Vaginal Sildenafil for Primary Dysmenorrhea: An Open-Label Mechanistic Study
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Change from baseline in number of uterine contractions during a 10-minute cine MRI acquisition
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Open-label vaginal sildenafil
All participants receive a single open-label 100 mg vaginal sildenafil citrate suppository during one menstrual treatment visit, self-administered after the pre-dose MRI. Uterine contractility, pain ratings, vital signs, and plasma concentrations are assessed before and after dosing within the same visit.
干预措施: Sildenafil citrate vaginal suppository (Drug)
结局指标
主要结局
Change from baseline in number of uterine contractions during a 10-minute cine MRI acquisition
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- Change from baseline in systolic blood pressure(Baseline (pre-dose), approximately 2 hours after dosing, and approximately 4 hours after dosing)
- Change from baseline in diastolic blood pressure(Baseline (pre-dose), approximately 2 hours after dosing, and approximately 4 hours after dosing)
- Change from baseline in heart rate(Baseline (pre-dose), approximately 2 hours after dosing, and approximately 4 hours after dosing)
- 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)
研究者
Kevin Hellman
Senior Research Scientist
Endeavor Health