308 postoperative participants after complete excision of focal adenomyosis are randomly assigned 1:1 to treatment group (triptorelin acetate) and control group. Patients will be recruited at 10 hospitals across Midwest China. All research units have been approved by the ethics committees. Every patient will sign an informed consent prior to this study. This report follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline (Additional file 1).
The inclusion criteria are as follows:
- Women aged ≥18 and ≤45 years;
- Women with pathological diagnosis focal adenomyosis;
- Women who accept complete excision of adenomyosis, did not take any steroid hormone therapy three months before surgery;
- Women who are health before and not pregnant;
- Women who can comply with the study procedures and give written informed consent.
- Women who are also participating in other clinical trials at the same time;
- Women who are concomitant with have been diagnosed with ovarian endometrioma, deep infiltrating endometriosis, multiple leiomyomas;
- Women with congenital uterine abnormalities such as uterine malformation (unicornis uterus, septate uterus, or duplex uterus) or acute genital inflammation or malignant tumor;
- Women who are pregnant;
- Women who were taken steroid hormone therapy three months before surgery;
- Women with hereditary disease, blood disease, liver and kidney dysfunction or malnutrition diseases that cause anemia;
- Women who cannot suffer from surgery or are allergic to triptorelin acetate;
- Women who are unable to comply with the study procedures and give written informed consent.
Screening and enrolment
Previous medical history and current medication status are reviewed with the standardized case report forms. A physical examination and imaging such as two/three-dimensional color doppler ultrasonography (2D/3D-CDUS) or magnetic resonance imaging (MRI) are performed. Laboratory measurements as serum follicle-stimulating hormone (FSH), Estradiol (E2), anti-muellerian hormone (AMH), cancer antigen 125 (CA125)，safety assays include blood routine, urine routine, liver function, renal function, hepatitis virus, HIV, syphilis, coagulation, electrocardiogram (ECG), x-rays are measured in the local department of study sites. Either laparoscopy or transabdominal surgery is performed to completely remove all clinically recognizable lesions in patients who are suspected as focal adenomyosis.
Written informed consent will be obtained from the patients after operation. Quality of life, degree of pain and menstrual volume will be recorded using the Short Form (36) Health Survey (SF-36), Female Sexual Function Index (FSFI), pictorial blood loss assessment chart (PBAC) score, Visual Analogue Scale (VAS) and Numeric Rating Scale (NRS) after confirming by histology. A schedule of enrollment, interventions, and assessment is provided as in the table below (Table 1).
Laparotomy, hysteroscopy or laparoscopy were all contained in this study. During the laparoscopy, patients are taken the lithotomy position under general anesthesia with endotracheal intubation. After sterilization, pneumoperitoneum was created with carbon dioxide gas at 13 mm Hg (Karl Storz GmbH & Co. KG, Tuttlingen, Germany). Surgery was performed with 4 trocars for surgical instruments. Supine position and median incision are suitable for laparotomy. Hysteroscopic surgery is conducted for type 0 or type 1 adenomyoma (Karl Storz GmbH & Co. KG, Tuttlingen, Germany). Surgical approach is adenomyomectomy. The principle of these surgical options included completely removal of clinical visible lesions, maintained the integrity of uterine wall and keep the integrity of the uterine cavity as much as possible. The length of the surgery, size of the focus, blood loss and the integrity of the uterine cavity should be kept in record.
Simple randomization is used to assign qualified participants to surgery only group (Group A) and surgery plus GnRH agonist group (Group B) with a 1:1 ratio. GnRH agonist was used for intervention group, using 3.75mg intramuscular injection (Diphereline, Ipsen, France) at the first day of the menstruation after surgery, then once every four weeks for six courses. The sign and symptoms of hypoestrogenism, including hot flushes, night sweat, sleep disorder, abnormal emotion and osteoporosis, could be caused by GnRH agonist, which should be carefully evaluated and could be treated with Tibolone 1.25 mg per day as add-back therapy to maintain estradiol at 30-50 pg/ml.
When intolerable adverse reaction is occurred on Group B patients, intervention will be discontinued or modified. Color doppler ultrasonography and steroid hormone test on the third and 6th month after conservative operation can help to monitor adherence. During the trial, other medication, such as use of steroid hormone or herbal medicine, or intervention, such as levonorgestrel-relesing intrauterine syste (LNG-IUS) will be prohibited.
Eligible participants were assigned subjects to two groups with a 1:1 ratio simple randomization. The sequence of randomization has been set up by biostatisticians in data coordinator center with Microsoft Excel, using function of RAND (). The original sequence is safely kept by the staff in the data coordinator center, and it has been input into the online central randomization system by these staff members, who are not involved in enrolling subjects. The sequence is not accessible to any investigators or study coordinators. If a subject fulfills the enrollment criteria, the authorized study coordinator will get the assignment for her. After randomization, both subjects and investigators are informed about the assignments.
