Male Erectile Disorder, Prostate Cancer, Radiation Toxicity
Conditions
Keywords
radiation toxicity, male erectile disorder, prostate cancer
Brief summary
RATIONALE: L-arginine supplements may improve the quality of life and erectile function in men who are prostate cancer survivors. PURPOSE: This randomized phase II trial is studying how well L-arginine supplementation works with or without enzyme inhibitors in treating erectile function and quality of life of prostate cancer survivors previously treated with radiation therapy.
Detailed description
OBJECTIVES: Primary * To determine the best dose (defined as the dose that shows the greatest improvement in the erectile function domain of the International Index of Erectile Function \[IIEF\] after 8 weeks of therapy) of an L-arginine/Korean ginseng/gingko biloba/damiana-based supplement (L-arginine) to be used in a subsequent phase III trial in prostate cancer survivors previously treated with radiotherapy. Secondary * Evaluate the toxicity of treatment with L-arginine with or without phosphodiesterase-5 inhibitors. * Estimate trial accrual, retention, adherence, and variability. * Assess changes in quality of life (QOL) and sexual function as defined by changes in the QOL of these patients using the Expanded Prostate Cancer Index Composite, changes in the other domains of the IIEF (i.e., orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), changes in the Sexual Encounter Profile, and changes in the percentage of yes (positive) responses to either of the two global efficacy questions. OUTLINE: Patients are stratified according to age (\< 65 years vs ≥ 65 years) and current use of phosphodiesterase-5 (PDE-5) inhibitors (yes vs no). Patients are randomized to 1 of 3 treatment arms. * Arm I: Patients receive oral placebo twice daily (total of 6 capsules per day). * Arm II: Patients receive oral L-arginine and oral placebo twice daily (total of 3 capsules of each per day). * Arm III: Patients receive oral L-arginine twice daily (total of 6 capsules per day). In all arms, treatment continues for 8 weeks in the absence of unacceptable toxicity. Patients may also receive oral sildenafil, tadalafil, or vardenafil (PDE-5 inhibitors). Patients complete the International Index of Erectile Function and the Expanded Prostate Cancer Index Composite-26 at baseline and at weeks 4 and 8. Patients also complete the Sexual Encounter Profile Questionnaire, FACT-P, and the Global Efficacy Questionnaire at weeks 4 and 8.
Interventions
OTHERPlacebo
Given orally
DRUGOral L-Arginine
Given orally 3 capsules ArginMax and 3 Placebo capsules
Sponsors
National Cancer Institute (NCI)
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male prostate cancer survivor previously treated with radiotherapy and who identifies himself as concerned with sexual quality of life, including erectile dysfunction. (seed implants are eligible) * Had successful sexual activity prior to the commencement of radiotherapy. * Erectile dysfunction, defined as inability to achieve or maintain an erection sufficient for satisfactory sexual performance * Interested in sexual activity and agrees to make at least one sexual intercourse attempt with a partner every week during the study. * The usage of PDE-5 inhibitors will be voluntary and will serve as a stratification factor. Patients taking PDE-5 inhibitors must agree to assume the responsibility for the cost of PDE-5 inhibitor treatment during the protocol period (8 week period) as this is not covered in the cost of the trial. * Patients currently taking PDE-5 inhibitors sildenafil (Viagra®, Pfizer Pharmaceuticals), tadalafil(Cialis®, Lilly ICOS, LLC), and vardenafil (Levitra®, Bayer Healthcare / Schering Plough Corp.)must agree to take the medication only as prescribed by their treating physician. * Patients taking PDE-5 inhibitors as part of this study must be on a stable dose of drug for at least one month prior to study entry. * Must be able to take oral medications. * \> 6 months following completion of all cancer therapy * No evidence of prostate cancer * Prior malignancies allowed if no evidence of recurrent disease. * If previously taken LHRH agonist androgen suppression (e.g, Lupron, Zoladex), anti-androgen (e.g., Casodex, Eulexin, Nilandron), or estrogenic (e.g., diethylstilbestrol) agents, serum testosterone must have returned to the laboratory normal range * No planned surgery while on protocol or for 4 weeks following completion of protocol * Prior cystoscopy is permitted. * Age \> 18 * ECOG performance status 0/1. * Patients must agree not to start taking an herbal product for erectile dysfunction during the eight weeks of study intervention.
