Medical Therapy Versus Radiofrequency Endometrial Ablation in the Initial Treatment of Menorrhagia (iTOM)

A Prospective Randomized Trial of Medical Therapy Versus Radiofrequency Endometrial Ablation in the Initial Treatment of Menorrhagia: Treatment Outcomes and Cost Utility Analysis

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.

Study Overview

• Status: Completed
• Conditions: Menorrhagia
• Intervention / Treatment: Drug: Estradiol 30mcg / Levonorgestrel 150mcg monophasic oral contraceptive pills; Drug: Naproxen sodium pills; Device: NovaSure® Radiofrequency Endometrial Ablation

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.

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 55 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 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).	Drug: Estradiol 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.; Other Names: Nordette®; Drug: Naproxen 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); Other Names: Naprosyn 250 mg tablets
ACTIVE_COMPARATOR: 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.	Device: NovaSure® 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Measured at 12 months following initial treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Measured at 12 months following initial treatment
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).	Measured at 12 months following initial treatment
Hemoglobin at 12 Months		Measured at 12 months following initial treatment
Change in Hemoglobin		baseline, 12 months
Ferritin at 12 Months		Measured at 12 months following initial treatment
Change in Ferritin From Baseline		Measured at 12 months following initial treatment
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.	Measured at 12 months following initial treatment
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.	Measured at 12 months following initial treatment
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).	Measured at 12 months following initial treatment
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.	Measured at 12 months following initial treatment
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.	Measured at 12 months following initial treatment

Collaborators and Investigators

• Sponsor: Abimbola Famuyide
• Collaborators: Hologic, Inc.
• Investigators: Principal Investigator: Abimbola O. Famuyide, MBBS, Mayo Clinic

Publications and helpful links

General Publications

• Famuyide AO, Laughlin-Tommaso SK, Shazly SA, Hall Long K, Breitkopf DM, Weaver AL, McGree ME, El-Nashar SA, Lemens MA, Hopkins MR. Medical therapy versus radiofrequency endometrial ablation in the initial treatment of heavy menstrual bleeding (iTOM Trial): A clinical and economic analysis. PLoS One. 2017 Nov 15;12(11):e0188176. doi: 10.1371/journal.pone.0188176. eCollection 2017.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (ACTUAL): September 1, 2015
• Study Completion (ACTUAL): October 1, 2015

Study Registration Dates

• First Submitted: July 9, 2010
• First Submitted That Met QC Criteria: July 15, 2010
• First Posted (ESTIMATE): July 19, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): January 20, 2017
• Last Update Submitted That Met QC Criteria: January 19, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Menorrhagia; Heavy menstrual bleeding; Endometrial ablation
• Additional Relevant MeSH Terms: Pathologic Processes; Uterine Diseases; Hemorrhage; Menstruation Disturbances; Uterine Hemorrhage; Menorrhagia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Gout Suppressants; Levonorgestrel; Estradiol; Contraceptive Agents; Contraceptives, Oral; Contraceptives, Oral, Combined; Naproxen
• Other Study ID Numbers: 08-007334

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO