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Dose-response studies of intracavernous injection therapy with alprostadil in Asian and Australian men with erectile dysfunction
CURRENT THERAPEUTIC RESEARCH@ VOL. 57, NO. 1, JANUARY
1996
DOSE-RESPONSE STUDIES OF INTRACAVERNOUS INJECTION THERAPY WITH ALPROSTADIL IN ASIAN AND AUSTRALIAN MEN WITH ERECTILE DYSFUNCTION ROGER J. GARCEAU,’
IRENE X. ZHANG,2 AND LIWEI JEN’
‘Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, and 2Phnrmacia & Upjohn, Inc., Regional Biostatistics and Data Management, Don Mills, Ontario, Canada
ABSTRACT
This is the first report on dose-response results with alprostadil (Caverjectc Sterile Powder), a formulation of prostaglandin E, (PGE,), for the treatment of erectile dysfunction (ED) in 365 Asian and Australian men, 21 to 75 years of age (mean, 48.9 years) with ED from 2 months’ to 35 years’ duration (mean, 3.8 years). Seven Asian centers conducted an open-label, dose-escalation study starting with 2.5- or 5-pg doses titrated up to a maximum of 40 or 60 pg. Two Australian centers used a double-masked, placebo-controlled, crossover protocol that randomized patients to 2.5-, 5-, lo-, or 20-yg dose levels of alprostadil in three formulations (Caverject Aqueous Injection, Caverject Sterile Powder, or Prostin VRe), with dose determined by the dose they had used at home. For all centers combined, 74.0% of patients (270/365) had optimal erectile responses (defined as full erection sufficient to achieve vaginal penetration and lasting from 30 to 60 minutes). The Asian optimal response was 83.0% (2441294). Optimal erectile response was achieved in 66.7% of Australian men (10115) using 20 pg of alprostadil sterile powder. Low doses (2.5 and 5 pg) produced optimal erectile response in 25.4% of all patients. No clear correlations were found between erectile response and country of origin, age, or duration of ED. In patients with psychogenic ED, 95% achieved optimal erectile response (mean dose, 11.5 pg) and 100% of patients with ED of neurogenic origin had an optimal erectile response (mean dose, 15.3 pg). Thirty-nine (10.7%) of 365 patients reported 53 episodes of penile pain or pain at the injection site; 1 patient discontinued the study. No significant differences were found when comparing erectile response between Australian and Asian men and those reported for men in European and North American countries. Low starting doses (2.5 to 5 pg) should be used and titrated slowly upward to determine each patient’s optimal effective response, regardless of the patient’s ethnic origin or age or the duration of ED. INTRODUCTION After
the intracavernous
Address correspondence MI 49001
injection
of vasoactive
to: Roger J. Garceau, Phannacia
agents
to treat
erectile
& Upjohn, Inc., 7000 Portage Road, Kalamazoo,
Received forpublication on October 19, 1995. Printed in the U.S.A. Reproduction
in whole or part is not permitted.
50
0011-393x/96/$3.50
R. J. GARCEAU
ET AL.
dysfunction (ED) was introduced in 1982,1Y2the diagnosis and treatment of male impotence developed rapidly. Intracavernous injection therapy is now recognized as the gold standard of treatment for patients with ED,3 with prostaglandin E, (PGEi) as the drug of choice. The use of PGE, to treat male impotence was first reported by Ishi et al4 in 1986. Currently, PGEi is considered to be comparable or superior to other intracavernous agents in its effectiveness for treatment of ED.5 PGEi, usually in the form of alprostadil, is also associated with a lower incidence of serious side effects, such as priapism, and other local penile complications.6 Governmental approval in Asian and Pacific countries for intracavernous injection therapy was facilitated in 1995 when the US Food and Drug Administration approved The Upjohn Company’s (Kalamazoo, Michigan) alprostadil sterile powder formulation (Caverject? Sterile Powder) for the treatment of ED. This formulation of alprostadil currently used for clinical and investigative purposes is a freeze-dried sterile powder (20 pg/vial), a form that was designed to facilitate sterile injections, eliminate inadvertent overdoses, and improve the convenience of administration. In the 13 years since Virag’s 1982 report,’ a number of clinical trials in the United States and Europe have reported on the success of vasoactive agents, and of PGE, in particular, for treating men with ED from European and North American countries (0. I. Linet, MD, et al, unpublished data, 1995X6s7However, few clinical reports of any size have yet been published on the efficacy of PGE, for male impotence in Asian and Australian countries, despite the promising results of the 1986 report by Ishi et al4 on the use of PGE, in Japanese men. Some Australian clinical experience with PGE, has been reported,**’ and several small Asian/ Oriental studies have been published,“-i2 but there are no published reports of any size for the combined Asian and Australian regions. The primary purpose of this article is to report the combined results of multicenter studies using alprostadil to treat ED in impotent men from Asian and Australian countries. In addition, we compared results between countries for any correlation between dose-response effect and country of origin, cause, age, duration of ED, and other variables. The Asian centers followed a dose titration-response protocol designed to measure the lowest dose of alprostadil that would achieve an optimal erectile response (defined as a full erection sufficient to achieve vaginal penetration and lasting from 30 to 60 minutes), starting with doses as low as 2.5 or 5 pg. The Australian centers were part of a multicenter study in which patients were randomized to 1 of 4 dose levels of alprostadil (2.5, 5, 10, or 20 pg) or placebo as determined by the previous dose they had used at home. This article is the first to report combined dose-response results for alprostadil across Asia and the South Pacific. 51
INTRACAVERNOUS
ALPROSTADIL
IN ERECTILE
DYSFUNCTION
PATIENTS AND METHODS
Patient Population A total of 365 men, 21 to 75 years of age (mean, 48.9 years), who had had ED from 2 months to 35 years (mean, 3.8 years) were enrolled in the study (Table I). The most common cause of ED was vascular (venogenic, arteriogenic, or vasculogenic) (41.1%) or psychogenic (27.7%). The seven countries included two sites in Australia and Korea, and one each in China, Taiwan, Thailand, Indonesia, and the Philippines (Table II). After signing an informed consent form, all patients had a physical examination (including vital signs, bulbocavernous reflex, cremasteric reflex, and sphincter tone) and laboratory evaluations (complete blood cell count and differential, urinalysis, and Venereal Disease Research Laboratories antigen test for syphilis). The medical history included the nature and duration of ED, as well as smoking habits. The probable cause of ED was also determined as per the physician’s routine practice. Patients were excluded if they had a history of or propensity for priapism or an underlying disease such as sickle cell anemia or trait, untreated endocrine disorders, cavernosal fibrosis or anatomical deformation of the penis, Peyronie’s disease, or a thyroid condition that could cause ED. Patients were also excluded if they had a recent onset of acute illness (eg, myocardial infarction, stroke, or arrhythmias), a history of sexually trans-
Table I. Demographic and pretreatment characteristics for 365 Asian and Australian men with erectile dysfunction (ED).
