Sildenafil Pivotal Trials: Oral Sildenafil in the Treatment of Erectile Dysfunction
The sildenafil pivotal trials were two sequential double-blind, placebo-controlled studies in 861 men with erectile dysfunction (ED) at 37 US centers: a 24-week fixed-dose study of sildenafil 25, 50 or 100 mg and a 12-week flexible-dose study. Scores for penetration and for maintenance of erection rose with dose (P < 0.001), and in the flexible-dose study 69% of intercourse attempts succeeded with sildenafil versus 22% with placebo (P < 0.001).[1]
- Design and population
- Two sequential double-blind placebo-controlled randomized studies. 861 men aged 18 or older with erectile dysfunction for at least 6 months at 37 US centers, in a stable relationship with a female partner (70% organic, 11% psychogenic, 18% mixed cause).
- Arms
- Oral sildenafil, fixed 25, 50 or 100 mg or flexible dosing from 50 mg versus placebo
- Report and follow-up
- 1998 · 24 weeks (dose-response study); 12 weeks (dose-escalation study); 32-week open-label extension in 225 men
| Endpoint | Results | Effect | Finding |
|---|---|---|---|
| Mean end-of-treatment score, scale 1-5 (24 weeks); sildenafil 25, 50 and 100 mg | 3.2 (25 mg), 3.5 (50 mg), 4.0 (100 mg) vs 2.2 | P <0.001 | Met |
| Mean end-of-treatment score, scale 1-5 (24 weeks); sildenafil 25, 50 and 100 mg | 3.1 (25 mg), 3.5 (50 mg), 3.9 (100 mg) vs 2.1 | P <0.001 | Met |
| Mean end-of-treatment score, scale 1-5 (12 weeks) | 3.9 vs 2.3 | P <0.001 | Met |
| Mean end-of-treatment score, scale 1-5 (12 weeks) | 3.6 vs 1.8 | P <0.001 | Met |
| Percentage of all attempts at intercourse that were successful, last 4 weeks, event log (dose-escalation study) | 69% vs 22% | P <0.001 | Met |
| Mean domain score, possible range 1-30 (dose-escalation study) | 22.1 vs 12.2 | P <0.001 | Met |
| Proportion answering yes at 24 weeks; sildenafil 25, 50 and 100 mg | 56% (25 mg), 77% (50 mg), 84% (100 mg) vs 25% | P <0.001 | Met |
| Proportion answering yes at 12 weeks, among men who responded to the question | 101/136 (74%) vs 23/118 (19%) | P <0.001 | Met |
Harms: Headache: Dose-escalation: 30/163 (18%); dose-response: 14/102 (14%) at 25 mg, 23/107 (21%) at 50 mg, 32/107 (30%) at 100 mg vs Dose-escalation: 6/166 (4%); dose-response: 14/216 (6%); Flushing: Dose-escalation: 30/163 (18%); dose-response: 13/102 (13%), 29/107 (27%), 21/107 (20%) at 25, 50, 100 mg vs Dose-escalation: 1/166 (1%); dose-response: 3/216 (1%); Dyspepsia: Dose-escalation: 9/163 (6%); dose-response: 3/102 (3%), 12/107 (11%), 17/107 (16%) at 25, 50, 100 mg vs Dose-escalation: 4/166 (2%); dose-response: 3/216 (1%)
Registry not recorded · Report DOI
Design
Men were 18 or older with ED of at least six months and a stable relationship with a female partner of at least six months. The investigators assigned cause from the history, physical examination and further testing (intracavernosal injection testing in 31%, RigiScan nocturnal tumescence testing in 26%, penile duplex ultrasonography in 21% and endocrine testing in 21%): 605 men (70%) had organic, 99 (11%) psychogenic and 157 (18%) mixed ED. Exclusions were penile anatomical defects, another primary sexual disorder such as premature ejaculation, spinal cord injury, poorly controlled diabetes, active peptic ulcer disease, an uncontrolled major psychiatric disorder, alcohol or substance abuse, major hematologic, renal or hepatic abnormality, stroke or myocardial infarction in the previous six months, and nitrate therapy. Other ED treatments were stopped four weeks before study drug.[1]
