Erectile DysfunctionPhase 3NCT00244023
Co-Administering Testosterone With PDE5 Inhibitors in ED Patients Non Responders to PDE5 Inhibitors Alone
A Phase 3 study testing Testosterone gel and testosterone in people with Erectile Dysfunction and Hypogonadism, run by SELARL du Dr Jacques BUVAT at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 45 to 80 years, men only
- Conditions the study is for
- Erectile Dysfunction, Hypogonadism
- What is being tested?
- Testosterone gel and testosterone
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 173 participants
- Where
- 1 siteFrance
- Study dates
- Oct 2005to Jul 2007
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 80 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- ED complaint ongoing for over 3 months;
- Age comprise between 45 and 80 years old;
- Had a stable heterosexual relationship for more than 3 months and anticipates having the same partner for all the study
- Has not responded adequately to the highest available dosage of Tadalafil or other PDE5 inhibitors (20 mg for Tadalafil and Vardenafil, 100 mg for Sildenafil) taken at least at 4 separate occasions, defined as: a score of 2,3 or 4 at Question 3 of the IIEF AND a score of 2 or 3 at Question 4 of the IIEF; measured prior to Visit 1
- Low or low-to-normal serum testosterone level (either on total or bioavailable testosterone levels) with respect to the range of men under aged than 50 y.o. (TT < 4 ng/ml and/or BT < 1 ng/ml) according to a first assay done prior to Visit 1 and a confirmation by a second assay at central laboratory Biolille on blood sampled at Visit 1
- Agrees to make at least 4 attempts at sexual intercourse on 4 separate days during the 4 weeks run-in period with daily Tadalafil 10 mg
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- At least 50% of attempts during this period must be unsuccessful according an answer "No" at one of the questions 1 ("were you able to achieve at least some erection (some enlargement of the penis)?"), 2 ("were you able to insert your penis in your partner's vagina?") or 3 ("did your erection last long enough for you to have successful intercourse?").
- At the end of the run in phase with Tadalafil 10 mg daily, the patient should provide: a score of 2, 3 or 4 at Question n°3 of the IIEF AND a score of 2, 3 at Question n°4 of the IIEF
- Agrees not to use any other ED drug or non-drug (devices) treatment during the full course of the study;
- Provides a signed informed consent.
Who cannot join
- Impotence caused by other primary sexual disorder (e.g. premature ejaculation);
- History of penile implant or significant penile deformity;
- Body mass index >35kg/m2;
- Diabetes mellitus that is uncontrolled (HbA1c level > 10%). HbA1c will be checked at screening for each diabetic patient or suspected to be;
- Uncontrolled thyroid disorders;
- Known hyperprolactinemia (serum prolactin > 30ng/ml in local laboratory);
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- Organic hypothalamic-pituitary pathology;
- History of alcohol, drug or substance abuse within 6 months before Visit 1;
- Renal insufficiency defined as receiving renal dialysis, having a creatinine clearance < 30 ml/mn, or serum creatinine > 30 mg/ml;
- Severe hepatic impairment, Child Pugh class C, elevation of AST and/or ALT > 3 x the ULN;
- Systolic Blood Pressure > 170 or < 90 mm Hg or diastolic blood pressure > 110 or < 50 mm Hg at screening;
- Cardiac disease contra-indicating any sexual activity;
- Unstable angina within 6 months before Visit 1;
- Angina during sexual intercourse within 6 months before Visit 1;
- Myocardial Infarction within 90 days before Visit 1;
- Coronary artery by-pass graft surgery or percutaneous coronary intervention (angioplasty or stent insert) within 90 days before Visit 1;
- Severe cardiac rhythm disturbances e.g. supraventricular arrhythmia with a ventricular response >100 bpm. at rest despite medical or device therapy, history of refractory spontaneous or induced sustained ventricular tachycardia (heart rate > 100 bpm. for > 30 sec) or fibrillation, automatic internal cardioverter-defibrillator, history of sudden cardiac arrest) within 6 months before Visit 1;
- Known new and significant conduction defect that was not evaluated with regard to significance within 90 days prior to Visit 1;
- Congestive heart failure (NYHA Class II or above) within 6 months before Visit 1;
- History of stroke within the 6 last months;
- Epilepsy not adequately controlled by treatment;
- Polycythemia with hematocrit >52% at study entry (i.e. screening visit/visit 1);
- Suspicion of current, or past history of prostate or breast cancer;
- Severe symptomatic Benign Prostate Hyperplasia;
- PSA value exceeding the age specific reference ranges published by Richardson and Oesterling, Urol Clin North Am, 1997, 24: 339-351
- Diagnosed sleep apnea;
- Extensive skin abnormalities that could affect absorption of the gel;
- Any clinically significant chronic disease that might, in the opinion of the investigator, compromise patient's safety, interfere with the evaluations, or preclude completion of the trial (e.g. hemochromatosis, chronic lung disease, chronic malabsorption disease);
- History of HIV infection;
- Severe psychiatric disease;
