| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| GENOTYPE POSITIVE SUBJECTS WITH FAMILIAL ADENOMATOUS POLYPOSIS |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10059327 |
| E.1.2 | Term | Familial adenomatous polyposis |
|
| 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 compare the time from randomization to treatment failure over a five year period for subjects treated with celecoxib versus subjects treated with placebo, where treatment failure is defined as the earliest occurrence of one or more of the following:
a. Appearance of ≥20 polyps (>2 mm in size) at any colonoscopy during the study;
OR
b. Diagnosis of colorectal malignancy. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the total number of polyps over 5 years for subjects treated with
celecoxib versus subjects treated with placebo
• To compare polyp burden over 5 years for subjects treated with celecoxib versus
subjects treated with placebo
• To compare the time to appearance of ≥ 5 colorectal adenomas for subjects treated
with celecoxib versus subjects treated with placebo |
|
| 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 |
| A Pharmacokinetic sub-study (PK sites) is part of the main study |
|
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Confirmed diagnosis of non-attenuated FAP based on central genetic testing
2. Male or female subjects aged 10 to 17 years inclusive at the time of enrollment.
3. Subject’s parent or legal guardian has provided written informed consent prior to enrollment in this study.
4. Subject has assented to participate prior to enrollment in this study.
5. Subject and parent/legal guardian, agree to comply with study requirements and are able to be at the clinic for all required study visits.
6. Willingness to abstain from the chronic use of NSAIDs (including aspirin, selective COX-2 inhibitors), oral adrenocorticosteroids, and other non-steroidal OTC products for the duration of the study. Chronic use of NSAIDs is defined as a frequency of 1 week (7 consecutive days) for more than 3 weeks per year.
7. If subject is female and of childbearing potential, she must meet all of the following
conditions:• Have been using adequate contraception (eg, abstinence, condom, IUD,
subdermal implant, birth control pill, diaphragm and spermicide foam/gel/cream/suppository combination) since her last menses; AND
• Be willing to use adequate contraception (as above) during the study; AND
• Not be breastfeeding; AND
• Have a negative urine or serum pregnancy test within 14 days prior to study drug administration. If the central serum pregnancy test results are >14 days prior to study drug administration the test must be repeated. This will be done locally by either serum or urine testing.
8. If subject is male and sexually active he must be willing to use a condom and be
instructed that his female partner should be using adequate contraception (eg, female condom, IUD, sub dermal implant, birth control pill, diaphragm and spermicidal foam/gel/cream/suppository combination).
9. The subject will be allowed to proceed to baseline colonoscopy so long as all of the following laboratory criteria (limits of normal for age as appropriate) are met on baseline evaluation:
• Hemoglobin >10.0 gm/dl;
• Platelet count >100,000/µl;
• WBC >3,000/µl;
• ALT <1.5 x upper limit of normal; AST <1.5 x upper limit of normal;
• Alkaline Phosphatase <1.5 x upper limit of normal;
• Total Bilirubin <1.5 x upper limit of normal unless the subject has Gilbert’s disease for which Total Bilirubin must be ≤2.0 x ULN;
• Calculated Creatinine Clearance >90 mL/min/1.73 to the power of 2
• No evidence of proteinuria or hematuria;
• Cholesterol <1.5x upper limit of normal;
• Microalbuminuria ≤23 mg/L;
• For tests not mentioned specifically, there must be no clinically significant abnormalities that in the opinion of the PI would preclude a subject’s safe participation.
Use of a local laboratory for safety tests in subjects who travel long distances can
be requested to the study medical monitor.
10. Intact Colon.
11. Colonoscopy will be performed at baseline according to the description provided in the Colonoscopy Procedures. To proceed to randomization, the subject must have all of the following:
• An assessable colon endoscopically evaluated following an adequate bowel preparation AND
• If <20 polyps (>2 mm in size), all must be removed so as to render the colon polyp-free and thus amenable to serial endoscopic surveillance.
12. Systolic and Diastolic Blood Pressure <95th percentile. Those subjects with blood pressure measurements within the ≥90 to <95th percentile group are eligible for enrollment. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
-1. Diagnosis of attenuated FAP
2. History of hypersensitivity to COX-2 inhibitors, sulfonamides, NSAIDs or salicylates
3. Subjects who are not heterozygous for the CYP2C9 variant Ile359Leu (CYP2C9 *3).
4. Use of any dose of NSAIDs or oral adrenocorticosteroids, at any frequency of 3 or more times per week during the three months prior to study entry will require a three-month washout period beginning with the time of last dose. Use of any dose of NSAIDs or oral adrenocorticosteroids, at any frequency of less than 3 times per week during the three months prior to study entry will require a one-month washout period beginning with the time of last dose. If chronic inhaled steroid use is required, the subject agrees to use mometasone. Use of mometasone is not restricted. In countries were mometasone is not available, only fluticasone will be permitted
5. Anticipated need for concurrent use of fluconazole or lithium
6. Active peptic ulcer disease documented by endoscopy. Significant renal, hepatic or hematologic dysfunction (to be determined by investigator). History of H. pylori related peptic ulcer disease that has been successfully treated with antibiotics will not be exclusionary
7. ≥20 polyps (> 2 mm without dye enhancement) at baseline colonoscopy
8. < 20polyps(> 2 mm without dye enhancement) that have not all been removed at
baseline colonoscopy
9. Known inability to participate in the scheduled follow-up tests
10. Significant medical or psychiatric problems, which, in the opinion of the site investigator, would make the subject a poor protocol candidate
11. Subject has undergone a colectomy or planned to have colectomy within the next 6 months
12. Subject has undergone chemotherapy within the past 6 months
13. Subject has received pelvic radiation
14. History of invasive carcinoma in the past five years
15. Familial hypercholesterolemia
16. Familial Hypertriglyceridemia
17. Diabetes
18. Coagulopathy
19. Use of any investigational agent within the last 3 months
20. ECG with any findings deemed by the investigator to be clinically significant.
21. Subjects with Inflammatory Bowel Disease.
22. Pre-existing renal disease such as glomerulonephritis, nephritic syndrome, renal
transplants, or uncorrected renal/bladder obstruction. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for this study is time to treatment failure defined as the time
from randomization to the earliest occurrence of the following events:
a. Appearance of ≥20 polyps (>2 mm in size) at any colonoscopy during the study;
OR
b. Diagnosis of colorectal malignancy. |
|
| 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 | Information not present in EudraCT |
| 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 | 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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| 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 | 20 |
| 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 |
|
| 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
|
| Study termination based on factors such as unacceptable adverse effects, lack of study drug efficacy, or poor accrual. |
|
| 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 |
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