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Collagenase Versus Placebo in the Treatment of Peyronie’s Disease: A Double-blind Study
0022-5347/93/1491-0056$03.00/0 THE JOURNAL OF UROLOGY
Vol. 149, 56-58, January 1993
Copyright © 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
COLLAGENASE VERSUS PLACEBO IN THE TREATMENT OF PEYRONIE'S DISEASE: A DOUBLE-BLIND STUDY MARTIN K. GELBARD, KATHLEEN JAMES, PAMELA RIACH AND FREDERICK DOREY From the Section of Urology, Department of Surgery and Department of Biostatistics, University of California School of Medicine, Los Angeles, California
ABSTRACT
We investigated 49 men with Peyronie's disease in a prospectively randomized piacebo controlled double-blind study, comparing the effects on plaque size and penile deformity of intralesional purified clostridial collagenase and saline placebo. For the group as a whole, treatment out-performed placebo (p <0.007). When patients were analyzed with respect to disease severity, those with lesser deformity responded more favorably to treatment. The absolute angular change in patients respond ing to treatment was small. No significant side effects were noted within a 3-month followup. KEY WORDS: penile erection, penis, penile induration, Clostridium histolyticum collagenase
Peyronie's disease is an idiopathic focal connective tissue disorder that results in regional loss of tunica albuginea com pliance. This may be associated early in its course with painful erections and subsequently with deformity of the erect penis. The evaluation of medical therapy for Peyronie's disease is difficult, based on the variability of this disease. Drug effect is not easily separated from the natural history of Peyronie's disease, which occasionally displays spontaneous resolution.1 Our study is a comparison of the effects of intralesional col lagenase to intralesional saline placebo in patients with Peyronie's disease, conducted in a randomized double-blind format. Clostridial collagenase is a chromatographically purified bac terial enzyme that selectively attacks collagen. This agent has been previously evaluated as a treatment for Peyronie's disease in a pilot study of 31 patients who received 470 to 2,730 units intralesionally at 1 session.2 Within this study group 20 patients showed some improvement in deformity while 13 of the 14 patients with painful erection experienced resolution of pain. Based on these results this study was continued as a phase 1 open trial under United States Food and Drug Administration IND No. 19,973, and involved 99 additional patients. Overall, the therapeutic results were similar to those observed in the pilot study. Our study was established to isolate drug effect from the hydraulic effect of injecting plaques with fluid under pressure, and to clarify what if any direct pharmacological effect exists.
30 to 60 degrees of angular deformity and/or 2 to 4 cm. of palpable plaque in maximal dimension. Category 3 patients were those with greater than 60 degrees of angular deviation and/or greater than 4 cm. of palpable plaque. At the entry evaluation, informed consent was obtained from all patients on a form approved by our human subject protection committee. Each patient in the study, designated as group 1, 2 or 3 based on the aforementioned entry evaluation received a unique study number on the day of treatment. The nurse study administrator then provided a prescription for collagenase study material to each patient, which was labeled with the study number, severity category and human subject protection committee number. These prescriptions were taken by the patient to our hospital pharmacy. The outpatient pharmacist was responsible for using the study number, severity category and randomization list provided by the department of biosta tistics to randomize patients in blocks of 10 within each severity category to either treatment or control arms. The pharmacist prepared 2,000 advance biofactor units of purified clostridial collagenase (nucleolysin) in 0.5 cc of a 0.9 sodium chloride diluent containing 2 mM. calcium chloride for patients random ized to treatment. Patients randomized to placebo received the same volume of diluent only. Category 1 patients had 3 such aliquots prepared (6,000 units in the treatment group), category 2 patients had 5 aliquots prepared (10,000 units in the treat ment group) and category 3 patients received 7 aliquots (14,000 units in the treatment group). These vials were then delivered back to the nurse study administrator, who drew each vial up for injection in a separate 1 cc tuberculin syringe with a unitary 25 gauge needle. Diluent alone could not be distinguished by appearance from diluent with dissolved