start date: October 2013
estimated completion: April 2019
last updated: September 30, 2020
phase of development: Phase 3
size / enrollment: 171
study design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
primary outcomes:
- Delaying time to the 1st occurrence of any FAP-related event. [ Time Frame:24 months from the start of treatment ] [ Designated as safety issue: No ]
secondary outcomes:
- Presence or absence of an ODC polymorphism [ Time Frame: 24 months from the start of treatment ] [ Designated as safety issue: No ]
Evaluate the potentially effect modifying properties of an ornithine decarboyxlase (ODC) polymorphism on primary outcome
- Excretion of 4 urinary polyamines [ Time Frame: 24 months from the start of treatment ] [ Designated as safety issue: No ]
Evaluate the potentially effect modifying properties of 4 urinary polyamines
inclusion criteria:
• Eligible Sexes: all
- Diagnosis of phenotypic classical FAP with disease involvement of the duodenum and/or colon/rectum/pouch.
1. Genotype: APC mutation (with or without family history) required
2. Classical FAP Phenotype: 100's to 1,000's of colorectal adenomatous polyps, usually appearing in teenage years
- UGI endoscopy/LGI endoscopy (proctoscopy/colonoscopy) performed within 30 days of randomization.
- Patients with an intact colon/rectum, except for clinical polyposis, and prophylactic surgery is being considered as a stratification site.
- Rectal/pouch polyposis as a stratification site as follows:
1. At least three years since colectomy with IRA/proctocolectomy with pouch, and demonstrating polyposis as defined by Stage 1, 2, 3, of the proposed InSiGHT 2011 Staging System (Appendix B) and summarized as follows: Stage 1: 10-25 polyps, all < 5 mm
Stage 2: 10-25 polyps, at least one > 1 cm
Stage 3: >25 polyps amenable to complete removal, or any incompletely removed sessile polyp, or any evidence of high grade dysplasia, even if completely removed. [Note: For staging purposes only.]
2. For all subjects, any rectal/pouch polyps > 5 mm must be excised at "baseline". - Duodenal polyposis as a stratification site; one or more of the following:
1. Current Spigelman Stage 3 or 4. (Refer to Appendix A for Modified Spigelman Score and Classification table).
2. Prior surgical endoscopic intervention within the past six months for Spigelman Stage 3 or 4 that may have been down staged to Spigelman 1 or 2.
- Hematopoietic Status (within 30 days prior to randomization):
1. No significant hematologic abnormalities
2. WBC at least 3,000/mm3
3. Platelet count at least 100,000/mm3
4. Hemoglobin at least 10.0 g/dL
5. No history of clinical coagulopathy
- Hepatic Status (within 30 days prior to randomization):
1. Bilirubin no greater than 1.5 times ULN
2. AST and ALT no greater than 1.5 times ULN
3. Alkaline phosphatase no greater than 1.5 times ULN
- Renal Status (within 30 days prior to randomization):
a) Creatinine no greater than 1.5 times ULN - Hearing:
a) No clinically significant hearing loss, defined in Section 6.2, number 9.
- If female, neither pregnant nor lactating.
- Negative pregnancy test if female of child-bearing potential. Fertile patients must use effective contraception*.
- Absence of gross blood in stool; red blood on toilet paper only acceptable.
- No discrete gastric or duodenal ulcer greater than 5 mm within the past year except Helicobacter pylori-related peptic ulcer disease treated with antibiotics.
- No invasive malignancy within the past 5 years except resected non-melanomatous skin cancer, papillary thyroid cancer, or precancerous cervical dysplasia.
- No other significant medical or psychiatric problems that would preclude study participation or interfere with capacity to give informed consent.
- Use of 81-100 mg daily aspirin or up to 700 mg aspirin not more than once a week are eligible.
- No concurrent warfarin, fluconazole, lithium, Pradaxa® or other direct thrombin inhibitors, Plavix®, cyclosporine, other NSAIDs (such as ibuprofen, aspirin, diflunisal), diuretics (furosemide and thiazides), DMSO, methotrexate, probenecid, propoxyphene hydrochloride, Tylenol® (acetaminophen) preparations containing aspirin or cytotoxic chemotherapy drugs.
- Willingness to forego concurrent use of supplements containing omega-3 fatty acids, corticosteroids, non-steroidal anti-inflammatory drugs or other FAP directed drug therapy.
- Able to provide informed consent and follow protocol requirements.
exclusion criteria: - Prior pelvic irradiation.
- Patients receiving oral corticosteroids within 30 days of enrollment.
- Treatment with other investigational agents in the prior 4 weeks.
- Use of other non-steroidal anti-inflammatory drugs (such as ibuprofen) exceeding 4 days per month, in the prior 6 weeks.
- Regular use of aspirin in excess of 700 mg per week.
- Treatment with other FAP directed drug therapy (including sulindac or celecoxib, fish oil) within 12 weeks of study enrollment.
- Hypersensitivity to cyclooxygenase-2 inhibitors, sulfonamides, NSAIDs, or salicylates; NSAID associated symptoms of gastritis.
- Patients must not have cardiovascular disease risk factors as defined below:
- Uncontrolled high blood pressure (systolic blood pressure > 150 mm Hg
- Unstable angina
- History of documented myocardial infarction or cerebrovascular accident
- New York Heart Association Class III or IV heart failure
- Known uncontrolled hyperlipidemia defined as LDL-C >= 190 mg/dL or triglycerides >= 500 mg/dL
- Patients with significant hearing loss are not eligible for study participation defined as hearing loss that affects everyday life and/or for which a hearing aid is required.
- Colon/rectum/pouch with high grade dysplasia or cancer on biopsy or a large polyp (>1 cm) not amenable to complete removal.
- Duodenal cancer on biopsy.
- Intra-abdominal desmoid disease, stage III or IV
- Inability to provide informed consent.
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