Daily Tadalafil as Adjunctive Therapy Versus Monotherapy for PDE5 Inhibitor-Resistant Erectile Dysfunction

Erectile dysfunction (ED) is a common male sexual disorder, and oral phosphodiesterase type 5 (PDE5) inhibitors are commonly used as first-line treatment. However, some men continue to report inadequate erectile function despite appropriate on-demand PDE5 inhibitor use, adequate sexual stimulation, and dose optimization.

This prospective, randomized, parallel-group trial will evaluate whether adding an on-demand PDE5 inhibitor to daily tadalafil 5 mg provides greater improvement in erectile function than daily tadalafil 5 mg alone in men with on-demand PDE5 inhibitor-resistant ED.

Eligible participants will be men aged 21 to 70 years with ED for at least 6 months who have used an on-demand PDE5 inhibitor for at least 3 months without satisfactory improvement. Inadequate response will be confirmed by an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score below 26, self-reported inability to achieve or maintain an erection sufficient for satisfactory intercourse in at least 50% of attempts, and documented appropriate medication use with adequate sexual stimulation.

Participants will be randomly assigned in a 1:1 ratio to one of two treatment groups for 12 weeks. The adjunct-therapy group will receive tadalafil 5 mg once daily together with the participant's established on-demand PDE5 inhibitor at the effective dose, taken before sexual activity according to the approved prescribing instructions and study restrictions. The monotherapy group will receive tadalafil 5 mg once daily without an additional on-demand PDE5 inhibitor.

The primary outcome will be the change in IIEF-EF score from baseline to Week 12. Secondary outcomes will include the proportion of treatment responders, Sexual Encounter Profile Question 2 success rate, Sexual Encounter Profile Question 3 success rate, Erection Hardness Score, erectile dysfunction treatment satisfaction, partner satisfaction where applicable, psychological well-being, treatment adherence, and safety.

Sexual Encounter Profile Question 2 will assess the percentage of evaluable sexual attempts during which vaginal penetration was achieved. Sexual Encounter Profile Question 3 will assess the percentage of evaluable sexual attempts during which the erection lasted long enough for successful intercourse. Participants will record these outcomes during the treatment period.

Safety assessments will include treatment-emergent adverse events, serious adverse events, treatment discontinuations because of adverse events, vital signs, and clinically relevant laboratory abnormalities. Participants will be assessed at baseline and at Weeks 4, 8, and 12.

Participants receiving nitrates, men with unstable cardiovascular disease, severe renal or hepatic impairment, uncontrolled blood pressure abnormalities, untreated hypogonadism, severe penile anatomical deformity, previous penile prosthesis, history of priapism, or other protocol-defined exclusion criteria will not be enrolled.

The study will be conducted at the Departments of Urology of Al-Hussein University Hospital and Al-Sayed Galal University Hospital, Al-Azhar University, Cairo, Egypt. The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice principles, and applicable regulatory requirements. Written informed consent will be obtained from every participant before any study-specific procedure.

Inclusion criteria

Age: 18 to 70 years.

Diagnosis: Erectile dysfunction for at least 6 months.

PDE5 inhibitor resistance: History of on-demand PDE5 inhibitor use for at least 3 months with inadequate response, defined as:

International Index of Erectile Function-Erectile Function score less than 26 despite optimal dosing.

Self-reported inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse in at least 50% of attempts.

Confirmed proper medication use with at least 4 to 8 attempts with adequate sexual stimulation.

Stable relationship: Sexually active with a female partner for at least 6 months.

Informed consent: Willing and able to provide written informed consent.

Exclusion criteria

Current use of nitrates.

Unstable cardiovascular disease, including recent myocardial infarction within 6 months, unstable angina, or severe heart failure.

Uncontrolled hypertension greater than 180 over 110 mmHg or severe hypotension less than 90 over 50 mmHg.

Severe hepatic impairment, Child-Pugh class C, or renal impairment with estimated glomerular filtration rate less than 30 mL per minute per 1.73 m².

Untreated hypogonadism, total testosterone less than 250 ng/dL.

Severe penile anatomic deformity or prior penile prosthesis.

History of priapism.

Severe untreated depression.

Pelvic surgery or radiation within 6 months.