Study of AA4500 in the Treatment of Peyronie's Disease
Condition: Peyronie's Disease
MeSH terms: Penile Induration
Intervention: AA4500; Placebo
Intervention description: 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.; 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.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 418.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Peyronie's Disease; penile plaque; penile curvature

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 400 (267 AA4500
      and 133 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 deformity (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 further treatment is not clinically indicated, 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.
    

Eligibility criteria:

        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 curvature deformity 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 curvature deformity

               -  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 non-steroidal anti-inflammatory drugs [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

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