Dysmenorrhea, Menstrual Pain
Conditions
Keywords
sildenafil, vaginal sildenafil, uterine contractility, cine MRI, dysmenorrhea, pelvic pain
Brief summary
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.
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.
Interventions
DRUGSildenafil 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.
A single matched placebo vaginal suppository without active sildenafil is administered during one treatment period of the crossover study.
Sponsors
Kevin Hellman
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Participants, investigators, MRI staff, and outcome assessors will remain blinded to treatment assignment. Study drug and placebo will be prepared in identical-appearing blinded containers with codes known only to the statistician and research pharmacy.
Intervention model description
Participants will receive sildenafil during one menstrual treatment visit and matching placebo during a second treatment visit in the subsequent menstrual cycle, or the reverse sequence, according to randomized treatment order.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in uterine contractions measured by cine MRI | Baseline, approximately 2 hours after dosing, and approximately 4 hours after dosing during each treatment visit | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Menstrual pain intensity AUC from 0 to 4 hours measured by 100-mm visual analog scale | Baseline through approximately 4 hours after dosing during each treatment visit | 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. |
| Plasma sildenafil concentration | Approximately 4 hours after dosing during each treatment visit | 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. |
| Change from baseline in systolic blood pressure | Baseline, approximately 2 hours after dosing, and approximately 4 hours after dosing during each treatment visit | Hemodynamic tolerability will be assessed by change from baseline in systolic blood pressure measured during each treatment visit. |
| Change from baseline in diastolic blood pressure | Baseline, approximately 2 hours after dosing, and approximately 4 hours after dosing during each treatment visit | Hemodynamic tolerability will be assessed by the change from baseline in diastolic blood pressure measured during each treatment visit. |
Countries
United States
Contacts
CONTACTKevin Hellman, PhD
PRINCIPAL_INVESTIGATORFrank Tu, MD, MPH
EndeavorHealth, Department of Obstetrics & Gynecology
Outcome results
None listed