In the dose-response study, 532 men were randomized to placebo (216) or sildenafil 25 mg (102), 50 mg (107) or 100 mg (107) for 24 weeks. In the dose-escalation study, 329 different men were randomized to placebo (166) or sildenafil starting at 50 mg (163) for 12 weeks; at each visit the dose could be doubled or reduced by 50% according to response and adverse effects. Men took one dose about an hour before planned sexual activity, no more than once daily, at home.[1]
Mean age was 57 to 60 years across the four groups. Men in the dose-escalation study had had ED longer (mean 4.7 years with placebo and 5.0 with sildenafil, versus 3.2 years in the dose-response groups) and fewer had organic disease (63% and 55%, versus 77% and 78%).[1][2] A history of radical prostatectomy was present in 9% to 12% of each group and diabetes mellitus in 8% to 15%.[1]
Efficacy was measured with questions 3 (frequency of penetration) and 4 (maintenance of erection after penetration) of the 15-item International Index of Erectile Function (IIEF), each scored from 1 (almost never or never) to 5 (almost always or always); the mean for 109 normal men of similar age was 4.3 on each. The IIEF was completed at 0, 12 and 24 weeks in the dose-response study and at 0 and 12 weeks in the dose-escalation study. Secondary measures were the five IIEF domain scores, a patient event log (erection hardness on a four-point scale and whether intercourse succeeded) and a yes-or-no global efficacy question. Analyses were intention-to-treat in randomized men who took treatment and had any assessment after baseline.[1]
Results
In the dose-response study, mean question 3 scores at 24 weeks were 3.2, 3.5 and 4.0 with 25, 50 and 100 mg versus 2.2 with placebo (baselines 2.0, 1.9, 2.0 and 2.1), and question 4 scores were 3.1, 3.5 and 3.9 versus 2.1 (baselines 1.4, 1.5, 1.7 and 1.7); the treatment effect was significant on both (P < 0.001). The increases from baseline were 60%, 84% and 100% for question 3 and 121%, 133% and 130% for question 4, versus 5% and 24% with placebo. Scores did not vary with the cause of ED.[1]
In the dose-response event log, erections hard enough for penetration (grade 3 or 4) during the last four weeks occurred in 72%, 80% and 85% of men taking 25, 50 and 100 mg versus 50% taking placebo (P < 0.001); 80% of grade 3 and 94% of grade 4 erections led to successful intercourse. At 24 weeks, 56%, 77% and 84% reported improved erections versus 25% with placebo (P < 0.001).[1]
In the dose-escalation study, mean question 3 scores were 3.9 with sildenafil versus 2.3 with placebo (baselines 2.0 and 2.1) and question 4 scores 3.6 versus 1.8 (baselines 1.5 and 1.6), both P < 0.001. The IIEF erectile-function domain score (range 1 to 30) was 22.1 versus 12.2 (P < 0.001); orgasmic-function, intercourse-satisfaction and overall-satisfaction domain scores were also higher with sildenafil (P < 0.001), and sexual desire was not different (P = 0.13). In the last four weeks, 69% of all intercourse attempts succeeded with sildenafil versus 22% with placebo (P < 0.001), with a mean of 5.9 versus 1.5 successful attempts (P < 0.001). On the global question, 101 of 136 responding sildenafil men (74%) and 23 of 118 placebo men (19%) reported improved erections (P < 0.001).[1]
By cause in the dose-escalation study, question 3 scores were 3.6 versus 2.0 in organic ED (81 and 90 men), 4.3 versus 2.3 in psychogenic ED (19 and 24) and 3.6 versus 2.8 in mixed ED (38 and 24), with P < 0.001, < 0.001 and 0.08; question 4 differences were significant in all three (P < 0.001, < 0.001 and 0.005).[1]