Exclusion criteria
* No other concurrent erectile dysfunction therapies permitted (i.e. vacuum pump,cavernosal injections, and other drug therapies). Past use of these and other therapies permitted if the patient can meet the inclusion criteria above. * No testosterone supplementation permitted. * Use of 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. * Prior prostate or lower genitourinary surgery (bladder, penis, urethra, testicles)including transurethral resection of prostate (TURP). (Prior vasectomy is allowed) * Serious cardiovascular disease (unstable angina, supraventricular arrhythmia, myocardial infarction, symptomatic congestive heart failure, cardiac arrhythmia, coronary artery bypass surgery within 6 months prior to registration). * Hypotension (\<90/50mm Hg), or uncontrolled hypertension (\>170/100 mm Hg) * Stroke or spinal cord injury within 6 months before registration. * Patients on Persantine, heparin, Lovenox, warfarin, ginkgo biloba, Plavix, Disalcid, other blood-thinning medication or with a history of bleeding disorders will be excluded.(Aspirin \< 325mg allowed) * Current use of cimetidine, ketoconazole, itraconazole, erythromycin, or ritonavir. Major medical or psychiatric illness which, in the opinion of the investigator, would prevent completion of treatment or would interfere with follow-up. * Current or prior use of any organic nitrate within the last 6 months (e.g., use of nitroglycerin) * May not receive other investigational agents or devices during 30 days prior to start of study drug. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to ArginMax (l-arginine, ginseng, or ginkgo biloba)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| International Index of Erectile Function (IIEF) | 8 weeks | The International Index of Erectile Function (IIEF) questionnaire consists of 15 questions, each of which is scored on a 0 to 5 or 1 to 5 scale. It is comprised of five domains, each scored as the sum of 2 to 5 questions. Erectile function is the sum of six questions with a range from 1 to 30. Higher scores indicate better functioning. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Retention | 8 weeks | Retention is the percentage of participants who complete the 8 week visit. |
| Adherence | 8 weeks | Adherence is the percentage of prescribed pills taken by the participants |
| Assessment of Quality of Life | 8 weeks | Quality of life is quantified by the Functional Assessment of Cancer Therapy - Prostate (FACT\_P) questionnaire. The FACT questionnaire is comprised of four subscales - social, emotional, functional, and physical. Each subscale is obtained by summing over 6-7 items, each of which is coded on a 0 to 4 scale. Negatively worded questions are reverse scored and higher scores for each subscale indicate better HRQOL. The social, functional, and physical subscales range from 0 to 28 while the emotional subscale ranges from 0 to 24. The overall score (FACT-G) is the sum over the four subscales and ranges from 0 to 108. Patients also completed 12 questions related to prostate cancer, and the prostate subscale score is the sum of those responses (with some items reverse scored). Scores range from 0 to 48, and as with the other FACT subscales higher scores indicate better HRQOL. FACT-P is the sum of FACT-G and the prostate subscale. This questionnaire was added half-way through the study. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I - Placebo Patients receive oral placebo twice daily (total of 6 capsules per day).
Placebo: Given orally | 48 |
| Arm II - Low Dose Patients receive oral L-arginine and oral placebo twice daily (total of 3 capsules of each per day).
Placebo: Given orally
Oral L-Arginine: Given orally 3 capsules ArginMax and 3 Placebo capsules | 45 |
| Arm III - High Dose Oral L-arginine twice daily = 6 capsules per day.
