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

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 persistence of
latent HPV DNA, and to determine whether celecoxib is acting through inhibition of COX-2, in
order to begin to determine mechanism of effects in vivo on RRP. 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.

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