Later reports extended the safety and durability data. A pooled analysis of double-blind studies (2,722 sildenafil and 1,552 placebo patients) found headache in 16% versus 4%, flushing in 10% versus 1% and dyspepsia in 7% versus 2%, with discontinuation for adverse events in 2.5% versus 2.3%.[3] In four open-label extension studies totaling 1,008 men, 92% at 36 weeks and 89% at 52 weeks reported improved erections.[4]
Surgery and treatment delivery
In the dose-response study, 285 of 316 sildenafil men (90%) and 180 of 216 placebo men (83%) completed 24 weeks. In the dose-escalation study, 154 of 163 (94%) and 153 of 166 (92%) completed 12 weeks. After 12 weeks the sildenafil dose was 100 mg in 121 men (74%), 50 mg in 38 (23%) and 25 mg in 4 (2%); the corresponding placebo regimens were 158 men (95%) at the 100 mg level and 8 (5%) at 50 mg. Of the men who completed the 12-week study, 225 entered a 32-week open-label sildenafil extension and 207 (92%) completed it.[1]
Adverse events
Headache, flushing, dyspepsia, rhinitis and transient visual disturbance (changes in the perception of color hue or brightness) were the most frequent adverse effects; their frequency rose with dose, and they were usually mild and lasted a few minutes to a few hours after dosing. At 100 mg in the dose-response study, headache occurred in 32 of 107 men (30%), flushing in 21 (20%), dyspepsia in 17 (16%), rhinitis in 12 (11%) and visual disturbance in 10 (9%), versus 14 of 216 (6%), 3 (1%), 3 (1%), 4 (2%) and 1 (<1%) with placebo. In the dose-escalation study, headache and flushing each occurred in 30 of 163 sildenafil men (18%), versus 6 of 166 (4%) and 1 of 166 (1%) with placebo, and dyspepsia in 9 (6%) versus 4 (2%).[1]
Treatment-related adverse effects led to discontinuation in 4 of 316 sildenafil men (1%) and 1 of 216 placebo men in the dose-response study, in 1 of 163 and 1 of 166 in the dose-escalation study, and in 4 of 225 (2%) in the extension. No man reported priapism, and laboratory tests showed no evidence of sildenafil-induced abnormalities.[1]
Limitations
Efficacy rested on the men's own reports in the home setting, and only 25% of partners completed the optional partner questionnaire. Double-blind treatment lasted 12 or 24 weeks against placebo alone. The population excluded men receiving nitrates, men with myocardial infarction or stroke in the previous six months, and men with spinal cord injury or poorly controlled diabetes. In the dose-response study, 36 of 216 placebo men (17%) and 31 of 316 sildenafil men (10%) discontinued, and IIEF analyses included 199 of 216 placebo and 302 of 316 sildenafil men. The 69% versus 22% figure counts attempts rather than men and comes from the dose-escalation study only. Pfizer supplied the study drug and grants, Pfizer staff assisted with study design and data analysis, and five authors were Pfizer consultants.[1]
In conversation
- Extended by REACTT (2013). Sildenafil trials established on-demand PDE5 inhibitor efficacy in erectile dysfunction; REACTT tested tadalafil started after prostatectomy for unassisted recovery.
The primary measures here were IIEF questions 3 and 4. The erectile-function domain score, which the AUA 2018 guideline uses to compare PDE5 inhibitors across trials, was a secondary measure.[1][5]
Guidelines and approvals
- AUA Erectile Dysfunction guideline (2018), statement 8. Inform men with ED about an FDA-approved oral PDE5 inhibitor, including its benefits and risks and burdens, unless contraindicated . The guideline's PDE5-inhibitor evidence base includes this report.[5]
- FDA (March 27, 1998). Sildenafil citrate (Viagra; NDA 020895) was approved; the label revised November 1998 states that it is indicated for the treatment of erectile dysfunction.[6]
Report history
| Published | Report | Cutoff | Headline results | Citation |
|---|---|---|---|---|
