Tadalafil in Preventing Erectile Dysfunction in Patients With Prostate Cancer Treated With Radiation Therapy

Study Overview
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Brief Summary
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RATIONALE: Tadalafil may help prevent erectile dysfunction (ED) in patients with prostate cancer that has been treated with radiation therapy. It is not yet known whether tadalafil is more effective than a placebo in preventing erectile dysfunction. PURPOSE: This randomized phase III trial is studying tadalafil to see how well it works compared with a placebo in preventing erectile dysfunction in patients with prostate cancer treated with radiation therapy.

Detailed Description
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OBJECTIVES: Primary To determine whether tadalafil maintains spontaneous (off-drug) erectile function, as measured by the International Index of Erectile Function (IIEF) as compared to placebo at weeks 28-30 after initiation of radiotherapy in patients with prostate cancer. Secondary Determine the difference in spontaneous (off-drug) erectile function between tadalafil and placebo at 1 and 2 years. Determine the difference in overall sexual function as measured by the IIEF between tadalafil and placebo at weeks 28-30 and at 1 and 2 years. Determine differences in patient and partner overall sexual satisfaction as measured by the Sexual Adjustment Questionnaire (SAQ) between tadalafil and placebo at weeks 28-30 and at 1 and 2 years. Determine differences in patient and partner marital adjustment as measured by Locke's Marital Adjustment Test (LMAT) between tadalafil and placebo at weeks 28-30 and at 1 and 2 years. Determine associations between patient and partner overall sexual satisfaction as measured by SAQ and patient and partner marital adjustment as measured by LMAT at weeks 28-30 and at 1 and 2 years. Determine patient-related factors (i.e., age, pretreatment sexual response, tobacco use, and comorbidities) that may predict response to tadalafil therapy at weeks 28-30 and at 1 and 2 years. Determine the difference in adverse events between tadalafil and placebo as assessed by Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0 criteria. Tertiary Characterization of preference and erectile function among patients who choose to stay on (or if on placebo, to start) tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor other than tadalafil, a non-PDE5-inhibitor erectile aide, or no PDE5 inhibitor or erectile aide at 28-30 weeks and at 1 and 2 years. Identification of radiotherapy factors (i.e., modality, prescribed total dose, planning target volume margin, penile bulb dose-volume parameters) associated with erectile function. Evaluation of the number of patients screened for eligibility, the number eligible that are presented the study, the number who refuse, and the number who are accrued. OUTLINE: This is a multicenter study. Patients are stratified according to age (≤ 65 years vs > 65 years) and radiotherapy treatment (external beam radiation therapy vs brachytherapy*). Patients are randomized to 1 of 2 treatment arms. Note: * Radiotherapy start date for brachytherapy patients is the date of the procedure. All patients undergo either external beam radiotherapy alone to the prostate ± seminal vesicles only or low-dose rate permanent brachytherapy alone. Arm I: Beginning ≤ 7 days after the start of radiotherapy, patients receive oral tadalafil once daily for 24 weeks in the absence of disease progression or unacceptable toxicity. Arm II: Beginning ≤ 7 days after the start of radiotherapy, patients receive oral placebo once daily for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients complete the International Index of Erectile Function (IIEF), the Sexual Adjustment Questionnaire (SAQ), the Locke's Marital Adjustment Test (LMAT) (if applicable), and the Expanded Prostate Cancer Index Composite Sexual Medications and Devices Evaluations Supplement questionnaires periodically. Partners or spouses complete the SAQ-Partner, LMAT (if applicable), and IIEF questionnaires periodically. After completion of study treatment, patients are followed at 28-30 weeks, and annually for up to 2 years.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase III Trial to Evaluate the Effectiveness of a Phosphodiesterase 5 Inhibitor, Tadalafil, in Prevention of Erectile Dysfunction in Patients Treated With Radiotherapy for Prostate Cancer

Conditions
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Prostate Cancer, Sexual Dysfunction

