Co-Administering Testosterone With PDE5 Inhibitors in ED Patients Non Responders to PDE5 Inhibitors Alone
Condition: Erectile Dysfunction; Hypogonadism
MeSH terms: Erectile Dysfunction; Hypogonadism
Study type: Interventional
Phase: Phase 3

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.
    

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).
    

Intervention name(s): Testosterone gel; testosterone; placebo gel
Intervention type(s): Drug; Drug; Other
Intervention description(s): one sachet of 50 mg applied once a day, possibly titrated to two sachets if insufficient improvement of erectile function; testosterone gel, one sachet of 50 mg applied once a day, possibly titrated to 100 mg if insufficient effect; one sachet of placebo gel once a day possibly titrated to 2 sachets if insufficient efficacy
Other intervention name(s): Androgel or Testogel; Testogel or Androgel
Intervention MeSH terms: Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Erectile Dysfunction; Testosterone; Testosterone Therapy; PDE V Inhibitor; Tadalafil