Lysteda Pediatric Research Equity Act (PREA) Pharmacokinetic Study in Adolescent Females With Heavy Menstrual Bleeding

• Maximum Concentrations Level (Cmax) [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  Cmax is the maximum measured plasma concentration over the time-span specified.
• Dose-normalized Maximum Concentrations Level (Cmax) [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  Cmax is the maximum measured plasma concentration over the time-span specified and normalized to the 1.3 g dose.
• Time to Maximum Concentration Level (Tmax) [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  Time of the maximum measured plasma concentration. If the maximum value occurs at more than one time point, Tmax is defined as the first time point with this value.
• Area Under the Concentration Versus Time Curve From 0 to the Last Time Point (AUC0-t) [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  The area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method.
• Dose Normalized Area Under the Concentration Versus Time Curve From 0 to the Last Time Point (AUC0-t) [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  The area under the plasma concentration versus time curve, from time 0 to the last measurable concentration normalized to the 1.3 g dose.
• Area Under the Concentration Versus Time Curve From 0 to Infinity (AUCinf) [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  The area under the plasma concentration versus time curve from time 0 to infinity. AUCinf is calculated as the sum of AUC0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant.
• Dose Normalized Area Under the Concentration Versus Time Curve From 0 to Infinity (AUCinf) [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  Dose-normalized AUCinf is calculated as the sum of AUC0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant, normalized to the 1.3 g dose.
• The Ratio of AUC0-t to AUCinf [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  Comparison of AUC0-t to AUCinf by creating a ratio.
• Elimination Half-life (t ½) [ Time Frame: Day 1 or Day 8 (before dosing and at the following times thereafter: 0.5, 0.75, 1, 2, 2.5, 3.0, 3.5, 4, 5, 6, 10, 14, and 24 hours post-dose) ] [ Designated as safety issue: No ]
  Apparent first-order terminal elimination half life

• PK parameters describing the pharmacokinetic profile of a single dose of 0.65 g and 1.3 g Lysteda [ Time Frame: 48 hours (two 24 hour periods) starting on Day 1 and ending on Day 2 and again starting on Day 8 and ending on Day 9 ] [ Designated as safety issue: No ]
• Assessment of the dose-proportionality [ Time Frame: 48 hours (two 24 hour periods) starting on Day 1 and ending on Day 2 and again starting on Day 8 and ending on Day 9 ] [ Designated as safety issue: No ]

• Safety evaluations based on the discontinuations due to AEs [ Time Frame: 4 weeks - duration of study participation ] [ Designated as safety issue: Yes ]
• Number of incidences and severity of treatment-emergent adverse events reported [ Time Frame: 4 weeks - duration of study participation ] [ Designated as safety issue: Yes ]
• Safety evaluations based on changes from screening to last assessment (post-study) in physical examinations [ Time Frame: 4 weeks - duration of study participation ] [ Designated as safety issue: Yes ]
• Safety evaluations based on static 12-lead ECGs [ Time Frame: 4 weeks - duration of study participation ] [ Designated as safety issue: Yes ]
• Safety evaluations based on vital signs, and clinical laboratory tests, including hematology, blood chemistry, and urinalysis [ Time Frame: 4 weeks - duration of study participation ] [ Designated as safety issue: Yes ]

This is a Phase 4, randomized, 2-way crossover, pharmacokinetic study of Lysteda (tranexamic acid) tablets administered as single doses of 0.65 g and 1.3 g in fasting adolescent female subjects ages 12-16 years with heavy menstrual bleeding.

• Experimental: 0.65 g / 1.3 g tranexamic acid
  Participants received a single dose of 0.65 g tranexamic acid on Day 1 and a single dose of 1.3 g tranexamic acid on Day 8.
  Intervention: Drug: tranexamic acid
• Experimental: 1.3 g / 0.65 g tranexamic acid
  Participants received a single dose of 1.3 g tranexamic acid on Day 1 and a single dose of 0.65 g tranexamic acid on Day 8.
  Intervention: Drug: tranexamic acid

Inclusion Criteria:

• Generally healthy non-smoking (for at least 3 months) adolescent females 12-16 years of age with a history of at least 1 year of cyclic heavy menstrual bleeding (HMB)
• Subjects must report regularly occurring menstrual periods ≤10 days in duration, with 21-45 days from the start of one period to the start of the next menstrual period

• Diagnosis of HMB based on the medical judgment of the Principal Investigator and will include the following criteria:

  1. Laboratory (including a bleeding disorders work-up) and Physical Findings;
  2. Limitations in Activities of Daily Living (ADL);
  3. Soiling, Staining and Clotting;
  4. Sanitary product usage and extent of MBL using a patient reported pictorial blood assessment chart (PBAC).

• Subjects should either be sexually inactive (abstinent) or be using one of the following acceptable birth control methods and agree to continue its use throughout the study:

  • copper intrauterine device (IUD) in place for at least 3 months;
  • barrier methods (condom, diaphragm) with spermicide for at least 1 month prior to the first dose and throughout the study.
• Negative pregnancy test results
• Subject's legally authorized representative (e.g., parent, guardian) must voluntarily sign a parental permission/informed consent form (ICF), and the subject must sign an assent, before the conduct of any study procedure

Exclusion Criteria:

• Breast-feeding, or a history of abortion in the last 6 months
• Known bleeding or coagulation disorders based on medical history and/or laboratory results
• Known systemic hematologic diseases (e.g., all types of sickle-cell disease, thalassemia of all types, multiple myeloma, hemolytic anemia)
• Clinical evidence of any significant chronic illness, including cardiovascular, renal, neurologic, hepatic, endocrine, gastric, central nervous system disease, any psychiatric illness which could affect the efficacy or safety of study medication
• Subjects treated with systemic steroids in the last 1 month or hormonal treatment in the last 3 months
• A history or presence of any drug abuse or alcohol abuse within the last 1 year
• History of subarachnoid hemorrhage.
• Active thromboembolic disease; history of thrombosis or thromboembolism, including retinal vein or artery occlusion; an intrinsic risk of thrombosis or thromboembolism
• Use of vaginal hormone products (rings, creams, and gels) within 4 weeks prior to screening. Use of oral estrogen-, progestin-, or selective estrogen receptor within 8 weeks prior to screening. Use of Lupron (3-month depot injection), estrogen pellet, or long-acting progestin injectables within 6 months prior to screening
• Subjects whose sitting blood pressure is less than 90/60 mmHg at screening
• Subjects whose pulse is lower than 50 b.p.m. at screening
• Subjects whose PR interval is >200 msec at screening and prior to dosing
• Subjects whose QTc interval >450 msec
• Subjects with positive tests for hepatitis B, C, or human immunodeficiency virus (HIV)