Age(~1 Mean
48.9
21-75
RaF$!!) p&Oriental F$iO
Hei ht (cm) 4 ean Bo??iight d ean Duzi;
169.3 120-200
(kg)
71.1 44.5-120.9
of ED (y)
3.8 0.2-35
Vasculogen‘ic Psychogevic pur;genlc Other
52
R. J. GARCEAU
ET AL
Table II. Research centers participating in the study.
Australian Centers
Man Centers
Reproductive Medicine Research Institute Nedlands 6009, Western Australia, Australia
Chulalongkorn University Hospital Bangkok, Thailand
Australian Centre for Sexual Health Potts Point, New South Wales, Australia
Beijing Medical University Beijing, P.R. of China Chang Gun Memorial Hospital Kweishan, Baoyuan Taiwan (R.O.C.) The Stone Center UPCM-PGH Medical Center Manila, Philippines Dr. Soetomo, Hospital Alrlangga Untverslty Surabaya, Indonesia Young Dong Severance Hospital Seoul, Korea Chung Ang University Seoul, Korea
mitted diseases within the preceding 6 months, or were taking other hormonal or investigational medications. One difference between the study sites was that Australian patients were all previous users of alprostadil at home, whereas the Asian patients were not allowed in the study if they had previously used intracavernosal injections for ED treatment. However, the Australian patients were not permitted to use alprostadil at home for at least 3 weeks before the study started. Studg Design and Dosage Regimens Asian Countries The six Asian countries followed an open-label, dose-escalation protocol that started with a 2.5- or 5-pg dose; low doses have been widely reported in clinical trials to have minimal or no side effects.13 This starting dose was then titrated upward to lo-, 15-, 20-, 30-, or 40-pg doses (in one protocol the maximum dose was 60 Fg) until the patient reached his optimal erectile response. Nonresponders and partial responders could receive the next higher dose up to the maximum 40- or 6Oq.g dose, as determined by the investigator. If the patient failed to achieve an optimal response at the 40- or 6Oqg dose, no additional higher doses were administered. Nonresponders were observed for at least 60 minutes after injection. Alprostadil sterile powder was the formulation used at all Asian sites. When reconstituted with 1 mL of sterile water, it contains 20 Fg/mL of 53
INTRACAVERNOUS
ALPROSTADIL
IN ERECTILE
DYSFUNCTION
alprostadil sterile powder, 172 mg/mL of lactose, and 47 pg/mL of sodium citrate with a pH of 4 to 6. Australian
Centers
These sites were part of a multicenter, double-masked, placebocontrolled, randomized, crossover protocol. Patients were all previous users of alprostadil and were randomized to receive 1 of 4 dose levels of alprostadil(2.5, 510, or 20 Fg) or placebo as determined by the dose they had used at home. They received one injection of each of three formulations of alprostadil (aqueous injection, sterile powder, or Prostin VR@ [The Upjohn Company]) or of placebo at the assigned formulation and dose for a total of three doses. If the home dose of alprostadil was ~10 Fg, the patient was randomized to receive either placebo or 2.5 or 5 pg of alprostadil. If the patient’s home dose was ~10 kg of alprostadil, he was randomized to placebo or to 10 or 20 pg of alprostadil treatment. Efficacy Measures All centers had similar efficacy end points: (1) optimal erectile response, (2) latency of erection, (3) duration of erection, (4) time to complete detumescence, and (5) the patient’s and physician’s evaluations of erectile response. Optimal dose response was defined as the patient’s ability to achieve a full erection sufficient to permit vaginal penetration and lasting from 30 to 60 minutes. All patients were followed up by the same trained observer for the duration of the 2-hour study period. All patients were followed up until they had achieved complete detumescence. The patient’s subjective evaluation of erectile response was also recorded; at the Asian sites, a three-point scale was used (full, partial, or absent), and at the Australian center, a five-point scale ranging from 0 (“not effective”) to 4 (“very effective”) was used. The differences between the Asian sites and the Australian centers were in the methods used to measure the efficacy end points. At the Asian sites erectile response was determined by the same trained observer to be absent, partial, or full at lo-minute intervals after an injection.
Safe tg Measures Side effects of the injection were recorded at the end of the 2-hour study period. The patient reported any side effects; pain was rated as mild, moderate, or severe. The patient was asked about the potential impact of the pain on the feasibility of intercourse. Patients were also evaluated for any medical events, and vital signs were recorded at injection baseline and thereafter at 5, 15, 60, and 120 minutes after injection. 54
R. J. GARCEAU
ET AL
Statistical Analysis The safety analysis was based on an “intent to treat” approach. Categorical variables (eg, race> were summarized by using frequency counts. Continuous variables (eg, age) were summarized by using the mean, standard deviation of the mean, and range. Efficacy analysis included table of counts and percentages of responders and was done in total and for each country and protocol individually. The proportion of erections was also displayed for each dose by setting etiology, along with mean duration and latency. RESULTS
Combined Asian and Australian
Results
Table III shows the optimal erectile-response results for the Asian and Australian sites by dose level and across all dose levels, from 2.5 kg to 60 kg. Optimal erectile results for the six Asian countries (244/294, 83.0%) were based on the clinical definition of full erectile response. Results for Australian center patients receiving alprostadil sterile powder (26/54, 48.1%) were based on clinical evaluation of full erectile response at all dosage levels. Doses as low as 2.5 and 5 p,g produced optimal responses for 25.4% (82/323). In the Asian centers, 41.8% of all patients (123/294) achieved an optimal erectile response at the lo-kg dose level. In the Australian centers, 40.0% (4/10) responded at the lo-pg level by clinical evaluation. By the 20-pg dose level, 66.7% of men (196/294) in the Asian centers were able to achieve an optimal response. The Australian data showed that 66.7% of men (lo/151 given a 20-p,g dose responded. In the Asian studies, an additional 16.3% of patients (48/294) were able to achieve an optimal erection when given doses higher than 20 pg. The cumulative response to alprostadil is shown in the figure. Table III. Optimal erectile-response effect across different dose levels for Asian and Australian men with erectile dysfunction (ED).
