MTA98-016 I. Appendix 9: Intracavernous Injections for Erectile Dysfunction (ED) A. RCTs only, single-dose studies Study Name Drugs and Doses Study Design, Duration and Size Participants and Etiology of Impotence Outcomes Adverse Events Linet (1996) Alprostadil (PGE1) 2.5 mg, 5 Multi-center, randomized, double Inclusions: RigiScan response defined as > 70% DOSE-RESPONSE mg, 10 mg, 20 mg or placebo. blind, placebo-controlled, single fixed ED of vasculogenic, neurogenic, psychogenic rigidity at tip or base of penis lasting > PGE1 (all doses): dose, parallel group. Dose or mixed origin; duration of ED > 4 months. 10 consecutive minutes. Clinical Penile pain 23% administered in clinic by researcher. Exclusions: response defined as penile rigidity Priapism 1% penile deformity; history of priapism; sickle-cell sufficient for intercourse as assessed by Prolonged erection 3% Overall N=296 (100% follow-up) trait; recent major illness; uncontrolled diabetes researcher palpation. No response to Placebo: MDRC Technology AssessmentProgram - Placebo n=59 or hypertension; major psychiatric disorder; placebo. For both outcomes the No data given PGE1 2.5 mg n=57 infection with HIV or “other transmittable differences between each dose of PGE1 PGE1 5 mg n=60 disease”; smoking > 40 cigs/day; endocrine and placebo were statistically significant PGE1 10 mg n=62 etiology of ED. (p<0.01). There was a statistically PGE1 20 mg n=58 Demographics: significant dose-response relationship Ages 21 - 74 (mean 54) for clinical response (p<0.001) but not Etiology of ED: RigiScan response. Vascular 44% Psychogenic 14% Neurogenic 13% Mixed 29% Previous therapy for ED: 2% had prior injection treatment Colli (1996) PGE1 5 mg, 10 mg or placebo. Single center, randomized, double Inclusions: Erectile response outcomes included: Penile pain: blind, placebo-controlled, fixed single ED > 6 months (1) reaching and maintaining 70% Placebo 0% dose administered by researcher, Exclusions: rigidity per RigiScan for > 10 minutes at PGE1 5 mg 0% cross-over study (1 week washout). Penile deformity; history of priapism; low free tip or base of penis; (2) researcher PGE1 10 mg 7% testosterone; elevated prolactin; BP > 150/100 palpation and rating of erection as ‘full’; Hematoma: Erectile Dysfunction Overall N=296 (100% follow-up) or hypotension; smoking > 40 cigs/day; and (3) subject rating of erection as Placebo 0% Placebo n=59 uncontrolled diabetes; sickle cell disease; ‘good’ or ‘excellent’. PGE1 5 mg 2% PGE1 2.5 mg n=57 coagulopathy; systemic or psychiatric disease RigiScan: PGE1 10 mg 0% PGE1 5 mg n=60 of recent onset; hematologic disease; current Placebo 0% PGE1 10 mg n=62 use of intracavernous PGE1. PGE1 5 mg 39% PGE1 20 mg n=58 PGE1 10 mg 56% Demographics: Ages 18 - 65 (mean 54) Researcher palpation: Etiology of ED: Placebo 0% Vasculogenic 27% PGE1 5 mg 27% January 1999 -PageA9- Psychogenic 53% PGE1 10 mg 51% Mixed 11% Subject rating: Neurogenic 4% Placebo 0% Diabetes 4% PGE1 5 mg 41% PGE1 10 mg 56% 1 MTA98-016 Appendix 9A (continued) Study Name Drugs and Doses Study Design, Duration and Size Participants and Etiology of Impotence Outcomes Adverse Events Bechara (1997) (1) PGE1 30 mg Single center, randomized, double Inclusions: Responses evaluated to manual and Prolonged erections: blind, placebo-controlled, fixed single ED > 6 months visual stimulation. Erections “allowing Placebo 0% (2) Papaverine 30 mg + dose self-injected, cross-over study penetration” considered positive. PGE1 15% Phentolamine 0.5 mg (PP) (subjects received one dose of each Exclusions: Response rates: PP 18% treatment; 1 week washout). ED from spinal cord injury or radical pelvic Placebo 0% MDRC Technology AssessmentProgram - (3) Placebo surgery; treatment with vasoactive injections PGE1 50% Pain: Overall N=60 (100% completed) PP 56% (p>0.05) Placebo 0% Demographics: PGE1 35% * Ages 22-78 (mean 58) PP 15% * *(p<0.05 vs placebo) Bechara (1996) (1) PGE1 40 mg Single center, randomized, patient- Inclusions: Erections defined as response at 15 Pain: blind, active-controlled, fixed single ED > 6 months; nonresponse to high doses of minutes after dose adequate to “allow... PGE1 41% (2)PGE1 5.8 mg + Papaverine dose, researcher injected, cross-over papaverine + phentolamine combo. penetration” (rating categories stated but PPP 12.5% 17.6 mg + Phentolamine 0.6 study (³ 1 week washout). manner in which erections placed into (p<0.05) mg (PPP) Demographics: categories not given) Overall N=32 (19 completed) Ages 26 - 71 (mean 61.3) Erections: PGE1 22% ED duration (months): PPP 50% (p<0.05) Mean 30.8 (range 6-51) Shenfeld (1995) (1) Papaverine 4.5 mg + Single center, randomized, double Inclusions: Erections rated by physician palpation Penile pain: Phentolamine 0.25 mg + blind, fixed single dose, administered Patients “newly entering our intracorporeal 15 minutes after injection as either ‘full’, PPP 15% Erectile Dysfunction PGE1 5 mg (PPP) by researcher, cross-over study injection program” ‘suboptimal... but sufficient for PP 0% (p>0.05) (washout 