Vaginal Sildenafil for Primary Dysmenorrhea

Dysmenorrhea is believed to be driven in part by excessive uterine contractility. Sildenafil, a phosphodiesterase-5 inhibitor, may reduce myometrial hypercontractility through enhanced nitric oxide-cGMP signaling. Prior vaginal sildenafil data suggested acute pain relief, but mechanism and systemic exposure were not well characterized.

This study is a mechanistic biomarker investigation in which uterine contractility measured by cine MRI serves as a functional pharmacodynamic marker of PDE5 inhibition. Participants complete a screening visit (medical history, vital signs, 12-lead ECG, screening laboratory tests, MRI safety screening, questionnaires) and a gynecologic examination visit before dosing. When a participant is menstruating and reporting cramping pain of at least 5 on a 0 to 10 scale, she attends a single treatment visit of approximately 6 hours. At that visit she undergoes a pre-dose cine MRI, self-administers a single 100 mg vaginal sildenafil citrate suppository, and undergoes a repeat MRI at approximately 4 hours after dosing. No MRI is obtained at the 2-hour timepoint. Pain ratings on a 100-mm visual analog scale, vital signs, adverse event assessment, and venous blood samples for plasma sildenafil and its N-desmethyl metabolite are obtained at approximately 2 and 4 hours after dosing. In a prespecified exploratory subset of 2 participants, an additional plasma sample is obtained at approximately 24 hours after dosing at a brief return blood-draw visit. Menstrual effluent is collected during the visit. Electronic side-effect questionnaires are sent at 6 and 24 hours after dosing, and a second gynecologic examination visit occurs within approximately one month after the treatment visit.

There is no placebo and no comparator group. The primary analysis is the within-participant change from pre-dose baseline in the number of uterine contractions during a standardized 10-minute cine MRI acquisition. The planned population of 10 participants comprises 6 participants with primary dysmenorrhea and no evidence of pelvic pathology, plus a separately analyzed exploratory subset of 4 participants (2 with known endometriosis and 2 with known uterine fibroids).

Plasma sampling in this study is deliberately sparse because participants are in acute menstrual pain. Formal pharmacokinetic parameters such as Cmax, Tmax, area under the concentration-time curve, and terminal half-life will not be derived from this study; the samples are intended to document whether measurable systemic exposure occurs after vaginal administration and to relate exposure to hemodynamic and adverse event outcomes.

• Sildenafil citrate vaginal suppository (Drug), also known as Vaginal sildenafil 100 mg: A single 100 mg vaginal sildenafil citrate suppository, compounded in an emulsifying MBK base, is self-administered once during the menstrual treatment visit. Treatment is open-label and known to participants and study staff.

Primary outcomes

• Change from baseline in number of uterine contractions during a 10-minute cine MRI acquisition [Baseline (pre-dose) and approximately 4 hours after dosing]: Uterine contractility will be quantified as the number of uterine contractions observed during a standardized 10-minute cine MRI acquisition. The primary analysis is the within-participant change from pre-dose baseline after a single open-label 100 mg vaginal dose of sildenafil citrate. A decrease indicates reduced uterine contractility.

