E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
GENOTYPE POSITIVE SUBJECTS WITH FAMILIAL ADENOMATOUS POLYPOSIS |
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E.1.1.1 | Medical condition in easily understood language |
Genetic disease that causes multiple abnormal growths (polyps) in the intestines, especially, the large intestine and rectum |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059327 |
E.1.2 | Term | Familial adenomatous polyposis |
E.1.2 | System Organ Class | 100000004850 |
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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 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. |
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E.2.2 | Secondary objectives of the trial |
To compare colorectal polyp burden over 5 years, and time to development of >20 polyps (>2 mm) or colorectal cancer for subjects treated with celecoxib versus subjects treated with placebo. |
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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 |
A Pharmacokinetic sub-study (PK sites) is part of the main study |
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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 FAP based on central genetic testing (see section 6.3 APC Genotype Mutation Testing in the protocol) or a personal history of > 2 colorectal adenomas and a parent with the diagnosis of FAP. FAP diagnosis will be based on one of three (A, B or C) criteria below:
A. Non Attenuated FAP Genotype
B. Attenuated FAP Genotype will be defined as the following:
2. Subjects with an APC genotype mutation listed as attenuated on Table 2 in the protocol (See Study Manual for Current Genotype Mutation Tables) may participate if they have a personal history of colorectal adenomas and a first degree relative (parent or sibling) with at least one of the following ‘by 40 years of age’:
• Colectomy;
• Diagnosis of colorectal cancer;
• Colonoscopically established evidence of profuse (>100) adenomas.
C. No Genotype Identified
3. Male or female subjects aged 10 to 17 years inclusive at the time of enrollment.
4. Subject’s parent or legal guardian has provided written informed consent prior to enrollment in this study.
5. Subject has assented to participate prior to enrollment in this study.
6. Subject and parent/legal guardian, agree to comply with study requirements and are able to be at the clinic for all required study visits.
7. 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.
8. 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.
9. 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).
10. 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.
11. Intact Colon.
12. 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 <30 polyps (>2 mm in size), all must be removed so as to render the colon polyp-free and thus amenable to serial endoscopic surveillance.
13. Systolic and Diastolic Blood Pressure <95th percentile. Those subjects with blood pressure measurements within the ≥90 to <95th percentile group are eligible for enrollment. |
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E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Diagnosis of attenuated FAP based on central genetic testing in the absence of a personal history of colorectal adenomas and a first degree relative (parent or sibling) with at least one of the following by the age of 40 years, or patients with a personal history of > 2 colorectal adenomas who do not have a parent with one of the following by the age of 40 years
• Colectomy
• Diagnosis of colorectal cancer
• Colonoscopically established evidence of profuse (> 100) adenomas.
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. ≥30 polyps (>2 mm in size) at baseline colonoscopy.
8. <30 polyps (>2 mm in size) 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. |
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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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Annual scheduled visits for colonoscopy, or unscheduled visits during which colonoscopy is performed. Colonoscopy is the passage of a tube through the rectum into the large bowel under mild anesthesia for the purpose of examining the large intestine. |
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E.5.2 | Secondary end point(s) |
To compare in the intent-to-treat population the time from randomization to treatment failure 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:
• Appearance of ≥20 polyps (>2 mm in size) at any colonoscopy during the study, or
• Diagnosis of colorectal malignancy, or
• Treatment related dropout. Treatment related dropout is defined as insufficient clinical response, progression of disease, death, adverse event, treatment-related laboratory abnormality, subject no longer willing to participate in study, and other reasons that may be related to treatment (will be determined by treating physicians in a blind fashion before database release).
To compare between subjects treated with celecoxib versus subjects treated with placebo the total number of colorectal polyps (>2 mm in size) detected over Years 1-5 cumulatively.
To compare colorectal polyp burden over 5 years. The polyp burden is defined as the sum of the largest diameters of all polyps (>2 mm in size) over Years 1-5 cumulatively. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Annual scheduled visits for colonoscopy, or unscheduled visits during which colonoscopy is performed. Colonoscopy is the passage of a tube through the rectum into the large bowel under mild anesthesia for the purpose of examining the large intestine. |
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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 | No |
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 | 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 | 2 |
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 | 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 |
Chile |
Czech Republic |
Hong Kong |
Hungary |
Israel |
Italy |
Slovakia |
South Africa |
Spain |
Sweden |
Ukraine |
United Kingdom |
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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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Study termination based on factors such as unacceptable adverse effects, lack of study drug efficacy, or poor accrual. |
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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 |