Australian Centers Oosebe)
Asian/Oriental Centers (n = 294)
n/N
%
2/l 3
15.4
‘Z 10/15
Not given Not given Not given Not given
ii:: 66.7
*Only Chinese, Taiwan, and Thailand sites (150 patients). +Only Philippines, Korean, and Indonesian sites (144 patients). 55
INTRACAVERNOUS
ALPROSTADIL
IN ERECTILE
DYSFUNCTION
Clinical evaluation 100
80
ul
E .Xi a 6 z 0” k a
60 40
m Australian - -Asian
20
2.5
5
10
15 Optimal
Figure.
20 Dose
30
40
60
(pg)
Percentage of patients demonstrating optimal response and dose at which optimal response occurred. Asian data are cumulative.
Cause of erectile dysfunction was a significant factor in determination of optimal erectile-response dosage. The mean optimal dose for vasculogenie patients was 19.1 Fg; for psychogenic patients, 11.5 pg; for neurogenie patients, 15.3 pg; and for patients with mixed etiology, 16.4 pg. The age of the patient had no effect on the ability to achieve an optimal erection. No correlation was seen between duration of erectile dysfunction (< 1 year, 1 to 3 years, ~3 years) and either optimal dose or percentage of responders. Table IV displays the overall regional results of mean erectile response at the optimal dose for the secondary end points of duration, latency, and time to complete detumescence. For all patients who reached their optimal erectile-response effect in the physician’s office, the full erection lasted a mean of 44.8 minutes; at the Asian centers the total duration of erection was 85.3 minutes, with a mean latency of 10.7 minutes.
Table IV. Mean erectile response variables
at optimal dose for Asian and Australian
Ereclile Response Variables (min)
Mean( *SD)
Duration of erection (n = 294)
Latency of erection (n = 244)’ Time to complete detumescence (n = 244)* *Australian centers not included. 56
44.8 212.7 10.66 k-2.78 85.3 I k22.5 I
men.
Il. J. GARCEAU
ET AL
Regional Results: Correlation Between Erect&-Response of Disease
and Origin
Optimal erectile-response effects for all Asian and Australian centers were compared for regional correlations with ethnic or country origin, cause, age, or duration of ED. There were no clear correlations between erectile-response effect and country of origin, age, or duration of ED. For all causes of ED, 67% of patients achieved optimal responses by the 20-pg dose; however, significantly more patients with ED of psychogenic and neurogenic origin responded at lower doses than did patients with ED of other origins. Erectile-response patterns were more variable for vascular causes, with responses spread across all doses up to at least 40 kg. When evaluating response by country (Table V), there appears to be a significant difference in percentage of patients responding, as well as in mean optimal dose. When adjusted for etiologic mix in each country, this difference is no longer apparent; however, the small numbers of patients with ED of various origins in certain countries make this analysis difficult. China, Korea, and Taiwan combined showed an overall response rate of 72.9% with a mean dose of 16.25 pg, which is similar to the overall mean optimal dose of 15.7 Fg for all Asian countries combined. Similar results were seen with various combinations, with no clear differences demonstrated for variables other than cause.
Safety In the 365 patients receiving alprostadil, 45 (12.3%) reported episodes of possible drug-related events. Thirty-nine (10.7%) patients reported 53 episodes (18 mild, 20 moderate, 15 severe> of penile pain or pain at the injection site, and one patient receiving Prostin VR discontinued the study as a result. No episode of pain was considered serious, and all patients recovered with no residual effects. Cold sweating (four episodes), the other
Table V. Response by country. Optimal Dose Reached n/N Australia China $ioesia Philippines
% FE’ loo:o ~~:~ 93.3 71.7
Thailand Taiwan *At 20 pg. 57
Mean Optimal Dose (~0) Not,re,r$rted
1~~“3: 13:88
:::1:
INTRACAVERNOUS
ALPROSTADIL
IN ERECTILE
DYSFUNCTION
possible drug-related event, was reported by two patients. Penile pain, pain at the injection site, and cold sweating did not appear to be dose related. Most of the patients with penile pain or pain at the injection site received additional doses without any further pain. There were no reports of penile hematoma, penile abnormalities, or abnormal clinical or laboratory results. DISCUSSION
This article is the first to present data on cross-country results from controlled multicenter studies on the use of alprostadil to treat ED in impotent men in the Asian and Australian regions. Although Ishi et al4 were the first to describe the use of PGE, for the treatment of ED in Japanese men, there have been few subsequent Asian studies since 1986, and none have followed a dose titration-response protocol.11,12To date, only Chiang et all2 have evaluated self-injection therapy in 51 patients treated for an average of 11.8 months with either PGEi (30 men) or papaverine (21 men). The starting dose of PGE, was 20 p,g, with the average effective dose ranging from 5 to 40 p,g; however, 20 p,g was the most effective dose for most patients (76.7%). In the other published Asian studies to date, the usual starting dose of PGE, was 20 pg. Perhaps the 1986 report by Ishi et a1,4 which described their success in treating ED using a 20-p,g dose, established a dosage tradition that has been followed since that time by Asian investigators. In Australian clinical studies, on the other hand, doses as low as 1 to 2 pg have been used to produce erections in patients with spinal cord injuries,5”4 and 5-p,g doses have been used to test large groups of clinic patients with ED.8l15 Recent dose-titration studies in Europe and the United States have also reported that considerably lower doses of alprostadil may be as effective as higher doses in providing satisfactory erectile responses for men with ED. The report by Linet et al (unpublished data, 1995) of six multicenter studies done using a similar dose-titration method in the United States on the use of the alprostadil sterile powder formulation for the treatment of ED observed significant dose-response relationships for doses of 2.5 to 20 pg. In the Asian studies as well, doses as low as 2.5 and 5 pg produced optimal erectile responses in 25% (82/323) of all Asian and Australian patients. By the 20-pg dose, two thirds (222/338) of all patients had achieved an optimal erectile-response effect. These results also support the results of comparable controlled studies on alprostadil for treatment of men with ED in the United States? and in Europe. 6,7,17In all these studies, significant dose-response relationships were found for satisfactory erectile response, latency, duration of erection, and other variables. The percentage of patients responding to alprostadil 58
R. J. GARCEAU
ET AL.
