Co-Administering Testosterone With PDE5 Inhibitors in ED Patients Non Responders to PDE5 Inhibitors Alone
Information source: SELARL du Dr Jacques BUVAT
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Erectile Dysfunction; Hypogonadism
Intervention: Testosterone gel (Drug); testosterone (Drug); placebo gel (Other)
Phase: Phase 3
Status: Completed
Sponsored by: SELARL du Dr Jacques BUVAT Official(s) and/or principal investigator(s): Jacques BUVAT, MD, Study Chair, Affiliation: SELARL du Dr Jacques BUVAT Eugene PLAS, MD, Principal Investigator, Affiliation: Lainz Hospital Vienna - Austria Claude SCHULMAN, MD, Principal Investigator, Affiliation: Erasme Hospital Brussels Francois GIULIANO, MD, Principal Investigator, Affiliation: Hopital Raymond Poincaré - Garches - France Béatrice CUZIN, MD, Principal Investigator, Affiliation: CHU Edouard Herriot - Lyon - France Marie Hélène COLSON, MD, Principal Investigator, Affiliation: Centre du Palais - Marseille - France Hartmut PORST, MD, Principal Investigator, Affiliation: Urological Office - Hamburg - Germany Christian STIEF, MD, Principal Investigator, Affiliation: Ludwig Maximilians Universität - Munchen - Germany Aksam YASSIN, MD, Principal Investigator, Affiliation: Urological Office - Hamburg - Germany Theodor KLOTZ, MD, Principal Investigator, Affiliation: Klinikum fur Urologie - Weiden - Germany Francesco MONTORSI, MD, Principal Investigator, Affiliation: Hospital San Raffaele - Milano - Italy Mario MAGGI, MD, Principal Investigator, Affiliation: Andrology Unit - Florence - Italy Anti KAIPIA, MD, Principal Investigator, Affiliation: Gynecologi - Ja Urologikeskus - Tampere - Finland Eric MEULEMAN, MD, Principal Investigator, Affiliation: Free University Medical Center - Amsterdam - The Netherlands Antonio MARTIN MORALES, MD, Principal Investigator, Affiliation: Hospital Carlos Haya - Malaga - SPAIN Ignacio MONCADA, MD, Principal Investigator, Affiliation: Hospital Gregorio Maranon - Madrid - SPAIN John DEAN, MD, Principal Investigator, Affiliation: Salisbury Clinic - Plymouth - UK Ian EARDLEY, MD, Principal Investigator, Affiliation: Leeds Hospital - Leeds - UK Jacques BUVAT, MD, Principal Investigator, Affiliation: CETPARP - Lille - France
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
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.
Clinical Details
Official title: Double-Blind, Placebo Controlled Randomized Study of Co-Administering Testosterone With PDE5 Inhibitors in Patients Non-Responders to PDE5 Inhibitors Alone
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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.
Secondary outcome: Rate of "responders" to treatmentRate of the patients having achieved a score > 26 at the EFD of the IIEF Mean scores at Questions 3 and 4 of the IIEF 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 % of "YES" responses at questions 2, 3, 4 and 5 of the SEP Percentage of "YES" responses to the GAQ Scores at the different domains of the AMS questionnaire
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 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:
1. 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
2. Analysis of variance (ANOVA): comparing the mean values of a continuous
quantitative variable between the level of categorical factors (e. g. 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 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).
Eligibility
Minimum age: 45 Years.
Maximum age: 80 Years.
Gender(s): Male.
Criteria:
Inclusion Criteria:
1. ED complaint ongoing for over 3 months;
2. Age comprise between 45 and 80 years old;
3. Had a stable heterosexual relationship for more than 3 months and anticipates having
the same partner for all the study
4. 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
5. 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
6. 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
7. 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?").
8. 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
9. Agrees not to use any other ED drug or non-drug (devices) treatment during the full
course of the study;
10. Provides a signed informed consent.
Exclusion Criteria:
1. Impotence caused by other primary sexual disorder (e. g. premature ejaculation);
2. History of penile implant or significant penile deformity;
3. Body mass index >35kg/m2;
4. Diabetes mellitus that is uncontrolled (HbA1c level > 10%). HbA1c will be checked at
screening for each diabetic patient or suspected to be;
5. Uncontrolled thyroid disorders;
6. Known hyperprolactinemia (serum prolactin > 30ng/ml in local laboratory);
7. Organic hypothalamic-pituitary pathology;
8. History of alcohol, drug or substance abuse within 6 months before Visit 1;
9. Renal insufficiency defined as receiving renal dialysis, having a creatinine
clearance < 30 ml/mn, or serum creatinine > 30 mg/ml;
10. Severe hepatic impairment, Child Pugh class C, elevation of AST and/or ALT > 3 x the
ULN;
11. Systolic Blood Pressure > 170 or < 90 mm Hg or diastolic blood pressure > 110 or < 50
mm Hg at screening;
12. Cardiac disease contra-indicating any sexual activity;
13. Unstable angina within 6 months before Visit 1;
14. Angina during sexual intercourse within 6 months before Visit 1;
15. Myocardial Infarction within 90 days before Visit 1;
16. Coronary artery by-pass graft surgery or percutaneous coronary intervention
(angioplasty or stent insert) within 90 days before Visit 1;
17. 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;
18. Known new and significant conduction defect that was not evaluated with regard to
significance within 90 days prior to Visit 1;
19. Congestive heart failure (NYHA Class II or above) within 6 months before Visit 1;
20. History of stroke within the 6 last months;
21. Epilepsy not adequately controlled by treatment;
22. Polycythemia with hematocrit >52% at study entry (i. e. screening visit/visit 1);
23. Suspicion of current, or past history of prostate or breast cancer;
24. Severe symptomatic Benign Prostate Hyperplasia;
25. PSA value exceeding the age specific reference ranges published by Richardson and
Oesterling, Urol Clin North Am, 1997, 24: 339-351
26. Diagnosed sleep apnea;
27. Extensive skin abnormalities that could affect absorption of the gel;
28. 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);
29. History of HIV infection;
30. Severe psychiatric disease;
31. 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;
32. Known hypersensitivity to Cialis(Tadalafil);
33. Hypersensitivity to the active substances or any of the excipients of Androgel®/
Testogel®;
34. Use of androgen therapy or anabolic steroids within 6 months of entry into the study
(i. e. screening visit/visit 1);
35. 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;
36. Patients unwilling to cease use of vacuum devices, intracavernosal injection, Viagra,
or other therapy for ED;
37. Patients seeking conception or on treatment for infertility;
38. 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;
39. Previous randomization into this study.
40. History of temporary or permanent partial or complete blindness
Locations and Contacts
CETPARP/SelarlJBuvat, Lille 59000, France
Additional Information
Starting date: October 2005
Last updated: August 22, 2008
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