Co-Administering Testosterone With PDE5 Inhibitors in ED Patients Non Responders to PDE5 Inhibitors Alone
30 to 50% of the patients presenting with Erectile Dysfunction (ED) do not respond to PDE V Inhibitor therapy, which is presently considered as the first choice treatment for most ED patients. Recent reports stated a high prevalence of low serum testosterone levels in such non responders, and an improvement of their response by combining testosterone therapy with the PDE V Inhibitor. This suggests there may be a minimum threshold level of blood testosterone for a full effectiveness of PDE V Inhibitor therapy. Two double blind, placebo controlled studies have added support to this hypothesis but one involved only 20 patients while in the other the benefit of combining testosterone was transient. This is a multi-centric study, double blind placebo controlled and randomized as concerns testosterone administration, that aims to objectively assess the efficacy of co-administering testosterone with the PDE 5 inhibitor Tadalafil to improve the erectile function of a large group of ED patients non-responders to PDE V inhibitors alone. Patients will be screened to ensure inclusion and exclusion criteria completion, including a serum testosterone level < 4 ng/ml for total testosterone or < 1 ng/ ml for bioavailable testosterone. They will then enter a four week run-in period in the meanwhile they will receive Tadalafil 10 mg only, once daily, in order to confirm their non responsiveness to PDE V inhibitors and their eligibility to enter the treatment phase based on IIEF scoring, SEP diaries and a Global Assessment Question (GAQ). The patients still non responders after 4 weeks of Tadalafil 10 mg daily will enter a 12 weeks treatment phase including visits at weeks 4, 8, 12 and 16. Treatment procedure will include: 1. continuation of Tadalafil at 10 mg dose daily followed by routine assessment using SEP diaries, IIEF scoring, GAQ and Aging Male Symptoms scale administered at each study visit. Safety assessments will be performed in addition during the last visit (physical examination including DRE, PSA and BCC). 2. Randomization in 2 parallel arms (Placebo gel + Tadalafil 10 mg daily, and Testosterone gel 50 mg + Tadalafil 10 mg daily). If indicated according to suboptimal clinical response of the patient, the dose of study medication will be increased at the 8 or 12 weeks visit to 100mg of testosterone or to 2 sachets of placebo gel. Up to 430 patients will be screened in order that 172 are enrolled in the double blind treatment phase.
Drug: Testosterone gel
Other: placebo gel
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Double-Blind, Placebo Controlled Randomized Study of Co-Administering Testosterone With PDE5 Inhibitors in Patients Non-Responders to PDE5 Inhibitors Alone|
- mean change from baseline in the Erectile Function Domain Score of the IIEF (questions 1-5 + 15) on Tadalafil + Testosterone compared to the one on Tadalafil + placebo. [ Time Frame: V3,V4,V5,End Point ] [ Designated as safety issue: No ]
- Rate of "responders" to treatment [ Time Frame: V3,V4,V5,End Point ] [ Designated as safety issue: No ]
- Rate of the patients having achieved a score > 26 at the EFD of the IIEF [ Time Frame: V3,V4,V5,End Point ] [ Designated as safety issue: No ]
- Mean scores at Questions 3 and 4 of the IIEF [ Time Frame: V3,V4,V5,End Point ] [ Designated as safety issue: No ]
- Mean scores at the 4 other domains of the IIEF (Orgasmic Function, Sexual Desire, Intercourse Satisfaction and Overall Satisfaction Domains), and at the whole IIEF [ Time Frame: V3,V4,V5,End Point ] [ Designated as safety issue: No ]
- % of "YES" responses at questions 2, 3, 4 and 5 of the SEP [ Time Frame: V3,V4,V5,End Point ] [ Designated as safety issue: No ]
- Percentage of "YES" responses to the GAQ [ Time Frame: V3,V4,V5,End Point ] [ Designated as safety issue: No ]
- Scores at the different domains of the AMS questionnaire [ Time Frame: V3,V4,V5,End Point ] [ Designated as safety issue: No ]
|Study Start Date:||October 2005|
|Study Completion Date:||July 2007|
|Primary Completion Date:||July 2007 (Final data collection date for primary outcome measure)|
Testosterone gel (intervention)
Drug: Testosterone gel
one sachet of 50 mg applied once a day, possibly titrated to two sachets if insufficient improvement of erectile function
Other Name: Androgel or TestogelDrug: testosterone
testosterone gel, one sachet of 50 mg applied once a day, possibly titrated to 100 mg if insufficient effect
Other Name: Testogel or Androgel
Placebo Comparator: 2
one sachet of placebo gel once a day, possibly titrated to 2 sachets if insufficient efficacy
Other: placebo gel
one sachet of placebo gel once a day possibly titrated to 2 sachets if insufficient efficacy
Other Name: placebo gel
Hide Detailed Description
Design and Methodology: This was a multicentre, randomised, double-blind, placebo-controlled study of the effects of co-administering testosterone with the PDE 5 inhibitor tadalafil in ED patients who do not respond to PDE 5 inhibitors alone.