collagenase. The total cumulative dose in patients randomized to treat ment was 6,000 units for category 1, 10,000 units for category 2 and 14,000 units for category 3. Patients randomized to the placebo or control arm received a total of 1.5 cc intralesionally in category 1, 2.5 cc sterile saline intralesionally in category 2 and 3.5 cc sterile saline diluent intralesionally in category 3. The anesthetic used was intracorporeal lidocaine. This was established by insufflation of the corpora using 0.25% plain lidocaine during atraumatic clamp occlusion of the penile base for 6 minutes. Patients were instructed to avoid intercourse for 2 weeks following treatment, and were seen 3 times for posttreatment evaluation (1 week, 1 month and 3 months). Adverse responses were recorded whenever reported. Subjective evaluation was documented on a symptom survey, global assessment of sexual function (a questionnaire), which was recorded at 1 month and 3 months on preprinted forms. Objective evaluation of plaque
MATERIALS AND METHODS
Between November 1987 and January 1989, 49 men 28 to 66 years old were entered in a prospective randomized parallel double-blind study with a crossover retreatment arm. This study was approved and monitored by our human subject protection committee. Entry criteria required that patients had the diagnosis of Peyronie's disease, stable or progressive, for at least 3 months. Patients with coagulopathy or significant erec tile deficit were excluded from the study. Entry evaluation was conducted before treatment, and in cluded the history, physical examination, laboratory screening with blood count and chemistry panel, and vacuum photogra phy of erectile deformity. Patients were stratified into 3 groups based on disease severity, using caliper measurement of plaque size, and the degree of deformity present during vacuum cham ber photography.3 A modification of the Kelami system for disease severity was used.4 Category 1 patients were character ized as those with a bend of 30 degrees or less, and/or palpable plaque less than 2 cm. in extent. Category 2 patients displayed Accepted for publication June 19,1992.
56
57
COLLAGENASE VERSUS PLACEBO IN TREATMENT OF PEYRONIE'S DISEASE
size, plaque extent, number and tenderness as well as bending was recorded at 1 week, 1 month and 3 months. Vacuum induced erectile photographs were taken 3 months after treat ment. The blood count and chemistry panels obtained at entry were redrawn at the l-week followup visit. The pretreatment and 3-month subjective responses of the patient were compared to identify those reporting benefit. If the reported improvement could be documented on the serial plaque measurements or photography, patient outcome was deemed positive. When no significant benefit was reported or if subjective and objective findings did not demonstrate a consistent pattern the outcome was deemed negative. Patients who experienced unsatisfactory or insufficient improvement were permitted to request a code break at 3 months. As a required prerequisite for breaking the code, all forms docu menting patient outcome had to be completed. If the code break demonstrated they had received placebo, they could elect to be treated with open label collagenase using the doses established previously. All patients subsequently requested a code break at 3 months, even those who demonstrated positive response. A total of 23 patients was found retrospectively to have been randomized to placebo and these patients all requested reinjection with colla genase. The responses of the patients receiving open label collagenase were assessed at 3 months after reinjection and they are listed separately. Patient outcome (positive or negative) in the treatment group was then compared to patient outcome in the control group for the study as a whole and within each of the 3 categories of disease severity. The differences obtained in these comparisons were tested for significance with Fisher's exact test. To estab lish that the different groups were comparable in a meaningful manner, treatment and control populations were studied with respect to age, disease duration, prior treatment and disease severity. This comparison failed to show any significant bias of either the treatment or placebo groups. RESULTS
