Study of AA4500 in the Treatment of Peyronie's Disease | NCT01221597

Description Module

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 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.

Label	Type	Description	Intervention Names
AA4500	Experimental	collagenase clostridium histolyticum	Biological: AA4500
Placebo	Placebo Comparator	placebo	Biological: Placebo

Name	Type	Description	Arm Group Labels	Other Names
AA4500	Biological	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.

Measure	Description	Time Frame
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.	Baseline and Week 52
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.	Baseline and Week 52

Measure	Description	Time Frame
A Responder Analysis Based on Subject Overall Global Assessment of Peyronie's Disease	A responder was defined as a subject who recorded his Peyronie's disease had either improved in a small but important way, moderately improved, or much improved in overall global assessment question.	Week 52
Change From Baseline in the Severity of Peyronie's Disease Physical and Psychological Symptoms

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Be a male and be ≥ 18 years of age
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
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
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
Be judged to be in good health, based upon the results of a medical history, physical examination, and laboratory profile
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
Be able to read, complete and understand the various rating instruments in English

Exclusion criteria

Has a penile curvature of less than 30° or greater than 90° at the screening visit
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)
Has previously undergone surgery for Peyronie's disease
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
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
Has an isolated hourglass deformity of the penis
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
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
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
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
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
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
Has significant erectile dysfunction that has failed to respond to oral treatment with phosphodiesterase type 5 (PDE5) inhibitors
Has a penile Duplex Doppler ultrasound evaluation at screening that shows compromised penile hemodynamics that in the opinion of the investigator is clinically significant
Has uncontrolled hypertension, as determined by the investigator
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
Is unwilling or unable to cooperate with the requirements of the study including completion of all scheduled study visits
Has received an investigational drug or treatment within 30 days before the first dose of study drug
Has a known systemic allergy to collagenase or any other excipient of AA4500
Has a known allergy to any concomitant medication required as per the protocol
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
Has received any collagenase treatments within 30 days of the first dose of study drug
Has, at any time, received AA4500 for the treatment of Peyronie's disease

-

Name	Affiliation	Role
Gregory J. Kaufman, MD	Auxilium Pharmaceuticals, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Urology Centers of Alabama, PC		Homewood	Alabama	35209	United States
HOPE Research Institute, LLC

PubMed Identifier	Type	Citation	Retractions
26199168	Derived	Hellstrom WJ, Feldman RA, Coyne KS, Kaufman GJ, Smith TM, Tursi JP, Rosen RC. Self-report and Clinical Response to Peyronie's Disease Treatment: Peyronie's Disease Questionnaire Results From 2 Large Double-Blind, Randomized, Placebo-Controlled Phase 3 Studies. Urology. 2015 Aug;86(2):291-8. doi: 10.1016/j.urology.2015.04.047. Epub 2015 Jul 18.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

Efficacy is based on the modified intent-to-treat population (mITT).

Posted

Mean

Standard Deviation

percentage of curvature change

Baseline and Week 52

ID	Title	Description
OG000	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.
OG001	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.

Units	Counts
Participants	OG000199 OG001104

Title

Denominators

Categories

Title	Measurements
	OG000-37.6± 30.29 OG001-21.3± 29.89

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		ANOVA		0.0005						2-Sided								Superiority or Other

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.

Efficacy is based on the mITT population.

Posted

Mean

Standard Deviation

units on a scale

Baseline and Week 52

ID	Title	Description
OG000	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.
OG001	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.

Secondary

A Responder Analysis Based on Subject Overall Global Assessment of Peyronie's Disease

A responder was defined as a subject who recorded his Peyronie's disease had either improved in a small but important way, moderately improved, or much improved in overall global assessment question.

Efficacy analysis was based on the mITT population.

Posted

Number

Number of particpants

Week 52

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Change From Baseline in the Severity of Peyronie's Disease Physical and Psychological Symptoms

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.

Efficacy analysis is based on the mITT population.

Posted

Mean

Standard Deviation

units on a scale

Baseline and Week 52

ID	Title	Description
OG000	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.
OG001	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.

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.

Efficacy analysis is based on the mITT population.

Posted

Mean

Standard Deviation

units on a scale

Baseline and Week 52

ID	Title	Description
OG000	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.
OG001	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.

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.

Efficacy analysis is based on the mITT population.

Posted

Mean

Standard Deviation

units on a scale

Baseline and Week 52

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Change From Baseline in Penile Length

A negative value represents a reduction in measurement from baseline.

Efficacy analysis is based on the mITT population.

Posted

Mean

Standard Deviation

centimeters

Baseline and Week 52

ID	Title	Description
OG000	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.
OG001	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.

Units	Counts
Participants

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.

Efficacy analysis 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.

Posted

Mean

Standard Deviation

units on a scale

Baseline and Week 52

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Composite Responder Based on Change in Curvature Deformity and Change in Peyronie's Disease Bother Score

A responder was defined as a subject who satisfied the following 2 criteria at that visit: a) percent reduction from baseline in curvature deformity was ≥20% and b) reduction from baseline in PDQ Peyronie's disease bother score was ≥1, or had a change from reporting no sexual activity at screening to reporting sexual activity.