- Illiteracy, lack of fluency in the language used for the writing of the protocol and questionnaires, unwillingness, medical, psychiatric or other conditions that compromise the patient's ability to understand the patient information, to give informed consent, to understand or complete diary or questionnaires or otherwise comply with the trial protocol, or to complete the study;
- Known hypersensitivity to Cialis(Tadalafil);
- Hypersensitivity to the active substances or any of the excipients of Androgel®/ Testogel®;
- Use of androgen therapy or anabolic steroids within 6 months of entry into the study (i.e. screening visit/visit 1);
- Concurrent use of the following medications:
- androgens including dehydroepiandrosterone (DHEA) and anabolic steroids, antiandrogens, estrogens, corticotrophin (ACTH), oxyphenylbutazone, clomipramine, Serotonin Reuptake Inhibitors, long or short-acting nitrates, NO donors, potent cytochrome P3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, saquinavir, macrolides like erythromycin), cancer chemotherapy;
- Patients unwilling to cease use of vacuum devices, intracavernosal injection, Viagra, or other therapy for ED;
- Patients seeking conception or on treatment for infertility;
- Concurrent participation in another clinical trial within 1 month of entry into this study (i.e. screening visit/visit 1) or throughout the duration of the study;
- Previous randomization into this study.
- History of temporary or permanent partial or complete blindness
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Double-Blind, Placebo Controlled Randomized Study of Co-Administering Testosterone With PDE5 Inhibitors in 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.
Read the 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
- Descriptive statistics:
- 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
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 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).
- Conditions
- Erectile Dysfunction, Hypogonadism
- Being tested
- Testosterone gel, testosterone, placebo gel
- Keywords
- Erectile Dysfunction, Testosterone, Testosterone Therapy, PDE V Inhibitor, Tadalafil
- Medical subject headings
- Erectile Dysfunction, Hypogonadism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Testosterone gelDrug
Also called Androgel or Testogel
one sachet of 50 mg applied once a day, possibly titrated to two sachets if insufficient improvement of erectile function
testosteroneDrug
Also called Testogel or Androgel
testosterone gel, one sachet of 50 mg applied once a day, possibly titrated to 100 mg if insufficient effect
placebo gelOther
one sachet of placebo gel once a day possibly titrated to 2 sachets if insufficient efficacy
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Testosterone gel (intervention) Receives: Drug: Testosterone gel; Drug: testosterone |
| 2 | Placebo comparator | one sachet of placebo gel once a day, possibly titrated to 2 sachets if insufficient efficacy Receives: Other: placebo gel |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: V3,V4,V5,End Point
Secondary outcomes (7)
Rate of "responders" to treatment
Measured: V3,V4,V5,End Point
Rate of the patients having achieved a score > 26 at the EFD of the IIEF
Measured: V3,V4,V5,End Point
Mean scores at Questions 3 and 4 of the IIEF
Measured: V3,V4,V5,End Point
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
Measured: V3,V4,V5,End Point
% of "YES" responses at questions 2, 3, 4 and 5 of the SEP
Measured: V3,V4,V5,End Point
Percentage of "YES" responses to the GAQ
Measured: V3,V4,V5,End Point
Scores at the different domains of the AMS questionnaire
Measured: V3,V4,V5,End Point
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Oct 2005 (estimated)
- Study startOct 2005
- Primary completionJul 2007
- Study completionJul 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Erectile DysfunctionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 173 participants (actual)
Sponsor and investigators
- Lead sponsor
- SELARL du Dr Jacques BUVAT
- Sponsor type
- University, hospital or other
- Collaborators
- Bayer
- Investigators
- Jacques BUVAT, MD, Study chair, SELARL du Dr Jacques BUVATEugene PLAS, MD, Principal investigator, Lainz Hospital Vienna - AustriaClaude SCHULMAN, MD, Principal investigator, Erasme Hospital BrusselsFrancois GIULIANO, MD, Principal investigator, Hopital Raymond Poincaré - Garches - FranceBéatrice CUZIN, MD, Principal investigator, CHU Edouard Herriot - Lyon - FranceMarie Hélène COLSON, MD, Principal investigator, Centre du Palais - Marseille - FranceHartmut PORST, MD, Principal investigator, Urological Office - Hamburg - GermanyChristian STIEF, MD, Principal investigator, Ludwig Maximilians Universität - Munchen - Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00244023
- Sponsor's protocol ID
- TADTEST
- Status last verified
- Aug 2008
- First submitted
- 23 Oct 2005
- Last updated
- 25 Aug 2008
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Lee H, Hwang EC, Oh CK, Lee S, Yu HS, Lim JS, Kim HW, Walsh T, Kim MH, Jung JH, Dahm P. Testosterone replacement in men with sexual dysfunction. Cochrane Database Syst Rev. 2024 Jan 15;1(1):CD013071. doi: 10.1002/14651858.CD013071.pub2.
