ORIGINAL RESEARCH–PEYRONIE'S DISEASE: The Use of Intralesional Clostridial Collagenase Injection Therapy for Peyronie's Disease: A Prospective, Single-Center, Non-Placebo-Controlled Study

Authors

  • Gerald H. Jordan MD, FACS, FAAP

    1. Department of Urology, Eastern Virginia Medical School, Norfolk, VA, USA; Devine Center for Genitourinary Reconstructive Surgery, Sentara Norfolk General Hospital, Norfolk, VA, USA
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Gerald H. Jordan, MD, FACS, FAAP, 400 W. Brambleton Avenue, Suite 100, Norfolk, VA 23510, USA. Tel: (757) 457-5125; Fax: (757) 626-0768; E-mail: ghjordan@sentara.com

ABSTRACT

Introduction.  Peyronie's disease afflicts at least 3% of sexually active men over the age of 30. Many pharmacologic therapies have been tried, but to date, no systemic or local therapy has been proven to provide predictable and lasting results.

Aim.  This study was designed to assess the efficacy and safety of intralesional clostridial collagenase injection therapy in a series of patients with Peyronie's disease.

Methods.  Twenty-five patients aged 21–75 years who were referred to a single institution with a well-defined Peyronie's disease plaque were treated with three intralesional injections of clostridial collagenase 10,000 units in a small volume (0.25 cm3 per injection) administered over 7–10 days, with a repeat treatment (i.e., three injections of collagenase 10,000 units/25 cm3 injection over 7–10 days) at 3 months. Primary efficacy measures were changes from baseline in the deviation angle and plaque size. Secondary efficacy end points were patient responses to a Peyronie's disease questionnaire and improvement according to the investigators' global evaluation of change.

Main Outcome Measure.  The primary efficacy measures were change in deviation angle and change in plaque size. Secondary end points were patient questionnaire responses and improvement according to the investigators’ global evaluation of change.

Results.  Significant decreases from baseline were achieved in the mean deviation angle at months 3 (P = 0.0001) and 6 (P = 0.0012), plaque width at months 3 (P = 0.0052), 6 (P = 0.0239), and 9 (P = 0.0484), and plaque length at months 3 (P = 0.0018) and 6 (P = 0.0483). More than 50% of patients in this series considered themselves “very much improved” or “much improved” at all time points in the study, and the drug was generally well tolerated.

Conclusion.  The benefits of intralesional clostridial collagenase injections in this trial lend support to prior studies supporting its use in the management of Peyronie's disease. A double-blind, placebo-controlled study is currently under development. Jordan GH. The use of intralesional clostridial collagenase injection therapy for Peyronie's disease: A prospective, single-center, non-placebo-controlled study. J Sex Med 2008;5:180–187.

Introduction

Peyronie's disease is a primary and progressive fibroblast proliferation of the tunica albuginea of the penis accompanied by collagen and, in some cases, calcium deposition [1]. Characterized by the development of scars (plaques), pain with erection, and penile deformity and shortening, in many cases, patients with Peyronie's disease develop erectile dysfunction. Most frequent in men aged 50–70 years, a recent community-based survey reported the prevalence in men aged >30 years as 3.2% [2]. Although not life threatening, because Peyronie's disease symptoms can negatively affect sexual function, the desire for effective therapy is understandable.

The course of Peyronie's disease is marked by two primary stages: an early, immature or acute stage, followed by a mature or quiescent stage [3,4]. The strategy and role of various therapeutic approaches are defined by the progressive nature of the disease [1], with early medical therapy directed at trying to stop disease progression and improve symptoms. Surgical therapy is indicated only during the quiescent stage, and is designed to correct curvature and restore sexual function; however, it does not reliably address penile shortening [5]. Pain with erection resolves as the process becomes quiescent. Unfortunately, there is currently no medical or local therapy that has been proven to provide predictable and lasting benefits for patients with this distressing problem.

A major concern about medical therapy for treatment of the immature stage of Peyronie's disease is the limited number of controlled trials reported in the literature to validate pharmacologic treatments, with most literature on pharmacologic treatment comprising observational reports of improvement or resolution [1]. Among the drugs currently regarded as valid options, clostridial collagenase is a chromatographically purified bacterial enzyme that selectively attacks collagen [6], shown to be the primary component of the Peyronie's disease scar [7].

