Adenomatous Polyposis Coli
Conditions
Keywords
FAP
Brief summary
To test whether celecoxib can be used to prevent colon polyp formation in children with familial adenomatous polyposis (FAP).
Detailed description
Per DMC recommendation, the study was terminated early (31Oct2013) due to low enrollment and low endpoint accumulation rate. No safety concerns were involved in the decision to terminate the study.
Interventions
DRUGCelecoxib
celecoxib, 16 mg/kg/day, for 5 years
DRUGPlacebo
Masked, placebo comparator
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Age 10-17 years * Confirmed deleterious FAP genotype based on central genetic testing or personal history ot \>2 colorectal adenomas and a parent with the diagnosis of FAP and either A, B or C below A: Non-attenuated FAP genotype B: Attenuated FAP genotype and a personal history of colorectal adenomas and a first degree relative with FAP C: No genotype identified with a personal history of \> 2 adenomas and have a parent with FAP * Less than 30 polyps, which need to be removed to render the colon polyp-free before study drug can be given
Exclusion criteria
* Diagnosis of attenuated FAP based on central genetic testing in the absence of a personal history of \>2 colorectal adenomas and a first degree relative (parent or sibling) with FAP. * Sensitivity to COX-2 inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression | 5 years | Time to disease progression was defined as the time from randomization to the earliest occurrence of one or more of the following events: 1. Appearance of ≥20 polyps (\>2 mm in size) at any colonoscopy during the study (Polyps); or 2. Diagnosis of colorectal malignancy (ColMal). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure | 5 years | Time to treatment failure was defined as time from randomization to the earliest occurrence of one or more of the following: * Appearance of ≥20 polyps (\>2 mm in size) at any colonoscopy during the study (Polyps), or * Diagnosis of colorectal malignancy (ColMal), or * Treatment related dropout (DO). The treatment related dropout was 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 might be related to treatment as determined by treating physicians in a blind fashion before database release. |
| Total Number of Colorectal Polyps | Years 1 - 5 | Total number of colorectal polyps \>2 mm in size, that were detected over Years 1 - 5 cumulatively. Weighted total number of colorectal polyps over Years 1 - 5 cumulatively was defined as the total number of colorectal polyps \>2 mm in size, that were detected over Years 1 - 5, divided by the number of colonoscopies that the participant had during the study. |
| Colorectal Polyp Burden | Years 1 - 5 | The polyp burden was defined as the sum of the largest diameters of all polyps (\>2 mm in size) over Years 1 - 5 cumulatively. Weighted colorectal polyp burden over Years 1 - 5 cumulatively was defined as the polyp burden over Years 1 - 5 divided by the number of colonoscopies that the participant had during the study. |
Countries
Belgium, Czechia, Hong Kong, Hungary, Israel, Italy, Puerto Rico, Slovakia, South Africa, Spain, Sweden, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 305 participants were screened, whereof 106 were randomized into the study, and of whom 101 took at least 1 dose of study drug. The clinical study was conducted in 18 centers across 13 countries: Belgium, Czech Republic, Hong Kong, Hungary, Israel, Italy, Slovakia, South Africa, Spain, Sweden, Ukraine, United Kingdom, and United States.
Pre-assignment details
The randomization was to be stratified by center, age (≥12 years old versus \<12 years old), and familial adenomatous polyposis (FAP) phenotype (negative versus positive). The participants were randomized 1:1 to one of the 2 treatments celecoxib or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Celecoxib Celecoxib, approximately 16 mg/kg/day (adjusted for changes in body weight). Maximum dose was 400 mg twice daily. | 55 |
| Placebo Matching placebo | 51 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Lack of Efficacy | 6 | 11 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Reason not specified | 2 | 0 |
| Overall Study | Study terminated by the sponsor | 34 | 31 |
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | Celecoxib | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 12.6 years STANDARD_DEVIATION 2.2 | 12.2 years STANDARD_DEVIATION 1.8 | 12.4 years STANDARD_DEVIATION 2 |
| Sex: Female, Male Female | 29 Participants | 28 Participants | 57 Participants |
| Sex: Female, Male Male | 26 Participants | 23 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 53 | 30 / 48 |
| serious Total, serious adverse events | 3 / 53 | 0 / 48 |
Outcome results
Primary
Time to Disease Progression
Time to disease progression was defined as the time from randomization to the earliest occurrence of one or more of the following events: 1. Appearance of ≥20 polyps (\>2 mm in size) at any colonoscopy during the study (Polyps); or 2. Diagnosis of colorectal malignancy (ColMal).
Time frame: 5 years
Population: ITT population (N: 106) consisted of all participants who were randomized and assigned to treatment. Primary outcome measure was met by 7 (Polyp:7,ColMal:0) participants in the Celecoxib group and 13 (13,0) in the placebo group. Study was early terminated due to low enrollment and lower than expected endpoint rate. No analysis was performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Celecoxib | Time to Disease Progression | 2.2 years | Standard Deviation 1.08 |
| Placebo | Time to Disease Progression | 1.8 years | Standard Deviation 1.3 |
Secondary
Colorectal Polyp Burden
The polyp burden was defined as the sum of the largest diameters of all polyps (\>2 mm in size) over Years 1 - 5 cumulatively. Weighted colorectal polyp burden over Years 1 - 5 cumulatively was defined as the polyp burden over Years 1 - 5 divided by the number of colonoscopies that the participant had during the study.
