Methods

Parallel randomised controlled trial.

Participants

150 women randomised.

Inclusion criteria: no details.

Exclusion criteria: no details.

Setting: Egypt.

Timing: no details.

Interventions

Monophasic oral contraceptive norethisterone 1 mg + ethinylestradiol 35 μg (PO).

Leuprolide 3.75 mg (IM).

3 months' treatment.

Outcomes

Biberoglu and Behram pain scores.

Notes

Conference abstract only.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomized;" no other details.

Allocation concealment (selection bias)

Unclear risk

No details.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Stated double blind but no details.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Stated double blind but no details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

No details on allocation to groups for final number of women analysed.

Selective reporting (reporting bias)

High risk

Protocol not available. Conference abstract with only 1 outcome reported.

Other bias

Unclear risk

Unable to judge due to lack of information.

Methods

Parallel randomised controlled trial.

Participants

47 women with endometriosis‐associated pain.

Inclusion criteria: > 18 years of age, premenopausal, pelvic pain ≥ 3 months' duration, diagnosis of endometriosis by laparoscopy or laparotomy within 3 years of study entry, moderate‐to‐severe pelvic pain associated with endometriosis, willingness to comply with study protocol.

Exclusion criteria: use of OCPs within 1 month of trial enrolment, use of leuprolide within previous 3 months if given monthly or 5 months if given 3 monthly, any contraindication to the use of OCPs or GnRH analogues, history of hysterectomy or bilateral salpingo‐oophrectomy, pregnant, breastfeeding, serious mental or chronic condition that would prevent the completion of the study.

Setting: medical centre, USA.

Timing: 2005‐2008.

Interventions

Monophasic oral contraceptive (norethisterone 1 mg + ethinylestradiol 35 μg) given daily + placebo

Leuprolide, 11.25 mg depot IM every 12 weeks with hormonal add‐back using norethisterone acetate 5 mg PO, daily + placebo;

48 weeks' treatment.

Outcomes

Biberoglu and Behrman pain scores, NRS, BDI and ISS.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomized;" no other details.

Allocation concealment (selection bias)

Unclear risk

No details.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No details.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Sample size calculation suggested 188 women required. Only 47 women randomised and 7 dropped out immediately after screening (3 from COCP group and 4 from leuprolide group).

Only 24 women completed the trial but unclear which groups they were in. Reasons given included lack of improvement in pain symptoms, adverse effects and a decision to proceed with alternative therapies such as surgery.

Selective reporting (reporting bias)

Unclear risk

Protocol not available. Adverse effects reported that were not prespecified in the study methods section.

Other bias

Low risk

Groups were balanced at baseline.

Methods

Multicentre (18 sites), parallel randomised controlled trial.

Participants

100 women randomised. Mean age: 31.7 (SD 5.6) years in OCP group; 31.5 (SD 6.3) years in placebo group.

Inclusion criteria: aged ≥ 18 years; regular menstrual cycles (28 ± 2 days); symptomatic endometriosis (diagnosed by laparoscopy or laparotomy) or ovarian
endometrioma (diagnosed by ultrasound or magnetic resonance imaging); normal cervical and endometrial smear cytology; moderate or severe dysmenorrhoea (evaluated by a modified pain scale) and no medical or surgical treatment for endometriosis within 8 weeks before entry into study, including hormonal agents, such as OCP, GnRH analogue and danazol.

Exclusion criteria: no details.

Setting: Japan.

Timing: no details.

Interventions

4 cycles of treatment.

Monophasic OCP (ethinylestradiol 0.035 mg + norethisterone 1 mg) for 21 days + placebo for 7 days.

Placebo for 28 days.

Women could continue to use analgesia of their choice during study.

Outcomes

VRS and VAS to measure the severity of disability because of dysmenorrhoea in daily life and non‐menstrual pain, and the women's use of analgesics. Clinical evaluation of pelvic induration and size of ovarian endometrioma.

Notes

All authors received consulting fees from Nobelpharma Co., Ltd. Tokyo, Japan, the pharmaceutical company provided the randomisation service.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

"Randomly assigned." "Randomization was done by the pharmaceutical company...using the permuted block method."

The pharmaceutical company appeared to have been responsible for randomisation of a trial of their own drug.