Aim

The objective of this study was to assess the efficacy and safety of intralesional collagenase injections in a series of patients with Peyronie's disease. This study was carried out in accordance with the ethical standards of our institutional review board. The protocol was approved and monitored by them throughout the term of the study.

Methods

Between November 1998 and July 1999, consecutive patients aged 21–75 years, who were referred to a single institution with a diagnosis of Peyronie's disease plaque, met the inclusion criteria, and accepted enrollment, were included in the trial. The presence of a Peyronie's plaque was verified by history and physical exam. All patients enrolled in the study signed a written institutional review board-approved informed consent before study participation.

Exclusion criteria included any of the following: substantial erectile deficits caused by or associated with Peyronie's disease; previous surgery for Peyronie's disease; extensive plaque calcification, a penile deviation <20 degrees; use of alternative therapies (i.e., X-ray therapy, potaba, vitamin E, oral or injectable steroids, and hydrocortisone with ultrasound) ≤1 month before study entry; bleeding disorders; impotence or major deficits in sexual function caused by a condition other than Peyronie's disease; history of blood dyscrasia; infectious illness ≤2 weeks before injection; diabetes mellitus; any concomitant disease potentially associated with peripheral neuropathy; psychosocial problems that could obscure evaluation; unwillingness or inability to cooperate or give informed consent; serious cardiac disorders; and any chronic or major debilitating illness.

Patients were treated with three injections of clostridial collagenase (Biospecifics Technologies, Lynbrook, NY, USA) 10,000 untis/0.25 cm3 per injection administered over 7–10 days. A repeat treatment (i.e., three injections of collagenase 10,000 untis/0.25 cm3 per injection) was administered over 7–10 days at 3 months. The plaque size and angle of deformity as documented with photography under vacuum-induced erection were evaluated at baseline, 3, 6, and 9 months. Because of the small volumes of pharmaceutical, the injection was focused at the point of maximal curvature as determined by physical examination and as compared with the photos of the erect penis. The penis was flaccid during the injection procedure. This study was conducted simultaneously with an injection study for Dupuytren's disease. In that study, decreasing the volume allowed an increased concentration. That change was carried into this study protocol.

Main Outcome Measure

The primary efficacy measures were changes from baseline in the deviation angle and plaque size. A ≥25% reduction from the pretreatment deviation angle or plaque size was considered a successful treatment response. The secondary efficacy end points were the patient questionnaire responses (Appendix A) and improvement according to the investigators’ global evaluation of change (Appendix B). The patient questionnaires—nonvalidated questionnaires developed locally—comprised subjective responses to visual analog scales (VAS) to evaluate pain reduction associated with penile bending (VAS 1 and 2) and restoration of sexual function (VAS 3 through 7), as reported on a 6-point scale ranging from “very much improved” to “very much worse.” Adverse events were recorded at 3-, 6-, and 9-month evaluations, and at the time of occurrence. Validated questionnaires were not available at the time this study was performed, and many believed the development of a validated questionnaire for use in the Peyronie's patient population was impossible. However, at the time of the submission, a “validated questionnaire” is well along in the process of development and will be used for all future studies.

T-tests were performed to show the significant differences from baseline. All computations were performed in SAS Version 6.12 (SAS, Cary, NC, USA) and at the 0.05 level for statistical significance.

Results

Twenty-five patients were enrolled in the study, received study drug, and were included in the efficacy analysis for the intent-to-treat population. Among these, 19 (72%) completed the full treatment course at 3 months, and there were 18 remaining for the 9-month evaluation. Despite reporting an “excellent response,” three patients (12%) discontinued the study because of an unsatisfactory therapeutic response, thus refusing further follow-up, and one each for the following reasons: intercurrent medical problem, failure to follow appointment schedule without a documented reason, and administrative reasons. A subset analysis was also performed for the 19 patients who completed the full course of treatment.

The mean age of enrolled patients was 55.4 years, and the mean duration of illness reported at enrollment was 39.2 months. Bending was the most frequent response (48%) to the question “How was the disease detected?”, followed by presence of nodule (32%), and pain with erection (20%). Most patients reported a gradual onset of symptoms (68%), while 32% reported a sudden or “overnight” onset. Baseline characteristics of the study population are summarized in Table 1.

