Peyronie's Disease
Conditions
Keywords
Peyronie's Disease, penile plaque, penile curvature
Brief summary
This study is a Phase 3, double-blind, randomized, placebo-controlled study of the safety and efficacy of AA4500 0.58 mg in subjects with Peyronie's disease. Approximately 300 (200 AA4500 and 100 placebo) men will be randomized. Subjects will be screened for study eligibility within 21 days before the initial injection of study drug in the first treatment cycle. Before dosing, subjects will be stratified by degree of penile curvature (ie, 30º to 60º or 61º to 90º) and then randomized into two treatment groups to receive in a 2:1 ratio either AA4500 0.58 mg or placebo. In this study, qualified subjects may receive up to four treatment cycles; each cycle will be separated by a period of 42 days (± 5 days). During each treatment cycle, subjects will receive two injections of study drug with at least 24 hours but not more than 72 hours between injections. After the final injection of each treatment cycle, the investigator or qualified designee will model the penile plaque in an attempt to stretch or elongate the plaque. If the subject's penile curvature is reduced to \< 15 degrees after the first, second, or third cycle of injections or if the investigator determines further treatment is not clinically indicated (eg, adverse events; allergic reaction), subsequent treatment cycles will not be administered. Following the maximum of four treatment cycles, each subject will be followed for additional safety and efficacy assessments on Days 169 (± 7 days), 232 (± 7 days), 295 (± 7 days), 365 (± 7 days) (nominal weeks 24, 33, 42 and 52). Subjects randomized to placebo may receive open-label AA4500 treatment after completing this study as part of another protocol.
Interventions
BIOLOGICALAA4500
2 injections separated by at least 24 hours but not more than 72 hours. At least 24 hours but not more than 72 hours after the 2nd injection of the treatment cycle, the investigator will model the plaque (ie, gradual, gentle stretching of the flaccid penis in the direction opposite to the curvature). Treatment may be repeated after 42 days (± 5 days) for up to 4 treatment cycles.
BIOLOGICALPlacebo
2 injections separated by at least 24 hours but not more than 72 hours. At least 24 hours but not more than 72 hours after the 2nd injection of the treatment cycle, the investigator will model the plaque (ie, gradual, gentle stretching of the flaccid penis in the direction opposite to the curvature). Treatment may be repeated after 42 days (± 5 days) for up to 4 treatment cycles.
Sponsors
Endo Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Be a male and be ≥ 18 years of age 2. Be in a stable relationship with a female partner/spouse for at least 3 months before screening and be willing to have vaginal intercourse with that partner/spouse 3. Have symptom(s) of Peyronie's disease for at least 12 months before the first dose of study drug and have evidence of stable disease as determined by the investigator 4. Have penile curvature of at least 30° in the dorsal, lateral, or dorsal/lateral plane at screening. It must be possible to delineate the single plane of maximal curvature for evaluation during the study 5. Be judged to be in good health, based upon the results of a medical history, physical examination, and laboratory profile 6. Voluntarily sign and date an informed consent agreement approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC). The subject must also sign an authorization form to allow disclosure of his protected health information (PHI). The PHI authorization form and informed consent form may be an integrated form or may be separate forms depending on the institution 7. Be able to read, complete, and understand the various rating instruments in English
Exclusion criteria
1. Has a penile curvature of less than 30° or greater than 90° at the screening visit 2. Has any of the following conditions: * Chordee in the presence or absence of hypospadias * Thrombosis of the dorsal penile artery and/or vein * Infiltration by a benign or malignant mass resulting in penile curvature * Infiltration by an infectious agent, such as lymphogranuloma venereum * Ventral curvature from any cause * Presence of an active sexually transmitted disease * Known active hepatitis B or C * Known immune deficiency disease or be positive for human immunodeficiency virus (HIV) 3. Has previously undergone surgery for Peyronie's disease 4. Fails to have an erection which in the opinion of the investigator is sufficient to accurately measure the subject's penile deformity after administration of prostaglandin E1 (PGE1) or trimix 5. Has a calcified plaque as evident by appropriate radiographic evaluation, penile x-ray or penile ultrasound that would prevent proper injection of study medication. Non-contiguous stippling of calcium is acceptable for inclusion provided the calcium deposit does not interfere with the injection of AA4500 into the plaque 6. Has an isolated hourglass deformity of the penis 7. Has the plaque causing curvature of the penis located proximal to the base of the penis, so that the injection of the local anesthetic would interfere with the injection of AA4500 into the plaque 8. Has previously received alternative medical therapies for Peyronie's disease administered by the intralesional route (including, but not limited to, steroids, verapamil, and the naturally occurring low molecular weight protein, interferon-α2b) within 3 months before the first dose of study drug or plans to use any of these medical therapies at any time during the