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

• Sponsor: Ferring Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01190150
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 8
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Menorrhagia	Drug: tranexamic acid	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: Randomized, 2-way Crossover, Pharmacokinetic Study of Lysteda (Xanodyne Modified-Immediate Release Tranexamic Acid) Tablets at 2 Doses in Fasting Adolescent Females With Evidence of Heavy Menstrual Bleeding
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: tranexamic acid; Either one or two modified-immediate release tranexamic acid tablets (0.65 g each) taken orally, administered with 240 mL of water, as a single dose, at approximately 8 AM.; Other Names: Lysteda modified-immediate release 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.	Drug: tranexamic acid; Either one or two modified-immediate release tranexamic acid tablets (0.65 g each) taken orally, administered with 240 mL of water, as a single dose, at approximately 8 AM.; Other Names: Lysteda modified-immediate release tranexamic acid

Outcome Measures

Primary Outcome Measures

1. Maximum Concentrations Level (Cmax) [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)]

   Cmax is the maximum measured plasma concentration over the time-span specified.

2. Dose-normalized Maximum Concentrations Level (Cmax) [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)]

   Cmax is the maximum measured plasma concentration over the time-span specified and normalized to the 1.3 g dose.

3. Time to Maximum Concentration Level (Tmax) [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)]

   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.

4. Area Under the Concentration Versus Time Curve From 0 to the Last Time Point (AUC0-t) [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)]

   The area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method.

5. Dose Normalized Area Under the Concentration Versus Time Curve From 0 to the Last Time Point (AUC0-t) [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)]

   The area under the plasma concentration versus time curve, from time 0 to the last measurable concentration normalized to the 1.3 g dose.

6. Area Under the Concentration Versus Time Curve From 0 to Infinity (AUCinf) [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)]

   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.

7. Dose Normalized Area Under the Concentration Versus Time Curve From 0 to Infinity (AUCinf) [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)]

   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.

8. The Ratio of AUC0-t to AUCinf [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)]

   Comparison of AUC0-t to AUCinf by creating a ratio.

9. Elimination Half-life (t ½) [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)]

   Apparent first-order terminal elimination half life

Secondary Outcome Measures

1. Participants With Treatment-emergent Adverse Events (TEAEs) [Day 1 up to week 4]

   Treatment-emergent AEs are summarized by total participants with TEAEs, participants with serious TEAEs, participants with TEAEs deemed by the investigator to be related to treatment, and participants who experienced TEAEs that caused permanent discontinuation from the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 16 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	West Coast Clinical Trials	Cypress	California	United States

Sponsors and Collaborators

• Ferring Pharmaceuticals

Investigators

• Study Director: Clinical Development Support, Ferring Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ferring Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01190150
• Other Study ID Numbers: FE999304 CS01
• First Posted: Aug 27, 2010
• Last Update Posted: Jul 16, 2012
• Last Verified: Jul 1, 2012

• Keywords provided by Ferring Pharmaceuticals: Cyclic Heavy Menstrual Bleed; Menorraghia
• Additional relevant MeSH terms: Menorrhagia; Tranexamic Acid

Study Results

Participant Flow

Arm/Group Title	0.65 g / 1.3 g Tranexamic Acid	1.3 g / 0.65 g Tranexamic Acid
Arm/Group Description	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.	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.
Period Title: First Treatment
STARTED	11	9
COMPLETED	10	9
NOT COMPLETED	1	0
Period Title: First Treatment
STARTED	10	9
COMPLETED	10	7
NOT COMPLETED	0	2
Period Title: First Treatment
STARTED	10	7
COMPLETED	10	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	0.65 g / 1.3 g Tranexamic Acid	1.3 g / 0.65 g Tranexamic Acid	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	11	9	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.5 (1.13)	14.3 (1.32)	14.4 (1.19)
Sex: Female, Male (Count of Participants)
Female	11 100%	9 100%	20 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 11.1%	1 5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	7 63.6%	6 66.7%	13 65%
White	4 36.4%	2 22.2%	6 30%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Concentrations Level (Cmax)
Description	Cmax is the maximum measured plasma concentration over the time-span specified.
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population includes all participants with at least one quantifiable PK concentration.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	19
Mean (Standard Deviation) [μg/mL]	6.9967 (2.08058)	10.9868 (3.38910)