varied by dose and by cause of ED, but in all studies the percentage of dose responders ranged from 63.6% at a 1Oq.g dose6 to 85% at a 2Oq.g dose.17 In our combined regional studies, 63.8% (2221348) of patients responded effectively to doses up to 20 pg of alprostadil. Based on these data, there are no significant differences in dose response between Asian and Australian men and men in European and North American countries. Furthermore, when we compared dose responses, adjusting for origin of ED, for correlations with separate countries within the Asian and Australian regions, we found no significant differences between countries or between the centers. Thus ethnic or country origin did not appear to be an important factor for determining an effective dosage level of alprostadil to use in treating ED in men from any country or area of the world. Although the combined regional data found no correlations between dose response and ethnic origin, there was a correlation with ED cause, particularly for ED of psychogenic or neurogenic origin. Significantly more patients with ED of psychogenic origin responded (95%) and this response occurred at lower doses than in patients with ED of other origins (mean optical dose, 11.5 pg). All Asian patients with ED of neurogenic origin were able to achieve an optimal response, with one third responding to the 2.5~Fg dose; the mean optimal dose for these patients was 15.3 pg. Again, our results mirror similar results reported in other studies in Europe5 and North America (0. I. Linet, M.D., unpublished data, 1995 and T. F. Gana, M.D., et al, unpublished data, 1995) for dose responses to alprostadil for patients with ED of psychogenic and neurogenic origin. CONCLUSION
Intracavernous injection therapy with alprostadil sterile powder offers safe and effective treatment of ED in Asian and Australian men with impotence of various origins. Side effects were neither serious nor did they interfere with patients’ ability to achieve an optimal erectile response. The most common side effect was penile pain, usually mild to moderate, which did not appear to be dose related or to occur at all injections for a given patient. Our results are similar to those of comparable controlled studies on alprostadil for men with ED in the United States and Europe. Optimal doses for Asian and Australian men were similar to those for men from European and North American countries. Ethnicity or country of origin is therefore not important for determining an effective dosage level for alprostadil in treating men with ED from any country or area of the world. Our combined regional data also support the use of low starting doses (2.5 to 5 p,g) that are individualized and carefully titrated to determine each patient’s optimal effective response. Doses between 2.5 and 20 Kg should produce satisfactory results for the majority of patients. 59
INTRACAVERNOUS
ALPROSTADIL
IN ERECTILE
DYSFUNCTION
Acknowledgments The following individuals are gratefully acknowledged: Dr. Edward Keogh, Dr. Chris McMahon, and Ms. Carolyn Earle, Australia; Dr. ZhaoYing Xue, China; Dr. Arif Adimoelja and Dr. Doddy Soebadi, Indonesia; Dr. Sae-Chul Kim, Korea; Dr. Telesforo Gana, Philippines; Dr. Hyung Ki Choi, and Dr. Charles C. J. Wu, Taiwan; Dr. Apichat Konganand, Thailand. References:
1. Virag R. Intracavernous injection of papervine for erectile failure. Lancet. I982;2:938. Letter. 2. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. NEJM. 1989;321:1648-1659. 3. Lue TF, Goldstein I. Introduction. In: Goldstein I, Lue TF, eds. The Role of Alprostadil
in the Diagnosis and Treatment of Erect& Dysfunction. Proceedings of a Symposium: Aug 34, 1993. Brook Lodge, Kalamaeao, Michigan. Princeton, NJ: Excerpta Medica; 1993:
l-2. 4. Ishi N, Watanabe H, Irisawa C, et al. Studies on male sexual impotence report 18: Therapeutic trial with prostaglandin E, for organic impotence. J Jpn Sot Ural. 1986;77: 954-962. 5. Linet 01, Neff LL. Intracavernous prostaglandin E, in erectile dysfunction. Clin Znuestig. 1994;72:139-149. 6. Porst H. Experience with alprostadil in diagnosis and therapy in Germany. In: Goldstein I, Lue TF, eds. The Role of Alprostadil in the Diagnosis and Treatment of Erectile Dysfunction. Proceedings of a Symposium: Aug 34,1993. gan. Princeton, NJ: Excerpta Medica; 1993:142-154.
Brook Lodge, Kalamazoo,
Michi-
7. Stack1 W, Hasun R, Marberger M. Intracavernous injection of prostaglandin E, in impotent men. J Ural. 1988;140:66-68. 8. Keogh EJ, Earle CM, Chew KK, et al. Experience with self-injection in Australia. In: Goldstein I, Lue TF, eds. The Role of Alprostadil in the Diagnosis and Treatment of Erectile Dysfunction. Proceedings of a Symposium: Aug 34, 1993. Brook Lodge, Kalamazoo, Michigan. Princeton, NJ: Excerpta Medica; 1993:155-166.
9. McMahom CG. Comparison of erectile response to differing doses of prostaglandin PGEi in an attempt to standardize pharmacological diagnosis of impotence. J Ural. 1992;147: 265A. Abstract. 10. Chen J-K, Hwang TI, Yang C-R. Comparison of effects following the intracorporeal injection of papaverine and prostaglandin E,. Br J Ural. 1992;69:404-407. 11. Hwang TI, Yang C-R, Wang S-J, et al. Impotence evaluated by the use of prostaglandin E,. J Ural. 1989;141:1357-1359. 12. Chiang H-S, Wen T-C, Wu C-C, Chiang W-H. Intracavemous self-injection therapy for the treatment of erectile dysfunction. J Formos Med Assoc. 1992;91:898-901. 13. Lee LM, Stevenson WD, Szasa G. Prostaglandin E, versus phentolamine/papaverine for 60
Ft. .I. GARCEAU
ET AL
the treatment of erectile impotence: A double-blind comparison. J Ural. 1989;141:549550. 14. Earle CM, Keogh EJ, Ker JK, et al. Intracavernosal injection therapy for impotence due to spinal cord injury. ZrztJ Zmpot Res. 1990;23(Suppl 2):297-298. 15. Earle CM, Keogh EJ, Wisnieweki ZS, et al. Prostaglandin E, therapy for impotence: Comparison with papervine. J Ural. 1990;143:57-59. 16. Data on file, The Upjohn Company, Kalamazoo, Michigan, 1995. 17. Schramek P, Waldhaueer M. Dose-dependent effect and side-effect of prostaglandin E, in erectile dysfunction. Br J Clin Phurmacol. 1989;28:567-571.
61
1996
DOSE-RESPONSE STUDIES OF INTRACAVERNOUS INJECTION THERAPY WITH ALPROSTADIL IN ASIAN AND AUSTRALIAN MEN WITH ERECTILE DYSFUNCTION ROGER J. GARCEAU,’
IRENE X. ZHANG,2 AND LIWEI JEN’
‘Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, and 2Phnrmacia & Upjohn, Inc., Regional Biostatistics and Data Management, Don Mills, Ontario, Canada
ABSTRACT
This is the first report on dose-response results with alprostadil (Caverjectc Sterile Powder), a formulation of prostaglandin E, (PGE,), for the treatment of erectile dysfunction (ED) in 365 Asian and Australian men, 21 to 75 years of age (mean, 48.9 years) with ED from 2 months’ to 35 years’ duration (mean, 3.8 years). Seven Asian centers conducted an open-label, dose-escalation study starting with 2.5- or 5-pg doses titrated up to a maximum of 40 or 60 pg. Two Australian centers used a double-masked, placebo-controlled, crossover protocol that randomized patients to 2.5-, 5-, lo-, or 20-yg dose levels of alprostadil in three formulations (Caverject Aqueous Injection, Caverject Sterile Powder, or Prostin VRe), with dose determined by the dose they had used at home. For all centers combined, 74.0% of patients (270/365) had optimal erectile responses (defined as full erection sufficient to achieve vaginal penetration and lasting from 30 to 60 minutes). The Asian optimal response was 83.0% (2441294). Optimal erectile response was achieved in 66.7% of Australian men (10115) using 20 pg of alprostadil sterile powder. Low doses (2.5 and 5 pg) produced optimal erectile response in 25.4% of all patients. No clear correlations were found between erectile response and country of origin, age, or duration of ED. In patients with psychogenic ED, 95% achieved optimal erectile response (mean dose, 11.5 pg) and 100% of patients with ED of neurogenic origin had an optimal erectile response (mean dose, 15.3 pg). Thirty-nine (10.7%) of 365 patients reported 53 episodes of penile pain or pain at the injection site; 1 patient discontinued the study. No significant differences were found when comparing erectile response between Australian and Asian men and those reported for men in European and North American countries. Low starting doses (2.5 to 5 pg) should be used and titrated slowly upward to determine each patient’s optimal effective response, regardless of the patient’s ethnic origin or age or the duration of ED. INTRODUCTION After
the intracavernous
Address correspondence MI 49001
injection
of vasoactive
to: Roger J. Garceau, Phannacia
agents
to treat
erectile
& Upjohn, Inc., 7000 Portage Road, Kalamazoo,
Received forpublication on October 19, 1995. Printed in the U.S.A. Reproduction
in whole or part is not permitted.
50
0011-393x/96/$3.50
R. J. GARCEAU
ET AL.
dysfunction (ED) was introduced in 1982,1Y2the diagnosis and treatment of male impotence developed rapidly. Intracavernous injection therapy is now recognized as the gold standard of treatment for patients with ED,3 with prostaglandin E, (PGEi) as the drug of choice. The use of PGE, to treat male impotence was first reported by Ishi et al4 in 1986. Currently, PGEi is considered to be comparable or superior to other intracavernous agents in its effectiveness for treatment of ED.5 PGEi, usually in the form of alprostadil, is also associated with a lower incidence of serious side effects, such as priapism, and other local penile complications.6 Governmental approval in Asian and Pacific countries for intracavernous injection therapy was facilitated in 1995 when the US Food and Drug Administration approved The Upjohn Company’s (Kalamazoo, Michigan) alprostadil sterile powder formulation (Caverject? Sterile Powder) for the treatment of ED. This formulation of alprostadil currently used for clinical and investigative purposes is a freeze-dried sterile powder (20 pg/vial), a form that was designed to facilitate sterile injections, eliminate inadvertent overdoses, and improve the convenience of administration. In the 13 years since Virag’s 1982 report,’ a number of clinical trials in the United States and Europe have reported on the success of vasoactive agents, and of PGE, in particular, for treating men with ED from European and North American countries (0. I. Linet, MD, et al, unpublished data, 1995X6s7However, few clinical reports of any size have yet been published on the efficacy of PGE, for male impotence in Asian and Australian countries, despite the promising results of the 1986 report by Ishi et al4 on the use of PGE, in Japanese men. Some Australian clinical experience with PGE, has been reported,**’ and several small Asian/ Oriental studies have been published,“-i2 but there are no published reports of any size for the combined Asian and Australian regions. The primary purpose of this article is to report the combined results of multicenter studies using alprostadil to treat ED in impotent men from Asian and Australian countries. In addition, we compared results between countries for any correlation between dose-response effect and country of origin, cause, age, duration of ED, and other variables. The Asian centers followed a dose titration-response protocol designed to measure the lowest dose of alprostadil that would achieve an optimal erectile response (defined as a full erection sufficient to achieve vaginal penetration and lasting from 30 to 60 minutes), starting with doses as low as 2.5 or 5 pg. The Australian centers were part of a multicenter study in which patients were randomized to 1 of 4 dose levels of alprostadil (2.5, 5, 10, or 20 pg) or placebo as determined by the previous dose they had used at home. This article is the first to report combined dose-response results for alprostadil across Asia and the South Pacific. 51
INTRACAVERNOUS
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DYSFUNCTION
PATIENTS AND METHODS
Patient Population A total of 365 men, 21 to 75 years of age (mean, 48.9 years), who had had ED from 2 months to 35 years (mean, 3.8 years) were enrolled in the study (Table I). The most common cause of ED was vascular (venogenic, arteriogenic, or vasculogenic) (41.1%) or psychogenic (27.7%). The seven countries included two sites in Australia and Korea, and one each in China, Taiwan, Thailand, Indonesia, and the Philippines (Table II). After signing an informed consent form, all patients had a physical examination (including vital signs, bulbocavernous reflex, cremasteric reflex, and sphincter tone) and laboratory evaluations (complete blood cell count and differential, urinalysis, and Venereal Disease Research Laboratories antigen test for syphilis). The medical history included the nature and duration of ED, as well as smoking habits. The probable cause of ED was also determined as per the physician’s routine practice. Patients were excluded if they had a history of or propensity for priapism or an underlying disease such as sickle cell anemia or trait, untreated endocrine disorders, cavernosal fibrosis or anatomical deformation of the penis, Peyronie’s disease, or a thyroid condition that could cause ED. Patients were also excluded if they had a recent onset of acute illness (eg, myocardial infarction, stroke, or arrhythmias), a history of sexually trans-
Table I. Demographic and pretreatment characteristics for 365 Asian and Australian men with erectile dysfunction (ED).