study 9. Has received alternative medical therapies for Peyronie's disease administered by the oral (including, but not limited to, vitamin E \[\> 500 U\], potassium aminobenzoate \[Potaba\], tamoxifen, colchicine, pentoxifylline, over-the-counter erectile dysfunction medications, or steroidal anti-inflammatory drugs) or topical routes (including, but not limited to, verapamil applied as a cream) within 3 months before the first dose of study drug or plans to use any of these medical therapies at any time during the study 10. Has had extracorporeal shock wave therapy (ESWT) for correction of Peyronie's disease within the 6-month period before screening or plans to have ESWT at any time during the study 11. Has used any mechanical type device for correction of Peyronie's disease within the 2-week period before screening or plans to use any these devices at any time during the study 12. Has used a mechanical device to induce a passive erection within the 2-week period before screening or plans to use any of these devices at any time during the study 13. Has significant erectile dysfunction that has failed to respond to oral treatment with phosphodiesterase type 5 (PDE5) inhibitors 14. Has a penile Duplex Doppler ultrasound evaluation at screening that shows compromised penile hemodynamics that in the opinion of the investigator is clinically significant 15. Has uncontrolled hypertension, as determined by the investigator 16. Has a known recent history of stroke, bleeding, or other significant medical condition, which in the investigator's opinion would make the subject unsuitable for enrollment in the study 17. Is unwilling or unable to cooperate with the requirements of the study including completion of all scheduled study visits 18. Has received an investigational drug or treatment within 30 days before the first dose of study drug 19. Has a known systemic allergy to collagenase or any other excipient of AA4500 20. Has a known allergy to any concomitant medication required as per the protocol 21. Has received anticoagulant medication (except for ≤ 165 mg aspirin daily or ≤ 800 mg of over-the-counter NSAIDS daily) during the 7 days before each dose of study drug 22. Has received any collagenase treatments within 30 days of the first dose of study drug 23. Has, at any time, received AA4500 for the treatment of Peyronie's disease -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Penile Curvature | Baseline and Week 52 | A negative value in the percentage change from baseline in penile curvature deformity (angle measured in degrees) indicates less curvature. |
| Change From Baseline in the Peyronie's Disease Bother Domain of the Peyronie's Disease Questionnaire (PDQ) | Baseline and Week 52 | Peyronie's disease bother score range 0 (no issue or not at all bothered) to 4 (extremely bothered) on 4 questions; total score range 0 to 16. A decrease in the change from baseline total score in the Peyronie's disease bother domain of the PDQ is indicated by a negative number. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Overall Satisfaction Domain of the International Index of Erectile Function (IIEF) | Baseline and Week 52 | Overall satisfaction domain of the IIEF score range 0 to 5 on 2 questions where higher scores indicate improved function or satisfaction; total score range 0 to 10. |
| Change From Baseline in Penile Plaque Consistency | Baseline and Week 52 | Penile plaque consistency score range 1 (non-palpable) to 5 (hard). A decrease in the change from baseline score in penile plaque consistency is indicated by a negative number. |
| A Responder Analysis Based on Subject Overall Global Assessment | Week 52 | Subject overall global assessment of Peyronie's disease score range -3 (much worse) to 3 (much improved). A score of 1 (improved in a small but important way), 2 (moderately improved), or 3 indicated a responder. |
| Change From Baseline in the Penile Pain Domain of the PDQ in Subjects With Baseline Penile Pain Score ≥4 | Baseline and Week 52 | Penile pain scale range 0 (no pain) to 10 (extreme pain) on 3 questions; total score range 0 to 30. A decrease in the change from baseline total score in the penile pain domain of the PDQ is indicated by a negative number. Subjects were required to have a penile pain score of 4 or greater at baseline. |
| A Composite Responder Analysis Based on Change From Baseline in Penile Curvature and in the Peyronie's Disease Bother Score | Week 52 | A composite responder is indicated by * a percent reduction from baseline in penile curvature greater than or equal to the threshold, and * a reduction from baseline in Peyronie's disease bother score greater than or equal to the threshold, or change in the overall sexual activity within the last 3 months to having vaginal intercourse from no vaginal intercourse at screening. |
| Change From Baseline in Penile Length | Baseline and Week 52 | A negative value represents a reduction in measurement from baseline. |
| Change From Baseline in the Severity of Peyronie's Disease Symptoms Domain of the PDQ | Baseline and Week 52 | Peyronie's disease symptoms (physical and psychological) severity score range 0 (none) to 4 (very severe) on 6 questions; total score range 0 to 24. A decrease in the change from baseline total score in the Peyronie's disease symptoms domain of the PDQ is indicated by a negative number. |
Countries
Australia, United States
Participant flow
Pre-assignment details
Includes all subjects who were randomized and received at least 1 dose of study drug; subjects who were randomized but not treated were excluded from the population.
