Van Den Boogard 2018.

Methods	Multicentre, 3‐arm randomized controlled trial Setting: 21 ICUs at university hospitals, teaching and non‐teaching hospitals Country: the Netherlands Groups: 3 arms: 2 arms each with different doses of haloperidol and a placebo arm Period: July 2013 to December 2016
Participants	Sample size: 1789 (353/734/706) Included Adult patients 18 years or older who were delirium free and with an expected ICU stay of more than 2 days. Excluded Delirium prior to inclusion Parkinson's disease Dementia Alcohol abuse Acute neurological condition History of psychiatric disease Use of antipsychotic agents History of clinically relevant ventricular arrhythmia in the last 12 months Corrected QT interval (QTc) time of at least 500 ms Pregnancy Breastfeeding Expected death within 2 days Known allergy or intolerance to haloperidol Unable to give consent Missing: 3 + 2 + 2 participants did not receive treatment (documented in flowchart)
Interventions	Intervention 1: Haloperidol 1 mg intravenously 3 times daily Intervention 2: Haloperidol 2 mg intravenously 3 times daily. Control: Placebo (0.9 % sodium chloride) intravenously 3 times daily.
Outcomes	Primary Number of days that patients survived up to 28 days after inclusion Secondary Number of days surviving up to 90 days following inclusion Delirium incidence Number of coma‐ and delirium‐free days up to 28 days Duration of mechanical ventilation Length of ICU and hospital stay Adverse effects Measured by: CAM‐ICU and ICDSC Adverse events: 5 serious adverse events were reported, 3 patients died, 1 in each group. The events were judged to be unrelated to the study medication. 2 patients in the 1 mg haloperidol group and 1 patient in the 2 mg haloperidol group developed monomorphic ventricular tachycardia, 1 patient in the 2 mg haloperidol group developed refractory shock, 1 patient in the placebo group developed a suspected malignant neuroleptic syndrome event.
Notes	Conclusions: The 1 mg haloperidol study arm was prematurely stopped due to futility. There was no difference in the median days patients survived within 28 days. No differences in effects on the secondary outcomes were found. The number of reported adverse events did not differ between groups. Data on delirium incidence and coma days could be retrieved from a total of 1506 patients (84.2%) from 14 of the 21 sites. Funding: funded partly by the ZonMw programme (dossier no 836031004). They had no influence on study design, conduct or publication. Conflict of interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Brüggemann reported that he received grant support and consultancy and speaker fees from Pfizer, Merck, Sharp, & Dohme, Astellas, and Gilead. Study number: clinicaltrials.gov identifier: NCT01785290 Contact with author: emailed for further information on missing data and data on ventilator‐free days 1 May 2018. Authors provided the data requested.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A permuted block randomization. Patients were allocated to each group in a 1:1:1 ratio
Allocation concealment (selection bias)	Low risk	The pharmacist who kept the randomization code and the members of the data and safety management board were the only people who were not blinded. The pharmacist was not involved in the clinical management of the patients.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data on delirium incidence and coma days could only be retrieved from a total of 1506 patients (84.2%) or from 14 of the 21 sites. Study authors have produced data to show that missing data were evenly distributed between groups.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported, with the exception of QoL which will be reported elsewhere in a subsequent publication (1‐ and 6‐month follow‐up)
Other bias	Low risk	Low risk of other potential biases
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Pharmacist with the randomization code and the members of the data and safety management board were the only people who were not blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were blinded