Results of the clinical trial

Recruitment and follow-up

The complete flow of participants through the trial is shown in Figure 5; 4471 women were approached for participation, of whom 1750 women were initially considered eligible based on clinical criteria. Of these women, 236 were randomised. Reasons for ineligibility and non-randomisation are provided in Table 2. MMAS questionnaires were completed at 12 months by 181/236 (77%) participants. Of the remainder, 17 were formally withdrawn from the trial (the majority at patient request) and 38 were lost to follow-up.

FIGURE 5 CONSORT diagram. This figure is reproduced from Whitaker et al.33 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. (Figure not reproduced here; see the original article.)

Participant characteristics

In all randomised participants, the minimisation algorithm ensured balance between groups in terms of age (mean 42.5 years overall), BMI (mean 30.8 kg/m² overall) and the proportion of women with fibroids (66% did not have any fibroids, 10% having a fibroid ≤ 2 cm with the remainder having a fibroid > 2 cm). Duration of symptoms was also balanced across groups in terms of being greater or less than one year, but the former characteristic dominated with 88% having a symptom length over one year. Overall, the median length of symptoms was 36 months, and this did vary from one group to the other (24 months for UPA vs. 48 months for LNG-IUS). Otherwise, the groups were well balanced for all other baseline characteristics (see Table 3). Women were overwhelmingly white in ethnicity (92%), which is likely to be reflective of typical populations at Scottish centres, where the majority of participants were recruited (31% Edinburgh, 20% Aberdeen, 15% Glasgow). Participants contributing to the main analysis (population A) were similar in nature to the full randomised population (see Table 4). Here, apart from the difference in symptom length, the groups appeared well balanced.

Adherence to treatment

The urgent safety measures had a substantial impact on adherence to treatment in the UPA group, with a total of 29 participants ending treatment as a result (Figure 6). A further 13 participants in this group chose to end treatment for other reasons, which were a mixture of side effects or dissatisfaction with the effect of treatment (see Table 5). Seventeen participants in the LNG-IUS group had the coil removed prior to 12 months; reasons here were frequently reported as lack of effective control of bleeding.

FIGURE 6 Adherence to allocated intervention. This figure is reproduced from Whitaker et al.33 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. (Figure not reproduced here; see the original article.)

Primary outcome: quality of life menorrhagia multi-attribute scale scores at 12 months

No evidence of a difference between groups was observed [median score category: 76–99, interquartile range (IQR) (51–75 to 100), n = 53 vs. 76–99, IQR (51–75 to 100), n = 50; adjusted OR 0.55, 95% CI 0.26 to 1.17; p = 0.12] (Table 6); estimates of treatment effect were very similar in both of the secondary populations and were robust to sensitivity analysis (see Appendix, Tables 18–20).

Secondary outcomes: quality of life menorrhagia multi-attribute scale scores at other assessment times and associated analyses

Scores in both groups were substantially improved from baseline [median score category: ≤ 50, IQR (≤ 50 to 51–75) for both groups] by 3 months, but more so with UPA, where the odds of being in a higher MMAS score category were higher than in the LNG-IUS group [median score category: 76-99, IQR (51–75 to 100) vs. 51–75, IQR (≤ 50 to 76-99); adjusted OR 2.22, 95% CI 1.24 to 3.96]. This was not apparent by six months [median score category: 76–99, IQR (≤ 50 to 100); vs. 76–99, IQR (61–75 to 100); adjusted OR 0.64, 95% CI 0.33 to 1.24] as participants in the LNG-IUS group continued to improve (see Appendix, Figure 24).

There was no evidence of varying treatment effect (p = 0.46) in the recruitment periods separated by the study suspension (see Appendix, Table 21), but power for this analysis was limited by lack of observations, particularly in the post USM1 recruitment period.

Other secondary outcomes

The proportion of women experiencing amenorrhoea was much higher in the UPA group compared with those in the LNG-IUS group across all time points (3 months: 56% vs. 5%, adjusted OR 29.3, 95% CI 7.37 to 116; 6 months: 53% vs. 10%, adjusted OR 11.7, 95% CI 3.78 to 36.0; 12 months: 64% vs. 25%, adjusted OR 7.12, 95% CI 2.29 to 22.2; Table 7). Results were similar in both secondary analysis populations (see Appendix, Tables 22 and 23). The proportion of women experiencing heavy bleeding was not noticeably different between groups.

There was no consistent evidence that the proportion of women reporting irregular or on-off bleeding menstrual cycles was different between the groups (see Table 8); similarly, cycle duration was not consistently different between groups across the assessment times (see Table 9).