Outcome and outcome assessments
The primary outcome is relapse, which defines as recurrence of dysmenorrhea or pelvic pain or menorrhagia or 2D/3D-CDUS / MRI confirmed local recurrence compared to the first follow up time after surgery. Regarding imaging relapse, maximal diameter of suspicious recrudescent focus increase > 1cm during the follow-up period, measuring by 2D/3D-CDUS or MRI. During the follow up, if a positive finding is found by the same imaging examination should be conducted as a further evidence. In addition, the VRS and NRS are applied for evaluation of dysmenorrhea or pelvic pain and the recurrence was defined as any rating (VRS and NRS) upgraded and participants asking for other medical treatments for symptom release at the same time during follow-up. PBAC score is used to predict coagulation disorders in women with menorrhagia and recurrence was defined as score > 100. The proportion of the recurrence at 3, 6, 9,12, 18, 24, 30, 36 months will be followed-up.
The secondary outcomes include quality of life, clinical pregnancy, ovarian reserve, and adverse events. The quality of life is assessed by SF-36 and FSFI, regarding as a measure of health status and sexual functioning in women. Ovarian reserve is evaluated by FSH, E2 and AMH, the first two are measured before surgery and during the follow-up period at the beginning of the menstrual cycle unless during the treatment of triptorelin acetate. AMH can be measured at any time before and after operation at the time of follow-up. Difference in score for eight dimensions (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role emotional and mental health) of SF-36 and FSFI and mean value of FSH, E2 and AMH for participants in each group at 3, 6, 9,12, 18, 24, 30, 36 months will be assessed for quality of life and ovarian reserve. The pregnancy intention, pregnancy rate and outcome are recorded in a standard case report form, including abortion, premature delivery, full-term production, to evaluate difference of pregnancy outcome in each treatment arm at 36 months.
The follow-up procedure is acquired from the outpatient department records. Follow-up visits occur at 3, 6, 12, 18, 24, 30, 36 months after conservative surgery.
Treatment-related adverse effects are monitored at each visit. Adverse events are any unfavorable medical occurrences associated with the subject’s participation in the research, whether considered related to the study intervention. Serious adverse events are events that are temporally associated with the subject’s participation in research that meet any of the following criteria: death, life-threatening, severely or permanently disabling, requiring in-patient hospitalization or prolongation of existing hospitalization, or any events deemed as serious by the local principal investigator. Difference in the proportion of patients for adverse events in each group would be assessed at 36 months.
Sample size calculation
Based on a prospective study revealed a relapse rate for only surgery group was about 49%, and for surgery and GnRH agonist treatment group was 28.1%. A two-tailed test with alpha set at 0.05 and 85% power is used to detect a minimum clinical meaningful difference between control and intervention groups. The minimal sample size is calculated as 139 for each group. In consideration of a dropout rate of 10%, we will totally recruit 308 subjects.
Data are collected with a standard case report form. Data are de-identified before being input into the database. Regular study site monitor and database checking are performed to ensure the accuracy of data collected. The data management, monitoring and reporting of this study will comply with the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines.
Data analysis plan
Data analysis and reporting will be conducted in accordance to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement, which were recorded in our flow chart (Fig. 1), including the number of eligible participants and lost to follow-up for various reasons. Data analysts will be blinded after assignment to interventions. Unblinding of a participant’s allocated intervention during the trial is permissible after blind verification and a submission of data locking proof by statistical analyst.
Intention to treat, which is based on the initial treatment intent, will be used as a foundation in our analysis. Participants begin the treatment is part of the trial, whether they finish it or not. The characteristics at baseline will be described between control and intervention groups. Continuous data will be summarized by means and standard deviation with Wilcoxon rank sum test to identify differences of baseline characteristic between two groups. Categorical data will be described by number and percentages, using Pearson chi-square test to compare discrepancy between groups.
The primary outcome measure is the recurrence rate between Group A and Group B after three years’ follow-up, which will be analyzed by Pearson chi-square test. For efficacy parameters, such as score of pelvic pain and dysmenorrhea, menstruation blood loss, size of uterus and lesion will be analyzed using generalized estimating equations (GEE) or mixed effects model repeated measures (MMRM) to account for correlations among these observations in different follow up points.
The parameters from secondary outcomes contains SF-36, FSFI, pregnancy rate and pregnancy outcome are calculated during 36 months’ follow-up are using generalized estimating equations (GEE) or mixed effects model repeated measures (MMRM) analysis to compare differences between Group A and Group B at different time points.
The number of participants with adverse events (AE) or serious adverse events (SAE) will be presented for each arm. We will not take any formal statistical testing.
The results of the study will be publicated in a peer-reviewed medical journal without use of professional writer. After agreement of the Steering Committee, source data will be shared available through national or international anonymised datasets.