The protocol for this study contained 6 patient evaluation forms: 1) admission criteria and demographic screen, 2) disease pattern, including history and symptoms of Peyronie's disease, 3) general medical history and medications, 4) parameters of disease severity, including plaque measurement and photogra phy, 5) laboratory evaluation and 6) patient questionnaire. The ability of the patient to provide this information in detail resulted in a considerable amount of data to correlate, since these forms were filled out initially, and at 1 week, 1 month and 3 months after treatment. For purposes of providing mean ingful clinical statistics, the data reported on these forms and evaluations needed to be simplified and condensed. We needed to decide whether each individual patient experienced benefit. Patients were only reported as positive responders if the ex amination and photographs confirmed the subjective responses indicating improvement (see figure). Patient outcome in the treatment group was compared to outcome in the placebo group in 4 different subsets of patients: all patients in categories 1 to 3 and the group of patients as a whole (see table). As described previously, plaque and penile angular measurement was used to divide the 49 patients into 3 severity groups. Category 1 contained 7 patients, category 2 contained 24 patients and category 3 contained 18 patients. Within category 1, 3 patients received treatment and 4 re ceived placebo. All 3 treatment patients experienced positive response with no patients in the treatment group failing to respond. Within the placebo group 1 patient experienced a positive response while 3 experienced no response. There was no statistical significance to the comparison between treatment and placebo groups in category 1, with a p value equaling 0.14. In category 2, 11 patients received treatment and 13 received placebo. Of the 11 patients receiving treatment 4 (36%) expe-
Patient in category 3 receiving 14,000 units of collagenase intrale sionally. A, before treatment. B, after treatment. Angular improvement is 15 to 20 degrees.
Category Overall: Treatment Placebo Category
1:
Treatment Placebo Category
2:
Treatment Placebo Category
3:
Treatment Placebo Reinjection (unblinded)
N o. Pts.
49 22 27 7 3 4 24 11 13 18 8 10 23
Pos. Response No
Difference
(%)
(p value)
No.
No.
8 (36) 1 (4)
14 (64) 26 (96)
<0.007
3 (100) 1 (25)
0 3 (75)
0.14
4 (36) 0
7 (64) 13 (100)
0.03
1 (13) 0 13 (56)
7 (87) 10 (100) 10 (44)
0.4 Not available
rienced a positive response and 7 (64%) experienced no re sponse. None of the placebo group experienced a positive re sponse. The difference between placebo and treatment groups in category 2 was significant at the p equals 0.03 level. Within category 3, 8 patients received treatment and 10 received pla cebo. Positive response was noted in 1 of the 8 patients receiving treatment (13%), while 7 (87%) failed to respond. There were
58
GELBARD AND ASSOCIATES
no positive responders in the placebo group. Statistical analysis did not demonstrate any significance between the response of the treatment and placebo groups in category 3. For the group as a whole, 22 patients received treatment and 27 received placebo. Positive responses were noted in 8 of the treatment group (36%), and in 1 of the placebo group (4%). For the study as a whole the response to collagenase exceeded that of placebo (p <0.007, Fisher's exact test). After the 3-month posttreatment evaluation in each patient had been completed, and the outcome was designated as posi tive or negative, the patients were allowed to request a code break. As would be expected, all patients exercised the code break option, which revealed that 27 of the 49 patients initially received placebo. Of these 27 patients 23 subsequently re quested reinjection, with 1 patient refusing reinjection and 3 undergoing surgery. The retreatment arm of the study was done for ethical reasons, since patients were generally not willing to enter a double-blind placebo controlled study if they were not assured that at some point they would receive the test agent. The results of this arm were not obtained in a blind fashion. Open label collagenase was used for reinjection and of the 23 patients retreated 13 (56%) responded positively. No adverse responses or allergic reactions5 occurred in rela tion to the injections. Laboratory studies done at entry and 1 week after injection showed no significant changes. One patient experienced a small tear of the tunica 3 weeks following injec tion, which was felt as a popping sensation during intercourse followed by a small ecchymosis noted after intercourse. The event did not cause detumescence and it occurred in a category 3 patient who was later determined to have collagenase. The condition was treated conservatively and resolved. Tenderness at the injection site was noted by most patients. This finding was observed in those receiving placebo as frequently as in those receiving collagenase. Within the 3-month followup no patient experienced progression or worsening of any parameter of the disease (pain, bending or ability for intercourse).