Age(~1 Mean
48.9
21-75
RaF$!!) p&Oriental F$iO
Hei ht (cm) 4 ean Bo??iight d ean Duzi;
169.3 120-200
(kg)
71.1 44.5-120.9
of ED (y)
3.8 0.2-35
Vasculogen‘ic Psychogevic pur;genlc Other
52
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ET AL
Table II. Research centers participating in the study.
Australian Centers
Man Centers
Reproductive Medicine Research Institute Nedlands 6009, Western Australia, Australia
Chulalongkorn University Hospital Bangkok, Thailand
Australian Centre for Sexual Health Potts Point, New South Wales, Australia
Beijing Medical University Beijing, P.R. of China Chang Gun Memorial Hospital Kweishan, Baoyuan Taiwan (R.O.C.) The Stone Center UPCM-PGH Medical Center Manila, Philippines Dr. Soetomo, Hospital Alrlangga Untverslty Surabaya, Indonesia Young Dong Severance Hospital Seoul, Korea Chung Ang University Seoul, Korea
mitted diseases within the preceding 6 months, or were taking other hormonal or investigational medications. One difference between the study sites was that Australian patients were all previous users of alprostadil at home, whereas the Asian patients were not allowed in the study if they had previously used intracavernosal injections for ED treatment. However, the Australian patients were not permitted to use alprostadil at home for at least 3 weeks before the study started. Studg Design and Dosage Regimens Asian Countries The six Asian countries followed an open-label, dose-escalation protocol that started with a 2.5- or 5-pg dose; low doses have been widely reported in clinical trials to have minimal or no side effects.13 This starting dose was then titrated upward to lo-, 15-, 20-, 30-, or 40-pg doses (in one protocol the maximum dose was 60 Fg) until the patient reached his optimal erectile response. Nonresponders and partial responders could receive the next higher dose up to the maximum 40- or 6Oq.g dose, as determined by the investigator. If the patient failed to achieve an optimal response at the 40- or 6Oqg dose, no additional higher doses were administered. Nonresponders were observed for at least 60 minutes after injection. Alprostadil sterile powder was the formulation used at all Asian sites. When reconstituted with 1 mL of sterile water, it contains 20 Fg/mL of 53
INTRACAVERNOUS
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alprostadil sterile powder, 172 mg/mL of lactose, and 47 pg/mL of sodium citrate with a pH of 4 to 6. Australian
Centers
These sites were part of a multicenter, double-masked, placebocontrolled, randomized, crossover protocol. Patients were all previous users of alprostadil and were randomized to receive 1 of 4 dose levels of alprostadil(2.5, 510, or 20 Fg) or placebo as determined by the dose they had used at home. They received one injection of each of three formulations of alprostadil (aqueous injection, sterile powder, or Prostin VR@ [The Upjohn Company]) or of placebo at the assigned formulation and dose for a total of three doses. If the home dose of alprostadil was ~10 Fg, the patient was randomized to receive either placebo or 2.5 or 5 pg of alprostadil. If the patient’s home dose was ~10 kg of alprostadil, he was randomized to placebo or to 10 or 20 pg of alprostadil treatment. Efficacy Measures All centers had similar efficacy end points: (1) optimal erectile response, (2) latency of erection, (3) duration of erection, (4) time to complete detumescence, and (5) the patient’s and physician’s evaluations of erectile response. Optimal dose response was defined as the patient’s ability to achieve a full erection sufficient to permit vaginal penetration and lasting from 30 to 60 minutes. All patients were followed up by the same trained observer for the duration of the 2-hour study period. All patients were followed up until they had achieved complete detumescence. The patient’s subjective evaluation of erectile response was also recorded; at the Asian sites, a three-point scale was used (full, partial, or absent), and at the Australian center, a five-point scale ranging from 0 (“not effective”) to 4 (“very effective”) was used. The differences between the Asian sites and the Australian centers were in the methods used to measure the efficacy end points. At the Asian sites erectile response was determined by the same trained observer to be absent, partial, or full at lo-minute intervals after an injection.
Safe tg Measures Side effects of the injection were recorded at the end of the 2-hour study period. The patient reported any side effects; pain was rated as mild, moderate, or severe. The patient was asked about the potential impact of the pain on the feasibility of intercourse. Patients were also evaluated for any medical events, and vital signs were recorded at injection baseline and thereafter at 5, 15, 60, and 120 minutes after injection. 54
R. J. GARCEAU
ET AL
Statistical Analysis The safety analysis was based on an “intent to treat” approach. Categorical variables (eg, race> were summarized by using frequency counts. Continuous variables (eg, age) were summarized by using the mean, standard deviation of the mean, and range. Efficacy analysis included table of counts and percentages of responders and was done in total and for each country and protocol individually. The proportion of erections was also displayed for each dose by setting etiology, along with mean duration and latency. RESULTS
Combined Asian and Australian
Results
Table III shows the optimal erectile-response results for the Asian and Australian sites by dose level and across all dose levels, from 2.5 kg to 60 kg. Optimal erectile results for the six Asian countries (244/294, 83.0%) were based on the clinical definition of full erectile response. Results for Australian center patients receiving alprostadil sterile powder (26/54, 48.1%) were based on clinical evaluation of full erectile response at all dosage levels. Doses as low as 2.5 and 5 p,g produced optimal responses for 25.4% (82/323). In the Asian centers, 41.8% of all patients (123/294) achieved an optimal erectile response at the lo-kg dose level. In the Australian centers, 40.0% (4/10) responded at the lo-pg level by clinical evaluation. By the 20-pg dose level, 66.7% of men (196/294) in the Asian centers were able to achieve an optimal response. The Australian data showed that 66.7% of men (lo/151 given a 20-p,g dose responded. In the Asian studies, an additional 16.3% of patients (48/294) were able to achieve an optimal erection when given doses higher than 20 pg. The cumulative response to alprostadil is shown in the figure. Table III. Optimal erectile-response effect across different dose levels for Asian and Australian men with erectile dysfunction (ED).
