Pharmacokinetics of a Single Treatment Cycle of AA4500 0.58 mg in Men With Peyronie's Disease
Condition: Peyronie's Disease
MeSH terms: Penile Induration
Intervention: AA4500
Intervention description: Two injections of AA4500 0.58 mg 24 hours apart
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Xiaflex; Xiapex; Collagenase clostridium histolyticum

Summary:

      This study is a Phase 2, open-label study to assess the pharmacokinetics (PK) and safety of
      AA4500 0.58 mg in men with Peyronie's disease. Subjects will be screened for study
      eligibility within 21 days before the initial injection of study drug. Two injections will be
      administered 24 hours apart.

      Subjects will be admitted to the study unit the day before the first injection of AA4500 (Day
      -1) and will remain in the study unit until after the PK sample is collected after
      investigator penile plaque modeling on Day 3. Subjects will return to the study unit on Day
      4, Day 8, and Day 29 for follow-up pharmacokinetic and safety assessments.Pharmacokinetic
      plasma samples will be collected at predetermined time points before (15 minutes
      pre-injection) and after each injection on Day 1 and Day 2 (5,10, 20, 30 minutes and
      1,2,3,4,8,12 hours after), and on Days 3, 4, 8, and 29.Plasma levels for AUX-I (clostridial
      type I collagenase) and AUX-II (clostridial type II collagenase) will be determined.
    

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 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:

        A subject will be excluded from study participation if he:

          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 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 an
             appropriate pharmacological stimulant (eg, prostaglandin E1 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 (curvature caused by a plaque that is
             noncontiguous with the hourglass deformity may be treated)

          7. Has the plaque causing curvature of the penis located proximal to the base of the
             penis, so that the injection of a 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 the 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 or contraindication 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 the first dose of study
             drug

         22. Has received tetracycline, doxycycline, or other tetracycline derivatives within 5
             days before the first dose of study drug or plans to use any of these drugs at any
             time during the study

         23. Has received any collagenase treatments within 30 days of the first dose of study drug

         24. Has, at any time, received AA4500 for the treatment of Peyronie's disease

         25. Has a positive alcohol breath test or positive urine drug screen for amphetamines,
             barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, and/or
             propoxyphene at screening and/or on Day -1

         26. Has a 12-lead electrocardiogram (ECG) finding that is outside 'normal limits' or
             interpreted as 'abnormal, clinically significant', as determined by the physician