Objective

The aim of this study is to assess whether the insertion of an LNG-IUS directly after EA is more effective in reducing the need for subsequent hysterectomy within two years of the EA in women with HMB and undergoing EA, as compared to EA alone. Also, the study will evaluate women’s satisfaction, reinterventions and complications, side effects, post-ablation menstrual bleeding patterns, quality of life, sick leave, and costs-effectiveness.

Study design

The MIRA2 study is a nationwide multicentre randomised controlled clinical trial (RCT) in the Netherlands investigating the superiority of EA combined with concurrent LNG-IUS compared over EA alone. An economic evaluation will be performed alongside the trial. The study will be performed within the infrastructure of the Dutch Consortium for studies in Women’s Health. This study will be conducted in accordance with the Declaration of Helsinki as well as the Netherlands Medical Research Involving Human Subjects Act (WMO) and was approved as a primary review by the Máxima Medical Center medical ethics committee. Trial registration is available in the Dutch Trial Register (NL7817).

A complete overview of the MIRA2 trial is presented in Fig. 1.

Fig. 1
figure 1

Flowchart of the MIRA2 trial. HMB = Heavy Menstrual Bleeding, CRF = Case Report Form, LNG-IUS = Levonorgestrel Intra-uterine system, EQ-5D-5L = The 5-level EuroQol version of quality-of-life questionnaire, MMAS-Shaw = menorrhagia multi-attribute scale questionnaire, PBAC = Pictorial Blood Loss Assessment Chart, iMCQ = iMTA Medical Consumption Questionnaire, iPCQ = iMTA Productivity Cost Questionnaire, SAE = Serious Adverse Event

Study population

Women suffering from HMB who opt for treatment with EA can participate in the trial. Women with contraindications for use of LNG-IUS are excluded from the trial. Other exclusion criteria are age of 60 years or older, suspicion of endometrial cancer and prior endometrial ablation. Moreover, women who are unable to read or speak Dutch or English to a level that allows them to fully understand the study description and informed consent cannot participate in the trial.

Participants recruitment, randomisation and collection of data

Participants meeting the eligibility criteria will be counselled about the study by their physician or a research nurse, who will provide them with written information about the study. Women will be counselled according to the ‘shared decision making’ principle. Women who agree to participate in the study must provide written informed consent before randomization can take place by a research nurse or researcher.

Randomisation will be stratified by the presence of pre-existing dysmenorrhoea at baseline (pain during menstruation for which most of the menstrual periods pain medication is necessary) and by age (under and above 45 years old). Variable block sizes of size 2, 4 and 6 will be used.

The online software tool Castor EDC (www.castoredc.com) will be used for randomisation, sending questionnaires, and data collection. The computer will randomly assign a unique numeric code for every subject, consisting of the hospital and the consecutive participant number. A coded data set will be handled, and only the local investigator and the research nurse on site will have access to the key (code to personal information linkage). These coded data are available to investigators, research staff, and quality assurance and monitoring personnel. After the study is complete, data will be archived for a period of 15 years. Personal data is handled in compliance with the EU General Data Protection Regulation and the Dutch Act on Implementing the General Data Protection Regulation.

Interventions

Hospitals using electrical, radiofrequency ablation (Novasure®, Hologic, Marlborough, MA, USA), the thermal balloon ablation (Thermablate®, Idoman Teoranta, Ireland and Librata®, Lina Medical, Denmark) or transcervical resection of the endometrium can participate in this trial. Hospitals performing this procedure must conduct a minimum of 15 procedures a year to assure quality and competency. The EA procedure may be performed under local anaesthesia in the outpatient office, under conscious sedation in an outpatient clinic or under general or spinal anaesthesia in an operating room, depending on the local conditions in the respective centre. In women allocated to EA + LNG-IUS, an LNG-IUS will be inserted immediately after finishing the EA procedure. The LNG-IUS can stay in place for a maximum of five years in case contraception is needed or longer in case contraception is not needed. Women allocated to the control group, only an EA will be performed.

Outcome measures

The primary outcome will be the hysterectomy rate at two years after endometrial ablation as treatment for HMB. This will be measured using questionnaires in the follow-up period and checked by consulting the individual participant file. Secondary outcomes will include women’s satisfaction (on a 6-point Likert scale), condition-specific quality of life and general Quality of Life, severity of cyclical and non-cyclical pelvic pain, presence of (inter)menstrual bleeding, non-hysterectomy reintervention rates (removal LNG-IUS, medical or other surgical interventions), number and type of complications and adverse effects of treatment. Costs will be evaluated from a societal perspective. Outcomes will be collected via an online questionnaire completed by participants and via an online Case Report Form (CRF) completed by researchers.

Questionnaires for participants

Prior to treatment, participants will be asked to complete a baseline questionnaire containing a validated condition-specific quality of life measure Menorrhagia Multi-Attribute Scale (MMAS) as well as a validated EuroQol 5-level questionnaire [17,18,19]. The English language version of the MMAS questionnaire is shown in Additional file 1. Also, menstrual blood loss with a written Pictorial Blood Loss Assessment Chart (PBAC) score will be measured at baseline (Additional file 2) [20]. Participants will complete a questionnaire at six months follow-up asking about contraceptive use and smoking habits (Additional file 3). At 6-, 12- and 24-months participants will receive a questionnaire containing the MMAS questionnaire, the EQ-5D-5L questionnaire, and PBAC scoring, and questions on women’s satisfaction (6-point Likert scale), side effects of the LNG-IUS, and the presence of cyclic pelvic pain (pain score 0–10).

Societal costs (healthcare costs, lost productivity costs and informal care costs) are assessed using specifically adapted versions of the iMTA Productivity Cost Questionnaire (iPCQ) and the iMTA Medical Consumption Questionnaire (iMCQ) at 6, 12, 18 and 24 months (Additional file 4) [21, 22]. Participants will be asked to complete a menstrual calendar for one month to evaluate the intermenstrual bleeding 24 months after treatment (Additional file 5). An overview of questionnaires and timepoints is shown in Table 1.

Table 1 Schematic overview of follow up questionnaires for participants

Electronic case report form for researchers

Baseline demographic characteristics, medical history, pre-existing dysmenorrhoea and current use of hormonal medication are recorded by the physician/research nurse in the electronic CRF. In addition, findings of the ultrasound examination will be collected in the eCRF, specifically, the existence of myomas (number, type and size) and presence of possible signs of adenomyosis.

At 6 weeks and 24 months after intervention the research nurse/physician will record post-treatment complications (expulsion or removal IUS, endometritis, uterine infection, bleeding (> 500 ml), uterine perforation caused by IUS insertion or EA) and reinterventions (including hysterectomy, removal of IUS, re-ablation or medical treatment).

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