Table 1.  Baseline characteristics of study population
VariableN = 25
Mean age, year (range)55.4 (40–70)
Caucasian, N (%)23 (92)
Mean duration of illness, month (range)39.2 (11–288)
Mean symptom duration before seeking medical care, month (range)5.2 (0.2–36)
Mean maximum plaque length, cm (range)5.8 (3.4–9.4)
Mean maximum plaque width, cm (range)0.8 (0.3–1.3)
Mean deviation angle, degree (range)52.8 (15.0–75.0)

Primary End Points

The mean deviation angle was 55.8 degrees at baseline. At each visit, the mean deviation angle was less than the baseline value, with significant mean changes from the mean baseline deviation angle at months 3 (12.7 degrees, P = 0.0001) and 6 (11.1 degrees, P = 0.0012) (Figure 1A). The positive treatment response, as measured by a 25% decrease in deviation angle, peaked at month 3 (N = 11, 57.89%) and declined at month 9 because of loss of successful patients; however, the same patients who experienced treatment success at month 3 were still successful at month 9 (Figure 1B, C).

Figure 1.

(A) Mean deviation angle at baseline, 3, 6, and 9 months. *P values represent significant changes from baseline. (B) Summary of success rate for deviation angle. (C) Summary of success rate for deviation angle. *All postbaseline visits are referencing last treatment).

The mean plaque length was 5.84 inches, and the mean plaque width was 0.8 inches at baseline. The mean width and length of the plaque was reduced compared with baseline at months 3, 6, and 9 (Figure 2A). The mean change from baseline in plaque width was significant at months 3 (0.0129 inches, P = 0.0052), 6 (0.153 inches, P = 0.0239), and 9 (0.122 inches, P = 0.0484), and in plaque length at months 3 (0.941 inches, P = 0.0018) and 6 (0.476 inches, P = 0.0483). The positive treatment response, as measured by a 25% decrease in plaque size, peaked at month 3 (N = 18, 94.74%) and declined at month 6 because of loss of successful patients; however, the same patients who experienced treatment success at month 3 were still successful at month 9 (Figure 2B, C).

Figure 2.

(A) Mean plaque length and width at baseline, 3, 6, and 9 months. *P values represent changes from baseline. (B) Summary of success rate for plaque size. (C) Summary of success rate for plaque size. *All postbaseline visits are referencing last treatment.

Secondary End Points

There was a significant mean change from baseline on the response to question 9 (“How your condition interferes with your ability to have a sex life?”) on the patient questionnaire at all time points (month 3: −25.64, P = 0.0085; month 6: −36.38, P = 0.0139; month 9: −39.62, P = 0.0114). Responses to questions 1, 2, 3, 6, and 7 did not change significantly from baseline at any time point. Question 5 was significant only at 6 months (P = 0.0524).

The investigators’ global evaluation indicated that the patients’ disease condition had improved. More than 50% of patients in this series were considered “very much improved” or “much improved” at all time points in the study, while approximately one-third were considered to show minimal improvement or no change, resulting in an investigator's assessment of “worse.” A consistently small number were nonresponders ( Figure 3). It is recognized that the investigators’ global evaluation could be skewed in the interpretation. However, during the development of the protocol, such a statement of the investigators’ overall assessment of results was strongly recommended for inclusion in the protocol by the Food and Drug Administration (FDA) reviewers.

Figure 3.

Investigators’ global evaluation.

Adverse Events

Collagenase therapy was generally safe and well tolerated. Adverse events occurred in 20 (80%) patients, with edema, penile pain, and ecchymosis as the most common. Serious adverse events (i.e., cardiac disorders, neoplasms) occurred in 2 (8%) patients, mild events in 18 (72%), and events of moderate intensity occurred in 8 (32%). Nineteen (72%) adverse events (most commonly, penile pain, contusions, ecchymosis) were considered to be related to the study drug, and all resolved on their own without requiring medical intervention. No serious adverse event was considered by the investigators to be directly attributable to the drug or injection protocol. Adverse events are summarized in Table 2.

Table 2.  Summary of adverse events considered related to study drug
Adverse eventRelationship to study drug, N (%)
PossiblyProbablyDefinitely
  1. NOS = not otherwise specified.

Reproductive system1 (4)1 (4)14 (56)
 Erectile disturbance0 (0)1 (4)0 (0)
 Penile disorder NOS0 (0)0 (0)5 (20)
 Penile pain1 (4)0 (0)12 (48)
 Penile swelling0 (0)0 (0)6 (24)
Skin and subcutaneous tissue disorders0 (0)2 (8)19 (76)
 Contusions0 (0)2 (8)14 (56)
 Ecchymosis0 (0)0 (0)11 (44)

Subgroup Analysis

Subgroup analysis of the 19 patients who completed all treatment applications yielded similar results. The mean age of enrolled patients was 55.8 years, and the mean duration of illness reported at enrollment was 43.6 months. Bending was the most frequent response (47.4%) to the question “How was the disease detected?”, followed by presence of nodule (26.3%), and pain with erection (26.3%). Most patients reported a gradual onset of symptoms (68.4%), while 31.6% reported a sudden or “overnight” onset.

