Recurrent Respiratory Papillomatosis
Conditions
Keywords
HPV, RRP
Brief summary
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
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.
Interventions
DRUGcelebrex (celecoxib)
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
DRUGplacebo
similar appearing capsules containing inert ingredients
Sponsors
National Institute on Deafness and Other Communication Disorders (NIDCD)
University of Iowa
Eastern Virginia Medical School
University of Alabama at Birmingham
University of California, San Francisco
Vanderbilt University
Sanford Health
Weill Medical College of Cornell University
Northwell Health
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in Papilloma Growth Rate at 12 Month Measurement Compared to Baseline | Baseline to 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Gender on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | Baseline to12 months | 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 |
| Effect of Juvenile Versus Adult Disease Onset on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | Baseline to 12 months | 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. |
| Percent of Patients With Positive Response to Treatment | Baseline to 12 months | Percent of patients with reduction in papilloma growth rate greater than 50% during the last 3 months of first treatment period compared to baseline |
| Correlation Between Mean Plasma Level of Celecoxib and Response. | Baseline to 12 months | 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. |
| Maintenance of Response Following Discontinuation of Celecoxib | End of first treatment period (month 12) to end of second treatment period (month 24) | 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. |
| Effect of HPV 6 Versus HPV 11 on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50% | Baseline to 12 months | 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. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from 7 participating sites throughout the U.S. (locations in NY, VA, SD, AL, CA, IA and TN) that had investigators experienced in the treatment of this disease.
Pre-assignment details
Patients initially entered a 6 month pre-treatment observation period prior to randomization into the 2 treatment arms. 9 subjects did not start the treatment period and are therefore not included in demographics or the results sections.
Participants by arm
| Arm | Count |
|---|---|
| Celecoxib First, Then Placebo 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
celebrex (celecoxib): Adults: 400 mg daily Pediatrics: 100 mg daily for weight between 12-25 kg or 200 mg daily for weight \>25 kg | 19 |
| Placebo First, Then Celecoxib 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.
celebrex (celecoxib): Adults: 400 mg daily Pediatrics: 100 mg daily for weight between 12-25 kg or 200 mg daily for weight \>25 kg | 22 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention 12 Months | Death | 1 | 0 |
| First Intervention 12 Months | Withdrawal by Subject | 2 | 1 |
| Second Intervention 12 Months | Adverse Event | 0 | 1 |
| Second Intervention 12 Months | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Celecoxib First, Then Placebo | Placebo First, Then Celecoxib | Total |
|---|---|---|---|
| Age, Customized Age < 20 | 9 participants | 11 participants | 20 participants |
| Age, Customized Age 20 - < 40 | 3 participants | 9 participants | 12 participants |
| Age, Customized Age 40 and above | 7 participants | 2 participants | 9 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 18 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 19 Participants | 36 Participants |
| Sex: Female, Male Female | 9 Participants | 16 Participants | 25 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 40 | 18 / 39 |
| serious Total, serious adverse events | 3 / 40 | 2 / 39 |
Outcome results
Primary
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.
Time frame: Baseline to 12 months
Population: All patients in each arm who completed the first 1 year treatment period. This is not a traditional cross-over study because we expected a sustained effect therefore no efficacy studies were done in segment C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Celecoxib First, Then Placebo | Mean Percent Change in Papilloma Growth Rate at 12 Month Measurement Compared to Baseline | -5.4 percent change in mean growth rate | Standard Deviation 50 |
| Placebo First, Then Celecoxib | Mean Percent Change in Papilloma Growth Rate at 12 Month Measurement Compared to Baseline | -15.2 percent change in mean growth rate | Standard Deviation 67.3 |
p-value: 0.57Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Baseline to 12 months
Population: All patients who were randomized to receive celecoxib first and completed the first treatment period. This is not a traditional cross-over study because we expected a sustained effect therefore no efficacy studies were done in segment C.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Celecoxib First, Then Placebo | Correlation Between Mean Plasma Level of Celecoxib and Response. | 151.3 pg. celecoxib/ml. plasma |
| Placebo First, Then Celecoxib | Correlation Between Mean Plasma Level of Celecoxib and Response. | 543.41 pg. celecoxib/ml. plasma |
p-value: >0.56t-test, 2 sided
Secondary
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
Time frame: Baseline to12 months
Population: All patients who completed first treatment period. This is not a traditional cross-over study because we expected a sustained effect therefore no efficacy studies were done in segment C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Celecoxib First, Then Placebo | Effect of Gender on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | 12.50 percent responders |
| Placebo First, Then Celecoxib | Effect of Gender on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | 40.00 percent responders |
| Celecoxib First- Females | Effect of Gender on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | 12.50 percent responders |
| Placebo First- Females | Effect of Gender on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | 0.00 percent responders |
p-value: >0.3Fisher Exact
Secondary
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.
Time frame: Baseline to 12 months
Population: Analysis conducted on all patients with HPV 6 or 11 infection who completed first treatment period. One patient with both HPV 6 and 11 and one patient with neither 6 or 11 were excluded. This is not a traditional cross-over study because we expected a sustained effect therefore no efficacy studies were done in segment C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Celecoxib First, Then Placebo | Effect of HPV 6 Versus HPV 11 on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50% | 9.09 percent of responders |
| Placebo First, Then Celecoxib | Effect of HPV 6 Versus HPV 11 on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50% | 42.86 percent of responders |
| Celecoxib First- Females | Effect of HPV 6 Versus HPV 11 on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50% | 25.00 percent of responders |
| Placebo First- Females | Effect of HPV 6 Versus HPV 11 on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50% | 0.00 percent of responders |
p-value: >0.5Fisher Exact
Secondary
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.
Time frame: Baseline to 12 months
Population: Analysis conducted on all patients who completed first treatment period. Juvenile onset is defined as \<18 years of age at time of diagnosis. Age of disease onset for 2 patients was not available. This is not a traditional cross-over study because we expected a sustained effect therefore no efficacy studies were done in segment C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Celecoxib First, Then Placebo | Effect of Juvenile Versus Adult Disease Onset on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | 12.50 percentage of responders |
| Placebo First, Then Celecoxib | Effect of Juvenile Versus Adult Disease Onset on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | 7.69 percentage of responders |
| Celecoxib First- Females | Effect of Juvenile Versus Adult Disease Onset on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | 12.50 percentage of responders |
| Placebo First- Females | Effect of Juvenile Versus Adult Disease Onset on Percent of Patients With Reduction in Papilloma Growth Rate Greater Than 50%. | 33.33 percentage of responders |
p-value: 1Fisher Exact
Secondary
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.
Time frame: End of first treatment period (month 12) to end of second treatment period (month 24)
Population: All patients with complete response to celecoxib in first treatment period who completed the second treatment period where they received placebo. Because the number of responders was so small, no statistical analysis was performed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Celecoxib First, Then Placebo | Maintenance of Response Following Discontinuation of Celecoxib | 100 percent of patients |
Secondary
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
Time frame: Baseline to 12 months
Population: All patients that completed first treatment period. This is not a traditional cross-over study because we expected a sustained effect therefore no efficacy studies were done in segment C.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Celecoxib First, Then Placebo | Percent of Patients With Positive Response to Treatment | 12.5 percent responders |
| Placebo First, Then Celecoxib | Percent of Patients With Positive Response to Treatment | 28.6 percent responders |
p-value: 0.43Fisher Exact