DISCUSSION
Followup in this study was deliberately short to separate drug-related improvement from spontaneous change in disease severity. Spontaneous resolution occasionally in patients with Peyronie's disease occurs during an interval of years, so obser vation of shorter term variation in disease severity should help to distinguish drug effects from spontaneous changes. Within this short-term period of observation the comparison of treat ment to control in effecting change in these patients should be significant, and reflect drug activity against the contracture responsible for most features of this disorder. The presence of change during a short period of observation, and the dose response relationship seen in the phase 1 open trial suggest that the improvement seen in some patients treated with collagenase is drug-related. Comparison of the effect of collagenase to placebo in our double-blind protocol confirms the ability of intralesional collagenase to improve some patients with Peyronie's disease. This conclusion can be drawn from the results of the study group as a whole, in which the treatment group response exceeded that of placebo (p <0.007). Other clinical factors have a role in analysis of the separate severity groups. It appeared that patients with minimal disease severity (category 1) were likely to respond to collagenase. The
small amounts of plaque and the angular deformity of these patients increased the margin of error in evaluating them; changes in parameters were slight enough to be produced by measurement error. Consequently, the only positive placebo response was recorded in this category. This fact, in association with the small number of patients, eliminated statistical signif icance to the difference between treatment and placebo groups in this category. Four patients in category 2 responded to collagenase, while no responses were observed in 13 patients with the same severity receiving placebo. The p value of 0.03 for this difference conferred moderate statistical significance. Although patients with severe disease (category 3) failed to respond to placebo, only 1 of 8 receiving collagenase responded. There was no statistically significant difference between responses in the treatment and placebo groups for these patients. In examining the overall data, it appears that the less scarring the patient had, the more likely he was to respond to collagen ase. Responses to the drug were noted in 100% of patients in category 1, 36% of those in category 2, and only 13% in category 3. This observation is consistent with the previously described dose-response relationship. Even though the dose of collagenase was increased for patients with more plaque, it seems that patients with severe deformity simply have too much collagen substrate for the enzyme to denature effectively. In the face of massive contracture, even considerable volumes of enzymatic collagenolysis appear unable to cause clinically apparent im provement in overall deformity. Enzymatic lysis of fibrous contractures is not without pre cedent. Good results have been obtained with enzymatic lysis of Dupuytren's contractures in patients who are not surgical candidates.6 Injection of these contractures by an enzyme mix ture is followed by forced hyperextension of the involved digit, then fixation in plaster. This sequence results in controlled rupture of the contracture and has produced reasonably good results in a small series. This technique is not widely accepted, however, and there are material differences between these patients and ours with a contracture of the tunica albuginea. Perhaps the most important conclusions regarding collagen ase can be drawn from review of the patient photographs. Improvement in the angulation of those patients experiencing a positive response was generally slight. The maximal angular improvement observed ranged from 15 to 20 degrees. This result produced acceptable clinical improvement only in category 1 patients. In those patients with more curvature the change produced was detectable but not clinically significant. REFERENCES 1. Gelbard, M. K, Dorey, F. and James, K: The natural history of Peyronie's disease. J. Uro!., 144: 1376,1990. 2. Gelbard, M. K, Lindner, A. and Kaufman, J. J.: The use of collagenase in the treatment of Peyronie's disease. J. Uro!., 134: 28,1985. 3. Gelbard, M. K: Controlled vacuum chamber for standardized pho tographic documentation of penile erectile deformity. Urology, 36: 367,1990. 4. Kelami, A.: Classification of congenital and acquired penile devia tion. Uro!. Int., 38: 229,1983. 5. Hamilton, R. G., Mintz, G. R. and Gelbard, M. K: Humoral immune responses in Peyronie's disease patients receiving clos tridial collagenase therapy. J. Uro!., 135: 641,1986. 6. Hueston, J. T.: Enzymatic fasciotomy. In: La Maladie. Edited by G. Dupuytren, J. T. Hueston and R. Tubiana. Paris: Expansion Scientifique Francaise, 1984.
