Effectiveness of Orally Dosed Emergency Contraception in Obese Women - UPA

Emergency contraception (EC) provides a woman with an additional line of defense against unintended pregnancy following an act of unprotected intercourse. Orally-dosed EC works by delaying ovulation and reduces the risk of pregnancy for a single act of unprotected intercourse by 50-70%. Unfortunately, obese women are significantly more likely than their normal BMI counterparts to experience failure of orally-dosed EC and in some instances EC is equivalent to placebo.

Our preliminary data provides evidence for testing a dose escalation strategy in an effort to provide improved efficacy from orally-dosed EC in obese women. We hypothesize that increasing the dose of orally-dosed EC agents will normalize the pharmacokinetics resulting in the expected treatment effect (delay in follicle rupture) in obese women. In the overall proposal, we plan to perform detailed pharmacokinetic and pharmacodynamic studies of UPA-based EC in obese women and expand upon our preliminary findings of LNG-based EC. This protocol registration is for the UPA aspect of the study procedures focused on the pharmacokinetics and pharmacodynamics of UPA and will include a dose escalation intervention.

• UPA-ECx1 (Drug), also known as Ella, Ella-One: Evaluating the pharmacodynamic and pharmacokinetic outcomes in obese women using 30mg of UPA-based EC
• UPA-ECx2 (Drug), also known as ella, ella-one: Evaluating the pharmacodynamic and pharmacokinetic outcomes in obese women using 60mg of UPA-based EC

Primary outcomes

• Number of Participants With Delay in Follicular Rupture Beyond 5 Days [1 menstrual cycle, assessed up to 38 days]: Follicular rupture (yes/no) beyond 5 days from EC dosing by ultrasound in participants with a BMI >/=30 kg/m2. The comparison is between menstrual cycles where 30 versus 60 mg of UPA was taken. Follicular rupture is defined as the disappearance of or >50% reduction in size of the leading follicle. The day of EC dosing is defined as day zero.

Secondary outcomes

• Maximum Serum Concentration of Ulipristal Acetate [24 hours]: Maximum serum concentration (Cmax) of UPA in participants with BMI >/=30 kg/m2 with 30 mg UPA, with BMI >/= 30 kg/m2 with 60 mg UPA, and normal BMI participants with 30mg UPA

Sex: Female, ages: 18 Years to 35 Years, accepts healthy volunteers

Inclusion Criteria:

* Generally healthy women
* Aged 18-35 years old
* Regular menses (every 21-35 days) experiencing an ovulatory screening cycle with a progesterone level of 3 ng/mL or greater
* Subjects must have a BMI of >30kg/m2 and weight at least 80kg or more OR a BMI <25kg/m2 and a weight of less than 80kg.

Exclusion Criteria:

* Metabolic disorders including uncontrolled thyroid dysfunction and Polycystic Ovarian Syndrome
* Impaired liver or renal function
* Actively seeking or involved in a weight loss program (must be weight stable) pregnancy, breastfeeding, or seeking pregnancy
* Recent (within last 8 weeks) use of hormonal contraception
* Current use of drugs that interfere with metabolism of sex steroids
* Smokers.

Participant flow

Outcome results

• Number of Participants With Delay in Follicular Rupture Beyond 5 Days (Primary), Count of participants, Participants: ECx1 BMI>/=30kg/m2 46; ECx2 BMI >/=30 43; ECx1 BMI <25kg/m2 12
• Maximum Serum Concentration of Ulipristal Acetate (Secondary), Mean, ng/mL: ECx1 BMI>/=30kg/m2 197.1 +/- 118.5; ECx2 BMI >/=30kg/m2 312.4 +/- 215.3; ECx1 BMI <25kg/m2 98.4 +/- 40.7

Adverse events

Time frame: Over approximately 3 months

• Study Protocol and Statistical Analysis Plan (PDF, 2016-03-01)
• Informed Consent Form (PDF, 2016-05-06)

• ALISON EDELMAN, MD, MPH, Principal investigator, Oregon Health and Science University