Time frame: Years 1 - 5
Population: ITT population (N: 106) consisted of all participants who were randomized and assigned to a treatment. Study was early terminated due to low enrollment and lower than expected endpoint rate and no analysis was performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Celecoxib | Colorectal Polyp Burden | Year 1 (N: 27, 30) | 4.0 mm | Standard Deviation 1.97 |
| Celecoxib | Colorectal Polyp Burden | Year 3 (N: 16, 14) | 9.6 mm | Standard Deviation 3.14 |
| Celecoxib | Colorectal Polyp Burden | Year 5 (N: 2, 2) | 20.0 mm | Standard Deviation 7.07 |
| Celecoxib | Colorectal Polyp Burden | Year 2 (N: 21, 25) | 6.9 mm | Standard Deviation 2.28 |
| Celecoxib | Colorectal Polyp Burden | Year 1 - 5 cumulatively (N: 33, 36) | 4.1 mm | Standard Deviation 1.68 |
| Celecoxib | Colorectal Polyp Burden | Year 4 (N: 8, 7) | 12.9 mm | Standard Deviation 3.31 |
| Placebo | Colorectal Polyp Burden | Year 1 - 5 cumulatively (N: 33, 36) | 4.3 mm | Standard Deviation 1.61 |
| Placebo | Colorectal Polyp Burden | Year 2 (N: 21, 25) | 8.1 mm | Standard Deviation 4.06 |
| Placebo | Colorectal Polyp Burden | Year 1 (N: 27, 30) | 4.2 mm | Standard Deviation 2.05 |
| Placebo | Colorectal Polyp Burden | Year 3 (N: 16, 14) | 11.6 mm | Standard Deviation 4.05 |
| Placebo | Colorectal Polyp Burden | Year 4 (N: 8, 7) | 18.7 mm | Standard Deviation 5.88 |
| Placebo | Colorectal Polyp Burden | Year 5 (N: 2, 2) | 20.0 mm | Standard Deviation 4.24 |
Secondary
Time to Treatment Failure
Time to treatment failure was defined as time from randomization to the earliest occurrence of one or more of the following: * Appearance of ≥20 polyps (\>2 mm in size) at any colonoscopy during the study (Polyps), or * Diagnosis of colorectal malignancy (ColMal), or * Treatment related dropout (DO). The treatment related dropout was 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 might be related to treatment as determined by treating physicians in a blind fashion before database release.
Time frame: 5 years
Population: ITT population (N: 106) consisted of all participants who were randomized and assigned to treatment. Secondary outcome measure was met by 14 (Polyp:7,ColMal:0,DO:14) participants in the Celecoxib and 14 (13,0,12) in the placebo group. Study was early terminated due to low enrollment and lower than expected endpoint rate. No analysis was performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Celecoxib | Time to Treatment Failure | 2.0 years | Standard Deviation 1.12 |
| Placebo | Time to Treatment Failure | 1.7 years | Standard Deviation 1.3 |
Secondary
Total Number of Colorectal Polyps
Total number of colorectal polyps \>2 mm in size, that were detected over Years 1 - 5 cumulatively. Weighted total number of colorectal polyps over Years 1 - 5 cumulatively was defined as the total number of colorectal polyps \>2 mm in size, that were detected over Years 1 - 5, divided by the number of colonoscopies that the participant had during the study.
Time frame: Years 1 - 5
Population: ITT population (N: 106) consisted of all participants who were randomized and assigned to a treatment. Study was early terminated due to low enrollment and lower than expected endpoint rate and no analysis was performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Celecoxib | Total Number of Colorectal Polyps | Year 1 (N: 27, 30) | 3.0 polyps | Standard Deviation 2.68 |
| Celecoxib | Total Number of Colorectal Polyps | Year 2 (N: 21, 25) | 8.8 polyps | Standard Deviation 6.63 |
| Celecoxib | Total Number of Colorectal Polyps | Year 3 (N: 16, 14) | 13.4 polyps | Standard Deviation 11.31 |
| Celecoxib | Total Number of Colorectal Polyps | Year 4 (N: 8, 7) | 18.6 polyps | Standard Deviation 17.65 |
| Celecoxib | Total Number of Colorectal Polyps | Year 5 (N: 2, 2) | 30.5 polyps | Standard Deviation 21.92 |
| Celecoxib | Total Number of Colorectal Polyps | Years 1 - 5 cumulatively (N: 33, 36) | 4.3 polyps | Standard Deviation 3.58 |
| Placebo | Total Number of Colorectal Polyps | Year 5 (N: 2, 2) | 46.5 polyps | Standard Deviation 34.65 |
| Placebo | Total Number of Colorectal Polyps | Year 1 (N: 27, 30) | 8.1 polyps | Standard Deviation 7.32 |
| Placebo | Total Number of Colorectal Polyps | Year 4 (N: 8, 7) | 36.4 polyps | Standard Deviation 22.5 |
| Placebo | Total Number of Colorectal Polyps | Year 2 (N: 21, 25) | 13.7 polyps | Standard Deviation 10.51 |
| Placebo | Total Number of Colorectal Polyps | Years 1 - 5 cumulatively (N: 33, 36) | 8.6 polyps | Standard Deviation 7.12 |
| Placebo | Total Number of Colorectal Polyps | Year 3 (N: 16, 14) | 22.3 polyps | Standard Deviation 11.74 |