The mean deviation angle at baseline was 55.8 degrees, and was decreased at each visit from the baseline value. The mean change in deviation angle from baseline was significant at months 3 and 6 (P < 0.05, for both). Treatment success as measured by a ≥25% reduction from baseline deviation angle was achieved in 10/19 patients (52%), with a peak at month 3 (58.82%) and a decline at month 6 because of loss of patients who experienced treatment success.

The plaque length was 5.9 inches, and the width was 0.8 inches at baseline. Mean plaque width and length decreased compared with baseline at months 3, 6, and 9. The mean change from baseline in plaque width was significant at months 3, 6, and 9; mean change in plaque length was significant at months 3 and 6. Treatment success as measured by a ≥25% reduction from baseline in plaque size peaked at month 3 (94.12%), declining because of loss of patients who experienced treatment success.

Patients indicated a significant improvement from baseline in question 9 (“How your condition interferes with your ability to have a sex life?”) at all time points (P < 0.05), whereas there were no other significant changes from baseline in responses to the patient questionnaire. The investigators’ global evaluation also indicated that most patients’ condition was either very much or much improved over the course of treatment (3 months: 58.8%; 6 months: 60%; 9 months: 55.6%).

The data were unavailable for publication because of the sale of the rights to the pharmaceutical. However, there have not been subsequent studies performed until the data were reviewed and made available.

Discussion

Collagenase is currently FDA-approved for debriding chronic dermal ulcers and severely burned tissues [8]. Early clinical studies using collagenase injections in humans involved intervertebral injections in patients with herniated lumbar disks [9–12]. Although in the majority of these reports, collagenase yielded good results (78–80% success) and was well tolerated with few complications, no laboratory abnormalities, or allergic or other toxic or infectious manifestations [9–11]; in one report, 8 of 11 cases were considered failures, with findings consistent with damage to adjacent normal structures [12]. The results of this report caused the FDA to temporarily halt clinical trials with collagenase [11]; however, research was later permitted to resume, and subsequent trials demonstrated the safety and efficacy of intervertebral collagenase injections for treatment of herniated lumbar disks in properly selected patients [13,14].

In 1982, a pilot study designed to test the feasibility of using purified clostridial collagenase in the clinical management of Peyronie's disease demonstrated collagenase injections reduced Peyronie's plaque fragments without damage to surrounding elastic tissue, vascular smooth muscle, or axon myelin sheaths [15]. A phase 1 clinical trial of intralesionally injected collagenase for treatment of Peyronie's disease that followed resulted in objective improvement of symptoms in 20 of 31 patients (65%), with pain during erection eliminated in 13 of the 14 (93%) who had reported pain at study entrance [16]. In this trial, collagenase (470–2,730 untis per injection on three consecutive days) was generally well tolerated, with pain on injection and ecchymosis as the most common adverse effects. To isolate the pharmacologic effect of collagenase from the hydraulic effect of injecting plaques with fluid under pressure, a prospective, randomized, placebo-controlled, double-blind study was conducted to compare the effects of intralesional purified clostridial collagenase vs. saline placebo on plaque size and penile deformity in 49 men with Peyronie's disease [6]. For the study as a whole, the response to collagenase exceeded that of placebo (P < 0.007); however, patients with less deformity (≤30 degree angle at baseline) were more likely to respond to collagenase compared with those with the most deformity (>60 degree angle at baseline), with a response ranging from 100% in patients with the least, compared with only 13% in those with the greatest amount of scarring. As in the previous study, collagenase was well tolerated, without allergic reactions, and tenderness at the injection site as the most commonly occurring adverse reaction to the injections.

In the present study, significant improvements in the mean baseline deviation angle, mean width and length of the Peyronie's plaque, and both patient and investigators’ opinion of treatment response indicate a favorable treatment response with collagenase injections for the treatment of Peyronie's disease in more than half of the treated patients.