Vol. 149, 56-58, January 1993
Copyright © 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
COLLAGENASE VERSUS PLACEBO IN THE TREATMENT OF PEYRONIE'S DISEASE: A DOUBLE-BLIND STUDY MARTIN K. GELBARD, KATHLEEN JAMES, PAMELA RIACH AND FREDERICK DOREY From the Section of Urology, Department of Surgery and Department of Biostatistics, University of California School of Medicine, Los Angeles, California
ABSTRACT
We investigated 49 men with Peyronie's disease in a prospectively randomized piacebo controlled double-blind study, comparing the effects on plaque size and penile deformity of intralesional purified clostridial collagenase and saline placebo. For the group as a whole, treatment out-performed placebo (p <0.007). When patients were analyzed with respect to disease severity, those with lesser deformity responded more favorably to treatment. The absolute angular change in patients respond ing to treatment was small. No significant side effects were noted within a 3-month followup. KEY WORDS: penile erection, penis, penile induration, Clostridium histolyticum collagenase
Peyronie's disease is an idiopathic focal connective tissue disorder that results in regional loss of tunica albuginea com pliance. This may be associated early in its course with painful erections and subsequently with deformity of the erect penis. The evaluation of medical therapy for Peyronie's disease is difficult, based on the variability of this disease. Drug effect is not easily separated from the natural history of Peyronie's disease, which occasionally displays spontaneous resolution.1 Our study is a comparison of the effects of intralesional col lagenase to intralesional saline placebo in patients with Peyronie's disease, conducted in a randomized double-blind format. Clostridial collagenase is a chromatographically purified bac terial enzyme that selectively attacks collagen. This agent has been previously evaluated as a treatment for Peyronie's disease in a pilot study of 31 patients who received 470 to 2,730 units intralesionally at 1 session.2 Within this study group 20 patients showed some improvement in deformity while 13 of the 14 patients with painful erection experienced resolution of pain. Based on these results this study was continued as a phase 1 open trial under United States Food and Drug Administration IND No. 19,973, and involved 99 additional patients. Overall, the therapeutic results were similar to those observed in the pilot study. Our study was established to isolate drug effect from the hydraulic effect of injecting plaques with fluid under pressure, and to clarify what if any direct pharmacological effect exists.
30 to 60 degrees of angular deformity and/or 2 to 4 cm. of palpable plaque in maximal dimension. Category 3 patients were those with greater than 60 degrees of angular deviation and/or greater than 4 cm. of palpable plaque. At the entry evaluation, informed consent was obtained from all patients on a form approved by our human subject protection committee. Each patient in the study, designated as group 1, 2 or 3 based on the aforementioned entry evaluation received a unique study number on the day of treatment. The nurse study administrator then provided a prescription for collagenase study material to each patient, which was labeled with the study number, severity category and human subject protection committee number. These prescriptions were taken by the patient to our hospital pharmacy. The outpatient pharmacist was responsible for using the study number, severity category and randomization list provided by the department of biosta tistics to randomize patients in blocks of 10 within each severity category to either treatment or control arms. The pharmacist prepared 2,000 advance biofactor units of purified clostridial collagenase (nucleolysin) in 0.5 cc of a 0.9 sodium chloride diluent containing 2 mM. calcium chloride for patients random ized to treatment. Patients randomized to placebo received the same volume of diluent only. Category 1 patients had 3 such aliquots prepared (6,000 units in the treatment group), category 2 patients had 5 aliquots prepared (10,000 units in the treat ment group) and category 3 patients received 7 aliquots (14,000 units in the treatment group). These vials were then delivered back to the nurse study administrator, who drew each vial up for injection in a separate 1 cc tuberculin syringe with a unitary 25 gauge needle. Diluent alone could not be distinguished by appearance from diluent with dissolved collagenase. The total cumulative dose in patients randomized to treat ment was 6,000 units for category 1, 10,000 units for category 2 and 14,000 units for category 3. Patients randomized to the placebo or control arm received a total of 1.5 cc intralesionally in category 1, 2.5 cc sterile saline intralesionally in category 2 and 3.5 cc sterile saline diluent intralesionally in category 3. The anesthetic used was intracorporeal lidocaine. This was established by insufflation of the corpora using 0.25% plain lidocaine during atraumatic clamp occlusion of the penile base for 6 minutes. Patients were instructed to avoid intercourse for 2 weeks following treatment, and were seen 3 times for posttreatment evaluation (1 week, 1 month and 3 months). Adverse responses were recorded whenever reported. Subjective evaluation was documented on a symptom survey, global assessment of sexual function (a questionnaire), which was recorded at 1 month and 3 months on preprinted forms. Objective evaluation of plaque