2. Primary Outcome

Title	Dose-normalized Maximum Concentrations Level (Cmax)
Description	Cmax is the maximum measured plasma concentration over the time-span specified and normalized to the 1.3 g dose.
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population includes all participants with at least one quantifiable PK concentration.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	19
Mean (Standard Deviation) [μg/mL]	13.9933 (4.16115)	10.9868 (3.38910)

3. Primary Outcome

Title	Time to Maximum Concentration Level (Tmax)
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population includes all participants with at least one quantifiable PK concentration.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	19
Mean (Standard Deviation) [hours]	3.17 (0.642)	3.11 (0.679)

4. Primary Outcome

Title	Area Under the Concentration Versus Time Curve From 0 to the Last Time Point (AUC0-t)
Description	The area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method.
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population includes all participants with at least one quantifiable PK concentration.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	19
Mean (Standard Deviation) [μg*h/mL]	38.8067 (10.56742)	56.7935 (19.27448)

5. Primary Outcome

Title	Dose Normalized Area Under the Concentration Versus Time Curve From 0 to the Last Time Point (AUC0-t)
Description	The area under the plasma concentration versus time curve, from time 0 to the last measurable concentration normalized to the 1.3 g dose.
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population includes all participants with at least one quantifiable PK concentration.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	19
Mean (Standard Deviation) [μg*h/mL]	77.6134 (21.13483)	56.7935 (19.27448)

6. Primary Outcome

Title	Area Under the Concentration Versus Time Curve From 0 to Infinity (AUCinf)
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population including all participants with three or more non-zero plasma concentrations. One participant withdrew on Day 7 and did not meet the requisite samples required for this PK parameter.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	18
Mean (Standard Deviation) [μg*h/mL]	39.8016 (10.71237)	61.2591 (15.45770)

7. Primary Outcome

Title	Dose Normalized Area Under the Concentration Versus Time Curve From 0 to Infinity (AUCinf)
Description	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.
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population including all participants with three or more non-zero plasma concentrations. One participant withdrew on Day 7 and did not meet the requisite samples required for this PK parameter.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	18
Mean (Standard Deviation) [μg*h/mL]	79.6032 (21.42474)	61.2591 (15.45770)

8. Primary Outcome

Title	The Ratio of AUC0-t to AUCinf
Description	Comparison of AUC0-t to AUCinf by creating a ratio.
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population including all participants with three or more non-zero plasma concentrations. One participant withdrew on Day 7 and did not meet the requisite samples required for this PK parameter.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	18
Mean (Standard Deviation) [ratio of AUC0-t / AUCinf]	0.9741 (0.00862)	0.9715 (0.01158)

9. Primary Outcome

Title	Elimination Half-life (t ½)
Description	Apparent first-order terminal elimination half life
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)

Outcome Measure Data

Analysis Population Description

Plasma PK population includes all participants with at least one quantifiable PK concentration.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	18
Mean (Standard Deviation) [hours]	5.06 (1.194)	5.42 (1.463)

10. Secondary Outcome

Title	Participants With Treatment-emergent Adverse Events (TEAEs)
Description	Treatment-emergent AEs are summarized by total participants with TEAEs, participants with serious TEAEs, participants with TEAEs deemed by the investigator to be related to treatment, and participants who experienced TEAEs that caused permanent discontinuation from the study.
Time Frame	Day 1 up to week 4

Outcome Measure Data

Analysis Population Description

The Safety Population consisted of all randomized participants who received at least one dose of tranexamic acid.

Arm/Group Title	0.65 g Tranexamic Acid	1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.	Participants were treated with a single dose of 1.3 g tranexamic acid.
Measure Participants	18	19
Participants with TEAEs	1 9.1%	2 22.2%
Participants with serious TEAEs	0 0%	0 0%
Participants with treatment-related TEAEs	0 0%	1 11.1%
Participants with TEAEs causing discontinuation	0 0%	0 0%

Adverse Events

Time Frame	Day 1 up to week 4
Arm/Group Title	0.65 g Tranexamic Acid		1.3 g Tranexamic Acid
Arm/Group Description	Participants were treated with a single dose of 0.65 g tranexamic acid.		Participants were treated with a single dose of 1.3 g tranexamic acid.
All Cause Mortality
	0.65 g Tranexamic Acid		1.3 g Tranexamic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	0.65 g Tranexamic Acid		1.3 g Tranexamic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	0.65 g Tranexamic Acid		1.3 g Tranexamic Acid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		2/19 (10.5%)
Nervous system disorders
Dizziness	0/18 (0%)		2/19 (10.5%)
Headache	0/18 (0%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders
Blister	1/18 (5.6%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.