The primary objective of this trial is to determine whether the combination of CPP-1X + sulindac is superior to either treatment individually, sulindac alone or CPP-1X alone, in delaying time to the first occurrence of any FAP-related event in the…
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Source
Brief title
Condition
- Gastrointestinal tract disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy End Point is the first occurrence of any FAP-related event in
the patient as a whole.
This includes:
1) FAP related excisional intervention involving the colon, rectum, pouch,
duodenum and/or
2) clinically important events which includes progression to more advanced
duodenal polyposis, cancer or death.
The timepoint(s) of evaluation of this endpoint:
Subjects will be assessed at 3, 6, 12, 18, and 24 months. Endoscopies (upper
and lower GI) will be carried out every 6 months.
For subjects participating in the treatment extension up to 2 additional
endosocpies will be performed (month 30 and 36).
For subjects participating in the prolonged treatment extension (month 36-48)
up to 2 additional endoscopies will be performed (month 42 and 48).
Secondary outcome
The secondary efficacy outcome in this study will include the following:
1. To evaluate the potentially effect modifying properties of :
a. Presence or absence of an ODC polymorphism
b. The excretion of 4 urinary polyamines (diacetylspermine,
n1-acetylspermidine, n8-acetylspermidine and decarboxylated SAM)
Other secondary outcomes will include the following:
1. Safety outcomes will be assessed by summary analysis of adverse events and
clinical laboratory abnormalities.
2. Pharmacokinetic outcomes will be assessed by evaluating the population
pharmacokinetics for CPP-1X (eflornithine) and sulindac.
3. Evaluate tissue and dietary polyamine levels.
4. Patient reported quality of life will be evaluated using HRQoL and patient
utilities.
5. A pilot evaluation of an FAP-specific assessment, the time to the first
FAP-related beneficent event, will be studied. This will involve analyzing
the endoscopic polyposis data for regression of pre-colectomy colorectal
polyposis, rectal/pouch polyposis, and regression of duodenal polyposis.
Background summary
Familial Adenomatous Polyposis (FAP) is a genetic disorder in which hundreds of
polyps are present in the colon. These polyps often occur at a young age. The
risk arising from the polyps is that cancer develops and this increases with
age. Eventually, almost everyone who has FAP will get colon cancer.
The current standard treatment consists of prophylactic removal of the large
intestine or the colon and rectum, followed by proctoscopic surgical
intervention in which the polyps to be removed for the rest of their lives
every 6-12 months
Prophylactic removal of the colon and where appropriate the rectosigmoid do not
"heal" the patients. FAP-related disease remains a major problem and leads to
significant morbidity and mortality. Surgical intervention is marginally
effective and there are no approved pharmacological agents.
The extension of the time to clinical worsening (FAP-related operation,
duodenal polyposis, cancer and death) is important in relation to the morbidity
and mortality of this genetic disease.
The use of low dose sulindac and CPP-1X may be able to extend to the occurrence
of clinically important FAP-related events over time. This creates a clinical
benefit and morbidity.
Study objective
The primary objective of this trial is to determine whether the combination of
CPP-1X + sulindac is superior to either treatment individually, sulindac alone
or CPP-1X alone, in delaying time to the first occurrence of any FAP-related
event in the patient as a whole. This includes: 1) FAP related excisional
intervention involving the colon, rectum, pouch, duodenum and/or 2) clinically
important events which includes progression to more advanced duodenal
polyposis, cancer or death.
Study design
A DOUBLE-BLIND, RANDOMIZED,SAFETY AND EFFICACY PHASE III TRIAL
Intervention
Patients will be randomized 1:1:1 to one of three treatment groups:
1) CPP-1X Plus Sulindac
-three (3) 250 mg CPP-1X tablets plus one (1) 150 mg Sulindac tablet
2) CPP-1X Plus Sulindac-Placebo
-three (3) 250 mg CPP-1X tablets plus one (1) Sulindac-Placebo tablet
3) CPP-1X-Placebo Plus Sulindac
-three (3) CPP-1X-Placebo tablets plus one (1) 150 mg Sulindac tablet
Daily oral dosing for a maximum duration of 48 months. 4 tablets taken once
daily with food same time of day.
Study burden and risks
The potential risks associated with study participation are those risks and
disadvantages as associated with the study medication (amongst others Cardiac
risk and Ototoxicity risk), Gastro-intestinal risk and the risks associated
with bloodsampling.
In relation with the Cardiac Risk, all patients will undergo a baseline medical
history evaluation and ECG for cardiovascular disease risk assessment. Only
subjects meeting the inclusion criteria will be enrolled in the study.
On-study cardiac risk assessments, for each patient, will take place throughout
the study via ongoing adverse event assessments and periodic EKG evaluations at
baseline, and months 3, 6, 12, 18 and 24 (end of treatment). For subjects
participating in the treatment extension up to 4 additional ECG will be
performed (Month 30, 36, 42 and 48)
Concerning the Ototoxicity Risk all patients will undergo air conduction
audiometry for hearing impairment as part of the screening process and at
months 12 and 24 (end of treatment). For subjects participating in the
treatment extension additonal audiometry tests will be performed at month 36
and month 48(EoT).
