Ignite Creation Date:
2024-05-05 @ 12:06 PM
Last Modification Date:
2024-10-26 @ 9:20 AM
Study NCT ID:
NCT00244023
Status:
COMPLETED
Last Update Posted:
2008-08-25
First Post:
2005-10-23
Brief Title:
Co-Administering Testosterone With PDE5 Inhibitors in ED Patients Non Responders to PDE5 Inhibitors Alone
Sponsor:
SELARL du Dr Jacques BUVAT
Organization:
SELARL du Dr Jacques BUVAT
Study Overview
Official Title:
Double-Blind Placebo Controlled Randomized Study of Co-Administering Testosterone With PDE5 Inhibitors in Patients Non-Responders to PDE5 Inhibitors Alone
Status:
COMPLETED
Status Verified Date:
2008-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 ngml 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
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
Statistical methods
1 Descriptive statistics
1 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
2 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
2 Inferential analysesComparisons between treatment groups were two-sided The significance level was set at 0050 All p-values were rounded to three decimal placesMain inferential analyses used one of the following tests
1 Chi two-Test or Fishers exact Test comparing the distributions of a categorical variable between the level of one factor eg treatment arm in reference to theoretical distributions When at least one theoretical frequency is less than 5 then the Fishers exact test was used in place of Chi two-Test
2 Analysis of variance ANOVA comparing the mean values of a continuous quantitative variable between the level of categorical factors eg treatment group centre
3 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
Efficacy results
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 170 and the rate of those patients with a score 26 for the EFD of the IIEF ie considered as no longer having ED was 148 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 448 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 ngml or less at baseline The results included a significantly higher increase in the primary criterion EFD score at V4 p0027after 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 p0028 in the Intercourse Satisfaction Domain at V4 p0005 in the Overall Satisfaction Domain at endpoint p0046 and in the total IIEF score at V4 p0008 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 p0033 and in the rate of totally successful intercourses SEP 3 at V4 p0038 and endpoint p0006 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 ngml 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 353 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 133 with no significant difference between groups
During the study a total of 79 emergent AEs were recorded in 53 patients 306 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 ngml or BT 1 ngml 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 ngml 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 ngml and not at our inclusion criterion of 4 ngml
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
Statistical methods
1 Descriptive statistics
1 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
2 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
2 Inferential analysesComparisons between treatment groups were two-sided The significance level was set at 0050 All p-values were rounded to three decimal placesMain inferential analyses used one of the following tests
1 Chi two-Test or Fishers exact Test comparing the distributions of a categorical variable between the level of one factor eg treatment arm in reference to theoretical distributions When at least one theoretical frequency is less than 5 then the Fishers exact test was used in place of Chi two-Test
2 Analysis of variance ANOVA comparing the mean values of a continuous quantitative variable between the level of categorical factors eg treatment group centre
3 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
Efficacy results
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 170 and the rate of those patients with a score 26 for the EFD of the IIEF ie considered as no longer having ED was 148 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 448 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 ngml or less at baseline The results included a significantly higher increase in the primary criterion EFD score at V4 p0027after 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 p0028 in the Intercourse Satisfaction Domain at V4 p0005 in the Overall Satisfaction Domain at endpoint p0046 and in the total IIEF score at V4 p0008 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 p0033 and in the rate of totally successful intercourses SEP 3 at V4 p0038 and endpoint p0006 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 ngml 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 353 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 133 with no significant difference between groups
During the study a total of 79 emergent AEs were recorded in 53 patients 306 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 ngml or BT 1 ngml 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 ngml 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 ngml and not at our inclusion criterion of 4 ngml
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None