Efficacy analysis is based on the mITT population.

Posted

Number

Number of participants

Week 52

ID	Title	Description
OG000	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.
OG001	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.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Road traffic accident	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG0002 events2 affected277 at risk EG0010 events0 affected140 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (13.1)	Non-systematic Assessment	EG0003 events3 affected277 at risk EG0010 events0 affected140 at risk
Fracture of penis	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Pleuritic pain	Respiratory, thoracic and mediastinal disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Mesenteric artery stenosis	Gastrointestinal disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Traumatic lung injury	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Penile hematoma	Reproductive system and breast disorders	MedDRA (13.1)	Non-systematic Assessment	EG0002 events2 affected277 at risk EG0010 events0 affected140 at risk
Drug withdrawal syndrome	General disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Grand mal convulsion	Nervous system disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Spinal compression fracture	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Colitis ulcerative	Gastrointestinal disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Post laminectomy syndrome	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Chest pain	General disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Incisional hernia	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Transient ischemic attack	Nervous system disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA (13.1)	Systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Intestinal performation	Gastrointestinal disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Bladder transitional cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Malignant melanoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Squamous cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0002 events2 affected277 at risk EG0011 events1 affected140 at risk
Orthostatic hypotension	Vascular disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
B cell lymphoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Deep vein thrombosis	Vascular disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Lung cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Sciatica	Nervous system disorders	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0011 events1 affected140 at risk
Clavicle fracture	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG0001 events1 affected277 at risk EG0010 events0 affected140 at risk
Appendicitis	Infections and infestations	MedDRA (13.1)	Non-systematic Assessment	EG0000 events0 affected277 at risk EG0011 events1 affected140 at risk
Hodgkin's disease	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0000 events0 affected277 at risk EG0011 events1 affected140 at risk
Carcinoma in situ penis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (13.1)	Non-systematic Assessment	EG0000 events0 affected277 at risk EG0011 events1 affected140 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA (13.1)	Non-systematic Assessment	EG0000 events0 affected277 at risk EG0011 events1 affected140 at risk
Diverticulum	Gastrointestinal disorders	MedDRA (13.1)	Non-systematic Assessment	EG0000 events0 affected277 at risk EG0011 events1 affected140 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Penile haematoma	Reproductive system and breast disorders	MedDRA (13.1)	Non-systematic Assessment	EG000394 events171 affected277 at risk EG00131 events19 affected140 at risk
Penile pain	Reproductive system and breast disorders	MedDRA (13.1)	Non-systematic Assessment	EG000244 events119 affected277 at risk EG00115 events11 affected140 at risk
Penile swelling	Reproductive system and breast disorders	MedDRA (13.1)	Non-systematic Assessment	EG000219 events114 affected277 at risk EG0011 events1 affected140 at risk
Injection site pain	General disorders	MedDRA (13.1)	Non-systematic Assessment	EG000127 events70 affected277 at risk EG00112 events5 affected140 at risk
Penile haemorrhage	Reproductive system and breast disorders	MedDRA (13.1)	Non-systematic Assessment	EG000181 events60 affected277 at risk EG00119 events14 affected140 at risk
injection site haematoma	General disorders	MedDRA (13.1)	Non-systematic Assessment	EG00066 events45 affected277 at risk EG00118 events14 affected140 at risk
Penile oedema	Reproductive system and breast disorders	MedDRA (13.1)	Non-systematic Assessment	EG00098 events45 affected277 at risk EG0011 events1 affected140 at risk
Injection site swelling	General disorders	MedDRA (13.1)	Non-systematic Assessment	EG00047 events30 affected277 at risk EG0010 events0 affected140 at risk
Contusion	Injury, poisoning and procedural complications	MedDRA (13.1)	Non-systematic Assessment	EG00040 events28 affected277 at risk EG0010 events0 affected140 at risk
Ecchymosis	Skin and subcutaneous tissue disorders	MedDRA (13.1)	Non-systematic Assessment	EG00039 events26 affected277 at risk EG0010 events0 affected140 at risk
Injection site haemorrhage	General disorders	MedDRA (13.1)	Non-systematic Assessment	EG00024 events15 affected277 at risk EG00116 events10 affected140 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (13.1)	Non-systematic Assessment	EG0009 events9 affected277 at risk EG0017 events7 affected140 at risk

ID	Term
D010409	Penile Diseases
D005832	Genital Diseases, Male
D000091662	Genital Diseases
D000091642	Urogenital Diseases
D052801	Male Urogenital Diseases
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases

ID	Term
D017364	Collagenases
D008666	Metalloendopeptidases
D010450	Endopeptidases
D010447	Peptide Hydrolases
D006867	Hydrolases
D004798	Enzymes
D045762	Enzymes and Coenzymes
D045726	Metalloproteases

ID	Title	Description
BG000	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.
BG001	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.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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.			27	277	248	277
EG001	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.			7	140	55	140