Secondary outcomes

• Menstrual pain intensity AUC from 0 to 4 hours measured by 100-mm visual analog scale [Baseline (pre-dose) through approximately 4 hours after dosing]: Menstrual pain intensity will be recorded using a 100-mm visual analog scale, where 0 indicates no pain and 100 indicates worst imaginable pain. Ratings are obtained pre-dose and at approximately 2 and 4 hours after dosing. Area under the curve from 0 to 4 hours will be calculated using the trapezoidal method; lower values indicate lower overall pain burden.
• Plasma sildenafil concentration [Approximately 2 and 4 hours after dosing in all participants; additionally approximately 24 hours after dosing in an exploratory subset of 2 participants]: Venous plasma sildenafil concentration will be measured to document whether measurable systemic exposure occurs after vaginal administration. Sampling is sparse by design; formal pharmacokinetic parameters such as Cmax, Tmax, AUC, and terminal half-life will not be derived in this study.
• Plasma N-desmethyl sildenafil concentration [Approximately 2 and 4 hours after dosing in all participants; additionally approximately 24 hours after dosing in an exploratory subset of 2 participants]: Venous plasma concentration of the active N-desmethyl metabolite of sildenafil will be measured to document whether measurable systemic exposure occurs after vaginal administration. Sampling is sparse by design; formal pharmacokinetic parameters such as Cmax, Tmax, AUC, and terminal half-life will not be derived in this study.
• Change from baseline in systolic blood pressure [Baseline (pre-dose), approximately 2 hours after dosing, and approximately 4 hours after dosing]: Hemodynamic tolerability will be assessed by change from pre-dose baseline in systolic blood pressure measured during the treatment visit.
• Change from baseline in diastolic blood pressure [Baseline (pre-dose), approximately 2 hours after dosing, and approximately 4 hours after dosing]: Hemodynamic tolerability will be assessed by change from pre-dose baseline in diastolic blood pressure measured during the treatment visit.
• Change from baseline in heart rate [Baseline (pre-dose), approximately 2 hours after dosing, and approximately 4 hours after dosing]: Hemodynamic tolerability will be assessed by change from pre-dose baseline in heart rate measured during the treatment visit.
• Number of participants with treatment-emergent adverse events, including local vaginal tolerability findings [From study drug administration through the post-treatment gynecologic examination, up to approximately 1 month after dosing]: Adverse events and symptoms potentially related to PDE5 inhibition or vaginal administration, including headache, flushing, dizziness or lightheadedness, visual disturbances, palpitations, syncope, vaginal irritation, local discomfort, abnormal discharge, and acute changes in bleeding, will be collected during the treatment visit, by electronic side-effect questionnaires at 6 and 24 hours after dosing, and at the post-treatment gynecologic examination visit.

Other outcomes

• Correlation between change in uterine contraction count and change in menstrual pain intensity [Baseline (pre-dose) and approximately 4 hours after dosing]: An exploratory mechanistic analysis will evaluate whether attenuation of uterine hypercontractility is associated with reduction in menstrual pain intensity during the acute observation window. The measure is the Spearman rank correlation coefficient between the within-participant change from pre-dose baseline in uterine contraction count on cine MRI and the within-participant change from pre-dose baseline in menstrual pain intensity on a 100-mm visual analog scale, both assessed at approximately 4 hours after dosing. Both changes are calculated as the post-dose value minus the pre-dose value, so a reduction is a negative change. The coefficient ranges from -1 to 1; a positive value indicates that larger reductions in contraction count accompany larger reductions in pain.

Sex: Female, ages: 18 Years to 35 Years

Inclusion Criteria:

* Female sex assigned at birth
* Age 18 to 35 years
* History of moderate-to-severe dysmenorrhea
* Regular menstrual cycles of approximately 21 to 35 days
* Willing and able to complete a single menstrual treatment visit
* Able to comply with study procedures, including MRI procedures and vaginal self-administration of study product
* Able to provide informed consent

Exclusion Criteria:

* Gross pelvic pathology identified by clinical history or by the prespecified review of the baseline research MRI. This criterion does not apply to participants enrolled in the prespecified exploratory cohort with known endometriosis or known uterine fibroids, who are analyzed separately.
* Known hypersensitivity to sildenafil or any formulation component
* Use of nitrates or nitric oxide donors
* Use of any CYP3A4 inhibitor or inducer, including dietary sources such as grapefruit
* Use of another phosphodiesterase type 5 inhibitor
* Use of any alpha-adrenergic blocker or any antihypertensive medication
* Uncontrolled hypertension, defined as systolic blood pressure at or above 140 mmHg or diastolic blood pressure at or above 90 mmHg
* Near-hypotension, defined as systolic blood pressure at or below 95 mmHg or diastolic blood pressure at or below 65 mmHg
* Cardiovascular disease
* Clinically significant electrocardiographic abnormality, as judged by the investigator
* Clinically significant laboratory abnormality, as judged by the investigator
* Hepatic impairment of any severity, assessed by screening hepatic laboratory testing and clinical history
* Severe renal impairment
* Platelet count below 100,000 per microliter or hemoglobin below 10 g/dL on screening complete blood count
* Bleeding disorder
* Peptic ulcer disease
* History of non-arteritic anterior ischemic optic neuropathy, risk factors for non-arteritic anterior ischemic optic neuropathy, or other retinal disorders
* Sickle cell disease
* Active pelvic infection
* Presence of an intrauterine device, because of MRI artifact affecting interpretability
* Other contraindication to MRI or factors that would impair MRI safety or interpretability, including certain metallic implants, metallic injury, or claustrophobia
* Pregnant or breastfeeding
* Any condition that, in the opinion of the investigator, would increase risk or interfere with study participation

• Frank Tu, MD, MPH, Principal investigator, EndeavorHealth, Department of Obstetrics & Gynecology