MATERIALS AND METHODS
Between November 1987 and January 1989, 49 men 28 to 66 years old were entered in a prospective randomized parallel double-blind study with a crossover retreatment arm. This study was approved and monitored by our human subject protection committee. Entry criteria required that patients had the diagnosis of Peyronie's disease, stable or progressive, for at least 3 months. Patients with coagulopathy or significant erec tile deficit were excluded from the study. Entry evaluation was conducted before treatment, and in cluded the history, physical examination, laboratory screening with blood count and chemistry panel, and vacuum photogra phy of erectile deformity. Patients were stratified into 3 groups based on disease severity, using caliper measurement of plaque size, and the degree of deformity present during vacuum cham ber photography.3 A modification of the Kelami system for disease severity was used.4 Category 1 patients were character ized as those with a bend of 30 degrees or less, and/or palpable plaque less than 2 cm. in extent. Category 2 patients displayed Accepted for publication June 19,1992.
56
57
COLLAGENASE VERSUS PLACEBO IN TREATMENT OF PEYRONIE'S DISEASE
size, plaque extent, number and tenderness as well as bending was recorded at 1 week, 1 month and 3 months. Vacuum induced erectile photographs were taken 3 months after treat ment. The blood count and chemistry panels obtained at entry were redrawn at the l-week followup visit. The pretreatment and 3-month subjective responses of the patient were compared to identify those reporting benefit. If the reported improvement could be documented on the serial plaque measurements or photography, patient outcome was deemed positive. When no significant benefit was reported or if subjective and objective findings did not demonstrate a consistent pattern the outcome was deemed negative. Patients who experienced unsatisfactory or insufficient improvement were permitted to request a code break at 3 months. As a required prerequisite for breaking the code, all forms docu menting patient outcome had to be completed. If the code break demonstrated they had received placebo, they could elect to be treated with open label collagenase using the doses established previously. All patients subsequently requested a code break at 3 months, even those who demonstrated positive response. A total of 23 patients was found retrospectively to have been randomized to placebo and these patients all requested reinjection with colla genase. The responses of the patients receiving open label collagenase were assessed at 3 months after reinjection and they are listed separately. Patient outcome (positive or negative) in the treatment group was then compared to patient outcome in the control group for the study as a whole and within each of the 3 categories of disease severity. The differences obtained in these comparisons were tested for significance with Fisher's exact test. To estab lish that the different groups were comparable in a meaningful manner, treatment and control populations were studied with respect to age, disease duration, prior treatment and disease severity. This comparison failed to show any significant bias of either the treatment or placebo groups. RESULTS
The protocol for this study contained 6 patient evaluation forms: 1) admission criteria and demographic screen, 2) disease pattern, including history and symptoms of Peyronie's disease, 3) general medical history and medications, 4) parameters of disease severity, including plaque measurement and photogra phy, 5) laboratory evaluation and 6) patient questionnaire. The ability of the patient to provide this information in detail resulted in a considerable amount of data to correlate, since these forms were filled out initially, and at 1 week, 1 month and 3 months after treatment. For purposes of providing mean ingful clinical statistics, the data reported on these forms and evaluations needed to be simplified and condensed. We needed to decide whether each individual patient experienced benefit. Patients were only reported as positive responders if the ex amination and photographs confirmed the subjective responses indicating improvement (see figure). Patient outcome in the treatment group was compared to outcome in the placebo group in 4 different subsets of patients: all patients in categories 1 to 3 and the group of patients as a whole (see table). As described previously, plaque and penile angular measurement was used to divide the 49 patients into 3 severity groups. Category 1 contained 7 patients, category 2 contained 24 patients and category 3 contained 18 patients. Within category 1, 3 patients received treatment and 4 re ceived placebo. All 3 treatment patients experienced positive response with no patients in the treatment group failing to respond. Within the placebo group 1 patient experienced a positive response while 3 experienced no response. There was no statistical significance to the comparison between treatment and placebo groups in category 1, with a p value equaling 0.14. In category 2, 11 patients received treatment and 13 received placebo. Of the 11 patients receiving treatment 4 (36%) expe-
Patient in category 3 receiving 14,000 units of collagenase intrale sionally. A, before treatment. B, after treatment. Angular improvement is 15 to 20 degrees.
