L-Citrulline and Tadalafil for Mild to Moderate Erectile Dysfunction

This is a prospective, randomized, three-arm, parallel-group, active-controlled clinical trial conducted at the Urology outpatient clinics of the Department of Urology, Faculty of Medicine, Beni-Suef University, Egypt.

Adult men with mild to moderate erectile dysfunction will be enrolled after written informed consent. Eligible participants will be randomized in a 1:1:1 ratio to receive one of three oral treatment regimens for 12 weeks: L-citrulline 1500 mg/day, tadalafil 5 mg/day, or combination therapy with L-citrulline 1500 mg/day plus tadalafil 5 mg/day.

The preferred design is double-blind and double-dummy, using active and matching placebo preparations when available. Participants will be assessed at baseline, week 4, week 8, and week 12. Baseline assessment will include medical and sexual history, review of comorbidities and medications, physical examination, relevant laboratory tests, and validated erectile function questionnaires.

The primary endpoint is change in the International Index of Erectile Function-Erectile Function domain score from baseline to 12 weeks. Secondary endpoints include change in IIEF-5/SHIM score, change in Erection Hardness Score, proportion of patients achieving Erection Hardness Score grade 4, change in affirmative SEP-3 responses, adherence, treatment-emergent adverse events, and discontinuation due to adverse events.

• L-Citrulline (Drug): Oral L-citrulline 1500 mg/day administered for 12 weeks as an active oral nitric oxide pathway supplement for men with mild to moderate erectile dysfunction.
• Tadalafil (Drug): Oral tadalafil 5 mg once daily administered for 12 weeks as active phosphodiesterase type 5 inhibitor therapy for men with mild to moderate erectile dysfunction.
• L-Citrulline Placebo (Drug): Oral placebo preparation matching L-citrulline, administered for 12 weeks as part of the double-dummy design
• Tadalafil Placebo (Drug): Oral placebo preparation matching tadalafil, administered for 12 weeks as part of the double-dummy study design.

Primary outcomes

• Change in International Index of Erectile Function-Erectile Function Domain Score [Baseline to 12 weeks]: Change in the International Index of Erectile Function-Erectile Function domain score from baseline to week 12. The Erectile Function domain score ranges from 1 to 30, with higher scores indicating better erectile function. A greater positive change indicates greater improvement in erectile function

Secondary outcomes

• Change in International Index of Erectile Function-5 Score [Baseline to 12 weeks]: Change in the International Index of Erectile Function-5 score, also known as the Sexual Health Inventory for Men score, from baseline to week 12. The score ranges from 5 to 25, with higher scores indicating better erectile function. A greater positive change indicates greater improvement.
• Treatment Adherence [From treatment initiation to 12 weeks]: Percentage of prescribed study medication doses taken during the 12-week treatment period, assessed by patient report and treatment accountability at follow-up visits. Higher percentages indicate better adherence
• Proportion of Participants Achieving Erection Hardness Score Grade 4 [12 weeks]: Percentage of participants achieving Erection Hardness Score grade 4 at week 12. Grade 4 indicates that the penis is completely hard and fully rigid.

Sex: Male, ages: 30 Years to 70 Years

Inclusion Criteria:

* Male patients aged 30 to 70 years.
* Erectile dysfunction for at least 3 months.
* Mild to moderate erectile dysfunction, defined by International Index of Erectile Function-Erectile Function domain score from 11 to 25.
* Stable sexual relationship during the study period.
* Willingness to attempt sexual activity during the study period.
* Ability to complete study questionnaires and attend follow-up visits.
* Written informed consent.

Exclusion Criteria:

* Severe erectile dysfunction, defined by International Index of Erectile Function-Erectile Function domain score of 10 or less.
* Current nitrate or nicorandil use.
* Contraindication or hypersensitivity to tadalafil or L-citrulline.
* Unstable cardiovascular disease, unstable angina, recent myocardial infarction or stroke, uncontrolled hypertension, or high-risk arrhythmia.
* Severe hepatic impairment.
* Severe renal impairment.
* Untreated hypogonadism requiring hormonal treatment.
* Hyperprolactinemia or uncontrolled endocrine disorder.
* Major neurogenic erectile dysfunction, spinal cord injury, or previous radical pelvic surgery causing severe erectile dysfunction.
* Significant Peyronie's disease preventing intercourse.
* Active major psychiatric illness impairing reliable assessment.
* Use of phosphodiesterase type 5 inhibitors, intracavernosal injection therapy, vacuum device therapy, testosterone therapy, L-arginine, L-citrulline, or erectile dysfunction nutraceuticals during the washout period before randomization.
* Participation in another clinical trial during the previous 3 months.

• Hany F Badawy, Principal investigator, Faculty of medicine Beni-Suef University