Participants by arm
| Arm | Count |
|---|---|
| AA4500 collagenase clostridium histolyticum
AA4500: 2 injections separated by at least 24 hours but not more than 72 hours. At least 24 hours but not more than 72 hours after the 2nd injection of the treatment cycle, the investigator will model the plaque (ie, gradual, gentle stretching of the flaccid penis in the direction opposite to the curvature). Treatment may be repeated after 42 days (± 5 days) for up to 4 treatment cycles. | 274 |
| Placebo Placebo
Placebo: 2 injections separated by at least 24 hours but not more than 72 hours. At least 24 hours but not more than 72 hours after the 2nd injection of the treatment cycle, the investigator will model the plaque (ie, gradual, gentle stretching of the flaccid penis in the direction opposite to the curvature). Treatment may be repeated after 42 days (± 5 days) for up to 4 treatment cycles. | 141 |
| Total | 415 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 7 | 1 |
| Overall Study | Other | 5 | 2 |
| Overall Study | Withdrawal by Subject | 19 | 8 |
Baseline characteristics
| Characteristic | AA4500 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 49 Participants | 29 Participants | 78 Participants |
| Age, Categorical Between 18 and 65 years | 225 Participants | 112 Participants | 337 Participants |
| Age, Continuous | 57.3 years STANDARD_DEVIATION 8.77 | 57.6 years STANDARD_DEVIATION 7.52 | 57.4 years STANDARD_DEVIATION 8.36 |
| Region of Enrollment Australia | 40 participants | 17 participants | 57 participants |
| Region of Enrollment United States | 234 participants | 124 participants | 358 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 274 Participants | 141 Participants | 415 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 237 / 274 | 51 / 141 |
| serious Total, serious adverse events | 12 / 274 | 4 / 141 |
Outcome results
Primary
Change From Baseline in the Peyronie's Disease Bother Domain of the Peyronie's Disease Questionnaire (PDQ)
Peyronie's disease bother score range 0 (no issue or not at all bothered) to 4 (extremely bothered) on 4 questions; total score range 0 to 16. A decrease in the change from baseline total score in the Peyronie's disease bother domain of the PDQ is indicated by a negative number.
Time frame: Baseline and Week 52
Population: Efficacy is based on the mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline in the Peyronie's Disease Bother Domain of the Peyronie's Disease Questionnaire (PDQ) | -2.4 units on a scale | Standard Deviation 3.62 |
| Placebo | Change From Baseline in the Peyronie's Disease Bother Domain of the Peyronie's Disease Questionnaire (PDQ) | -1.6 units on a scale | Standard Deviation 3.52 |
p-value: 0.0496ANOVA
Primary
Percentage Change From Baseline in Penile Curvature
A negative value in the percentage change from baseline in penile curvature deformity (angle measured in degrees) indicates less curvature.
Time frame: Baseline and Week 52
Population: Efficacy is based on the modified intent-to-treat (mITT) population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Percentage Change From Baseline in Penile Curvature | -30.5 percentage of curvature change | Standard Deviation 27.7 |
| Placebo | Percentage Change From Baseline in Penile Curvature | -15.2 percentage of curvature change | Standard Deviation 28.6 |
p-value: 0.0059ANOVA
Secondary
A Composite Responder Analysis Based on Change From Baseline in Penile Curvature and in the Peyronie's Disease Bother Score
A composite responder is indicated by * a percent reduction from baseline in penile curvature greater than or equal to the threshold, and * a reduction from baseline in Peyronie's disease bother score greater than or equal to the threshold, or change in the overall sexual activity within the last 3 months to having vaginal intercourse from no vaginal intercourse at screening.
Time frame: Week 52
Population: Composite responder analysis is based on the ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AA4500 | A Composite Responder Analysis Based on Change From Baseline in Penile Curvature and in the Peyronie's Disease Bother Score | Responder - No | 143 participants |
| AA4500 | A Composite Responder Analysis Based on Change From Baseline in Penile Curvature and in the Peyronie's Disease Bother Score | Responder - Yes | 105 participants |
| AA4500 | A Composite Responder Analysis Based on Change From Baseline in Penile Curvature and in the Peyronie's Disease Bother Score | Responder - Missing | 26 participants |
| Placebo | A Composite Responder Analysis Based on Change From Baseline in Penile Curvature and in the Peyronie's Disease Bother Score | Responder - Yes | 41 participants |
| Placebo | A Composite Responder Analysis Based on Change From Baseline in Penile Curvature and in the Peyronie's Disease Bother Score | Responder - No | 93 participants |
| Placebo | A Composite Responder Analysis Based on Change From Baseline in Penile Curvature and in the Peyronie's Disease Bother Score | Responder - Missing | 7 participants |
p-value: 0.0249Cochran-Mantel-Haenszel
Secondary
A Responder Analysis Based on Subject Overall Global Assessment
Subject overall global assessment of Peyronie's disease score range -3 (much worse) to 3 (much improved). A score of 1 (improved in a small but important way), 2 (moderately improved), or 3 indicated a responder.
Time frame: Week 52
Population: Efficacy is based on the mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AA4500 | A Responder Analysis Based on Subject Overall Global Assessment | Responder Status - No | 90 participants |
| AA4500 | A Responder Analysis Based on Subject Overall Global Assessment | Responder Status - Yes | 112 participants |
| Placebo | A Responder Analysis Based on Subject Overall Global Assessment | Responder Status - No | 75 participants |
| Placebo | A Responder Analysis Based on Subject Overall Global Assessment | Responder Status - Yes | 32 participants |
p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Penile Length
A negative value represents a reduction in measurement from baseline.
Time frame: Baseline and Week 52
Population: Efficacy is based on the mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline in Penile Length | 0.5 centimeters | Standard Deviation 1.34 |
| Placebo | Change From Baseline in Penile Length | 0.2 centimeters | Standard Deviation 1.49 |
p-value: 0.0248ANOVA
Secondary
Change From Baseline in Penile Plaque Consistency
Penile plaque consistency score range 1 (non-palpable) to 5 (hard). A decrease in the change from baseline score in penile plaque consistency is indicated by a negative number.
Time frame: Baseline and Week 52
Population: Efficacy is based on the mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline in Penile Plaque Consistency | -0.8 units on a scale | Standard Deviation 0.97 |
| Placebo | Change From Baseline in Penile Plaque Consistency | -0.4 units on a scale | Standard Deviation 0.86 |
p-value: 0.0144ANOVA
Secondary
Change From Baseline in the Penile Pain Domain of the PDQ in Subjects With Baseline Penile Pain Score ≥4
Penile pain scale range 0 (no pain) to 10 (extreme pain) on 3 questions; total score range 0 to 30. A decrease in the change from baseline total score in the penile pain domain of the PDQ is indicated by a negative number. Subjects were required to have a penile pain score of 4 or greater at baseline.
Time frame: Baseline and Week 52
Population: Efficacy is based on the mITT population; this population only includes those subjects in the mITT population with a baseline penile pain score of 4 or greater.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline in the Penile Pain Domain of the PDQ in Subjects With Baseline Penile Pain Score ≥4 | -3.8 units on a scale | Standard Deviation 5.93 |
| Placebo | Change From Baseline in the Penile Pain Domain of the PDQ in Subjects With Baseline Penile Pain Score ≥4 | -4.5 units on a scale | Standard Deviation 5.39 |
p-value: 0.6949ANOVA
Secondary
Change From Baseline in the Severity of Peyronie's Disease Symptoms Domain of the PDQ
Peyronie's disease symptoms (physical and psychological) severity score range 0 (none) to 4 (very severe) on 6 questions; total score range 0 to 24. A decrease in the change from baseline total score in the Peyronie's disease symptoms domain of the PDQ is indicated by a negative number.
Time frame: Baseline and Week 52
Population: Efficacy is based on the mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change From Baseline in the Severity of Peyronie's Disease Symptoms Domain of the PDQ | -2.6 units on a scale | Standard Deviation 4.83 |
| Placebo | Change From Baseline in the Severity of Peyronie's Disease Symptoms Domain of the PDQ | -1.0 units on a scale | Standard Deviation 4.78 |
p-value: 0.034ANOVA
Secondary
Change in the Overall Satisfaction Domain of the International Index of Erectile Function (IIEF)
Overall satisfaction domain of the IIEF score range 0 to 5 on 2 questions where higher scores indicate improved function or satisfaction; total score range 0 to 10.
Time frame: Baseline and Week 52
Population: Efficacy is based on the mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AA4500 | Change in the Overall Satisfaction Domain of the International Index of Erectile Function (IIEF) | 1.0 units on a scale | Standard Deviation 2.33 |
| Placebo | Change in the Overall Satisfaction Domain of the International Index of Erectile Function (IIEF) | 0.3 units on a scale | Standard Deviation 2.35 |
p-value: 0.1168ANOVA