Patient diaries will indicate the presence of symptoms and will instruct the
patient to contact the treating doctor for assessment. Furthermore the patient
will undergo a clinical assessment for ototoxicity adverse events symptoms by
the research nurse or other medically qualified individual.
Gastrointestinal Risk: Endoscopies will be done by an experienced study team
member. Also patient*s diaries will indicate presence of symptoms and will
instruct the patient to contact the treating doctor for assessment and the
patient will undergo a clinical assessment for gastrointestinal adverse events
symptoms by the research nurse
As a general Safety Evaluation will be done continuously throughout the study
and will be followed from the start of treatment through 30 days after
treatment discontinuation. Serious adverse events will be followed until
resolved or returned to baseline, even if longer than 30 days from the
subject*s off study treatment or off study date.
1760 E. River Road Suite 250
Tucson AZ 85718
US
1760 E. River Road Suite 250
Tucson AZ 85718
US
Listed location countries
Age
Inclusion criteria
Subjects (male and female), * 18 years
1. Diagnosis of phenotypic classical FAP with disease involvement of the duodenum and/or colon/rectum/pouch.
a. Genotype: APC mutation (with or without family history) required
b. Classical FAP Phenotype: 100*s to 1,000*s of colorectal adenomatous polyps, usually appearing in teenage years
2. UGI endoscopy/LGI endoscopy (proctoscopy/colonoscopy) performed within 30 days of randomization.
3. Patients with an intact colon/rectum and prophylactic surgery is being considered as a stratification site.
4. Rectal/pouch polyposis as a stratification site as follows:
4.a 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 (protocol 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 prior evidence of high grade dysplasia, even if completely removed. [Note: For staging purposes only.]
4.b For all subjects, any rectal/pouch polyps > 5 mm must be excised at *baseline*.
5. Duodenal polyposis as a stratification site; one or more of the following:
5.a Current Spigelman Stage 3 or 4. (Refer to protocol Appendix A for Modified Spigelman Score and Classification table).
5.b 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.
6. Hematopoietic Status (within 30 days prior to randomization):
a) No significant hematologic abnormalities
b) WBC at least 3000/mm3
c) Platelet count at least 100,000/mm3
d) Hemoglobin at least 10.0 g/dL
e) No history of clinical coagulopathy
7. Hepatic Status (within 30 days prior to randomization):
a) Bilirubin no greater than 1.5 times ULN
b) AST and ALT no greater than 1.5 times ULN
c) Alkaline phosphatase no greater than 1.5 times ULN
8. Renal Status (within 30 days prior to randomization):
a) Creatinine no greater than 1.5 times ULN
9. Hearing:
a) No clinically significant hearing loss, defined in Section 6.2, number 9.
10. If female, neither pregnant nor lactating.
11. Negative pregnancy test if female of child-bearing potential. Fertile patients must use effective contraception. Confirmation of postmenopausal status unless surgically sterile.
12. Absence of gross blood in stool; red blood on toilet paper only acceptable.
13. No discrete gastric or duodenal ulcer greater than 5 mm within the past year except Helicobacter pylori-related peptic ulcer disease treated with antibiotics.
14. No invasive malignancy within the past 5 years except resected non-melanomatous skin cancer, papillary thyroid cancer, or precancerous cervical dysplasia.
15. No other significant medical or psychiatric problems that would preclude study participation or interfere with capacity to give informed consent.
16. Use of 81 to 100 mg daily aspirin or up to 700 mg aspirin not more than once a week are eligible.
17. 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.
18. Willingness to forego concurrent use of supplements containing omega-3 fatty acids, corticosteroids, non-steroidal anti-inflammatory drugs or other FAP directed drug therapy.
19. Able to provide written informed consent and follow protocol requirements.
Exclusion criteria
1. Prior pelvic irradiation.
2. Patients receiving oral corticosteroids within 30 days of enrollment.
3. Treatment with other investigational agents in the prior 4 weeks.
4. Use of other non-steroidal anti-inflammatory drugs (such as ibuprofen) exceeding 4 days per month, in the prior 6 weeks.
5. Regular use of aspirin in excess of 700 mg per week.
6. Treatment with other FAP directed drug therapy (including sulindac or celecoxib, fish oil) within 12 weeks of study enrollment.
7. Hypersensitivity to cyclooxygenase-2 inhibitors, sulfonamides, NSAIDs, or salicylates; NSAID associated symptoms of gastritis.
8. 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 (Refer to Appendix C);
* Known uncontrolled hyperlipidemia defined as LDL-C * 190 mg/dL or triglycerides * 500 mg/dL.
9. Patients with significant hearing loss are not eligible for study participation as defined below.
* Hearing loss that affects everyday life and/or for which a hearing aid is required.
10. Colon/rectum/pouch with high grade dysplasia or cancer on biopsy or a large polyp (>1 cm) not amenable to complete removal.
11. Duodenal cancer on biopsy.
12. Intra-abdominal desmoid disease, stage III or IV (staging criteria in protocol Appendix D).
13. Inability to provide informed consent.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 01483144 |
| EudraCT | EUCTR2012-000427-41-NL |
| CCMO | NL45085.018.13 |