Objective
We sought to assess the efficacy and safety of 2 dosing regimens of a novel, oral tranexamic acid formulation (Lysteda; Ferring Pharmaceuticals Inc, Parsippany, NJ) in women with cyclic heavy menstrual bleeding.
Study Design
This was a multicenter, double-blind, placebo-controlled, randomized, parallel-group trial for 3 menstrual cycles (n = 304). Women with mean menstrual blood loss (MBL) of ≥80 mL/cycle were randomized to receive either 1.95 g/d or 3.9 g/d of tranexamic acid or placebo for up to 5 days of menstrual bleeding. Primary efficacy endpoints were mean MBL reduction from baseline, mean MBL reductions that were considered “meaningful” by subjects, and mean MBL reductions from baseline >50 mL/cycle. Adverse events (AEs) were also assessed.
Results
Only the 3.9 g/d group met all 3 primary efficacy endpoints. AEs did not significantly differ among the 3 groups. There were no serious study-related AEs.
Conclusion
The 3.9-g/d dose met all 3 primary efficacy endpoints, whereas the 1.95 g/d dose met 2 primary efficacy endpoints. Both doses were well tolerated.
Heavy menstrual bleeding (HMB) associated with menorrhagia is quantitatively defined as menstrual blood loss (MBL) >80 mL/cycle. Up to 30% of women will consult with a physician regarding HMB during their reproductive years. HMB creates a clinically significant burden for affected women by interfering with daily activities and negatively impacting health-related quality of life (HRQL). The impact of HMB on HRQL derives from both the mechanics of managing bleeding and the consequences of excessive blood loss, such as fatigue and iron deficiency anemia.
Tranexamic acid has been shown to reduce the increased fibrinolytic activity observed in the endometrial tissue of women with HMB. Tranexamic acid is a nonhormonal, antifibrinolytic, competitive plasmin inhibitor that is administered only during HMB for up to 5 days. It has a well-established safety profile, and does not appear to affect fertility. For >4 decades, an immediate-release formulation of tranexamic acid has been used outside the United States to treat HMB. Gastrointestinal (GI) adverse events (AEs) have limited patients’ tolerability of previously studied immediate-release tranexamic acid; however, a novel, orally administered, modified-release formulation of tranexamic acid (TA, Lysteda; Ferring Pharmaceuticals, Inc, Parsippany, NJ) was recently approved in the United States for the treatment of cyclic HMB. TA was developed to effectively treat HMB with increased tolerability via a modified-release formulation. In phase I studies, TA was shown to be bioequivalent to immediate-release tranexamic acid and was well tolerated. In a previous phase III study, TA was shown to be effective and safe for women with HMB. This phase III study was conducted in an independent population from the previous report, to assess the efficacy and safety of 2-dosage regimens of TA (1.95 g/d and 3.9 g/d) for the reduction of MBL in women with HMB.
Materials and Methods
Patients
Women aged 18-49 years with a history of cyclic HMB were eligible to participate in the study if they met a minimum MBL requirement during 2 pretreatment cycles (average MBL ≥80 mL/cycle as assessed by a validated alkaline hematin method), had at least 6 months of regularly occurring menstrual cycles (21-35 days apart) with menstrual periods lasting not >10 days, had normal findings on pelvic examination, had no abnormal findings at cervical cytology screening, and had normal findings on transvaginal ultrasonograms. Though it is noted that fibroids are not a normal finding during pelvic examinations or transvaginal ultrasounds, for the purpose of this study, women with fibroids were not excluded unless, based on the opinion of the investigator of the size and number, the fibroids required surgical management.
Subjects were excluded from the study based on history or presence of clinically significant disease, anovulatory dysfunctional uterine bleeding, metrorrhagia, menometrorrhagia, polymenorrhea, endometrial polyps, endometrial hyperplasia, endometrial carcinoma, cervical carcinoma, myocardial infarction, ischemic disease, cerebrovascular accident, stroke, transient ischemic attack, thrombosis, thromboembolic disease, or coagulopathy. Additional exclusion criteria consisted of clinically significant abnormalities that could confound the study or be detrimental to the subject noted at physical examination such as abnormalities noted on electrocardiograms, and laboratory test results indicating a potential pituitary-prolactin secreting or producing tumor (prolactin ≥30 μg/L), uncontrolled hypothyroidism, or severe anemia (hemoglobin <8 g/dL). Women with a history of bilateral oophorectomy or hysterectomy, or who were pregnant, breast-feeding, planning to become pregnant during the study, or became pregnant during the study were also excluded.
