Study of Celebrex (Celecoxib) in Patients With Recurrent Respiratory Papillomatosis

Study Overview
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Brief Summary
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This is a randomized double blind controlled study to determine if celebrex (celecoxib), a selective COX-2 inhibitor, can decrease the rate of recurrence in adult and pediatric patients with recurrent respiratory papillomatosis. All patients will be evaluated for disease severity at enrollment and at 3 month intervals for 30 months. After randomization, patients in the early treatment arm will begin celecoxib 6 months after enrollment. The delayed treatment arm will begin celecoxib 18 months after enrollment. All patients will receive celecoxib for 1 year. During the time that patients do not receive celecoxib, they will receive a placebo capsule with the same appearance. Follow-up visits will occur at three month intervals for the duration of the study.

Detailed Description
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This is a randomized double blind placebo-controlled study,with plans to include 5 additional U.S. centers in the near future. The primary goal of this study is to determine whether celecoxib has efficacy in elimination or reduction of recurrent disease in patients with RRP. Our secondary goals are to determine whether continued celecoxib is required to maintain response, to correlate response with select patient demographics and with plasma levels of celecoxib. The study design encompasses a 30-month period, which can be divided into three segments: Segment A: This is a 6 month run-in period in which all patients are assessed by direct laryngoscopy/bronchoscopy for disease severity, to permit growth rate stabilization and confirm accuracy of training of participating physicians. Patients will be treated by conventional surgery at three months and six months after enrollment. Segment B: Patients begin 12 months of 400mg(adults), 100 mg (pediatric weight between 12 and 25 kg)or 200 mg (pediatric weight > 25kg) celecoxib daily or placebo treatment in addition to surgical removal of all papillomas at each 3 month interval. This segment directly tests the hypothesis that celecoxib is an efficacious treatment for moderate to severe RRP and forms the basis for the primary statistical analyses. Segment C: The primary purpose of this segment is to determine whether gains made during celecoxib therapy are maintained after it is discontinued, or whether celecoxib will need to be taken indefinitely. This will be determined by a 12 month period on placebo after cessation of celecoxib for the early treatment group. This is not a traditional cross-over study because we expected a sustained effect therefore no efficacy studies were done in segment C. However, the placebo first group was given celecoxib so that they could gain any possible benefits equivalent to those that received the celecoxib first.

Official Title
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A Multicentered Randomized Study of Celebrex (Celecoxib) in Patients With Recurrent Respiratory Papillomatosis

Conditions
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Recurrent Respiratory Papillomatosis

Intervention / Treatment
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* Drug: celebrex (celecoxib)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Moderate to severe disease, defined as: Patients who have rapid regrowth of papillomas, requiring endoscopic removal at least 3 times within the past 12 months AND A papilloma growth rate from 0.03 to 0.06 (moderate) or >0.06 (severe) at time of initial direct endoscopy OR Having tracheal and/or bronchial or pulmonary papillomatosis (severe) Age > 2 years Gender- no restriction Race- no restriction Exclusion Criteria: Fewer than 3 surgical procedures in previous year, without tracheal disease Age < 2 years Pregnancy, trying to become pregnant, breastfeeding or not willing to comply with birth control methods if sexually active female Serum creatinine > 1.5 X normal History of documented peptic ulcer disease or gastritis persisting despite treatment Abnormal liver function tests, as total bilirubin >1.5 X normal and SGOT > 3 X normal Allergy to NSAIDs, sulfa containing drugs or symptoms of Stevens-Johnson Syndrome Patients with connective tissue diseases such as SLE, Raynaud's or Systemic Sclerosis Patients with known diabetes Patients on warfarin, or on loop or thiazide diuretics Patients with a history of cardiovascular disease, myocardial infarct or stroke Patients with congestive heart failure Patients regularly taking > 81 mg of aspirin/day Patients with uncontrolled hypertension Patients with RRP associated malignancy currently receiving chemotherapy and/or radiation

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: celecoxib first, then placebo<br>Patients randomized to start celecoxib 6 months after enrollment. Then cross over to placebo after 1 year. Celecoxib dosing will be given orally 400mg once a day for adults, 200 mg once a day for pediatric patients between 12-25kg, 100mg once a day for pediatric patients < 12kg | Drug: celebrex (celecoxib)<br>* Adults: 400 mg celebrex (celecoxib) daily Pediatrics: 100 mg celebrex (celecoxib) daily for weight between 12-25 kg or 200 mg Celebrex (celecoxib) daily for weight >25 kg<br>* Other names: Celebrex;Drug: placebo<br>* similar appearing capsules containing inert ingredients<br>|
| Placebo Comparator: Placebo first, then celecoxib<br>Patients randomized to start placebo 6 months after enrollment. One placebo capsule will be taken orally once a day. Placebo will match appearance of active celecoxib capsules. Cross over to 12 months of treatment with celecoxib after 1 year. | Drug: celebrex (celecoxib)<br>* Adults: 400 mg celebrex (celecoxib) daily Pediatrics: 100 mg celebrex (celecoxib) daily for weight between 12-25 kg or 200 mg Celebrex (celecoxib) daily for weight >25 kg<br>* Other names: Celebrex;Drug: placebo<br>* similar appearing capsules containing inert ingredients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percent Change in Papilloma Growth Rate at 12 Month Measurement Compared to Baseline | Change in mean growth rates during the last 3 months of the first treatment period compared to the mean values at baseline. Endoscopy and removal of all tumor was done every 3 months. Growth rate is calculated as the scored amount of papilloma recurrence in a 3 month period divided by the exact number of days since last endoscopy and removal of all tumor. | Baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Patients With Positive Response to Treatment | Percent of patients with reduction in papilloma growth rate greater than 50% during the last 3 months of first treatment period compared to baseline | Baseline to 12 months | 
| Effect of Gender on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | Percent of patients of each gender with reduction in papilloma growth rate greater than 50% during the last 3 months of first treatment period compared to baseline | Baseline to12 months | 
| Effect of Juvenile Versus Adult Disease Onset on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | Percent of juvenile versus adult onset patients with reduction in papilloma growth rate greater than 50% during the last 3 months of first treatment period compared to baseline. | Baseline to 12 months | 
| Effect of HPV 6 Versus HPV 11 on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50% | Percent of patients with HPV 6 versus patients with HPV 11 with reduction in papilloma growth rate greater than 50% during the last 3 months of first treatment period compared to baseline. | Baseline to 12 months | 
| Correlation Between Mean Plasma Level of Celecoxib and Response. | Mean plasma levels of celecoxib over months 3-12 in first treatment period correlated with reduction in papilloma growth rate greater than 50% during the last 3 months of first treatment period compared to baseline. | Baseline to 12 months | 
| Maintenance of Response Following Discontinuation of Celecoxib | Percent of patients who responded to celecoxib with increase in papilloma growth rate of no greater than 0.01 at end of second treatment period compared to growth rate at end of first treatment period. | End of first treatment period (month 12) to end of second treatment period (month 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV, RRP