Australian Centers Oosebe)
Asian/Oriental Centers (n = 294)
n/N
%
2/l 3
15.4
‘Z 10/15
Not given Not given Not given Not given
ii:: 66.7
*Only Chinese, Taiwan, and Thailand sites (150 patients). +Only Philippines, Korean, and Indonesian sites (144 patients). 55
INTRACAVERNOUS
ALPROSTADIL
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DYSFUNCTION
Clinical evaluation 100
80
ul
E .Xi a 6 z 0” k a
60 40
m Australian - -Asian
20
2.5
5
10
15 Optimal
Figure.
20 Dose
30
40
60
(pg)
Percentage of patients demonstrating optimal response and dose at which optimal response occurred. Asian data are cumulative.
Cause of erectile dysfunction was a significant factor in determination of optimal erectile-response dosage. The mean optimal dose for vasculogenie patients was 19.1 Fg; for psychogenic patients, 11.5 pg; for neurogenie patients, 15.3 pg; and for patients with mixed etiology, 16.4 pg. The age of the patient had no effect on the ability to achieve an optimal erection. No correlation was seen between duration of erectile dysfunction (< 1 year, 1 to 3 years, ~3 years) and either optimal dose or percentage of responders. Table IV displays the overall regional results of mean erectile response at the optimal dose for the secondary end points of duration, latency, and time to complete detumescence. For all patients who reached their optimal erectile-response effect in the physician’s office, the full erection lasted a mean of 44.8 minutes; at the Asian centers the total duration of erection was 85.3 minutes, with a mean latency of 10.7 minutes.
Table IV. Mean erectile response variables
at optimal dose for Asian and Australian
Ereclile Response Variables (min)
Mean( *SD)
Duration of erection (n = 294)
Latency of erection (n = 244)’ Time to complete detumescence (n = 244)* *Australian centers not included. 56
44.8 212.7 10.66 k-2.78 85.3 I k22.5 I
men.
Il. J. GARCEAU
ET AL
Regional Results: Correlation Between Erect&-Response of Disease
and Origin
Optimal erectile-response effects for all Asian and Australian centers were compared for regional correlations with ethnic or country origin, cause, age, or duration of ED. There were no clear correlations between erectile-response effect and country of origin, age, or duration of ED. For all causes of ED, 67% of patients achieved optimal responses by the 20-pg dose; however, significantly more patients with ED of psychogenic and neurogenic origin responded at lower doses than did patients with ED of other origins. Erectile-response patterns were more variable for vascular causes, with responses spread across all doses up to at least 40 kg. When evaluating response by country (Table V), there appears to be a significant difference in percentage of patients responding, as well as in mean optimal dose. When adjusted for etiologic mix in each country, this difference is no longer apparent; however, the small numbers of patients with ED of various origins in certain countries make this analysis difficult. China, Korea, and Taiwan combined showed an overall response rate of 72.9% with a mean dose of 16.25 pg, which is similar to the overall mean optimal dose of 15.7 Fg for all Asian countries combined. Similar results were seen with various combinations, with no clear differences demonstrated for variables other than cause.
Safety In the 365 patients receiving alprostadil, 45 (12.3%) reported episodes of possible drug-related events. Thirty-nine (10.7%) patients reported 53 episodes (18 mild, 20 moderate, 15 severe> of penile pain or pain at the injection site, and one patient receiving Prostin VR discontinued the study as a result. No episode of pain was considered serious, and all patients recovered with no residual effects. Cold sweating (four episodes), the other
Table V. Response by country. Optimal Dose Reached n/N Australia China $ioesia Philippines
% FE’ loo:o ~~:~ 93.3 71.7
Thailand Taiwan *At 20 pg. 57
Mean Optimal Dose (~0) Not,re,r$rted
1~~“3: 13:88
:::1:
INTRACAVERNOUS
ALPROSTADIL
IN ERECTILE
DYSFUNCTION
possible drug-related event, was reported by two patients. Penile pain, pain at the injection site, and cold sweating did not appear to be dose related. Most of the patients with penile pain or pain at the injection site received additional doses without any further pain. There were no reports of penile hematoma, penile abnormalities, or abnormal clinical or laboratory results. DISCUSSION
This article is the first to present data on cross-country results from controlled multicenter studies on the use of alprostadil to treat ED in impotent men in the Asian and Australian regions. Although Ishi et al4 were the first to describe the use of PGE, for the treatment of ED in Japanese men, there have been few subsequent Asian studies since 1986, and none have followed a dose titration-response protocol.11,12To date, only Chiang et all2 have evaluated self-injection therapy in 51 patients treated for an average of 11.8 months with either PGEi (30 men) or papaverine (21 men). The starting dose of PGE, was 20 p,g, with the average effective dose ranging from 5 to 40 p,g; however, 20 p,g was the most effective dose for most patients (76.7%). In the other published Asian studies to date, the usual starting dose of PGE, was 20 pg. Perhaps the 1986 report by Ishi et a1,4 which described their success in treating ED using a 20-p,g dose, established a dosage tradition that has been followed since that time by Asian investigators. In Australian clinical studies, on the other hand, doses as low as 1 to 2 pg have been used to produce erections in patients with spinal cord injuries,5”4 and 5-p,g doses have been used to test large groups of clinic patients with ED.8l15 Recent dose-titration studies in Europe and the United States have also reported that considerably lower doses of alprostadil may be as effective as higher doses in providing satisfactory erectile responses for men with ED. The report by Linet et al (unpublished data, 1995) of six multicenter studies done using a similar dose-titration method in the United States on the use of the alprostadil sterile powder formulation for the treatment of ED observed significant dose-response relationships for doses of 2.5 to 20 pg. In the Asian studies as well, doses as low as 2.5 and 5 pg produced optimal erectile responses in 25% (82/323) of all Asian and Australian patients. By the 20-pg dose, two thirds (222/338) of all patients had achieved an optimal erectile-response effect. These results also support the results of comparable controlled studies on alprostadil for treatment of men with ED in the United States? and in Europe. 6,7,17In all these studies, significant dose-response relationships were found for satisfactory erectile response, latency, duration of erection, and other variables. The percentage of patients responding to alprostadil 58
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ET AL.