There was no evidence of a difference in the other patient-reported outcomes (see Table 10); the uncertainty around the treatment effect estimates was either too large to rule out no effect or there was lack of consistency across the assessment times.

The number of women reporting a surgical intervention was low at the 12-month follow-up in all those randomised. Two hysterectomies were reported in the UPA group. One participant in the LNG-IUS group reported a ureteric stenting, sigmoidoscopy and biopsy, another having a cystectomy and another a prophylactic bilateral salpingo-oophorectomy.

A greater reduction in endometrial thickness with LNG-IUS was observed compared with UPA (adjusted mean difference 2.6 mm, 95% CI 0.8 to 4.4), along with more of an increase in haemoglobin (adjusted mean difference 5 g/l, 95% CI 1 to 10; Table 11). There was no evidence of a consistent difference in the other clinical measurements in any of the analysis populations (see Appendix, Tables 24–25).

No participants treated with UPA had evidence of malignancy following endometrial biopsy out to a maximum of 12 months (timing of biopsy was earlier in those who ceased treatment earlier; Figure 7). Seven participants (8%) had evidence of PAEC in their initial biopsy, reducing to one at subsequent biopsy after a further 3 months and none at a further following 3 months.

FIGURE 7 Endometrial biopsy result.1Timing dependent on when participant stopped UPA in some cases; if prior to 12-month follow-up, the first assessment was at first opportunity thereafter; repeat assessment (if required) would be after a further 3 and 6 months. 2Does not include 3 participants missing diagnosis, 4 with insufficient sample and 22 participants who withdrew or were lost to follow-up prior to 12 months assessment. This figure is reproduced from Whitaker et al.33 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. (Figure not reproduced here; see the original article.)

Two participants in the UPA group (5%) had a clinically significant LFT result while on treatment; this increased to five (9%) in the post treatment period. When considered in conjunction with whether transaminase levels were greater than three times the upper level of normal in any of the tests, these numbers reduced to one (3%) and three (5%), respectively (see Table 12).

There were six SAE reports in the UPA group and five in the LNG-IUS group (p = 0.76). SAEs in the UPA group were predominantly related to hospital admissions, typically for elective surgery or management of unrelated conditions. One participant developed breast cancer but had only a short period on UPA treatment due the early termination of the study. A further participant in the UPA arm was admitted for pain control in the context of expulsion of an endometrial cast but had previously discontinued UPA and had an IUS inserted prior to the SAE. There was only one directly related SAE, where the participant was diagnosed with complex endometrial hyperplasia with atypia at the end of study biopsy.

In the LNG-IUS group there were more directly related SAEs: one participant was admitted for pelvic pain control and had their IUS removed, and one underwent risk-reducing surgery in view of a family history of breast cancer. A further participant was recommended hysterectomy for identification of a mitotic active cervical fibroid, excised at the time of LNG-IUS insertion. One patient with previous multiple myomectomies developed hydronephrosis with associated hypertension from an undiagnosed desmoid tumour, thought to be related to her previous fibroid surgery. She required admission for examination under anaesthesia, including biopsy of the lesion and insertion of ureteric stent. As part of her clinical management, despite achieving bleeding control, her IUS was removed and complete ovarian suppression with a GnRH agonist and letrozole was commenced. A final SAE in the IUS group was related to an elective admission for excision of a symptomatic sesamoid bone and ganglion.

There was one suspected unexpected serious adverse reaction (SUSAR), development of an acute hepatitis during the final course of UPA. This occurred prior to the initial USM. At initial presentation there was concern that this could represent a DILI and was thus reported as a SUSAR. However, the strong family history of autoimmune hepatitis led to her hepatology clinicians to conclude that this was the likely aetiology, and liver biopsy demonstrated widespread lymphoplastic hepatitis. The diagnosis of autoimmune hepatitis was not adjusted following the USM. Her symptoms resolved with high-dose steroids and the participant continues on long-term azathioprine with normal liver function.

Adverse events categorised using MedDRA coding were varied, with no obvious evidence of a difference between groups (see Appendix, Table 26).

Follow-up of participants in the UPA group who ceased treatment early due to the urgent safety measure was analysed separately (population C).

These participants had inconsistent MMAS scores treatment with UPA (Figure 8). A number of women had returned to PBAC scores associated with heavy menstrual bleeding by 12 months (Figure 9).

FIGURE 8 Individual participant plot of menorrhagia multi-attribute scale scores over time for those women who ceased treatment early due to the urgent safety measure. (Figure not reproduced here; see the original article.)

FIGURE 9 Individual participant plot of pictorial blood loss assessment chart bleeding diary scores over time for those women who ceased treatment early due to the urgent safety measure. (Figure not reproduced here; see the original article.)