The patients were randomised into two parallel groups: the Control group (tadalafil plus placebo) and the Test group (tadalafil plus testosterone).
The study lasted a maximum of 16 weeks for each patient and was divided into two parts:
- Run-in phase: four week period from visit 1 (V1) to V2 where patients received a dose of 10 mg tadalafil per day. Non-response to tadalafil was assessed by the SEP diary, the IIEF questionnaire and the GAQ. Patients had to attempt to have intercourse at least four times during this phase. Non-responders were randomised at V2.
- Treatment phase: 12 week period from the day after V2 to V5 with visits at weeks 8, 12 and 16. The patient response was assessed by the SEP diary, the IIEF and AMS questionnaires and the GAQ at each visit. Patients were to apply the testosterone or placebo gel to their skin once a day, preferably in the morning. There was an option to increase the dose of testosterone or placebo at V3 or V4 if the patient had a suboptimal clinical response (patient felt insufficiently improved and achieved scores lower than 5 for questions 3 or 4 of the IIEF).
Test product. The products given during this study are licensed under the names of Cialis (tadalafil) and Androgel and Testogel (testosterone gel).
All patients were treated with 10 mg tadalafil tablets once daily over the four week run-in phase then, if randomised, for the following 12 week treatment phase.
Patients in the Test group were treated with 5 g sachets of testosterone gel (50 mg testosterone) once daily for the 12 week treatment phase, with an option to increase to two 5 g sachets (100 mg testosterone) per day from V3 or V4 if the patient had a suboptimal clinical response (patient felt insufficiently improved and achieved scores lower than 5 for questions 3 or 4 of the IIEF questionnaire). Patients in the Control group received 5 g sachets of placebo gel once daily for the 12 week treatment phase, again with an option to increase to two 5 g sachets per day from V3 or V4.
- Categorical variables were summarised using classical frequency statistics: number of non-missing observations (N) and percentages (%) by categories. Percentages were calculated within each treatment group on the number of non-missing observations and were displayed using one decimal.
- Continuous variables were summarised using standard quantitative statistics. number of non-missing observations (N), mean, standard deviation (SD), median and range (minimum and maximum observed values).
The number of missing observations (N missing) was also specified. The 95% confidence interval (CI) was displayed when relevant.
Inferential analyses:Comparisons between treatment groups were two-sided. The significance level was set at 0.050. All p-values were rounded to three decimal places.Main inferential analyses used one of the following tests:
- Chi two-Test or Fisher's exact Test comparing the distributions of a categorical variable between the level of one factor (e.g. treatment arm), in reference to theoretical distributions. When at least one theoretical frequency is less than 5, then the Fisher's exact test was used in place of Chi two-Test
- Analysis of variance (ANOVA): comparing the mean values of a continuous quantitative variable between the level of categorical factors (e.g. treatment group, centre)
- Analysis of covariance (ANCOVA) ANOVA adjusted for treatment group and centre effects and baseline value as covariate: The primary efficacy criterion was analysed by an ANCOVA, including the covariate 'baseline value of the primary criterion' and the factor 'treatment group'. The ANCOVA estimated the difference between the two treatments as well as its two-sided 95% CI.
Summary and conclusions
Of the 173 patients included in this study, 35 were prematurely withdrawn. Therefore 138 patients completed the study. The ITT population consisted of 167 patients and the PP population of 120; 47 patients in the ITT population were excluded for major protocol deviations.
No statistically significant differences were found between the testosterone and the placebo groups as concerns the primary criterion in either the ITT or the PP populations. The EFD score of the IIEF questionnaire increased between baseline (V2 for efficacy results) and endpoint (V5 or withdrawal visit) for both groups, indicating an overall improvement in erectile function during the study.
Apart from the hormone levels, there were no statistically significant differences for any of the secondary criteria in either the ITT or the PP populations. As expected, for certain hormones there were significant differences between the two groups (total testosterone (TT), bioavailable testosterone (BT), Dihydrotestosterone (DHT), oestradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), calculated FT (cFT) and calculated BT (cBT)). Significant differences were also found for all these hormones for the treatment responders.
There was no statistically significant difference for the additional analysis; the percentage of successful sexual intercourse attempts amongst treatment responders was similar between groups.
At V2, after the run-in phase of four weeks of tadalafil treatment alone, the responder rate was 17.0% and the rate of those patients with a score > 26 for the EFD of the IIEF i.e. considered as no longer having ED, was 14.8%. For all domains of the IIEF, the score was higher at V2 than at V1, indicating an increase in erectile function after the run-in phase. Almost half of the selected patients (44.8%) thought that the tadalafil treatment had improved their erections. However, the results of these exploratory analyses may be biased as they were performed on the Selected population (who responded to the IIEF at both V1 and V2) and not on the Randomised population.