Oral L-Arginine: Given orally 3 capsules ArginMax and 3 Placebo capsules
Oral L-Arginine: Patients will take 6 capsules of ArginMax twice daily | 47 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Multiple Reasons | 3 | 0 | 2 |
| Overall Study | Never Started | 2 | 2 | 4 |
| Overall Study | Toxicity | 1 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 6 | 2 |
Baseline characteristics
| Characteristic | Total | Arm I - Placebo | Arm II - Low Dose | Arm III - High Dose |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 100 Participants | 34 Participants | 32 Participants | 34 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 14 Participants | 13 Participants | 13 Participants |
| Age, Continuous | 68 years | 68 years | 68 years | 67 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 133 Participants | 45 Participants | 43 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 47 Participants | 13 Participants | 17 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 91 Participants | 35 Participants | 28 Participants | 28 Participants |
| Region of Enrollment United States | 140 participants | 48 participants | 45 participants | 47 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 140 Participants | 48 Participants | 45 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 41 | 16 / 42 | 10 / 42 |
| serious Total, serious adverse events | 1 / 41 | 1 / 42 | 0 / 42 |
Outcome results
Primary
International Index of Erectile Function (IIEF)
The International Index of Erectile Function (IIEF) questionnaire consists of 15 questions, each of which is scored on a 0 to 5 or 1 to 5 scale. It is comprised of five domains, each scored as the sum of 2 to 5 questions. Erectile function is the sum of six questions with a range from 1 to 30. Higher scores indicate better functioning.
Time frame: 8 weeks
Population: All participants providing data at any time.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm I - Placebo | International Index of Erectile Function (IIEF) | 14.62 units on a scale | Standard Error 1.09 |
| Arm II - Low Dose | International Index of Erectile Function (IIEF) | 14.26 units on a scale | Standard Error 1.13 |
| Arm III - High Dose | International Index of Erectile Function (IIEF) | 11.82 units on a scale | Standard Error 1.11 |
Secondary
Adherence
Adherence is the percentage of prescribed pills taken by the participants
Time frame: 8 weeks
Population: Participants who returned pill diaries.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I - Placebo | Adherence | 96.5 percentage of prescribed pills |
| Arm II - Low Dose | Adherence | 95.0 percentage of prescribed pills |
| Arm III - High Dose | Adherence | 95.0 percentage of prescribed pills |
Secondary
Assessment of Quality of Life
Quality of life is quantified by the Functional Assessment of Cancer Therapy - Prostate (FACT\_P) questionnaire. The FACT questionnaire is comprised of four subscales - social, emotional, functional, and physical. Each subscale is obtained by summing over 6-7 items, each of which is coded on a 0 to 4 scale. Negatively worded questions are reverse scored and higher scores for each subscale indicate better HRQOL. The social, functional, and physical subscales range from 0 to 28 while the emotional subscale ranges from 0 to 24. The overall score (FACT-G) is the sum over the four subscales and ranges from 0 to 108. Patients also completed 12 questions related to prostate cancer, and the prostate subscale score is the sum of those responses (with some items reverse scored). Scores range from 0 to 48, and as with the other FACT subscales higher scores indicate better HRQOL. FACT-P is the sum of FACT-G and the prostate subscale. This questionnaire was added half-way through the study.
Time frame: 8 weeks
Population: All participants who completed the FACT\_P at any time.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm I - Placebo | Assessment of Quality of Life | 128.54 units on a scale | Standard Error 3.11 |
| Arm II - Low Dose | Assessment of Quality of Life | 128.67 units on a scale | Standard Error 3.08 |
| Arm III - High Dose | Assessment of Quality of Life | 127.41 units on a scale | Standard Error 3.15 |
Secondary
Retention
Retention is the percentage of participants who complete the 8 week visit.
Time frame: 8 weeks
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I - Placebo | Retention | 79.2 percentage of participants |
| Arm II - Low Dose | Retention | 75.6 percentage of participants |
| Arm III - High Dose | Retention | 78.7 percentage of participants |