Miki 2016.

Study characteristics
Methods	Study setting: multicentre study (57 research centres) in Japan Study period: November 2012 to February 2014 Study design: parallel Duration therapy: no information on duration of washout phase. Two weeks single‐blind placebo run‐in, one week mirtazapine 15 mg/d, 12 weeks mirtazapine 30 mg/d fixed dose
Participants	Participants: Mirtazapine: N = 211; 82.5% women, 100% Japanese, mean age 45.0 (SD 10.0) years; pain baseline (0 ‐ 10) 5.9 (SD 1.1): years after diagnosis 4.4 (SD 4.0) Placebo: N = 211; 82 % women, 100% Japanese, mean age 45.3 (SD 10.3) years; pain baseline (0 ‐ 10) 6.0 (SD 1.1): years after diagnosis 4.4 (SD 4.4) Inclusion criteria: ACR 1990 criteria; age 20 to 64 years; pain score of ≥ 40 on a 100 VAS during screening period Exclusion criteria: VAS pain score reduced by ≥ 30% at week ‐1 or 0 compared with week ‐2 or a NRS pain score reduced by ≥ 2 at week 0 compared with week ‐1. Participants with refractory FM, which was defined as participants who were simultaneously taking 3 drugs (pregabalin + an antidepressant + another antiepileptic drug) or a narcotic analgesic. Any coexisting inflammatory disease (e.g. rheumatoid arthritis) as indicated by an erythrocyte sedimentation rate > 40 mm/hour, C‐reactive protein ≥ 1.0 mg/dL, antinuclear antibody titre ≥ 320‐fold, or rheumatoid factor level >100 IU/mL. Presence of pain from any nonorganic disease other than FM. Established diagnosis of chronic fatigue syndrome, sleep apnoea syndrome, or restless leg syndrome. Any concomitant or previous clinically important disease (e.g. uncontrolled autoimmune, hepatic or renal disease) or psychoneurological disorder (e.g. schizophrenia, manic depressive psychosis, and epilepsy). Participants who met the criteria for major depression episodes according to diagnosis module A of the Mini‐International Neuropsychiatric Interview or participants with a total score of ≥ 6 points for the risk of suicide in module C12. National Glycohemoglobin standardisation Programme haemoglobin A1c ≥ 6.9%. Use of any monoamine oxidase inhibitor within 14 days before randomisation. Previous use of mirtazapine for pain control
Interventions	Active drug: one week mirtazapine 15 mg/d, 12 weeks mirtazapine 30 mg/d fixed Placebo: 13 weeks Rescue medication and allowed co‐therapies: subjects were prohibited from using any nonstudy drug (e.g. antidepressants, antiepileptics, pregabalin, narcotics, and narcotic analogs) or nonpharmacological treatment (e.g. surgery, electroconvulsive therapy, electrostimulation therapy, acupuncture and moxibustion, and nerve block) that might affect pain scoring. Participants using analgesics discontinued these drugs in the washout period, and concomitant analgesics were prohibited during the treatment period. As‐needed use of acetaminophen (up to 1.5 g/d), aspirin (up to 300 mg/d), any nonsteroidal anti‐inflammatory drug (up to 3 days), and dextromethorphan was permitted. Subjects were allowed to receive a drug to treat any stably controlled concomitant condition without modification of its dosage throughout the treatment period if the drug had been instituted before the start of the run‐in period. Subjects were also allowed to receive any nonpharmacological anti‐FM treatment, such as physical (e.g. exercise and hyperthermia) and psychological therapy (e.g. biofeedback treatment and cognitive behavioral therapy), without modification of its protocol, provided that the treatment had been instituted ≥ 30 days before the start of the run‐in period
Outcomes	Primary outcomes Participant‐reported pain relief of 50% or greater: last 24 hours diary mean pain (NRS 0 ‐ 10). Number of responders reported PGIC very much improved: not assessed Serious AEs: during the double‐blind treatment period, subjects in both groups were asked about their symptoms in an open‐ended fashion. Symptoms collected in this way and abnormal physical and laboratory findings observed were reported as AEs. Withdrawal due to AEs: reported Secondary outcomes Participant‐reported pain relief of 30% or greater: last 24 hours diary mean pain (NRS 0 ‐ 10). Number of responders reported PGIC much improved: not assessed Participant‐reported sleep problems: Japanese Insomnia Severity Index (NRS 0 ‐ 28); SD provided on request Participant‐reported fatigue: SF‐36 subscale vitality (0 ‐ 100) Participant‐reported mean pain intensity: last 24 hours diary mean pain (NRS 0 ‐ 10): SD provided on request Participant‐reported improvement of health‐related quality of life of 20% or greater: Japanese version of the FIQVAS 0‐100). Mean and SDs provided on request. Responder rates calculated by imputation method (Furukawa 2005) Participant‐reported negative mood: Beck Depression Inventory II (0 ‐ 63), provided on request Withdrawal due to lack of efficacy: reported Any AEs: during the double‐blind treatment period, subjects in both groups were asked about their symptoms in an open‐ended fashion. Symptoms collected in this way and abnormal physical and laboratory findings observed were reported as AEs. Specific AEs: during the double‐blind treatment period, subjects in both groups were asked about their symptoms in an open‐ended fashion. Symptoms collected in this way and abnormal physical and laboratory findings observed were reported as AEs. Data provided on request
Notes	Funding sources: Funded by Meiji Seika Pharma Co, Ltd. Declaration of interest of primary investigators: K. Miki, M. Murakami, H. Oka, K. Osada received honorarium from Meiji Seika Pharma Co, Ltd. K. Onozawa and S. Yoshida are employees of Meiji Seika Pharma Co, Ltd.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated allocation sequence, which was delivered by a telephone randomisation service (randomisation manager) not involved in subject recruitment or treatment to ensure allocation concealment
Allocation concealment (selection bias)	Low risk	The randomisation manager securely kept the randomisation list and confirmed that the blinding was maintained until the official decoding of the randomisation list
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The manager also checked and confirmed the similarity between the active and placebo tablets regarding appearance, shape, size, packaging, and labelling
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participant‐reported outcomes; participants were adequately blinded to intervention. Blinding of outcome assessors of safety not adequately described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Last observation carried forward (LOCF) method
Selective reporting (reporting bias)	Low risk	All outcomes reported as outlined in JapicCTI‐101176
Sample size	Low risk	> 200 participants per study arm
Group similarity at baseline	Low risk	No significant differences in demographic and clinical baseline characteristics of the study groups