Heavy Menstrual Bleeding, Menorrhagia, Uterine Fibroids
Conditions
Keywords
Menorrhagia, FIbroids, Menstrual Bleeding, Heavy Bleeding, Menses, Uterine Fibroids
Brief summary
This is a randomized controlled trial (RCT) to assess the comparative effectiveness of Levonorgestrel Intrauterine System (LNG-IUS) to Tranexamic Acid (TA) for the treatment of heavy menstrual bleeding (HMB) in women with clinically-significant fibroids.
Detailed description
Uterine fibroids are common and debilitating problem for some women. Nearly 60% of women with fibroids report that symptoms affect their quality of life and impede physical activity, and 24% report that fibroid symptoms prevent them from reaching their true potential at work. Heavy menstrual bleeding, the most common symptom of uterine fibroids, affects approximately 1.4 million women per year. Medical therapy is the first line treatment for heavy menstrual bleeding, but further studies need to be done to prove the effectiveness of these treatments. The goal of this study is to determine the effectiveness of non-estrogenic medical therapy in women with a range of fibroid sizes, locations, and number. Two effective medical treatments for heavy menstrual bleeding have limited data in women with fibroids. The Levonorgestrel intrauterine system was FDA approved for the treatment of heavy menstrual bleeding in 2009 and is highly effective for decreasing menstrual bleeding, treating anemia and improving quality of life. Moreover, it can be used continuously for 5 years. Tranexamic Acid is widely used outside the U.S. and was also FDA approved for heavy menstrual bleeding in 2009. Tranexamic Acid reduces menstrual blood loss in 40% of women and improves quality of life. In women with fibroids, Tranexamic Acid has been shown to decrease heavy menstrual bleeding and cause necrosis of the fibroids, especially larger fibroids, which should improve its efficacy for women with fibroids. This randomized controlled trial will assess the comparative effectiveness of Levonorgestrel intrauterine system to Tranexamic Acid for the treatment of heavy menstrual bleeding in women with uterine fibroids
Interventions
LNG-IUS was FDA-approved for the treatment of heavy menstrual bleeding in 2009 and previously for contraception in 2000. The LNG-IUS is a T-shaped device with a polyethylene body containing a hormone reservoir, holding a total of 52 mg of levonorgestrel. LNG-IUS initially releases 20 micrograms of the progestin per day, which decreases to less than half that amount after 5 years of use. The levonorgestrel causes stromal pseudodecidualization, decreases endometrial thickness, and lowers uterine vascular density.
DRUGTranexamic Acid
Tranexamic Acid was FDA-approved for the treatment of heavy menstrual bleeding in 2009. Tranexamic Acid is a plasminogen-activator inhibitor that blocks fibrinolysis and reduces plasmin activity. A special formulation was designed for the treatment of heavy menstrual bleeding that reduces gastrointestinal side effects, brand name Lysteda which will be prescribed as 1300 mg to be taken three times per day for up to 5 days of the menstrual period.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Shannon K. Laughlin-Tommaso
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
25 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Premenopausal women ages 25 -50 * Monthly menses * Image-confirmed uterine fibroids of at least 1 cm in size, either submucosal or intramural * Seeking treatment for heavy menstrual bleeding following completed clinical evaluation * Self-reported heavy menstrual bleeding for three months or longer * Completed evaluation for heavy menstrual bleeding within one year of study enrollment * Understands the English language for consent and questionnaires * Able and willing to provide informed consent
Exclusion criteria
* Class 0 fibroids confirmed by hysteroscopy, saline-infused sonogram, or 3D ultrasound * Uterine sounding length ≥ 14 cm * Uterine size ≥ 20 weeks gestational size * Abnormal endometrial biopsy or incomplete clinical testing to rule out malignancy * Needs or is using hormonal contraception, including estrogen-containing medications * Venous thromboembolic history, clotting disorder, or strong family history of venous thromboembolic events * Breast, uterine, or cervical malignancy * Liver disease or liver tumor * Pelvic inflammatory disease, gonorrhea or chlamydia infection during the past three months * Hemoglobin \< 8 mg/dL. For women with hemoglobin 8.0 - 12.0 mg/dL, iron supplement is recommended * Serum creatinine ≥ 1.4 * Current pregnancy or currently lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Self-Reported Menorrhagia Scores | Baseline, 3 months | The Menorrhagia Multi-Attribute Scale (MMAS) questionnaire captures the subjective consequences of menorrhagia on six domains: practical difficulties; social life; psychological wellbeing; physical health; work routine; and family life. Each of the six domains has four statements that represent four levels of response. Respondents indicate the statement that best matches their feelings for each domain. The statement scores derive from a weighting of the domains and a weighting of the statements in level of severity by women in the original study. Scores range from 0 (worst possible state in all domains) to 100 (best possible state in all domains). |
