Vaginal Sildenafil for Primary Dysmenorrhea (SILDYS)

Vaginal Sildenafil for Primary Dysmenorrhea: A Randomized, Double-Blind, Placebo-Controlled, Two-Period Crossover Mechanistic Study

This phase 1 randomized, double-blind, placebo-controlled, two-period crossover trial will evaluate whether a single 100 mg vaginal sildenafil citrate suppository reduces uterine hypercontractility during menstruation in adults with moderate-to-severe dysmenorrhea. Uterine contractility will be measured using cine magnetic resonance imaging (MRI). Key secondary objectives are to evaluate acute menstrual pain reduction over 4 hours, characterize limited systemic exposure using a single 4-hour plasma sildenafil concentration, and assess short-term safety and tolerability.

Study Overview

• Status: Not yet recruiting
• Conditions: Dysmenorrhea; Menstrual Pain
• Intervention / Treatment: Drug: Sildenafil citrate vaginal suppository; Drug: Placebo vaginal suppository

Detailed Description

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 mechanistic target-engagement study uses a randomized, double-blind, placebo-controlled, two-period crossover design. Participants will complete a screening visit and two menstrual treatment visits during separate cycles. At each treatment visit, participants with active menstrual pain will undergo baseline MRI, self-administer either vaginal sildenafil citrate 100 mg or matching placebo, and then complete repeat MRI assessments approximately 2 and 4 hours after dosing. Pain ratings, vital signs, adverse event assessments, pregnancy testing, and a single 4-hour blood draw for plasma sildenafil concentration will be obtained. Menstrual effluent samples will also be collected.

The primary objective is to determine whether vaginal sildenafil produces measurable reductions in uterine hypercontractility during menstruation. Secondary objectives are to evaluate the effect of treatment on menstrual pain intensity over the 4-hour observation window, assess systemic exposure after vaginal administration, and characterize short-term hemodynamic and clinical tolerability.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kevin Hellman, PhD; Phone Number: 847-570-2622; Email: kevin.hellman@endeavorhealth.org

Study Locations

• United States
  • Illinois
    • Evanston, Illinois, United States, 60201
      • Evanston Hospital
      • Contact: Frank Tu, MD, MPH; Phone Number: 847-644-0494; Email: frank.tu@endeavorhealth.org
      • Contact: Kevin
      • Principal Investigator: Frank Tu, MD, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female sex assigned at birth
• Age 18 to 35 years
• History of moderate-to-severe primary dysmenorrhea
• Regular menstrual cycles of approximately 21 to 35 days
• Willing and able to complete 2 menstrual treatment visits in separate menstrual cycles
• Able to provide informed consent
• Able to comply with study procedures, including MRI procedures and vaginal self-administration of study product

Exclusion Criteria:

• Known hypersensitivity to sildenafil or any formulation component
• Current use of nitrates or nitric oxide donors
• Current use of potent CYP3A4 inhibitors or potent CYP3A4 inducers
• Current use of another phosphodiesterase type 5 inhibitor
• Uncontrolled hypertension, near-hypotension, or other clinically significant hemodynamic instability
• Clinically significant cardiovascular disease
• Clinically significant electrocardiographic abnormality, as judged by the investigator
• Clinically significant laboratory abnormality, as judged by the investigator
• Severe hepatic impairment or severe renal impairment
• Active pelvic infection
• Contraindication to MRI or factors that would impair MRI safety or interpretability, including certain metallic implants, metallic injury, claustrophobia, or intrauterine device-related artifact
• Pregnant or breastfeeding
• Any condition that, in the opinion of the investigator, would increase risk or interfere with study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vaginal sildenafil; Participants receive a single 100 mg vaginal sildenafil citrate suppository during one menstrual treatment visit. In the crossover design, the same participants receive matching placebo during the other menstrual treatment visit.	Drug: Sildenafil citrate vaginal suppository; A single 100 mg vaginal sildenafil citrate suppository compounded in an emulsifying MBK base is administered during one treatment period of the crossover study.; Other Names: Vaginal sildenafil 100 mg
Placebo Comparator: Placebo; Participants receive a single matched placebo vaginal suppository during one menstrual treatment visit. In the crossover design, the same participants receive vaginal sildenafil during the other menstrual treatment visit.	Drug: Placebo vaginal suppository; A single matched placebo vaginal suppository without active sildenafil is administered during one treatment period of the crossover study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in uterine contractions measured by cine MRI	Uterine contractility will be quantified as the number of uterine contractions observed during a standardized 10-minute cine MRI acquisition. The primary analysis will compare the within-participant change from baseline after vaginal sildenafil versus placebo in the 2-period crossover design.	Baseline, approximately 2 hours after dosing, and approximately 4 hours after dosing during each treatment visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Menstrual pain intensity AUC from 0 to 4 hours measured by 100-mm visual analog scale	Menstrual pain intensity will be recorded using a 100-mm visual analog scale, where 0 indicates no pain and 100 indicates worst imaginable pain. Area under the curve from 0 to 4 hours will be calculated using the trapezoidal method; lower values indicate lower overall pain burden.	Baseline through approximately 4 hours after dosing during each treatment visit
Plasma sildenafil concentration	A single venous plasma sample will be collected approximately 4 hours after study drug administration to characterize detectable systemic exposure after vaginal dosing and support exploratory exposure-response analyses.	Approximately 4 hours after dosing during each treatment visit
Change from baseline in systolic blood pressure	Hemodynamic tolerability will be assessed by change from baseline in systolic blood pressure measured during each treatment visit.	Baseline, approximately 2 hours after dosing, and approximately 4 hours after dosing during each treatment visit
Change from baseline in diastolic blood pressure	Hemodynamic tolerability will be assessed by the change from baseline in diastolic blood pressure measured during each treatment visit.	Baseline, approximately 2 hours after dosing, and approximately 4 hours after dosing during each treatment visit

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-emergent adverse events and local vaginal tolerability	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 and by electronic side-effect questionnaires at 6 and 24 hours after dosing.	From study drug administration through 24 hours after each treatment visit
Association between change in uterine contractility and change in menstrual pain intensity	An exploratory mechanistic analysis will evaluate whether attenuation of uterine hypercontractility is associated with reduction in menstrual pain intensity during the acute observation window.	Baseline through 4 hours after study drug administration during each menstrual treatment visit

Collaborators and Investigators

• Sponsor: Kevin Hellman
• Investigators: Principal Investigator: Frank Tu, MD, MPH, EndeavorHealth, Department of Obstetrics & Gynecology

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: March 31, 2026
• First Posted (Actual): April 2, 2026

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: sildenafil; dysmenorrhea; pelvic pain; uterine contractility; vaginal sildenafil; cine MRI
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pathologic Processes; Menstruation Disturbances; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pelvic Pain; Dysmenorrhea
• Other Study ID Numbers: SILDYS-RCT-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data underlying the results reported in this study will be shared. This includes:

Participant-level demographic and baseline characteristics (e.g., age, menstrual history, eligibility variables)

Treatment assignment and study period information (crossover sequence and visit-level indicators)

Primary outcome data: uterine contraction frequency derived from cine MRI at baseline and post-dose time points

Pharmacokinetic data: plasma sildenafil concentrations

Adverse event and safety monitoring data

Derived variables and analysis datasets used to generate reported results

Data will be shared in a de-identified format consistent with applicable privacy regulations.

• IPD Sharing Time Frame: Data will be available beginning approximately 6 months after publication of the primary results and will remain available indefinitely.
• IPD Sharing Access Criteria: Access to de-identified individual participant data and supporting documents will be provided to qualified researchers upon reasonable request and approval of a research proposal by the study investigators. A data use agreement will be required. Data will be shared via a secure, controlled-access mechanism.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No