2 wks). penetration’ or ‘not sufficient’. (2) Papaverine 9 mg + Exclusions: Full erections: Erection > 60 mins: Phentolamine 0.5 mg (PP) Overall N=20 None given PPP 73% PPP 10% PP 28% (p<0.05) PP 5% (p>0.05) Demographics: Ages 44 - 71 (mean 57.5) Etiology of ED: Arteriogenic 60% January 1999 -PageA9- Neurogenic 15% Other 25% 2 MTA98-016 Appendix 9A (continued) Study Name Drugs and Doses Study Design, Duration and Size Participants and Etiology of Impotence Outcomes Adverse Events Vanderschuere 3 unique formulations of Multi-centered, stratified [subjects Inclusions: Erectile response outcomes included: Penile pain: n (1995) PGE1: using low doses of PGE1 at home ED > 4 months; known stable responders to (1) penile radial rigidity > 70% for >10 Placebo 11% (1) pediatric sterile solution, (2) prior to study (<10 mg) received one intracavernous PGE1. minutes; (2) patient assessment, 0 = not Pediatric solution 9% sterile powder, (3) nonalcohol of 3 possible doses within the study: Exclusions: effective to 3 = very effective; (3) Sterile powder 14% sterile solution. For each placebo, 2.5 mg PGE1 or 5 mg PGE1; Penile deformity; Peyronie’s disease; history of investigator evaluation that erection is Nonalcohol 17% formulation the following doses subjects using high doses of PGE1 at priapism; “suffering from major diseases or took sufficient for vaginal penetration. For all were available: PGE1 2.5 mg, home prior to study (>10 mg) were drugs that could substantially affect the these measures, there were no 5 mg, 10 mg, 20 mg and leigible to receive placebo, 10 mg evaluation of the ED. significant differences between the 3 placebo. Demographics: formulations at any dose. (p>0.1) MDRC Technology AssessmentProgram - PGE1 or 20 mg PGE1)], randomized double blind, placebo-controlled, fixed Ages 29 - 70 (mean 53.1) single dose, cross-over (washout > 3 ED duration (years): days) Mean 4.8 (range 0.5-41) Etiology of ED: N=210 (11 dropouts) Vasculogenic 21% Psychogenic 36% Neurogenic 7% Diabetes 7% Mixed 15% Other 15% Sogari (1997) (1 = PPPA) PGE1 10 mg + Single center, randomized, non- Inclusions: Erectile response assessed 15 minutes Painful sensation: papaverine 50 mg + blinded, active-controlled, fixed single consecutive ED patients seen in a Urology clinic after injection by examiner palpation as PPPA 50.0% Phentolamine 0.2 mg + dose, parallel group study. Dose Exclusions: “full erection”, “poor erection”, or PPP 53.8% (p = 0.4 Atropine 0.075 mg administered by researcher. partial penile amputation “tumescence”. Demographics: % with full erection: (2 = PPP) PGE1 10 mg + Overall N=230 (2 excluded after Age in years [mean (range)]: PPPA 45.6% papaverine 50 mg + randomization) PPPA 53.2 (24 - 75) PPP 45.6% (p = 1.0) Phentolamine 0.2 mg PPPA n=114 PPP 52.7 (22 - 78) PPP n=114 Mean ED duration in months: Erectile Dysfunction PPPA 32.2 (range 1 - 240) PPP 33.5 (range 2 - 360) Comorbid conditions: No difference between treatment groups in number of risk factors for ED, or in prevalence of any individual risk factors except stroke. Kattan (1995) (1) PGE1 20 mg Single center, randomized, double Inclusions: Investigator rated erection as “normal”, Penile pain: blind, active-controlled, fixed single January 1999 -PageA9- Previously experienced pain with intracavernosal “adequate”, “inadequate” or “none”. PGE1 87.5% dose, administered by researcher, (2) PGE1 20 mg + Lidocaine injections of PGE1 % adequate or normal erections: P + L 47.8% (p < 0.01) cross-over study (washout 1 week) 1% (P + L) Exclusions: PGE1 27.2% MI; uncontrolled hypertension P + L 63.6% (p < 0.01) Analysis not intention to treat. Demographics: Ages 40-60 (mean 53) 3 N=25 (3 dropouts) MTA98-016 B. Long-term RCTs only Study Name Drugs and Doses Study Design, Duration and Size Participants Outcomes Adverse Events Buvat (1998) Alprostadil alpha- Multi-centered, active-control, parallel-group Inclusions: Erectile response outcomes in clinic were: (1) Penile pain during cyclodextrin 5-20 µg study of self-injections age 18-70; ED >6 months “buckling test,” and (2) physician evaluation of Injection(%): CL AH or Moxisylate adequacy of erection for intercourse. Only Alprostadil 13 25 chlorhydrate 5-20 mg . DOSING PHASE Exclusions: outcomes from the at-home phase are detailed Moxisylate 15 15 Subjects were randomized to either Alprostadil drug or alcohol addiction; unstable here: Penile pain during or Moxisylate. Optimal treatment dose was angina or MI <3 months prior to erection(%): CL AH determined via double blinded in-clinic titration. study; urologic or hormonal etiology % of subjects with at least 1 rigid erection after Alprostadil* 17 24 MDRC Technology AssessmentProgram - OPEN-LABEL PHASE for ED; concomitant vasoactive self-injection: Moxisylate 3 5 Responders from dosing phase performed up to therapy Alprostadil* 85 Penile pain after 6 at-home self-injections of the treatment to Moxisylate 61 erection(%): CL AH which they had been randomized in the dosing Age, mean yrs (range): Alprostadil* 7 19 phase.