L-Arginine Supplementation With or Without Enzyme Inhibitors Treating Erectile Function of Prostate Cancer Survivors

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Completed
• CT.gov ID: NCT01105130
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 140
• Location: 1
• Arms: 3
• Actual Duration (Months): 40.1
• Patients Per Site Per Month: 3.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Male Erectile Disorder; Prostate Cancer; Radiation Toxicity	Other: Placebo; Drug: Oral L-Arginine; Drug: Oral L-Arginine	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Randomized Phase II Dose Finding Study of ArginMax for Its Effect on Erectile Function and Quality of Life in Survivors of Prostate Cancer Previously Treated With Radiotherapy
• Actual Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Feb 4, 2014
• Actual Study Completion Date: Feb 4, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Arm I - Placebo Patients receive oral placebo twice daily (total of 6 capsules per day).	Other: Placebo; Given orally
Experimental: Arm II - low dose Patients receive oral L-arginine and oral placebo twice daily (total of 3 capsules of each per day).	Other: Placebo; Given orally; Drug: Oral L-Arginine; Given orally 3 capsules ArginMax and 3 Placebo capsules; Other Names: ArginMax Placebo
Experimental: Arm III - high dose Oral L-arginine twice daily = 6 capsules per day.	Drug: Oral L-Arginine; Given orally 3 capsules ArginMax and 3 Placebo capsules; Other Names: ArginMax Placebo ; Drug: Oral L-Arginine; Patients will take 6 capsules of ArginMax twice daily; Other Names: ArginMax

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Retention [8 weeks]

   Retention is the percentage of participants who complete the 8 week visit.

2. Adherence [8 weeks]

   Adherence is the percentage of prescribed pills taken by the participants

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	W F Baptist Health	Winston-Salem	North Carolina	United States	27157

Sponsors and Collaborators

• Wake Forest University Health Sciences
• National Cancer Institute (NCI)

Investigators

• Study Chair: James J. Urbanic, MD, Wake Forest University Health Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT01105130
• Other Study ID Numbers: IRB00012793; U10CA081851; REBACCCWFU 98110
• First Posted: Apr 16, 2010
• Last Update Posted: Sep 28, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Wake Forest University Health Sciences: radiation toxicity; male erectile disorder; prostate cancer
• Additional relevant MeSH terms: Prostatic Neoplasms; Erectile Dysfunction

Study Results

Participant Flow

Arm/Group Title	Arm I - Placebo	Arm II - Low Dose	Arm III - High Dose
Arm/Group Description	Patients receive oral placebo twice daily (total of 6 capsules per day). Placebo: Given orally	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	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
Period Title: Overall Study
STARTED	48	45	47
COMPLETED	38	34	37
NOT COMPLETED	10	11	10

Baseline Characteristics

Arm/Group Title	Arm I - Placebo	Arm II - Low Dose	Arm III - High Dose	Total
Arm/Group Description	Patients receive oral placebo twice daily (total of 6 capsules per day). Placebo: Given orally	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	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	Total of all reporting groups
Overall Participants	48	45	47	140
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 29.2%	13 28.9%	13 27.7%	40 28.6%
>=65 years	34 70.8%	32 71.1%	34 72.3%	100 71.4%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68	68	67	68
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	48 100%	45 100%	47 100%	140 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.1%	1 2.2%	0 0%	2 1.4%
Not Hispanic or Latino	45 93.8%	43 95.6%	45 95.7%	133 95%
Unknown or Not Reported	2 4.2%	1 2.2%	2 4.3%	5 3.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	2 4.3%	2 1.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	13 27.1%	17 37.8%	17 36.2%	47 33.6%
White	35 72.9%	28 62.2%	28 59.6%	91 65%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	48 100%	45 100%	47 100%	140 100%

Outcome Measures

1. Primary Outcome

Title	International Index of Erectile Function (IIEF)
Description	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

Outcome Measure Data

Analysis Population Description

All participants providing data at any time.