Category Overall: Treatment Placebo Category
1:
Treatment Placebo Category
2:
Treatment Placebo Category
3:
Treatment Placebo Reinjection (unblinded)
N o. Pts.
49 22 27 7 3 4 24 11 13 18 8 10 23
Pos. Response No
Difference
(%)
(p value)
No.
No.
8 (36) 1 (4)
14 (64) 26 (96)
<0.007
3 (100) 1 (25)
0 3 (75)
0.14
4 (36) 0
7 (64) 13 (100)
0.03
1 (13) 0 13 (56)
7 (87) 10 (100) 10 (44)
0.4 Not available
rienced a positive response and 7 (64%) experienced no re sponse. None of the placebo group experienced a positive re sponse. The difference between placebo and treatment groups in category 2 was significant at the p equals 0.03 level. Within category 3, 8 patients received treatment and 10 received pla cebo. Positive response was noted in 1 of the 8 patients receiving treatment (13%), while 7 (87%) failed to respond. There were
58
GELBARD AND ASSOCIATES
no positive responders in the placebo group. Statistical analysis did not demonstrate any significance between the response of the treatment and placebo groups in category 3. For the group as a whole, 22 patients received treatment and 27 received placebo. Positive responses were noted in 8 of the treatment group (36%), and in 1 of the placebo group (4%). For the study as a whole the response to collagenase exceeded that of placebo (p <0.007, Fisher's exact test). After the 3-month posttreatment evaluation in each patient had been completed, and the outcome was designated as posi tive or negative, the patients were allowed to request a code break. As would be expected, all patients exercised the code break option, which revealed that 27 of the 49 patients initially received placebo. Of these 27 patients 23 subsequently re quested reinjection, with 1 patient refusing reinjection and 3 undergoing surgery. The retreatment arm of the study was done for ethical reasons, since patients were generally not willing to enter a double-blind placebo controlled study if they were not assured that at some point they would receive the test agent. The results of this arm were not obtained in a blind fashion. Open label collagenase was used for reinjection and of the 23 patients retreated 13 (56%) responded positively. No adverse responses or allergic reactions5 occurred in rela tion to the injections. Laboratory studies done at entry and 1 week after injection showed no significant changes. One patient experienced a small tear of the tunica 3 weeks following injec tion, which was felt as a popping sensation during intercourse followed by a small ecchymosis noted after intercourse. The event did not cause detumescence and it occurred in a category 3 patient who was later determined to have collagenase. The condition was treated conservatively and resolved. Tenderness at the injection site was noted by most patients. This finding was observed in those receiving placebo as frequently as in those receiving collagenase. Within the 3-month followup no patient experienced progression or worsening of any parameter of the disease (pain, bending or ability for intercourse).
