Bioequivalence Study of the Oral Contraceptive (OC) Tablet Containing Norgestimate (NGM)/Ethinyl Estradiol (EE) With or Without Folic Acid in Healthy Women.
Condition: Pharmacokinetics; Therapeutic Equivalency; Contraceptives, Oral
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of the study is to determine the bioequivalence of Norgestimate (NGM) and Ethinyl
      Estradiol (EE) in 2 formulations of 250 mcg NGM/25 mcg EE, 1 without folic acid and 1
      containing 400 mcg folic acid. The pharmacokinetics of blood folate from the formulation of
      250 mcg NGM/25 mcg EE containing 400 mcg folic acid and from 400 mcg folic acid administered
      alone is characterized.
    

Detailed description: 
      This is a single-center, open-label, randomized (study drug assigned by chance), 3-way
      crossover bioequivalence study of a single dose of 250 mcg NGM/25 mcg EE with or without
      folic acid. The study consisted of a pretreatment phase (a screening period lasting up to 21
      days), an open-label treatment phase (consisting of 3 periods during which a single dose of
      study drug was administered followed by up to 72 hours of serial blood sample collections for
      pharmacokinetic analysis), and a posttreatment phase (consisting of safety evaluations at the
      completion of the third open-label treatment period or at early withdrawal). All healthy
      volunteers received the following treatments (1 during each period): Treatment A: 250 mcg
      NGM/25 mcg EE; Treatment B: 250 mcg NGM/25 mcg EE plus folic acid 400 mcg (combined
      formulation); Treatment C: folic acid 400 mcg. Healthy volunteers were randomly assigned to 1
      of 6 treatment sequence groups (ABC, ACB, BAC, BCA, CAB, or CBA) on Day 1 of the first
      open-label treatment period. Healthy volunteers received a single dose of study drug on Day 1
      in each period according to their assigned treatment sequence. There was a washout period
      between treatments of at least 4 weeks. Healthy volunteers were confined to the study unit
      from the evening before dosing (Day -1) until after vital signs were measured following
      collection of the 24-hour (Treatment C) or 48-hour (Treatments A or B) postdose blood sample.
      Blood samples were collected at specified times for 24 hours after dosing for the
      determination of plasma levels of folate and for 72 hours after dosing for the determination
      of blood levels of norelgestromin (NGMN), and norgestrel (NG) [the active breakdown products
      of NGM], and EE. Safety was evaluated based on the following: the incidence, type, and
      severity of adverse events; clinical laboratory tests; vital sign and electrocardiogram (ECG)
      measurements; and physical and gynecological (including breast) examinations. Oral
      temperature, heart rate, respiratory rate, and blood pressure were measured at screening,
      before each dose, and at least 15 minutes after the 24-hour (all treatments) and 48- and
      72-hour (healthy volunteers who received Treatments A or B) pharmacokinetic blood samples in
      each period, or at early withdrawal. In Period 3, the end-of-study assessments were
      considered the 24-hour (for healthy volunteers who received Treatment C) and the 72-hour (for
      healthy volunteers who received Treatments A and B) measurements. Physical and gynecologic
      examinations and ECG were performed at screening, and at least 1 hour after the last
      pharmacokinetic blood sample on Day 58 for healthy volunteers who received Treatment C in
      Period 3, on Day 60 for healthy volunteers who received Treatments A or B in Period 3, or at
      early withdrawal. Blood samples for blood chemistry, hematology, and urine samples for
      urinalysis were collected at screening, after the last pharmacokinetic blood sample on Day 58
      for healthy volunteers who received Treatment C in the third treatment period, on Day 60 for
      healthy volunteers who received Treatments A or B in Period 3, or at early withdrawal. The
      total duration of the study, not including the pretreatment phase, was approximately 9 weeks.
      Treatment A (250 mcg NGM/25 mcg EE) was administered as a single tablet corresponding to Days
      15 to 21 in the commercial dialpak of the OC study drug; Treatment B (250 mcg NGM/25 mcg EE
      plus 400 mcg of folic acid) was administered as a single tablet; and Treatment C (400 mcg of
      folic acid) was administered as single United States Pharmacopoeia (USP) tablet.
    

Intervention name(s): Norgestimate; Ethinyl Estradiol; Folic acid.
Intervention type(s): Drug
Intervention MeSH terms: Folic Acid; Ethinyl Estradiol; Norgestimate; Estradiol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Ortho Tri-Cyclen Lo; Contraceptives, Oral; Norgestimate; Ethinyl Estradiol; Folic Acid; Female Contraception