| Number of Participants to Complete Study | 9 months | Total number of study participants to complete assigned treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quality of Life, as Measured by the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) | Baseline, 3 months | The Uterine Fibroid Symptom and Health Related Quality of Life (HRQL) Questionnaire consists of an 8-item symptom severity scale and 29 HRQL items comprising 6 domains: Concern, Activities, Energy/Mood, Control, Self-consciousness, and Sexual Function. All items are scored on a 5-point Likert scale, ranging from not at all to a very great deal for symptom severity items and none of the time to all of the time for the HRQL items. Symptom severity and HRQL subscale scores are summed and transformed into a 0-100 point scale. Higher HRQL subscale scores indicate better HRQL. |
| Change in Pain Score | Baseline, 3 months | Pain will be measured by a 10 cm visual analog scale (VAS) which uses a 100 point score, with 0 indicating no pain and 100 indicating worst pain ever. Change was determine by subtracting the 3 month score from baseline, a negative score indicates a decrease in pain. |
| Change in Fibroid Size | 9 months | Fibroid size will be reported as millimeters (mm). |
| Change in Symptoms, as Measured by the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) | Baseline, 3 months | The Uterine Fibroid Symptom and Health Related Quality of Life (HRQL) Questionnaire consists of an 8-item symptom severity scale and 29 HRQL items comprising 6 domains: Concern, Activities, Energy/Mood, Control, Self-consciousness, and Sexual Function. All items are scored on a 5-point Likert scale, ranging from not at all to a very great deal for symptom severity items and none of the time to all of the time for the HRQL items. Symptom severity and HRQL subscale scores are summed and transformed into a 0-100 point scale. Higher Symptom Severity scores indicating greater symptoms. |
| Change in Quality of Life | Baseline, 3 months | Measured by the RAND 36-Item Health Survey (Version 1.0). Physical function and mental well-being on scale range from 0-100. A high score defines a more favorable health state. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Levonorgestrel IUS Levonorgestrel-releasing intrauterine system (Mirena) contains 52 mg of levonorgestrel, a progestin, and is intended to provide an initial release of approximately 20 mcg/day. Levonorgestrel intrauterine system is effective immediately upon placement in the uterus and can be kept in place for up to 5 years.
Levonorgestrel IUS: LNG-IUS was FDA-approved for the treatment of heavy menstrual bleeding in 2009 and previously for contraception in 2000. The LNG-IUS is a T-shaped device with a polyethylene body containing a hormone reservoir, holding a total of 52 mg of levonorgestrel. LNG-IUS initially releases 20 micrograms of the progestin per day, which decreases to less than half that amount after 5 years of use. The levonorgestrel causes stromal pseudodecidualization, decreases endometrial thickness, and lowers uterine vascular density. | 9 |
| Tranexamic Acid Tranexamic Acid (Lysteda) is an antifibrinolytic drug. Tranexamic Acid will be dosed at 1300mg by mouth three times a day at the start of menses and used during the days that bleeding is heaviest (not to exceed 5 days per menstrual cycle).
Tranexamic Acid: Tranexamic Acid was FDA-approved for the treatment of heavy menstrual bleeding in 2009. Tranexamic Acid is a plasminogen-activator inhibitor that blocks fibrinolysis and reduces plasmin activity. A special formulation was designed for the treatment of heavy menstrual bleeding that reduces gastrointestinal side effects, brand name Lysteda which will be prescribed as 1300 mg to be taken three times per day for up to 5 days of the menstrual period. | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Intolerance of medication | 0 | 1 |
| Overall Study | IUD Expulsion | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Treatment change | 0 | 3 |
Baseline characteristics
| Characteristic | Tranexamic Acid | Total | Levonorgestrel IUS |
|---|---|---|---|
| Age, Continuous | 44.7 years STANDARD_DEVIATION 4.8 | 43.6 years STANDARD_DEVIATION 5.2 | 42.5 years STANDARD_DEVIATION 5.6 |
| Baseline ferritin | 10 mcg/L | 7 mcg/L | 6 mcg/L |
| Baseline hemoglobin | 12.22 g/dL STANDARD_DEVIATION 1.9 | 12.2 g/dL STANDARD_DEVIATION 1.8 | 12.1 g/dL STANDARD_DEVIATION 1.7 |
| Fibroid largest diameter | 2.5 cm | 3.5 cm | 3.6 cm |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 13 Participants | 6 Participants |
| Region of Enrollment United States | 9 participants | 18 participants | 9 participants |
| Sex: Female, Male Female | 9 Participants | 18 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 1 / 9 | 5 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
Change in Self-Reported Menorrhagia Scores
The Menorrhagia Multi-Attribute Scale (MMAS) questionnaire captures the subjective consequences of menorrhagia on six domains: practical difficulties; social life; psychological wellbeing; physical health; work routine; and family life. Each of the six domains has four statements that represent four levels of response. Respondents indicate the statement that best matches their feelings for each domain. The statement scores derive from a weighting of the domains and a weighting of the statements in level of severity by women in the original study. Scores range from 0 (worst possible state in all domains) to 100 (best possible state in all domains).
