Menorrhagia
Conditions
Keywords
Menorrhagia, Endometrial ablation, Heavy menstrual bleeding
Brief summary
Excessive menstrual loss (menorrhagia) is a common condition that affects women of reproductive age, and can result in anemia, chronic fatigue and lost wages from work. The traditional first line management involves treatment with oral contraceptives or non-steroidal anti-inflammatory agents. Many women ultimately undergo hysterectomy, a major operative procedure associated with increased costs, loss of feeling of womanhood, debilitating complications and on rare occasions, death. The newer global endometrial ablation (GEA) devices allow the destruction of the endometrial lining, without the removal of the uterus, in an ambulatory surgery setting. GEA offers a safe and effective alternative to hysterectomy with minimal risks and without unpleasant side-effects. Presently, global endometrial ablation is offered as an alternative to hysterectomy, after medical intervention has failed. This study will determine the role of global endometrial ablation in the initial management of menorrhagia. Women seeking treatment for menorrhagia will be randomized to either the medical treatment arm or the global endometrial ablation arm. This study will be the first to compare clinical efficacy and costs between oral contraceptive pills and global endometrial ablation in the initial management of menorrhagia and could potentially change the management of menorrhagia and impact millions of women who suffer from this condition.
Detailed description
Goal of study: To evaluate the safety, effectiveness as well as cost- effectiveness of Global Endometrial Ablation (GEA) as an initial treatment for menorrhagia. Specific aim #1: To determine if global endometrial ablation (GEA) is more effective than medical therapy in the initial management of menorrhagia. Specific aim #2: To determine disease-specific resource utilization and costs associated with the treatment alternatives and the cost effectiveness of global endometrial ablation (GEA) compared with medical treatment (oral contraceptive pills) in the initial management of menorrhagia.
Interventions
DRUGEstradiol 30mcg / Levonorgestrel 150mcg monophasic oral contraceptive pills
Each packet consists of a fixed dose of 30mcg estradiol and a 150mcg dose of levonorgestrel for the first 21 days of the cycle, followed by a 7 day pill free period. Subjects will be instructed to administer the pills orally, starting 5 days after the start of menstrual blood flow, continuing cyclically, thus allowing for withdrawal bleeding after the 21 day pill cycle.
DRUGNaproxen sodium pills
As an alternative to oral contraceptive pills, subjects may take Naproxen 500 mg with onset of menses, then 250 mg three times daily for the duration of the menses (or maximum of five days)
DEVICENovaSure® Radiofrequency Endometrial Ablation
Radiofrequency endometrial ablation is performed in the outpatient surgery department. Subjects receive intravenous medication, determined by the attending anesthesiologist, sufficient to induce conscious sedation during the procedure.
Sponsors
Hologic, Inc.
Abimbola Famuyide
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
30 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Adult female, ages 30-55, who is pre-menopausal and for whom childbearing is complete 2. Subjective symptom of excessive menstrual loss 3. Normal uterine cavity length (≥ 4cm) with a sound measurement of ≤10cm documented by sonohysterogram or hysteroscopy in the preceding 6 months 4. At least one normal Pap Test and no unexplained abnormal Pap Tests within 6 months of procedure 5. Prior history of permanent sterilization or use of reliable non-hormonal contraception during the 14 month study period or history of vasectomy in partner 6. Freely agree to participate in the study including all study related procedures and evaluations, and document this agreement by signing the informed consent document
Exclusion criteria
1. Pregnancy or desire for future childbearing 2. Active lower genital infection at the time of procedure 3. Active urinary tract infection at the time of procedure 4. Active pelvic inflammatory disease (PID) or recurrent chronic PID 5. Endometrial neoplasia, determined by endometrial biopsy taken within 12 months of study entry 6. Current or past history of cervical or endometrial cancer 7. Uterine sound measurement greater than 10cm 8. Submucous leiomyoma greater than 2cm or cavity distorting leiomyoma 9. History of myomectomy or classical cesarean section 10. Previous endometrial ablation 11. Oral hormonal treatment in the preceding 3 months, hormone releasing intrauterine contraceptive in the preceding month, or injectable hormone treatment in the preceding 12 months 12. Contraindication to hormonal therapy and non-steroidal anti-inflammatory agents. 13. History of a coagulopathy or endocrinopathy 14. Inability to follow up at 12 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Menstrual Blood Loss (MBL) as Measured by Pictorial Blood Loss Assessment Chart (PBLAC). | Measured at 12 months following initial treatment | The PBLAC is a simple, pictorial tool used in women with menorrhagia to assess menstrual blood loss. The total score is calculated by adding up the sum of all scores for the tampons or sanitary napkin used in the menstrual cycle. For tampons: 1 for lightly stained, 5 for moderately soiled and 10 for completely saturated tampons. For sanitary napkins: 1 for lightly stained, 5 for moderately soiled, and 20 for completely saturated pads. Clots were given a score of 1 for small and 5 for large clots. Abnormal PBLAC bleeding score greater than or equal to 100, which correlates with menorrhagia, defined as greater than 80 mL of menstrual blood loss. Normal bleeding is defined as a score of 75 or less. A score of 0 indicates amenorrhea, or absence of menstruation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ferritin at 12 Months | Measured at 12 months following initial treatment | — |
| Change in Ferritin From Baseline | Measured at 12 months following initial treatment | — |
| Hemoglobin at 12 Months | Measured at 12 months following initial treatment | — |
| Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | Measured at 12 months following initial treatment | Quality of life (QoL) was measured by the SF-12 questionnaire. The SF-12 is a multipurpose short form survey with 12 questions, all selected from the SF-36 Health Survey. Physical and Mental Health Composite Scores are computed (combined, scored, and weighted) using the scores of the 12 questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. Improvement was defined as a change of ≥ 6 points. |
| Quality of Life as Measured by the Menorrhagia Multi-Attribute Scale (MMAS ) | Measured at 12 months following initial treatment | The 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). |
| Change in Hemoglobin | baseline, 12 months | — |
| Indirect Medical Costs | Measured at 12 months following initial treatment | Indirect cost A refers to cost of sanitary products and lack of activity, indirect cost B refers to cost of sanitary products and reduced work days, and indirect cost C refers to cost of sanitary products, lack of activity, and reduced work days. |
| Bleeding Pattern at 12 Months | Measured at 12 months following initial treatment | The menstruation pattern of the subjects was evaluated. A bleeding episode was defined as any set of one or more bleeding days bounded at each end by two or more bleeding-free days. The bleeding pattern was analyzed using a 90 day reference period and divided into groups, (based on World Health Organization (WHO) classification of clinically important bleeding patterns). The groups are Amenorrhea (no bleeding during the reference period); Infrequent bleeding (fewer than 3 bleeding episodes); Irregular bleeding (between 3 and 5 episodes with less than 3 bleeding-free intervals of length 14 days or more); Prolonged bleeding (1 or more bleeding episodes lasting 14 days or more); Eumenorrhea normal pattern (none of the above patterns). |
| Pain at 12 Months as Measured by the Pain Visual Analog Scale (VAS) | Measured at 12 months following initial treatment | The pain VAS is a continuous scale comprised of a horizontal (HVAS) line, 100 mm in length. Possible scores range from 0 (no pain) to 100 (worst possible pain). The patient marks on the line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimeters from the left hand end of the line to the point that the patient marks. |
| Subject Satisfaction at 12 Months | Measured at 12 months following initial treatment | Subject satisfaction was ascertained by asking study participants to choose from one of four categories relating to their general satisfaction with treatment: totally satisfied, generally satisfied, acceptable improvement in symptoms, or unacceptable treatment. |
| Direct Medical Costs | Measured at 12 months following initial treatment | Direct Medical Costs consisted of two categories: primarily hospital billed services, and primarily physician billed services. Primary hospital billed services were as defined by Medicare billing practice. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited at Mayo Clinic in Rochester, Minnesota from September 2009 to February 2013.
Pre-assignment details
77 subjects were initially consented, but 10 subjects were not randomized because 4 declined participation after consent, 4 reported spontaneous improvement during initial evaluation, 1 had an abnormal Pap smear indicating treatment, and 1 had a polypoid mass on hysteroscopy.
Participants by arm
| Arm | Count |
|---|---|
| Medical Therapy Subjects will be prescribed monthly packets of Estradiol 30mcg / Levonorgestrel 150mcg monophasic oral contraceptive pills. Subjects who are unable to tolerate oral contraceptive pills or are unwilling to take oral contraceptive pills will be prescribed naproxen sodium pills. The latter will be administered as follows; 500mg with onset of menses, then 250mg three times daily for the duration of the menses (or maximum of five days). | 33 |
| Radiofrequency Endometrial Ablation Subjects will undergo NovaSure® radiofrequency endometrial ablation within 4 weeks of randomization. The procedure will occur at any time during the menstrual cycle, without endometrial pre-treatment. Endometrial thinning will be carried out using suction curettage in 50% of the cases included in the ablation group. Random assignment for this treatment will be included in the overall randomization plan. | 34 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 11 | 3 |
| Overall Study | Subject not available for contact | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Medical Therapy | Radiofrequency Endometrial Ablation | Total |
|---|---|---|---|
| Age, Continuous | 42.8 years STANDARD_DEVIATION 5.5 | 41.9 years STANDARD_DEVIATION 6 | 42.3 years STANDARD_DEVIATION 5.8 |
| Region of Enrollment United States | 33 participants | 34 participants | 67 participants |
| Sex: Female, Male Female | 33 Participants | 34 Participants | 67 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 | — / — | — / — |
| other Total, other adverse events | 12 / 33 | 1 / 34 |
| serious Total, serious adverse events | 0 / 33 | 0 / 34 |
Outcome results
Primary
Menstrual Blood Loss (MBL) as Measured by Pictorial Blood Loss Assessment Chart (PBLAC).
The PBLAC is a simple, pictorial tool used in women with menorrhagia to assess menstrual blood loss. The total score is calculated by adding up the sum of all scores for the tampons or sanitary napkin used in the menstrual cycle. For tampons: 1 for lightly stained, 5 for moderately soiled and 10 for completely saturated tampons. For sanitary napkins: 1 for lightly stained, 5 for moderately soiled, and 20 for completely saturated pads. Clots were given a score of 1 for small and 5 for large clots. Abnormal PBLAC bleeding score greater than or equal to 100, which correlates with menorrhagia, defined as greater than 80 mL of menstrual blood loss. Normal bleeding is defined as a score of 75 or less. A score of 0 indicates amenorrhea, or absence of menstruation.
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Therapy | Menstrual Blood Loss (MBL) as Measured by Pictorial Blood Loss Assessment Chart (PBLAC). | 15 units on a scale |
| Radiofrequency Endometrial Ablation | Menstrual Blood Loss (MBL) as Measured by Pictorial Blood Loss Assessment Chart (PBLAC). | 0 units on a scale |
p-value: 0.003Wilcoxon (Mann-Whitney)
Secondary
Bleeding Pattern at 12 Months
The menstruation pattern of the subjects was evaluated. A bleeding episode was defined as any set of one or more bleeding days bounded at each end by two or more bleeding-free days. The bleeding pattern was analyzed using a 90 day reference period and divided into groups, (based on World Health Organization (WHO) classification of clinically important bleeding patterns). The groups are Amenorrhea (no bleeding during the reference period); Infrequent bleeding (fewer than 3 bleeding episodes); Irregular bleeding (between 3 and 5 episodes with less than 3 bleeding-free intervals of length 14 days or more); Prolonged bleeding (1 or more bleeding episodes lasting 14 days or more); Eumenorrhea normal pattern (none of the above patterns).
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Medical Therapy | Bleeding Pattern at 12 Months | Amenorrhea | 5 participants |
| Medical Therapy | Bleeding Pattern at 12 Months | Irregular/Infrequent bleeding | 4 participants |
| Medical Therapy | Bleeding Pattern at 12 Months | Prolonged bleeding | 2 participants |
| Medical Therapy | Bleeding Pattern at 12 Months | Eumenorrhea | 8 participants |
| Radiofrequency Endometrial Ablation | Bleeding Pattern at 12 Months | Eumenorrhea | 9 participants |
| Radiofrequency Endometrial Ablation | Bleeding Pattern at 12 Months | Amenorrhea | 16 participants |
| Radiofrequency Endometrial Ablation | Bleeding Pattern at 12 Months | Prolonged bleeding | 0 participants |
| Radiofrequency Endometrial Ablation | Bleeding Pattern at 12 Months | Irregular/Infrequent bleeding | 6 participants |
Secondary
Change in Ferritin From Baseline
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Therapy | Change in Ferritin From Baseline | 4.0 ug/L |
| Radiofrequency Endometrial Ablation | Change in Ferritin From Baseline | 10.0 ug/L |
p-value: 0.42Wilcoxon (Mann-Whitney)
Secondary
Change in Hemoglobin
Time frame: baseline, 12 months
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Therapy | Change in Hemoglobin | 0.0 g/dL |
| Radiofrequency Endometrial Ablation | Change in Hemoglobin | 0.5 g/dL |
p-value: 0.12Wilcoxon (Mann-Whitney)
Secondary
Direct Medical Costs
Direct Medical Costs consisted of two categories: primarily hospital billed services, and primarily physician billed services. Primary hospital billed services were as defined by Medicare billing practice.
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Medical Therapy | Direct Medical Costs | Primarily hospital billed services | 1300 dollars | Standard Deviation 1170 |
| Medical Therapy | Direct Medical Costs | Primarily physician billed services | 1601 dollars | Standard Deviation 1576 |
| Radiofrequency Endometrial Ablation | Direct Medical Costs | Primarily hospital billed services | 3494 dollars | Standard Deviation 4006 |
| Radiofrequency Endometrial Ablation | Direct Medical Costs | Primarily physician billed services | 1837 dollars | Standard Deviation 1602 |
Secondary
Ferritin at 12 Months
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Therapy | Ferritin at 12 Months | 25.0 ug/L |
| Radiofrequency Endometrial Ablation | Ferritin at 12 Months | 26.5 ug/L |
p-value: 0.6Wilcoxon (Mann-Whitney)
Secondary
Hemoglobin at 12 Months
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Therapy | Hemoglobin at 12 Months | 13.2 g/dL |
| Radiofrequency Endometrial Ablation | Hemoglobin at 12 Months | 13.4 g/dL |
p-value: 0.38Wilcoxon (Mann-Whitney)
Secondary
Indirect Medical Costs
Indirect cost A refers to cost of sanitary products and lack of activity, indirect cost B refers to cost of sanitary products and reduced work days, and indirect cost C refers to cost of sanitary products, lack of activity, and reduced work days.
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Medical Therapy | Indirect Medical Costs | Indirect costs C | 968 dollars | Standard Deviation 1534 |
| Medical Therapy | Indirect Medical Costs | Indirect costs A | 741 dollars | Standard Deviation 1174 |
| Medical Therapy | Indirect Medical Costs | Indirect costs B | 264 dollars | Standard Deviation 467 |
| Radiofrequency Endometrial Ablation | Indirect Medical Costs | Indirect costs C | 138 dollars | Standard Deviation 421 |
| Radiofrequency Endometrial Ablation | Indirect Medical Costs | Indirect costs A | 124 dollars | Standard Deviation 403 |
| Radiofrequency Endometrial Ablation | Indirect Medical Costs | Indirect costs B | 27 dollars | Standard Deviation 79 |
Secondary
Pain at 12 Months as Measured by the Pain Visual Analog Scale (VAS)
The pain VAS is a continuous scale comprised of a horizontal (HVAS) line, 100 mm in length. Possible scores range from 0 (no pain) to 100 (worst possible pain). The patient marks on the line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimeters from the left hand end of the line to the point that the patient marks.
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Therapy | Pain at 12 Months as Measured by the Pain Visual Analog Scale (VAS) | 0.4 mm |
| Radiofrequency Endometrial Ablation | Pain at 12 Months as Measured by the Pain Visual Analog Scale (VAS) | 0.0 mm |
p-value: 0.08Wilcoxon (Mann-Whitney)
Secondary
Quality of Life as Measured by the Menorrhagia Multi-Attribute Scale (MMAS )
The 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: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Therapy | Quality of Life as Measured by the Menorrhagia Multi-Attribute Scale (MMAS ) | 100 units on a scale |
| Radiofrequency Endometrial Ablation | Quality of Life as Measured by the Menorrhagia Multi-Attribute Scale (MMAS ) | 100 units on a scale |
p-value: 0.12Wilcoxon (Mann-Whitney)
Secondary
Quality of Life Score Using the Short Form-12 (SF-12) Health Survey
Quality of life (QoL) was measured by the SF-12 questionnaire. The SF-12 is a multipurpose short form survey with 12 questions, all selected from the SF-36 Health Survey. Physical and Mental Health Composite Scores are computed (combined, scored, and weighted) using the scores of the 12 questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. Improvement was defined as a change of ≥ 6 points.
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Medical Therapy | Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | SF-12 Mental Scale | 49.8 units on a scale | Standard Deviation 10 |
| Medical Therapy | Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | SF-12 Physical Scale | 54.2 units on a scale | Standard Deviation 5.9 |
| Radiofrequency Endometrial Ablation | Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | SF-12 Physical Scale | 54.5 units on a scale | Standard Deviation 4.2 |
| Radiofrequency Endometrial Ablation | Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | SF-12 Mental Scale | 53.8 units on a scale | Standard Deviation 6.6 |
Comparison: Comparison between the groups for the SF-12 Physical Scale.p-value: 0.82t-test, 2 sided
Comparison: Comparison between the groups for the SF-12 mental scale.p-value: 0.11t-test, 2 sided
Secondary
Subject Satisfaction at 12 Months
Subject satisfaction was ascertained by asking study participants to choose from one of four categories relating to their general satisfaction with treatment: totally satisfied, generally satisfied, acceptable improvement in symptoms, or unacceptable treatment.
Time frame: Measured at 12 months following initial treatment
Population: Only subjects who completed the 12 month visit were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Medical Therapy | Subject Satisfaction at 12 Months | Totally satisfied | 12 participants |
| Medical Therapy | Subject Satisfaction at 12 Months | Generally satisfied | 4 participants |
| Medical Therapy | Subject Satisfaction at 12 Months | Acceptable improvement | 2 participants |
| Medical Therapy | Subject Satisfaction at 12 Months | Unacceptable | 1 participants |
| Radiofrequency Endometrial Ablation | Subject Satisfaction at 12 Months | Unacceptable | 0 participants |
| Radiofrequency Endometrial Ablation | Subject Satisfaction at 12 Months | Totally satisfied | 30 participants |
| Radiofrequency Endometrial Ablation | Subject Satisfaction at 12 Months | Acceptable improvement | 0 participants |
| Radiofrequency Endometrial Ablation | Subject Satisfaction at 12 Months | Generally satisfied | 1 participants |