varied by dose and by cause of ED, but in all studies the percentage of dose responders ranged from 63.6% at a 1Oq.g dose6 to 85% at a 2Oq.g dose.17 In our combined regional studies, 63.8% (2221348) of patients responded effectively to doses up to 20 pg of alprostadil. Based on these data, there are no significant differences in dose response between Asian and Australian men and men in European and North American countries. Furthermore, when we compared dose responses, adjusting for origin of ED, for correlations with separate countries within the Asian and Australian regions, we found no significant differences between countries or between the centers. Thus ethnic or country origin did not appear to be an important factor for determining an effective dosage level of alprostadil to use in treating ED in men from any country or area of the world. Although the combined regional data found no correlations between dose response and ethnic origin, there was a correlation with ED cause, particularly for ED of psychogenic or neurogenic origin. Significantly more patients with ED of psychogenic origin responded (95%) and this response occurred at lower doses than in patients with ED of other origins (mean optical dose, 11.5 pg). All Asian patients with ED of neurogenic origin were able to achieve an optimal response, with one third responding to the 2.5~Fg dose; the mean optimal dose for these patients was 15.3 pg. Again, our results mirror similar results reported in other studies in Europe5 and North America (0. I. Linet, M.D., unpublished data, 1995 and T. F. Gana, M.D., et al, unpublished data, 1995) for dose responses to alprostadil for patients with ED of psychogenic and neurogenic origin. CONCLUSION
Intracavernous injection therapy with alprostadil sterile powder offers safe and effective treatment of ED in Asian and Australian men with impotence of various origins. Side effects were neither serious nor did they interfere with patients’ ability to achieve an optimal erectile response. The most common side effect was penile pain, usually mild to moderate, which did not appear to be dose related or to occur at all injections for a given patient. Our results are similar to those of comparable controlled studies on alprostadil for men with ED in the United States and Europe. Optimal doses for Asian and Australian men were similar to those for men from European and North American countries. Ethnicity or country of origin is therefore not important for determining an effective dosage level for alprostadil in treating men with ED from any country or area of the world. Our combined regional data also support the use of low starting doses (2.5 to 5 p,g) that are individualized and carefully titrated to determine each patient’s optimal effective response. Doses between 2.5 and 20 Kg should produce satisfactory results for the majority of patients. 59
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ALPROSTADIL
IN ERECTILE
DYSFUNCTION
Acknowledgments The following individuals are gratefully acknowledged: Dr. Edward Keogh, Dr. Chris McMahon, and Ms. Carolyn Earle, Australia; Dr. ZhaoYing Xue, China; Dr. Arif Adimoelja and Dr. Doddy Soebadi, Indonesia; Dr. Sae-Chul Kim, Korea; Dr. Telesforo Gana, Philippines; Dr. Hyung Ki Choi, and Dr. Charles C. J. Wu, Taiwan; Dr. Apichat Konganand, Thailand. References:
1. Virag R. Intracavernous injection of papervine for erectile failure. Lancet. I982;2:938. Letter. 2. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. NEJM. 1989;321:1648-1659. 3. Lue TF, Goldstein I. Introduction. In: Goldstein I, Lue TF, eds. The Role of Alprostadil
in the Diagnosis and Treatment of Erect& Dysfunction. Proceedings of a Symposium: Aug 34, 1993. Brook Lodge, Kalamaeao, Michigan. Princeton, NJ: Excerpta Medica; 1993:
l-2. 4. Ishi N, Watanabe H, Irisawa C, et al. Studies on male sexual impotence report 18: Therapeutic trial with prostaglandin E, for organic impotence. J Jpn Sot Ural. 1986;77: 954-962. 5. Linet 01, Neff LL. Intracavernous prostaglandin E, in erectile dysfunction. Clin Znuestig. 1994;72:139-149. 6. Porst H. Experience with alprostadil in diagnosis and therapy in Germany. In: Goldstein I, Lue TF, eds. The Role of Alprostadil in the Diagnosis and Treatment of Erectile Dysfunction. Proceedings of a Symposium: Aug 34,1993. gan. Princeton, NJ: Excerpta Medica; 1993:142-154.
Brook Lodge, Kalamazoo,
Michi-
7. Stack1 W, Hasun R, Marberger M. Intracavernous injection of prostaglandin E, in impotent men. J Ural. 1988;140:66-68. 8. Keogh EJ, Earle CM, Chew KK, et al. Experience with self-injection in Australia. In: Goldstein I, Lue TF, eds. The Role of Alprostadil in the Diagnosis and Treatment of Erectile Dysfunction. Proceedings of a Symposium: Aug 34, 1993. Brook Lodge, Kalamazoo, Michigan. Princeton, NJ: Excerpta Medica; 1993:155-166.
9. McMahom CG. Comparison of erectile response to differing doses of prostaglandin PGEi in an attempt to standardize pharmacological diagnosis of impotence. J Ural. 1992;147: 265A. Abstract. 10. Chen J-K, Hwang TI, Yang C-R. Comparison of effects following the intracorporeal injection of papaverine and prostaglandin E,. Br J Ural. 1992;69:404-407. 11. Hwang TI, Yang C-R, Wang S-J, et al. Impotence evaluated by the use of prostaglandin E,. J Ural. 1989;141:1357-1359. 12. Chiang H-S, Wen T-C, Wu C-C, Chiang W-H. Intracavemous self-injection therapy for the treatment of erectile dysfunction. J Formos Med Assoc. 1992;91:898-901. 13. Lee LM, Stevenson WD, Szasa G. Prostaglandin E, versus phentolamine/papaverine for 60
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the treatment of erectile impotence: A double-blind comparison. J Ural. 1989;141:549550. 14. Earle CM, Keogh EJ, Ker JK, et al. Intracavernosal injection therapy for impotence due to spinal cord injury. ZrztJ Zmpot Res. 1990;23(Suppl 2):297-298. 15. Earle CM, Keogh EJ, Wisnieweki ZS, et al. Prostaglandin E, therapy for impotence: Comparison with papervine. J Ural. 1990;143:57-59. 16. Data on file, The Upjohn Company, Kalamazoo, Michigan, 1995. 17. Schramek P, Waldhaueer M. Dose-dependent effect and side-effect of prostaglandin E, in erectile dysfunction. Br J Clin Phurmacol. 1989;28:567-571.
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