DISCUSSION
Followup in this study was deliberately short to separate drug-related improvement from spontaneous change in disease severity. Spontaneous resolution occasionally in patients with Peyronie's disease occurs during an interval of years, so obser vation of shorter term variation in disease severity should help to distinguish drug effects from spontaneous changes. Within this short-term period of observation the comparison of treat ment to control in effecting change in these patients should be significant, and reflect drug activity against the contracture responsible for most features of this disorder. The presence of change during a short period of observation, and the dose response relationship seen in the phase 1 open trial suggest that the improvement seen in some patients treated with collagenase is drug-related. Comparison of the effect of collagenase to placebo in our double-blind protocol confirms the ability of intralesional collagenase to improve some patients with Peyronie's disease. This conclusion can be drawn from the results of the study group as a whole, in which the treatment group response exceeded that of placebo (p <0.007). Other clinical factors have a role in analysis of the separate severity groups. It appeared that patients with minimal disease severity (category 1) were likely to respond to collagenase. The
small amounts of plaque and the angular deformity of these patients increased the margin of error in evaluating them; changes in parameters were slight enough to be produced by measurement error. Consequently, the only positive placebo response was recorded in this category. This fact, in association with the small number of patients, eliminated statistical signif icance to the difference between treatment and placebo groups in this category. Four patients in category 2 responded to collagenase, while no responses were observed in 13 patients with the same severity receiving placebo. The p value of 0.03 for this difference conferred moderate statistical significance. Although patients with severe disease (category 3) failed to respond to placebo, only 1 of 8 receiving collagenase responded. There was no statistically significant difference between responses in the treatment and placebo groups for these patients. In examining the overall data, it appears that the less scarring the patient had, the more likely he was to respond to collagen ase. Responses to the drug were noted in 100% of patients in category 1, 36% of those in category 2, and only 13% in category 3. This observation is consistent with the previously described dose-response relationship. Even though the dose of collagenase was increased for patients with more plaque, it seems that patients with severe deformity simply have too much collagen substrate for the enzyme to denature effectively. In the face of massive contracture, even considerable volumes of enzymatic collagenolysis appear unable to cause clinically apparent im provement in overall deformity. Enzymatic lysis of fibrous contractures is not without pre cedent. Good results have been obtained with enzymatic lysis of Dupuytren's contractures in patients who are not surgical candidates.6 Injection of these contractures by an enzyme mix ture is followed by forced hyperextension of the involved digit, then fixation in plaster. This sequence results in controlled rupture of the contracture and has produced reasonably good results in a small series. This technique is not widely accepted, however, and there are material differences between these patients and ours with a contracture of the tunica albuginea. Perhaps the most important conclusions regarding collagen ase can be drawn from review of the patient photographs. Improvement in the angulation of those patients experiencing a positive response was generally slight. The maximal angular improvement observed ranged from 15 to 20 degrees. This result produced acceptable clinical improvement only in category 1 patients. In those patients with more curvature the change produced was detectable but not clinically significant. REFERENCES 1. Gelbard, M. K, Dorey, F. and James, K: The natural history of Peyronie's disease. J. Uro!., 144: 1376,1990. 2. Gelbard, M. K, Lindner, A. and Kaufman, J. J.: The use of collagenase in the treatment of Peyronie's disease. J. Uro!., 134: 28,1985. 3. Gelbard, M. K: Controlled vacuum chamber for standardized pho tographic documentation of penile erectile deformity. Urology, 36: 367,1990. 4. Kelami, A.: Classification of congenital and acquired penile devia tion. Uro!. Int., 38: 229,1983. 5. Hamilton, R. G., Mintz, G. R. and Gelbard, M. K: Humoral immune responses in Peyronie's disease patients receiving clos tridial collagenase therapy. J. Uro!., 135: 641,1986. 6. Hueston, J. T.: Enzymatic fasciotomy. In: La Maladie. Edited by G. Dupuytren, J. T. Hueston and R. Tubiana. Paris: Expansion Scientifique Francaise, 1984.