2)
Note: the area within 1 cm of the pouch staple, or pouch suture line, is not considered evaluable
5. Symptomatic disease (stool frequency): Subjects must demonstrate increased stool frequency compared to what is considered “normal” after their IPAA operation (“baseline”). Stool frequency must be an absolute value of ≥ 6 stools per day, and ≥ 3 stools per day above the post-IPAA “baseline”.
Note: The measurement of stool frequency will be a 7-day average rounded to the nearest integer. The most recent 7 days of data will be used to calculate the average.
6. Histology: evidence of disease (Score ≥2 on PDAI)
7. Overall PDAI score > 7
8. Must have Chronic Antibiotic Refractory Pouchitis
Chronic Antibiotic Refractory Pouchitis is defined as remaining in active disease despite antibiotic therapy for at least 2 continuous weeks. There is no requirement for antibiotic use to be current, or within a defined time-window. Antibiotics must be stopped 4 weeks before the Randomisation Visit which is effectively 2 weeks before the Screening Visit. As a minimum the antibiotic regime will comprise ciprofloxacin 1g/day, or metronidazole 15 – 20 mg/kg/day. Subjects must have been in active disease for a minimum of 4 weeks at the point of randomisation.
OPEN LABEL ACCESS INCLUSION CRITERIA
1. Written informed consent;
2. Previous participation to Week 26 of double blind phase
3. Demonstrated compliance with previous alicaforsen/blinded treatment
4. Current evidence of active disease, based on clinical symptoms
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E.4 | Principal exclusion criteria |
1. Lack of effective contraception
2. Women who are pregnant or breastfeeding;
3. History of allergy or adverse event to oligonucleotides including
alicaforsen hydroxymethylcellulose, methyl or propylparabens.
4. Changes in dose to strong analgesia, such as opioid containing compounds within 4 weeks of the Screening Visit.
5. History of regular NSAID use.
6. Oral 5-aminosalicylate (5-ASA) compounds; exclude subjects who have discontinued or changed doses of oral 5-ASA within 4 weeks of the Screening Visit.
7. Oral budesonide > 6.0 mg / day is not permitted; exclude subjects who have received budesonide for < 6 weeks, or who have changed doses of budesonide within 4 weeks of the Screening Visit.
8. Oral steroids other than budesonide; exclude subjects who exceed a daily dose of 15 mg prednisolone or equivalent, who have received oral steroids for < 6 weeks, or who have changed dose within 4 weeks of the Screening Visit.
9. Use of rectal compounds is not permitted; these agents must be discontinued at the Screening Visit.
10. Immunosuppressant therapy (azathioprine, 6-mercaptopurine, methotrexate, cyclosporin); exclude subjects who have received treatment for < 12 weeks, or who have changed doses within 8 weeks of the Screening Visit.
11. Biological agents: Anti-tumour necrosis factor (anti – TNF) therapy and / or vedolizumab; are not permitted within 8 weeks of the Screening Visit.
12. Previous use of alicaforsen is permitted: treatment course must have completed at least 12 weeks prior to the Screening Visit. (Alicaforsen pre-treated subjects may not contribute to the primary efficacy analysis.)
13. All other agents targeted to pouchitis, including experimental agents, must have been discontinued at least 8 weeks prior to the Screening Visit, or for a period equivalent to 5 half-lives (t½) of the agent (whichever is longer)
14. Anastomotic stricture
15. Unable to undertake endoscopic evaluation
16. Faecal incontinence due to anal sphincter dysfunction
17. Infections to cytomegalovirus or Clostridium Difficile
18.Faecal transplantation within 12 weeks of screening
19. Intestinal malabsorption
20. Pancreatic maldigestion
21. Suspected irritable pouch syndrome
22. Cuffitis (inflammation of the anal mucosa). Subjects with active antibiotic refractory pouchitis as the predominant condition, but who also have cuffitis, may be enrolled
23. Crohn’s disease of the pouch: defined as either: a) complex perianal
or pouch fistula and/or b) extensive pre-pouch ileitis with deep
ulceration
24. Subjects with a history of neoplastic disease except for basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin
25. Subjects who are receiving or have received nasogastric/nasoenteric bottle feeding, an elemental diet, or total parenteral nutrition within the 2 weeks prior to Day 1
26. Subjects with a history of clinically significant and/or persistent; haematologic, renal, hepatic, metabolic, psychiatric, CNS, pulmonary or cardiovascular disease; which in the investigators opinion, would exclude entry into the study
27. Subjects with any laboratory tests considered clinically significant at screening
28. Subjects who may be unavailable for the duration of the trial, likely to be noncompliant with the protocol, or who are felt to be unsuitable by the Investigator for any other reason including, for example, inability to retain an enema formulation
29. Pelvic sepsis should be excluded as a differential diagnosis within 12 months of randomization.
OPEN LABEL ACCESS EXCLUSION CRITERIA
1. Lack of effective contraception
2. Women who are pregnant or breastfeeding;
3. History of allergy or adverse event to hydroxymethylcellulose, methyl or propylparabens.
4. Concurrent use of experimental agents
5. Subjects with any laboratory tests considered clinically significant
6. Subjects who may be unavailable for the duration of the treatment course, likely to be noncompliant, or who are felt to be unsuitable by the Investigator for any other reason
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-Primary Endpoints:
1. Proportion of subjects with endoscopic remission; defined as absence of friability and ulceration, represented by a score of ≤ 1 (endoscopy component of a modified MAYO score) at Week 10.
Note : the area within 1 cm of the pouch suture line will not be included in the endoscopic evaluation.
2. Proportion of subjects with a stool frequency represented by a MAYO
subscore of ≤ 1 at Week 10 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Percentage change in stool frequency from baseline compared to placebo; Week 6 and Week 10.
2. Change in urgency score from baseline compared to placebo; Week 6.
3. Change in rectal bleeding score from baseline compared to placebo;
Week 6.
4. Proportion of subjects who achieve overall PDAI <5 at both Week 6 and Week 10.
5. Mean change from baseline in CGQL at Week 6.
6. Proportion of subjects by Week 26, who have not received additional
treatment for pouchitis flares, since commencing study. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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 | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Belgium |
Canada |
France |
Ireland |
Israel |
Italy |
Netherlands |
Switzerland |
United Kingdom |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |