Recurrent Respiratory Papillomatosis
Conditions
Brief summary
Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm of the larynx in the pediatric population. The impact of the disease on patients and families can be tremendous due to the need for frequent treatment. It would be highly beneficial to develop effective medical therapies as adjunctive measures to surgical ablation with the goal of reducing the frequency of reoccurrence.
Detailed description
The focus of the present study is to evaluate the usefulness of cidofovir injection in diminishing the frequency and magnitude of papilloma recurrences in adult and pediatric RRP patients. Briefly, patients will be randomized into either a treatment (cidofovir injection) or a placebo group. The following measures will be made at each of 6 data collection time points, over the course of one year: (1) tumor load, based upon a published staging system for papilloma, (2) degree of respiratory obstruction for phonation, as assessed by phonation threshold pressures, and (3) general health, on validated health inventories (SF12 and Voice Handicap Index for adults; PedsQL (Trademarked) for children) and via measures of height weight and days absent from school or daycare, where applicable, for children. A repeated measures analysis will allow examination of time by treatment interactions to determine if the cidofovir injection group has fewer, or less severe, recurrences than the placebo group. Specifically, we will answer the following questions in this investigation: 1. Does cidofovir injection reduce the frequency of RRP recurrences? 2. Does cidofovir injection reduce the magnitude of RRP, as assessed with a proposed staging system for RRP (Derkay et al., 1998) and measures of phonatory threshold pressure? 3. Does cidofovir injection improve general health, as assessed by height, weight and days absent from school in pediatric patients and health inventories (general health and voice-related) in children and adults?
Interventions
DRUGCidofovir
With regard to cidofovir concentration, the FDA has allowed us to inject a concentration of 5 mg/ml into both children and adults. The injection will add less than 2 additional minutes to the surgery time and discharge time will not be affected. Because the volumes of cidofovir injected into the airway will be reasonably small (typically less than 2 mL), the total systemic dose of cidofovir administered per visit will be far below the FDA-approved systemic limit of 5 mg/kg for HIV-related CMV retinitis.
DRUGPlacebo
On the baseline study day, patients will be randomized into either a treatment group (cidofovir injection) or a placebo group. A restricted randomization procedure, in groups of 4, will be used to encourage uniformity in sample sizes between groups.
Sponsors
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 4 surgeries for RRP in last 12 months
Exclusion criteria
* Renal insufficiency * Nephrotoxic drugs in the last 7 days * Sulfa allergies * Currently treated with systemic or topical HPV chemotherapeutic agents * Females of childbearing potential with a positive pregnancy test * Women who are breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Papilloma Severity | Baseline, 2 months, and 12 months | Derkay Severity Score. Minimum Score is Zero. Maximum score is 86. Treatment of RRP with cidofovir injection will be considered efficacious if drug group patients experience clinically or statistically significant changes in papilloma severity and inter-surgery time intervals (relative to pre-treatment assessments), when compared with placebo group patients. The scale rates - Voice (normal 0, abnormal 1, aphonic 2) Stridor (absent 0, present with activity 1, present at rest 2) Urgency of the intervention (scheduled 0, elective 1, urgent 2, emergent 3) Respiratory distress (none 0, mild 1, mod 2, severe 3, extreme 4). For multiple anatomical sites (18 or more) in the upper airway, left and right sides, lesions are rated as 0=none, 1=surface lesion, 2=raised lesion, and 3=bulky lesion). A higher rating value indicates more advanced disease and a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 12-month Change in Voice Handicap Index (VHI) Score | 2 months, and 12 months | Voice Handicap Index. This scale rates a patient's perception of voice related handicap in the domains of functional, physical, and emotional. There are 10 questions for each domain. Each question is rated by the subject on a 5-point scale, never =0, almost never =1, sometimes =2, almost always =3, always =4). A lower total score or domain score indicates improved, or less, voice handicap. Thus, the maximum total score is 4 X 30 = 120. For each domain, the maximum score is 4 X 10 = 40. Scores of 0 are the lowest possible score. In the paper we say that the Maximum score is 100, but obviously is it actually 120. Complete scale = 0-120. Lower score indicates improved perceived voice-realted quality of life. |
Participant flow
Recruitment details
The participants in this randomized, double-blind, placebo-controlled clinical trial were 19 consecutive adult or pediatric patients who presented to the University of Wisconsin Otolaryngology-Head and Neck Surgery Clinic with a diagnosis of RRP who met inclusio/exclusion criteria and gave informed consent to participate.
Pre-assignment details
Before inclusion in this study, and 48 hours before each cidofovir injection, laboratory tests confirmed that the (female) participants were not pregnant and that laboratory findings were not exclusionary for study participation.
Participants by arm
| Arm | Count |
|---|---|
| Cidofovir On the baseline study day, patients will be randomized into either a treatment group (cidofovir injection) or a placebo group. A restricted randomization procedure, in groups of 4, will be used to encourage uniformity in sample sizes between groups. | 10 |
| Placebo On the baseline study day, patients will be randomized into either a treatment group (cidofovir injection) or a placebo group. A restricted randomization procedure, in groups of 4, will be used to encourage uniformity in sample sizes between groups. | 9 |
| Total | 19 |
Baseline characteristics
| Characteristic | Placebo | Cidofovir | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 8 Participants | 14 Participants |
| Age, Continuous | 29 years STANDARD_DEVIATION 12 | 33 years STANDARD_DEVIATION 18 | 31 years STANDARD_DEVIATION 15 |
| Region of Enrollment United States | 9 participants | 10 participants | 19 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 8 Participants | 8 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 | 0 / 10 | 0 / 9 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 |
Outcome results
Primary
Change in Papilloma Severity
Derkay Severity Score. Minimum Score is Zero. Maximum score is 86. Treatment of RRP with cidofovir injection will be considered efficacious if drug group patients experience clinically or statistically significant changes in papilloma severity and inter-surgery time intervals (relative to pre-treatment assessments), when compared with placebo group patients. The scale rates - Voice (normal 0, abnormal 1, aphonic 2) Stridor (absent 0, present with activity 1, present at rest 2) Urgency of the intervention (scheduled 0, elective 1, urgent 2, emergent 3) Respiratory distress (none 0, mild 1, mod 2, severe 3, extreme 4). For multiple anatomical sites (18 or more) in the upper airway, left and right sides, lesions are rated as 0=none, 1=surface lesion, 2=raised lesion, and 3=bulky lesion). A higher rating value indicates more advanced disease and a worse outcome.
Time frame: Baseline, 2 months, and 12 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cidofovir | Change in Papilloma Severity | Baseline | 13.2 scores on a scale |
| Cidofovir | Change in Papilloma Severity | 2 months | 3.7 scores on a scale |
| Cidofovir | Change in Papilloma Severity | 12 months | 2.7 scores on a scale |
| Placebo | Change in Papilloma Severity | Baseline | 12 scores on a scale |
| Placebo | Change in Papilloma Severity | 2 months | 3.6 scores on a scale |
| Placebo | Change in Papilloma Severity | 12 months | 5.1 scores on a scale |
Secondary
12-month Change in Voice Handicap Index (VHI) Score
Voice Handicap Index. This scale rates a patient's perception of voice related handicap in the domains of functional, physical, and emotional. There are 10 questions for each domain. Each question is rated by the subject on a 5-point scale, never =0, almost never =1, sometimes =2, almost always =3, always =4). A lower total score or domain score indicates improved, or less, voice handicap. Thus, the maximum total score is 4 X 30 = 120. For each domain, the maximum score is 4 X 10 = 40. Scores of 0 are the lowest possible score. In the paper we say that the Maximum score is 100, but obviously is it actually 120. Complete scale = 0-120. Lower score indicates improved perceived voice-realted quality of life.
Time frame: 2 months, and 12 months
Population: \[raw data no longer exist for this study, there a no data to report for a Baseline measure\]
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cidofovir | 12-month Change in Voice Handicap Index (VHI) Score | 2 months | 22 scores on a scale |
| Cidofovir | 12-month Change in Voice Handicap Index (VHI) Score | 12 months | 31 scores on a scale |
| Placebo | 12-month Change in Voice Handicap Index (VHI) Score | 2 months | 32 scores on a scale |
| Placebo | 12-month Change in Voice Handicap Index (VHI) Score | 12 months | 42 scores on a scale |