Intervention / Treatment
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* Drug: Tadalafil
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical stage T1b-T2b (AJCC, 6th ed.) adenocarcinoma of the prostate within 6 months of registration Clinically negative lymph nodes as established by imaging (pelvic ± abdominal CT or MR), nodal sampling, or dissection within 3 months prior to registration. Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are ≤ 1.5 cm. Lymph node assessment is optional, and at investigator discretion, for patients with Gleason Score <7. No evidence of bone metastases (M0) on bone scan within 3 months prior to registration. Equivocal bone scan findings are allowed if plain films are negative for metastasis. Bone metastases assessment is optional, and at investigator discretion, for patients with Gleason Score <7. Baseline serum prostatic specific antigen (PSA) value performed with an FDA-approved assay (e.g., Abbott, Hybritech) within 3 months prior to registration. -4.1 Any of the following combinations of factors (NOTE: tumor found in 1 or both lobes on biopsy, but not palpable, will not alter T stage): T1b-T2b disease, Gleason Score <7 and serum total PSA that is <20 ng/ml or T1b-T2b disease, Gleason Score ≥7 and PSA that is <15 ng/ml Serum total testosterone level prior to the initiation of radiation therapy (RT) within normal range according to institutional guidelines Zubrod Performance Status 0 or 1 (Appendix III) Age ≥ 18 years Treatment that will consist of either external beam RT alone to the prostate ± seminal vesicles only at a dose between 75 Gy and 79.2 Gy or brachytherapy alone (NOTE: treatment with combined external RT and brachytherapy excludes patient participation) Pretreatment (before starting prostate cancer treatment) erectile function as measured by IIEF Question 1, How often were you able to get an erection during sexual activity? - with responses of: sometimes (about half the time) [response 3] or most times (much more than half the time) [response 4] or almost always/always [response 5] History of prior tadalafil use: Document usual dosage per sexual encounter, date of last dose, and patient's response (No; Yes-Unsatisfactory Response; Yes-Satisfactory Response). Regardless of past experience, the patient is eligible if he agrees to adhere to protocol and take only tadalafil or placebo prescribed on study. Although patients with partners are targeted for recruitment, patients without partners or without partners willing to participate are eligible. Patients (and spouses/partners, if willing to participate) must be able to provide study-specific informed consent. Exclusion Criteria: The patient's participation in another medical research study that involves the treatment of ED Previous or concomitant invasive cancer (American Joint Committee on Cancer [AJCC] Stage >0), other than localized basal cell or squamous cell skin carcinoma (AJCC Stage 0-II), or a hematological malignancy (e.g., leukemia, lymphoma, myeloma) unless continually disease free for at least 5 years History of myocardial infarction within the last year Heart failure in the last 6 months Uncontrolled arrhythmias, hypotension (<90/50mm Hg), or uncontrolled hypertension (>170/100 mm Hg) Stroke within the last 6 months Use of luteinizing hormone-releasing hormone (LHRH) agonist androgen suppression (e.g., Lupron, Zoladex), anti-androgen (e.g., Casodex, Eulexin, Nilandron), or estrogenic (e.g., diethylstilbestrol) agents within the last 6 months Current use of any organic nitrate or as needed nitrates (e.g., use of nitroglycerin) Current use of cimetidine, ketoconazole, itraconazole, erythromycin, or ritonavir Known moderate to severe renal insufficiency or end-stage renal disease Known severe hepatic impairment Use of mechanical (vacuum) devices, intracorporeal, intraurethral, topical, or oral (sildenafil, tadalafil, vardenafil) agents as therapy for ED or supplements to enhance sexual function within 5-7 days prior to the start of RT. Patients who discontinue these therapies remain eligible if they can meet eligibility criteria Pretreatment (before starting prostate cancer treatment) ED as measured by IIEF Question 1, How often were you able to get an erection during sexual activity? - with responses of: no sexual activity [response 0] or almost never/never [response 1] or a few times (much less than half the time) [response 2] Prior penile implant or history of bilateral orchiectomy Prior prostatectomy, prostatic cryosurgery or high-intensity focused ultrasound (HIFU), radionuclide prostate brachytherapy, or chemotherapy for prostate cancer Prior or anticipated combined external RT and brachytherapy Prior or anticipated external RT to the pelvic ± para-aortic lymph nodes Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immunocompromised patients. Anatomical genital abnormalities or concurrent conditions that in the estimation of the physician would prohibit sexual intercourse or prevent study completion Major medical or psychiatric illness which, in the opinion of the investigator, would prevent completion of treatment or would interfere with follow-up