Allocation concealment (selection bias)

High risk

"Randomization was done by the pharmaceutical company." "Allocation concealment was accomplished centrally by the company, not broken until after all data were collected."

The pharmaceutical company appeared to have been responsible for allocation concealment. There were no details as to whether sequentially number opaque envelopes were used.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Both the patients and the doctors were blinded regarding the medication."

As the trial was funded by the pharmaceutical company that was responsible for randomisation and allocation concealment, it is likely that it may also have communicated with the doctors who were involved in conducting the trial.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No details provided on blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

51 women randomised to OCP; 1 became pregnant and 1 was lost to follow‐up. 49 randomised to placebo; 2 lost to follow‐up.

14 women (7 in each group) discontinued study but had data included in the analysis. 4 women in OCP group were discontinued because of adverse effects (1 rupture of ovarian cyst; 1 nausea and headache; 1 ovarian haemorrhagic cyst; 1 oedema), 2 women were lost to follow‐up, and 1 woman took a prohibited drug. 7 women in placebo group terminated: 3 had adverse effects (1 oedema and headache; 1 ovarian haemorrhagic cyst; 1 worsened dysmenorrhoea), 3 were lost to follow‐up, and 1 used a prohibited drug.

Selective reporting (reporting bias)

Unclear risk

No protocol available. All prespecified outcomes appeared to be reported.

Other bias

High risk

Some women had radiological diagnosis of endometriosis rather than surgical diagnosis as most women had endometrioma. Groups were balanced at baseline. All authors received consulting fees from Nobelpharma Co., Ltd. Tokyo, Japan, the pharmaceutical company that provided the randomisation service.

Methods

Parallel, multicentre (32 sites), randomised controlled trial.

3 treatment arms (1 not used in this review).

Participants

Inclusion criteria: aged ≥ 20 years with a clinical diagnosis of endometriosis who had pelvic tenderness, induration in the cul de sac or uterine immobility; diagnosed as having endometriosis by laparotomy/laparoscopy or by identification of endometriomas. Pelvic pain (defined as a VAS score ≥ 40 mm) and regular menstrual cycles (25‐38 days) during the baseline observation phase and a normal or clinically insignificant cervical smear not requiring further follow‐up collected during screening or documented within the previous 6 months. Women willing to use a barrier method of contraception for duration of study.

Exclusion criteria: surgical treatment for endometriosis by laparotomy or laparoscopy within 2 months of start of study; antiphospholipid antibody syndrome; requirement for analgesics for medical reasons other than relief of endometrial pain during study (occasional use was permitted; prophylaxis was not permitted); aged ≥ 40 years with endometriomas for which the largest diameter was > 10 cm; endometriomas containing solid components; any disease or condition that was likely to worsen under hormonal treatment; receipt of hormone preparations containing progestin, oestrogen, GnRH analogues, testosterone derivatives, oestrogen antagonists, aromatase inhibitors, medications or their derivatives that were presumed to affect the secretion of sex hormones, or St John's Wort within 2 months prior to the baseline observation phase; pregnant or breastfeeding; undiagnosed abnormal vaginal bleeding; known hypersensitivity to any ingredient in study drug; and aged > 35 years who smoked or those of any age who smoked ≥ 15 cigarettes/day.

Setting: Japan.

Timing: October 2012 to December 2014.

Interventions

Ethinylestradiol 20 μg + drospirenone 3 mg (FlexibleMIB) (130 women), 1 tablet per day. Treatment began between the first and fifth day of menstruation. Tablets administered continuously for 120 days, followed by a 4‐day tablet‐free interval. In the event of ≥3 consecutive days of spotting or bleeding (or both) on days 25‐120 of the cycle, women began and completed the 4‐day tablet‐free interval, then started next cycle of treatment.

Placebo (129 women), 1 tablet daily following the same instructions as the FlexibleMIB group for 24 weeks, after which these women were changed to FlexibleMIB for the open‐label extension phase.

There was also an unblinded reference arm that received dienogest (53 women). This arm was used as the reference for the extension phase and was, therefore, not included in this analysis. Randomisation was 2.5:2.5:1.

Outcomes

Primary outcome: change in most severe endometriosis associated pelvic pain (VAS scale 0‐100 mm).