Arm/Group Title	Arm I - Placebo	Arm II - Low Dose	Arm III - High Dose
Arm/Group Description	Patients receive oral placebo twice daily (total of 6 capsules per day). Placebo: Given orally	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	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
Measure Participants	46	43	46
Least Squares Mean (Standard Error) [units on a scale]	14.62 (1.09)	14.26 (1.13)	11.82 (1.11)

2. Secondary Outcome

Title	Retention
Description	Retention is the percentage of participants who complete the 8 week visit.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Arm I - Placebo	Arm II - Low Dose	Arm III - High Dose
Arm/Group Description	Patients receive oral placebo twice daily (total of 6 capsules per day). Placebo: Given orally	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	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
Measure Participants	48	45	46
Number (95% Confidence Interval) [percentage of participants]	79.2 165%	75.6 168%	78.7 167.4%

3. Secondary Outcome

Title	Adherence
Description	Adherence is the percentage of prescribed pills taken by the participants
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Participants who returned pill diaries.

Arm/Group Title	Arm I - Placebo	Arm II - Low Dose	Arm III - High Dose
Arm/Group Description	Patients receive oral placebo twice daily (total of 6 capsules per day). Placebo: Given orally	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	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
Measure Participants	42	41	40
Mean (Full Range) [percentage of prescribed pills]	96.5	95.0	95.0

4. Secondary Outcome

Title	Assessment of Quality of Life
Description	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

Outcome Measure Data

Analysis Population Description

All participants who completed the FACT_P at any time.

Arm/Group Title	Arm I - Placebo	Arm II - Low Dose	Arm III - High Dose
Arm/Group Description	Patients receive oral placebo twice daily (total of 6 capsules per day). Placebo: Given orally	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	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
Measure Participants	24	26	27
Least Squares Mean (Standard Error) [units on a scale]	128.54 (3.11)	128.67 (3.08)	127.41 (3.15)

Adverse Events

Time Frame	8 weeks of treatment plus 4 weeks after treatment ends
Adverse Event Reporting Description	The sample size for this section was the number of participants in each arm who had post-randomization toxicity data recorded.
Arm/Group Title	Arm I - Placebo		Arm II - Low Dose		Arm III - High Dose
Arm/Group Description	Patients receive oral placebo twice daily (total of 6 capsules per day). Placebo: Given orally		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		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
All Cause Mortality
	Arm I - Placebo		Arm II - Low Dose		Arm III - High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I - Placebo		Arm II - Low Dose		Arm III - High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/41 (2.4%)		1/42 (2.4%)		0/42 (0%)
Gastrointestinal disorders
Vomiting	0/41 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/41 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I - Placebo		Arm II - Low Dose		Arm III - High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/41 (31.7%)		16/42 (38.1%)		10/42 (23.8%)
Gastrointestinal disorders
Constipation	1/41 (2.4%)	1	2/42 (4.8%)	2	0/42 (0%)	0
Diarrhea	0/41 (0%)	0	2/42 (4.8%)	2	0/42 (0%)	0
Dyspepsia	4/41 (9.8%)	4	1/42 (2.4%)	1	3/42 (7.1%)	3
Gastrointestional Disorder - Other	0/41 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Nausea	2/41 (4.9%)	2	2/42 (4.8%)	2	2/42 (4.8%)	3
Vomiting	1/41 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
General disorders
Agitation	0/41 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Breast Pain	1/41 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Fatigue	1/41 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Headache	3/41 (7.3%)	3	0/42 (0%)	0	1/42 (2.4%)	1
Hot Flashes	1/41 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Pain	1/41 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Infections and infestations
Infections and Infestations - Other	0/41 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Penile Infection	1/41 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Nervous system disorders
Dizziness	1/41 (2.4%)	1	2/42 (4.8%)	2	1/42 (2.4%)	1
Psychiatric disorders
Insomnia	0/41 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Renal and urinary disorders
Hematuria	0/41 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
urinary retention	0/41 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	2
Reproductive system and breast disorders
Ejaculation Disorder	0/41 (0%)	0	2/42 (4.8%)	2	0/42 (0%)	0
Erectile Dysfunction	1/41 (2.4%)	2	1/42 (2.4%)	2	1/42 (2.4%)	2
Libido Increased	0/41 (0%)	0	1/42 (2.4%)	2	0/42 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/41 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Dyspnea	2/41 (4.9%)	2	0/42 (0%)	0	0/42 (0%)	0
Respiratory, thoracic and mediastinal disorder - other	0/41 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Skin and subcutaneous tissue disorders
Bruising	0/41 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Rash maculo-papular	1/41 (2.4%)	2	0/42 (0%)	0	0/42 (0%)	0
Rash pustular	0/41 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Urticaria	1/41 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.