PubMed 38224135
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Double-Blind, Placebo Controlled Randomized Study of Co-Administering Testosterone With PDE5 Inhibitors in Patients Non-Responders to PDE5 Inhibitors Alone
- ClinicalTrials.gov ID
- NCT00244023
- Acronym / sponsor ID
- TADTEST
- Conditions
- Erectile Dysfunction, Hypogonadism
- Keywords
- Erectile Dysfunction, Testosterone, Testosterone Therapy, PDE V Inhibitor, Tadalafil
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 173 participants (actual)
- Lead sponsor
- SELARL du Dr Jacques BUVATUniversity, hospital or other
- Collaborators
- Bayer
- Study start
- Oct 2005
- Primary completion
- Jul 2007 (actual)
- Study completion
- Jul 2007 (actual)
- First posted
- 25 Oct 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Descriptive statistics:
- 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
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 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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Testosterone gel, Drug: testosteroneTestosterone gel (intervention) |
| 2 | Placebo comparator | Other: placebo gelone sachet of placebo gel once a day, possibly titrated to 2 sachets if insufficient efficacy |
Who may qualify
- Ages
- 45 to 80 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- ED complaint ongoing for over 3 months;
- Age comprise between 45 and 80 years old;
- Had a stable heterosexual relationship for more than 3 months and anticipates having the same partner for all the study
- Has not responded adequately to the highest available dosage of Tadalafil or other PDE5 inhibitors (20 mg for Tadalafil and Vardenafil, 100 mg for Sildenafil) taken at least at 4 separate occasions, defined as: a score of 2,3 or 4 at Question 3 of the IIEF AND a score of 2 or 3 at Question 4 of the IIEF; measured prior to Visit 1
- Low or low-to-normal serum testosterone level (either on total or bioavailable testosterone levels) with respect to the range of men under aged than 50 y.o. (TT < 4 ng/ml and/or BT < 1 ng/ml) according to a first assay done prior to Visit 1 and a confirmation by a second assay at central laboratory Biolille on blood sampled at Visit 1
Key exclusion criteria (41 listed)
- Impotence caused by other primary sexual disorder (e.g. premature ejaculation);
- History of penile implant or significant penile deformity;
- Body mass index >35kg/m2;
- Diabetes mellitus that is uncontrolled (HbA1c level > 10%). HbA1c will be checked at screening for each diabetic patient or suspected to be;
- Uncontrolled thyroid disorders;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Testosterone gelAlso: Androgel or Testogelone sachet of 50 mg applied once a day, possibly titrated to two sachets if insufficient improvement of erectile function | Drug | 1 |
| testosteroneAlso: Testogel or Androgeltestosterone gel, one sachet of 50 mg applied once a day, possibly titrated to 100 mg if insufficient effect | Drug | 1 |
| placebo gelone sachet of placebo gel once a day possibly titrated to 2 sachets if insufficient efficacy | Other | 2 |
Primary outcome
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
7 secondary outcomes
Rate of "responders" to treatment
Time frame: V3,V4,V5,End Point
Rate of the patients having achieved a score > 26 at the EFD of the IIEF
Time frame: V3,V4,V5,End Point
Mean scores at Questions 3 and 4 of the IIEF
Time frame: V3,V4,V5,End Point
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
% of "YES" responses at questions 2, 3, 4 and 5 of the SEP
Time frame: V3,V4,V5,End Point
Percentage of "YES" responses to the GAQ
Time frame: V3,V4,V5,End Point
Scores at the different domains of the AMS questionnaire
Time frame: V3,V4,V5,End Point
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Aug 2008.
- Derived from this study: PubMed 38224135Lee H, Hwang EC, Oh CK, Lee S, Yu HS, Lim JS, Kim HW, Walsh T, Kim MH, Jung JH, Dahm P. Testosterone replacement in men with sexual dysfunction. Cochrane Database Syst Rev. 2024 Jan 15;1(1):CD013071. doi: 10.1002/14651858.CD013071.pub2.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jacques BUVAT, MD study chair
SELARL du Dr Jacques BUVAT
Eugene PLAS, MD principal investigator
Lainz Hospital Vienna - Austria
Claude SCHULMAN, MD principal investigator
Erasme Hospital Brussels
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Testosterone gel and testosterone in people with Erectile Dysfunction and Hypogonadism, run by SELARL du Dr Jacques BUVAT at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 41 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Aug 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00244023, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2008.