Additional exploratory analyses were performed to determine the testosterone threshold from which a possible improvement would be obtained by testosterone gel. The results of these analyses found statistically significant differences between the two groups, in favour of the Test group, in the ITT patients with a TT level of 3 ng/ml or less at baseline. The results included a significantly higher increase in the primary criterion (EFD score) at V4 (p=0.027),after 8 weeks of testosterone gel, and significantly greater improvements in various secondary criteria. For the IIEF questionnaire: significant improvements were shown in the score of the Orgasmic Function Domain at V4 (p=0.028), in the Intercourse Satisfaction Domain at V4 (p=0.005), in the Overall Satisfaction Domain at endpoint (p=0.046) and in the total IIEF score at V4 (p=0.008). For the SEP diary a significantly higher increase was shown in the rate of attempts of intercourse resulting in vaginal penetration (SEP 2) at V4 (p=0.033), and in the rate of totally successful intercourses (SEP 3) at V4 (p=0.038) and endpoint (p=0.006). These results suggest that testosterone gel significantly improved erectile function compared to placebo gel in ED patients who are non-responders to PDE5 inhibitors with a baseline testosterone level of 3 ng/ml or less, and that this effect is discernible from the second month of administration (assessments done at V4).
Safety results Overall, 61 of the 173 Safety population patients (35.3%) experienced at least one AE during the study (111 AEs were reported in total) with more AEs reported in the Control group than in the Test group. In the Safety population, 32 pre-treatment AEs were recorded in 23 patients (13.3%) with no significant difference between groups.
During the study, a total of 79 emergent AEs were recorded in 53 patients (30.6%), 34 AEs in 22 Test group patients and 45 AEs in 31 Control group patients. All AEs were of mild or moderate intensity, except four AEs considered as severe, all of which were reported in the Test group (pneumopathy, arrythmia, bowel obstruction and exacerbation of back pain). The latter was the only severe AE related to one of the study products.
Five emergent AEs were considered as serious for three Test group patients (coronary stenosis and diabetes, pneumopathy and arrhythmia, and bowel obstruction). These SAEs were unrelated to the study product. The patient with the bowel obstruction was withdrawn from the study after V4.
A total of 11 patients (four in the Test group -diabetes impaired by corticotherapy, itching, bowel obstruction, nausea- and seven in the Control group) were withdrawn from the study due to an AE.
Conclusions In conclusion, in this study, testosterone gel did not improve the efficacy of tadalafil in a population of ED patients with a low or low-to-normal testosterone level (TT < 4 ng/ml or BT < 1 ng/ml) who were non-responders to tadalafil 10 mg once-a-day alone. However additional exploratory analyses found significant improvements with tadalafil plus testosterone gel compared to tadalafil plus placebo gel in a subgroup of the ITT population restricted to those patients with a serum TT level <3 ng/ml at baseline. These results agree with the scientific literature, which places the threshold level below which a man may be considered hypogonadal (testosterone deficient) at 3 ng/ml (and not at our inclusion criterion of 4 ng/ml).
|Lille, France, 59000|
|Study Chair:||Jacques BUVAT, MD||SELARL du Dr Jacques BUVAT|
|Principal Investigator:||Eugene PLAS, MD||Lainz Hospital Vienna - Austria|
|Principal Investigator:||Claude SCHULMAN, MD||Erasme Hospital Brussels|
|Principal Investigator:||Francois GIULIANO, MD||Hopital Raymond Poincaré - Garches - France|
|Principal Investigator:||Béatrice CUZIN, MD||CHU Edouard Herriot - Lyon - France|
|Principal Investigator:||Marie Hélène COLSON, MD||Centre du Palais - Marseille - France|
|Principal Investigator:||Hartmut PORST, MD||Urological Office - Hamburg - Germany|
|Principal Investigator:||Christian STIEF, MD||Ludwig Maximilians Universität - Munchen - Germany|
|Principal Investigator:||Aksam YASSIN, MD||Urological Office - Hamburg - Germany|
|Principal Investigator:||Theodor KLOTZ, MD||Klinikum fur Urologie - Weiden - Germany|
|Principal Investigator:||Francesco MONTORSI, MD||Hospital San Raffaele - Milano - Italy|
|Principal Investigator:||Mario MAGGI, MD||Andrology Unit - Florence - Italy|
|Principal Investigator:||Anti KAIPIA, MD||Gynecologi - Ja Urologikeskus - Tampere - Finland|
|Principal Investigator:||Eric MEULEMAN, MD||Free University Medical Center - Amsterdam - The Netherlands|
|Principal Investigator:||Antonio MARTIN MORALES, MD||Hospital Carlos Haya - Malaga - SPAIN|
|Principal Investigator:||Ignacio MONCADA, MD||Hospital Gregorio Maranon - Madrid - SPAIN|
|Principal Investigator:||John DEAN, MD||Salisbury Clinic - Plymouth - UK|
|Principal Investigator:||Ian EARDLEY, MD||Leeds Hospital - Leeds - UK|
|Principal Investigator:||Jacques BUVAT, MD||CETPARP - Lille - France|