Double-Blind, Placebo Controlled Randomized Study of Co-Administering Testosterone With PDE5 Inhibitors in Patients Non-Responders to PDE5 Inhibitors Alone
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 173
- 试验地点
- 1
- 主要终点
- 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.
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 45 Years 至 80 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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);
- •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
研究组 & 干预措施
1
Testosterone gel (intervention)
干预措施: Testosterone gel (Drug)
1
Testosterone gel (intervention)
干预措施: testosterone (Drug)
2
one sachet of placebo gel once a day, possibly titrated to 2 sachets if insufficient efficacy
干预措施: placebo gel (Other)
结局指标
主要结局
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.
时间窗: V3,V4,V5,End Point
次要结局
- Rate of "responders" to treatment(V3,V4,V5,End Point)
- Rate of the patients having achieved a score > 26 at the EFD of the IIEF(V3,V4,V5,End Point)
- Mean scores at Questions 3 and 4 of the IIEF(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(V3,V4,V5,End Point)
- % of "YES" responses at questions 2, 3, 4 and 5 of the SEP(V3,V4,V5,End Point)
- Percentage of "YES" responses to the GAQ(V3,V4,V5,End Point)
- Scores at the different domains of the AMS questionnaire(V3,V4,V5,End Point)