Except for the use of acetaminophen and opioids (permitted at any time during the study), nonsteroidal antiinflammatory drugs, and cyclooxygenase-2 inhibitors (permitted only during the intermenstrual phase of the cycle), subjects using medications to relieve symptoms associated with HMB before screening were allowed to enter the study after a washout period of up to 8 weeks. Anticoagulants; aspirin; dong quai; aminocaproic acid; hydroxychloroquine; and oral, transdermal, injectable, and vaginal hormonal contraceptives were not allowed at any time during the study. Women must have been surgically sterile or must have been using a copper intrauterine device or another acceptable barrier method (eg, condom or diaphragm) with spermicide for the duration of the study.
Study design
This was an outpatient, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The study consisted of a screening phase of 2 menstrual periods (no treatment) to determine eligibility. Eligible subjects had an average MBL of ≥80 mL across both cycles. The treatment phase spanned 3 menstrual periods to assess the efficacy and safety of TA at oral doses of 0.65 g or 1.3 g administered 3 times daily for total doses of 1.95 g/d or 3.9 g/d. Either TA dose or placebo was administered for up to 5 consecutive days (maximum of 15 doses) during menstruation. Soiled sanitary products were collected at each study site visit. A follow-up telephone call occurred approximately 30 days (range, 25–35 days) after the last day the study drug was administered to remind subjects to mail completed diaries to their study sites, review medication use, and review any AEs.
The protocol was approved by the institutional review board at each of the 63 participating US study sites before screening began. The study was conducted from December 4, 2006, through May 29, 2008. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice and the applicable regulatory requirements.
Assessments
Efficacy
The 3 primary efficacy endpoints were achieved if: (1) mean MBL reduction from baseline with TA treatment was significantly greater than placebo; (2) MBL reduction from baseline exceeded a threshold (36 mL/cycle) that was perceived as “meaningful” to subjects as determined by a receiver operator characteristic analysis ; and (3) mean reduction in MBL with TA treatment exceeded 50 mL/cycle. Reductions in MBL were assessed by a validated alkaline hematin method that involves using mechanical agitation to extract the blood from soiled sanitary products using 5% sodium hydroxide. The hemoglobin captured in the sanitary products is converted to alkaline hematin (standardized to the subject’s venous blood provided) and measured spectrophotometrically. The prespecified secondary efficacy outcomes measured subjective improvement using items from the Menorrhagia Impact Questionnaire (MIQ) regarding limitations in physical activities and limitations in social or leisure activities, and the proportion of subjects with a decrease from baseline in the number of large stains reported in diaries.
Safety
Safety was assessed via AE monitoring (conducted at each study visit), physical examinations, 12-lead electrocardiograms, vital sign measurements, and laboratory evaluations. Ophthalmologic acuity, color blindness, intraocular pressure, and dilated fundus examinations were performed at baseline and at study endpoint or at an early termination study visit. The causal relationship between an AE and the study drug was determined by the investigator based on his or her clinical judgment.
Statistical methods
To have a 90% chance of detecting a 50-mL difference between the mean change from pretreatment MBL in the active treatment and placebo groups (2:1 allocation), at least 92 subjects in the active treatment group and 46 subjects in the placebo group were required. This sample size calculation assumed a 65-mL reduction in MBL in the active treatment group, a 15-mL reduction in MBL in the placebo group, and the SD of the change from baseline data to be σ = 85 mL. The SD of σ = 85 mL used in the calculations was based on observed SDs from previous MBL studies. The sample size was based on a 2-sided α = .05 level of significance and the assumption that the response data were normally distributed.
Efficacy
Efficacy data are reported for the modified intent-to-treat (mITT) population. The mITT population included all randomized subjects who received at least 1 dose of study drug and had sufficient daily primary efficacy data to construct 1 period of data after the first dose of study drug. For the primary efficacy endpoints, change in MBL was calculated by subtracting the mean on-treatment MBL (average of MBL from all 3 cycles) from the mean pretreatment MBL (average of MBL from 2 baseline cycles). The percent reduction from baseline in MBL was calculated by dividing the mean change in MBL during treatment by the mean MBL pretreatment and multiplying by 100. Between-group comparisons of primary or secondary endpoint changes from baseline were conducted using an analysis of covariance with treatment group and baseline values from the endpoint as covariates. Within-group assessments of the changes from baseline were performed using paired difference t tests. All secondary analyses were considered strictly supportive to the primary analysis.
Safety
Safety data are reported for the intent-to-treat (ITT) population. The ITT population included all randomized subjects who received at least 1 dose of study drug. Safety data were summarized by the evaluation time point. Summaries for quantitative variables included appropriate descriptive statistics. Frequency counts were compiled for classification of qualitative variables. Analyses for safety parameters were not adjusted for multiplicity.
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