Jia 2016.

Study characteristics
Methods	Design: randomised, double‐blind, placebo‐controlled trial Location/setting: 15 academic medical centres in China Date of study: 29 June 2009 to 2 May 2015 (participants screening: September 2008 to December 2009) Sample size: 563 people with a diagnosis of subcortical vascular cognitive impairment without dementia were enrolled and assessed for eligibility. 282 were excluded and 281 entered the study and underwent randomisation. Randomisation: among the 281 people who underwent randomisation, 141 were assigned to DL‐3‐n‐butylphthalide (117/141 completed the 24 weeks' treatment) and 140 were assigned to placebo (126/140 completed the 24 weeks' treatment). Participants were randomly assigned in a 1:1 ratio to receive kits containing DL‐3‐n‐butylphthalide 200 mg or placebo, which were labelled with sequential numbers according to a randomisation list (stratified by investigation site, in blocks of 4) generated by an independent statistician.
Participants	Number in study: 281 Participant diagnosis: subcortical vascular cognitive impairment without dementia Inclusion criteria Han Chinese Aged: 50–70 years With a consistent carer who accompanied the participants ≥ 4 days a week Complaint or informant (or both) report of cognitive impairment involving memory or other cognitive domains (or both) lasting ≥ 3 months Neither normal nor demented according to the criteria of the DSM‐IV, with CDR ≥ 0.5 on ≥ 1 domain and global score ≤ 0.5 MMSE score ≥ 20 (primary school education) or ≥ 24 (junior school or above education) Normal or slightly impaired ADL defined by total score ≤ 1.5 on the 3 functional CDR domains (home and hobbies, community affairs and personal care) MRI brain criteria as follows: multiple (i.e. ≥ 3) supratentorial subcortical small infarcts (3–20 mm in diameter), with or without WML of any degree; or moderate to severe WML (score 2 according to the Fazekas Rating Scale) with or without small infarct; or ≥ 1 strategically located subcortical small infarcts in the caudate nucleus, globus pallidus, or thalamus absence of cortical and watershed infarcts, haemorrhages, hydrocephalus, and WMLs with specific causes (e.g. multiple sclerosis) no hippocampal or entorhinal cortex atrophy (scored 0 according to medial temporal lobe atrophy scale of Scheltens) all scans read by a central neuroimaging reader to determine eligibility, ensuring consistent application of the criteria Exclusion criteria Severe aphasia Physical disabilities or any other factor that may precluded completion of neuropsychological testing Disorders other than subcortical vascular cognitive impairment without dementia that may affect cognition HAMD score > 17, or schizophrenia New stroke within 3 months before baseline Inherited or inflammatory small vessel disease Clinically significant gastrointestinal, renal, hepatic, respiratory, infectious, endocrine or cardiovascular system disease Cancer Alcoholism Drug addiction Use of medications that may affect cognitive functioning (including tranquilisers, anxiolytics, hypnotics, nootropics and cholinomimetic agents) Known hypersensitivity to celery Inability to undergo brain MRI Mean age: DL‐3‐n‐butylphthalide: 68.0 (SD 8.8) years; placebo: 66.7 (SD 7.7) years Females: DL‐3‐n‐butylphthalide: 48 participants (34.3%); placebo: 48 participants (34.3%) Education: DL‐3‐n‐butylphthalide: < 5 years: 50 participants (35.7%); > 5 years: 90 participants (64.3%); placebo: < 5 years: 52 participants (37.1%); > 5 years: 88 participants (62.9%) Baseline comorbidities Hypertension: DL‐3‐n‐butylphthalide: 70%; placebo: 65.7% Diabetes mellitus: DL‐3‐n‐butylphthalide: 18.6%; placebo: 17.1% Atrial fibrillation: DL‐3‐n‐butylphthalide: 3.6%; placebo: 2.1% Previous stroke: DL‐3‐n‐butylphthalide: 74.3%; placebo: 77.9% TIA: DL‐3‐n‐butylphthalide: 11.4%; placebo 9.3% Baseline concomitant aspirin: DL‐3‐n‐butylphthalide: 61.4%; placebo: 65.7% Consent: written informed consent
Interventions	Pharmacological intervention: DL‐3‐n‐butylphthalide 200 mg for 24 weeks Control: placebo for 24 weeks
Outcomes	Primary outcomes (all measured at baseline and after 6 months of treatment) Changes in 12‐item ADAS‐Cog CIBIC‐plus  Secondary outcomes (all measured at baseline and after 6 months of treatment) MMSE CDR CDR‐SB ADL NPI Withdrawal from trial drug Of the 280 participants initially included: DL‐3‐n‐butylphthalide: 3 had drug‐related adverse events, 10 lost to follow‐up, 4 comorbidities worsened, 4 withdrew from treatment in the group; placebo: 8 lost to follow‐up, 1 comorbidity worsened and 3 withdrew from treatment. 37 participants discontinued treatment across both arms, therefore only 243 participants completed the 24 weeks of either DL‐3‐n‐butylphthalide or placebo treatment.
Notes	PubMed link: www.ncbi.nlm.nih.gov/pubmed/26086183 Chinese Clinical Trial Registry number: ChiCTR‐TRC‐09000440 Funding source: "Eleven Five‐Year" Scientific Support Plan Project of State Science and Technology Commission: Diagnosis and Intervention of Mild Cognitive Impairment. The State Science and Technology Commission had no other role in the study. Research protocol approval: institutional review board at each participating institution Study medication: donated by Shijiazhuang Pharmaceutical Group Company. It was stated that, "The company had no other role in the study." Conduct, safety and adherence to protocol monitoring: by an independent data and safety monitoring board. Declaration of interest: (quote) "Authors declared that they have no conflicts of interest."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomly assigned in a 1:1 ratio to received three times daily oral DL‐3‐n‐butylphthalide 200 mg or placebo of identical appearance for 24 weeks. The randomisation list (stratified by investigation site, in blocks of four) was generated by an independent statistician."
Allocation concealment (selection bias)	Low risk	Quote: "Every site was supplied with kits of study drug that were labelled with sequential numbers corresponding to the randomisation list."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Patients, caregivers and site investigators were blinded to the treatment allocation." Comment: the trial drug and placebo were of identical appearance.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The clinician completing the CIBIC‐plus was blind to the other psychometric assessments and adverse events."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition rate: DL‐3‐n‐butylphthalide: 23/140 (16.4%) participants; placebo: 14/140 (10%) participants.
Selective reporting (reporting bias)	Unclear risk	Comment: outcome measures were reported as adjusted mean, but the adjustments made were not clearly stated. Multiple outcomes listed as primary on trial register. Sample size in protocol and sample size reported in study did not correspond.
Other bias	Unclear risk	Industry support Quote: "The Shijiazhuang Pharmaceutical Group Company donated the study medication but had no other role in the study." Sample size Quote: "Thus, the sample size was under‐estimated, and the desired power was not achieved." Potential "significant‐result bias."