Secondary outcomes: pelvic pain, dyspareunia, defecation pain, rated 0‐10 or by VAS) induration in the cul de sac, limitation of uterine mobility, pelvic tenderness, size and number of endometriomas, endometrial thickness, serum oestrogen and progesterone levels. Clinical Global Improvement/Change subscale of the Clinical Global Impression rating scale. Treatment satisfaction. Adverse events.

Notes

At the end of the blinded 24‐week treatment phase, the arms were unblinded and the women who had been allocated to the placebo group were given the OCP for an extension phase of the trial.

Trial registration: NCT01697111.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

"Randomization was via an Interactive Web Response system, with numbers generated by a Randomization Management Group from Bayer and was stratified by baseline visual analog scale (VAS) score <60mm vs 60mm or more."

Randomisation is conducted by the pharmaceutical company sponsoring and running the trial. No details on how random numbers were generated.

Allocation concealment (selection bias)

Unclear risk

No details.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

States that placebo tablets were the same as FlexibleMIB to maintain masking but paper does not state who was blinded. Blinding was unmasked at the end of the treatment phase and women in the placebo group changed to FlexibleMIB in the extension phase.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No details

Incomplete outcome data (attrition bias)
All outcomes

High risk

20% in each group discontinued the study by 24 weeks of treatment.

OCP: 130 women. 26 withdrawals: adverse event (12), withdrawal of consent (11), protocol deviation (2), wish for pregnancy (1).

Placebo: 1 women did not receive treatment. 128 women. 17 withdrawals: adverse event (2), withdrawal of consent (9), lost to follow‐up (2), protocol deviation (1), wish for pregnancy (0), other (3).

Selective reporting (reporting bias)

Low risk

Outcomes appeared matched those of manuscript and those registered in the clinical trials registry.

Other bias

High risk

Declaration in paper stated that the trial was supported by Bayer Yakuhin Ltd., which participate in trial design and managed all operational aspects of the study, including monitoring data collection, statistical analysis and writing the report. The first author reported that they received advisory fees from Bayer, 1 author received speakers bureau fees from multiple pharmaceutical companies including Bayer. The other authors reported that they had nothing to disclose.

Methods

Parallel randomised controlled trial.

Participants

57 women with laparoscopically diagnosed endometriosis and ≥ 1 moderate or severe pain symptom as judged by both a VRS and VAS.

Exclusion criteria: any treatment for endometriosis other than non‐steroidal anti‐inflammatory drugs in the preceding 3 months; ≥ 1 moderate or severe symptom on 2 separate pain scales.

Setting: University Hospital, Milan, Italy.

Timing: not stated.

Interventions

Goserelin 3.6 mg subcutaneous depot formulation monthly for 6 months.
Cyclic low‐dose monophasic OCP, containing ethinylestradiol 0.02 mg + desogestrel 0.15 mg (dose increased to ethinylestradiol 0.03 mg if spotting occurred).

Outcomes

Change in pain scores (VAS and VRS) after 6 months' treatment and after 6 months' follow‐up.
Occurrence of adverse effects.

Notes

Power calculation completed. Funded by a grant from the Italian National Research Council Applied Project "Prevention and Control of Disease Factors" subproject 5 (Fertility Control), grant no 91.00131.PF41.115.05532, Milan Italy.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Stated that "a randomization list" was used to allocate participants to treatment group but no further details were provided.

Allocation concealment (selection bias)

Unclear risk

No details were provided of method used to conceal sequence of allocation to treatment groups.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the treatment administration (injection vs oral tablet) blinding of study participants or investigators was not undertaken.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No details provided of blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

29 women were randomised to the goserelin group and data were presented for 26 women. There was 1 loss to follow‐up and 2 women did not complete the follow‐up ‐ 1 due to pregnancy and 1 requested additional hormonal therapy at end of treatment period.

28 women were randomised to OCP group and data were presented on 24 women. There was 1 loss to follow‐up. 1 woman withdrew because of headaches, and 2 women did not complete follow‐up due to requesting additional hormonal therapy at end of treatment period.

Selective reporting (reporting bias)

Low risk

Protocol did not appear to be available; however, all outcomes prespecified in the materials and methods section of the article were reported on.

Other bias

Low risk

Groups appeared balanced for age and parity.