Vaginal Sildenafil for Primary Dysmenorrhea

Overview

This open-label, non-randomized mechanistic study will evaluate whether a single 100 mg vaginal sildenafil citrate suppository reduces uterine hypercontractility during menstruation in adults with moderate-to-severe dysmenorrhea. Ten participants will each receive one open-label dose during a single menstrual treatment visit and will serve as their own control: 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. Uterine contractility will be measured with cine magnetic resonance imaging (MRI) before dosing and approximately 4 hours after dosing. Additional objectives are to evaluate acute menstrual pain over the 4-hour observation window, to document systemic exposure using sparse plasma sampling at approximately 2 and 4 hours after dosing, and to assess short-term safety and local tolerability.

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.