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tadalafil<br>Tadalafil | Drug: Tadalafil<br>* Beginning ≤ 7 days after the start of radiotherapy, patients receive oral tadalafil 5mg once daily for 24 weeks.<br>|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* Beginning ≤ 7 days after the start of radiotherapy, patients receive oral placebo once daily for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Maintaining Spontaneous (Off-drug) Erectile Function (EF) at Weeks 28-30 After Initiation of Radiation Therapy (RT) | EF is measured by Question 1 of the International Index of Erectile Function (IIEF). The IIEF is a validated 15-item for measuring patient-reported erectile function. Question 1 asks How often were you able to get an erection during sexual activity? Responses ranged from 0=no sexual activity, to 5=Almost always or always. Higher scores indicated better functioning. All patients have erectile function prior to initiation of RT, indicated by a score of 3, 4, or 5 on IIEF Q1. Patients with a lower IIEF Q1 score at weeks 28-30 than at baseline will have less erectile function and be categorized as nonresponders. Patients with similar or improved erectile function will be categorized as responders (maintaining). Patient-related predictors of at erectile function at this time point are also reported with this outcome measure. | Baseline and 30 weeks from the start of radiation therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Maintaining Spontaneous (Off-drug) EF at Years 1 and 2 After Initiation of RT | The International Index of Erectile Function (IIEF) is a validated 15-item for measuring patient-reported erectile function. Question 1 asks How often were you able to get an erection during sexual activity? Responses ranged from 0=no sexual activity, to 5=Almost always or always. Higher scores indicated better functioning. All patients have erectile function prior to initiation of RT, indicated by a score of 3, 4, or 5. Patients with a lower IIEF Q1 score at weeks 28-30 than at baseline will have less erectile function and be categorized as nonresponders. Patients with similar or improved erectile function will be categorized as responders (maintaining). Patient-related predictors of at erectile function at Years 1 and 2 are also reported with this outcome measure. | Baseline, 1 and 2 years from the start of tadalafil or placebo | 
| Overall Sexual Function as Measured by Change From Baseline in the International Index of Erectile Function (IIEF) | The IIEF is a validated 15-item for measuring patient-reported erectile function. A score of 0-5 is given to each of the 15 questions that examine 5 main domains of male sexual function: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Domain scores are the sum of each item. The erectile function domain has 5 items with a score range of 1-30, orgasmic function has 2 items with a score range of 0-10, sexual desire has 2 items with a score range of 0-10, intercourse satisfaction has 3 items with a score range of 0-15, and overall satisfaction has 2 items with a score range of 2-10. Total score ranges from 0-70, with higher scores indicated better functioning. Change from baseline is calculated by subtracting baseline score from score at the time point of interest. | Baseline, week 30, and years 1 and 2 from start of treatment | 
| Overall Patient Sexual Satisfaction as Measured by Change From Baseline in the Sexual Adjustment Questionnaire (SAQ) Score | The Sexual Adjustment Questionnaire (SAQ) is a 20-item questionnaire with an overall score range between 8 and 100 including the following domains: desire, ranging between 5 and 30; dysfunction, 0 and 25; activity, 0 and 10; satisfaction, 1 and 10; and fatigue, 1 and 5. The change in SAQ score is calculated by subtracting the baseline score from the follow-up score. A positive change indicates an improvement in sexual well-being. | Baseline, week 30 and years 1 and 2 after the start of treatment | 
| Overall Partner Sexual Satisfaction as Measured by Change From Baseline in the Sexual Adjustment Questionnaire-Partner (SAQ-P) Score | The SAQ-P is an 18-item questionnaire with an overall score range between 0 and 90 including the following domains: desire, dysfunction, activity, satisfaction, and fatigue. The change in SAQ score is calculated by subtracting the baseline score from the follow-up score. A positive change indicates an improvement in sexual well-being. | Baseline, week 30 and years 1 and 2 after the start of treatment | 
| Patient Marital Adjustment as Measured by the Locke's Marital Adjustment Test | The Locke Marital Adjustment Test (LMAT) is a 16-item questionnaire with scores ranging from 48 to 138 for participants. Higher scores indicate greater sexual function, sexual wellbeing, or marital adjustment. The change in LMAT score is calculated by subtracting the baseline score from the follow-up score. | Baseline, week 30 and years 1 and 2 after the start of treatment | 
| Partner Marital Adjustment as Measured by the Locke's Marital Adjustment Test | The Locke Marital Adjustment Test (LMAT) is a 16-item questionnaire with scores ranging from 48 to 138 for participants. Higher scores indicate greater sexual function, sexual wellbeing, or marital adjustment. The change in LMAT score is calculated by subtracting the baseline score from the follow-up score. | Baseline, week 30 and years 1 and 2 after the start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sexual dysfunction, stage IIB prostate cancer, stage IIA prostate cancer, adenocarcinoma of the prostate