Time frame: Baseline, 3 months
Population: Data was not collected or analyzed for 2 subjects in the Levonorgestrel IUS study arm and 3 subjects in the Tranexamic Acid study arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levonorgestrel IUS | Change in Self-Reported Menorrhagia Scores | 59.1 score on a scale |
| Tranexamic Acid | Change in Self-Reported Menorrhagia Scores | 25.4 score on a scale |
p-value: 0.11Wilcoxon (Mann-Whitney)
Primary
Number of Participants to Complete Study
Total number of study participants to complete assigned treatment.
Time frame: 9 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levonorgestrel IUS | Number of Participants to Complete Study | 7 Participants |
| Tranexamic Acid | Number of Participants to Complete Study | 2 Participants |
Secondary
Change in Fibroid Size
Fibroid size will be reported as millimeters (mm).
Time frame: 9 months
Population: Data not collected or analyzed for 1 subject in the Tranexamic Acid arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levonorgestrel IUS | Change in Fibroid Size | 3 mm |
| Tranexamic Acid | Change in Fibroid Size | 10.5 mm |
Secondary
Change in Pain Score
Pain will be measured by a 10 cm visual analog scale (VAS) which uses a 100 point score, with 0 indicating no pain and 100 indicating worst pain ever. Change was determine by subtracting the 3 month score from baseline, a negative score indicates a decrease in pain.
Time frame: Baseline, 3 months
Population: Data was not collected or analyzed for 2 subjects in the Levonorgestrel IUS study arm and 3 subjects in the Tranexamic Acid study arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levonorgestrel IUS | Change in Pain Score | -57.5 units on a scale |
| Tranexamic Acid | Change in Pain Score | 0 units on a scale |
p-value: 0.64Wilcoxon (Mann-Whitney)
Secondary
Change in Quality of Life
Measured by the RAND 36-Item Health Survey (Version 1.0). Physical function and mental well-being on scale range from 0-100. A high score defines a more favorable health state.
Time frame: Baseline, 3 months
Population: Data was not collected or analyzed for 2 subjects in the Levonorgestrel IUS study arm and 3 subjects in the Tranexamic Acid study arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Levonorgestrel IUS | Change in Quality of Life | Physical Function | 11.1 units on a scale |
| Levonorgestrel IUS | Change in Quality of Life | Mental Well-being | -1.0 units on a scale |
| Tranexamic Acid | Change in Quality of Life | Mental Well-being | 3.3 units on a scale |
| Tranexamic Acid | Change in Quality of Life | Physical Function | 1.7 units on a scale |
Comparison: Physical composite scorep-value: 0.32Wilcoxon (Mann-Whitney)
Comparison: Mental composite scorep-value: 0.26Wilcoxon (Mann-Whitney)
Secondary
Change in Quality of Life, as Measured by the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL)
The Uterine Fibroid Symptom and Health Related Quality of Life (HRQL) Questionnaire consists of an 8-item symptom severity scale and 29 HRQL items comprising 6 domains: Concern, Activities, Energy/Mood, Control, Self-consciousness, and Sexual Function. All items are scored on a 5-point Likert scale, ranging from not at all to a very great deal for symptom severity items and none of the time to all of the time for the HRQL items. Symptom severity and HRQL subscale scores are summed and transformed into a 0-100 point scale. Higher HRQL subscale scores indicate better HRQL.
Time frame: Baseline, 3 months
Population: Data was not collected or analyzed for 2 subjects in the Levonorgestrel IUS study arm and 3 subjects in the Tranexamic Acid study arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levonorgestrel IUS | Change in Quality of Life, as Measured by the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) | 32.8 score on a scale |
| Tranexamic Acid | Change in Quality of Life, as Measured by the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) | 21.6 score on a scale |
p-value: 0.33Wilcoxon (Mann-Whitney)
Secondary
Change in Symptoms, as Measured by the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL)
The Uterine Fibroid Symptom and Health Related Quality of Life (HRQL) Questionnaire consists of an 8-item symptom severity scale and 29 HRQL items comprising 6 domains: Concern, Activities, Energy/Mood, Control, Self-consciousness, and Sexual Function. All items are scored on a 5-point Likert scale, ranging from not at all to a very great deal for symptom severity items and none of the time to all of the time for the HRQL items. Symptom severity and HRQL subscale scores are summed and transformed into a 0-100 point scale. Higher Symptom Severity scores indicating greater symptoms.
Time frame: Baseline, 3 months
Population: Data was not collected or analyzed for 2 subjects in the Levonorgestrel IUS study arm and 3 subjects in the Tranexamic Acid study arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levonorgestrel IUS | Change in Symptoms, as Measured by the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) | -28.1 score on a scale |
| Tranexamic Acid | Change in Symptoms, as Measured by the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) | -15.6 score on a scale |
p-value: 0.4Wilcoxon (Mann-Whitney)