The volume of injectate was decreased (0.25–1.0 mL), and the concentration was increased— yielding a higher dosage (10,000–40,000 untis/mL)—in the present study compared with the volume of 1.5–3.5 mL containing 3,300 untis/mL administered in a previous reported trial [6]; however, the treatment was still well tolerated. In addition, when administered to patients with a wide range of baseline symptoms of severity (deviation angle ranged from 15.0 to 75.0 degrees), an overall response rate of 52% was achieved among the patients who completed the treatment regimen, suggesting that intralesional collagenase may be a good treatment option for patients with varying disease severity.

Limitations of the current study include the small population treated and the short-term follow-up period. Because Peyronie's disease is progressive, with symptoms that can take a period of months to years to stabilize, definitive research evaluating long-term efficacy of pharmacologic treatments may require longer follow-up in greater numbers of patients. In addition, the patients in this study presented with a range of baseline symptoms, making it difficult to define whether patients with a specific baseline symptom range could be identified who would potentially benefit most from treatment with collagenase injection. Additional study design limitations include lack of placebo control and blinding.

Conclusion

This study is compared with other intralesional injection agents, few of which have been subjected to placebo-controlled, double-blinded studies. The authors recognize that controlled trials are more revealing. There is clearly a need for continued controlled clinical trials with all pharmacologic agents for the treatment of Peyronie's disease. Breakthroughs in the understanding of the role of extracellular matrix macromolecules, including collagen, will enhance our ability to offer reasonable and effective nonsurgical therapies for early management of this difficult and widespread problem. The benefits of intralesional collagenase injections in this trial lend support to existing literature, which suggests that this mode of therapy is an option for management of Peyronie's disease; however, further research is needed to more clearly define those patients who would benefit most from the treatment. A double-blind, placebo-controlled multicenter study is currently well into the process of development and is expected to begin enrollment soon.

Conflict of Interest: Gerald H. Jordan is a consultant and an investigator at Auxillium Pharmaceuticals.

Appendices

Appendix A. Patient Peyronie's Disease Questionnaire

PEYRONIE'S PATIENT QUESTIONNAIRE

1. How many times have you attempted sexual intercourse?0 = No attempts
1 = One to two attempts
2 = Three to four attempts
3 = Five to six attempts
4 = Seven to ten attempts
5 = Eleven+ attempts
2. When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner?0 = Did not attempt intercourse
1 = Almost never/never
2 = A few times (much less than half the time)
3 = Sometimes (about half the time)
4 = Most times (much more than half the time)
5 = Almost always/always
3. When you attempts sexual intercourse, how often was it satisfactory for you?0 = Did not attempts intercourse
1 = Almost never/never
2 = A few times (much less than half the time)
3 = Sometimes (about half the time)
4 = Most times (much more than half the time)
5 = Almost always/always
4. How much have you enjoyed sexual intercourse?0 = No intercourse
1 = No enjoyment
2 = Not very enjoyable
3 = Fairly enjoyable
4 = Highly enjoyable
5 = Very highly enjoyable
5. How satisfied have you been with your overall sex life?1 = Very dissatisfied
2 = Moderately dissatisfied
3 = About equally satisfied and dissatisfied
4 = Moderately satisfied
5 = Very satisfied
6. How satisfied have you been with your sexual relationship with your partner?1 = Very dissatisfied
2 = Moderately dissatisfied
3 = About equally satisfied and dissatisfied
4 = Moderately satisfied
5 = Very satisfied
7. How much pain are you experiencing upon erection?1 = Most pain imaginable
2 = Severe pain
3 = Moderate pain
4 = Minimal pain
5 = No pain
8. How much pain are you experiencing without erection?1 = Most pain imaginable
2 = Severe pain
3 = Moderate pain
4 = Minimal pain
5 = No pain
9. How much does your condition interfere with your ability to have a satisfying sex life?1 = Most interference imaginable
2 = Severe interference
3 = Moderate interference
4 = Minimal interference
5 = No interference

Appendix B. Physicians’ Global Evaluation of Change

INVESTIGATOR GLOBAL ASSESSMENT

Considering my total clinical experience, I consider the severity of this patient's Peyronie's Disease to be: (circle one)

Normal (No Peyronie's disease)   Moderate   Moderate/Severe   Severe

Compared to the disease severity at entry into the study, I assess the change in the Peyronie's disease to be:

□ No Change   □ Changed

If changed, circle one of the following:

 Minimally Improved   Much Improved   Very Much Improved

 Minimally Worse   Much Worse   Very Much Worse

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