| 1998-05-14 | Dose-response and dose-escalation studies · primary | — | Mean end-of-treatment score, scale 1-5 (24 weeks); sildenafil 25, 50 and 100 mg: 3.2 (25 mg), 3.5 (50 mg), 4.0 (100 mg) vs 2.2; P <0.001 Met Mean end-of-treatment score, scale 1-5 (24 weeks); sildenafil 25, 50 and 100 mg: 3.1 (25 mg), 3.5 (50 mg), 3.9 (100 mg) vs 2.1; P <0.001 Met Mean end-of-treatment score, scale 1-5 (12 weeks): 3.9 vs 2.3; P <0.001 Met Mean end-of-treatment score, scale 1-5 (12 weeks): 3.6 vs 1.8; P <0.001 Met Percentage of all attempts at intercourse that were successful, last 4 weeks, event log (dose-escalation study): 69% vs 22%; P <0.001 Met Mean domain score, possible range 1-30 (dose-escalation study): 22.1 vs 12.2; P <0.001 Met Proportion answering yes at 24 weeks; sildenafil 25, 50 and 100 mg: 56% (25 mg), 77% (50 mg), 84% (100 mg) vs 25%; P <0.001 Met Proportion answering yes at 12 weeks, among men who responded to the question: 101/136 (74%) vs 23/118 (19%); P <0.001 Met Proportion of men with such erections during the last 4 weeks of event-log review; sildenafil 25, 50 and 100 mg: 72% (25 mg), 80% (50 mg), 85% (100 mg) vs 50%; P <0.001 Mean end-of-treatment score, scale 1-5, by investigator-assigned cause: 3.6 organic (n=81); 4.3 psychogenic (n=19); 3.6 mixed (n=38) vs 2.0 organic (n=90); 2.3 psychogenic (n=24); 2.8 mixed (n=24); P <0.001 organic; <0.001 psychogenic; 0.08 mixed Between-group comparison of mean domain score: No significant difference; orgasmic-function, intercourse-satisfaction and overall-satisfaction domain scores were higher with sildenafil (P<0.001).; P 0.13 | Goldstein I, Lue TF, Padma-Nathan H, et al. "Oral Sildenafil in the Treatment of Erectile Dysfunction." *N Engl J Med.* 1998;338(20):1397-1404. doi:10.1056/NEJM199805143382001 DOI |
| 1998 | Pooled safety analysis · secondary | — | — | Morales A, Gingell C, Collins M, et al. "Clinical Safety of Oral Sildenafil Citrate (VIAGRA) in the Treatment of Erectile Dysfunction." *Int J Impot Res.* 1998;10(2):69-73. doi:10.1038/sj.ijir.3900354 DOI |
| 1998-07-02 | Published correction · correction | — | — | "Oral Sildenafil in the Treatment of Erectile Dysfunction" [correction]. *N Engl J Med.* 1998;339(1):59. doi:10.1056/NEJM199807023390121 DOI |
| 2001 | Long-term extension studies · secondary | — | Proportion answering that treatment improved their erections (open-label extension, n=1008): 92% at 36 weeks; 89% at 52 weeks; — | Steers W, Guay AT, Leriche A, et al. "Assessment of the Efficacy and Safety of Viagra (Sildenafil Citrate) in Men with Erectile Dysfunction during Long-Term Treatment." *Int J Impot Res.* 2001;13(5):261-267. doi:10.1038/sj.ijir.3900714 DOI |
References
1. Goldstein I, Lue TF, Padma-Nathan H, et al. "Oral Sildenafil in the Treatment of Erectile Dysfunction." N Engl J Med. 1998;338(20):1397-1404. doi:10.1056/NEJM199805143382001
2. "Oral Sildenafil in the Treatment of Erectile Dysfunction" [correction]. N Engl J Med. 1998;339(1):59. doi:10.1056/NEJM199807023390121
3. Morales A, Gingell C, Collins M, et al. "Clinical Safety of Oral Sildenafil Citrate (VIAGRA) in the Treatment of Erectile Dysfunction." Int J Impot Res. 1998;10(2):69-73. doi:10.1038/sj.ijir.3900354
4. Steers W, Guay AT, Leriche A, et al. "Assessment of the Efficacy and Safety of Viagra (Sildenafil Citrate) in Men with Erectile Dysfunction during Long-Term Treatment." Int J Impot Res. 2001;13(5):261-267. doi:10.1038/sj.ijir.3900714
5. Burnett AL, Nehra A, Breau RH, et al. "Erectile Dysfunction: AUA Guideline." J Urol. 2018;200(3):633-641. doi:10.1016/j.juro.2018.05.004
6. U.S. Food and Drug Administration. "Approval Date(s) and History, Letters, Labels, Reviews for NDA 020895." accessdata.fda.gov