deliVERy of Optimal blood pressure coNtrol in afrICA (VERONICA)-Nigeria study: Rationale and Design of a Randomised Clinical Trial.

BACKGROUND: Blood pressure (BP) control among treated patients in Africa is very suboptimal, with low levels of combination therapy use and therapeutic inertia being among the major barriers to effective control of hypertension. The VERONICA-Nigeria study aims to evaluate, among Black African adults with hypertension, the effectiveness and safety of a triple pill-based treatment protocol compared to Nigeria hypertension treatment protocol for the treatment of hypertension. METHODS: This study involves a randomised, parallel-group and open-label trial. Adults with uncontrolled hypertension (n=300), untreated or receiving monotherapy, with no contraindication to study treatments will be randomly assigned 1:1 to treatment with a triple pill based-treatment protocol or Nigeria hypertension treatment protocol. Follow-up is for 6 months, with interim follow up visits at month 1, 2, and 3. In a non-comparative extension treatment period, participants completing the 6 months randomised period and on ≤3 BP-lowering drugs will receive treatment with the triple pill-based treatment protocol for 12 months. The primary outcome is change in home mean SBP from baseline to month 6, and key secondary efficacy outcome is percentage of participants with clinic BP <140/90 mmHg at month 6. The primary safety outcome is discontinuation of trial treatment due to adverse events from randomization to month 6. Economic evaluation will be conducted to assess the cost-effectiveness of the triple pill-based treatment protocol, and process evaluation will be conducted to understand the context in which the trial was conducted, implementation of the trial and interventions and mechanisms of effect, and potential barriers and facilitators to implementing the intervention in clinical practice. CONCLUSION: The VERONICA-Nigeria trial will provide evidence of effectiveness and safety of the triple-based treatment protocol for the pharmacological management of hypertension, in Black African adults. TRIAL REGISTRATION: PACTR202107579572114.

Shop-to-Stop Hypertension: A multicenter cluster-randomized controlled trial protocol to improve screening and text message follow-up of adults with high blood pressure at health kiosks in hardware retail stores.

High blood pressure (BP) is the leading preventable risk factor for death, but only one in three patients achieve target BP control. A key contributor to this problem is poor population awareness of high BP, as the majority of patients are asymptomatic. The Shop-To-Stop Hypertension study is a multicenter, cluster-randomized controlled trial to identify, refer and follow adults in need of hypertension care, whilst raising population-wide awareness. In participants with high BP measured by SiSU Health Stations located in major hardware chain stores across New South Wales, Australia, we will determine whether text message-based nudges will encourage repeat BP checks and visits to their doctor. Based on pilot data, we anticipate 65,340 participants will be screened over 12 months, of which 18% will have high BP. Thirty hardware stores will be randomized (1:1) to: (i) Intervention: participants detected with high BP (≥140/≥90 mmHg) will receive text message-based nudges to return for a repeat SiSU Health Station BP check and to visit their general practitioner (GP) to check and manage their BP; (ii) Control: participants with high BP will not receive text messages. The primary outcome is the difference in the proportion of participants with high BP having a repeat BP check at hardware Health Stations in the intervention vs. control group at 12 months. This novel setting for screening utilises a novel 'citizen science' approach inviting the general public to perform their own BP screening at health kiosks and foster behavioral change. This will allow screening in a low-stress environment.

Prescription and dispensing duration of medicines for hypertension and other chronic conditions: a review of international policies and evidence to inform the Australian setting.

The duration of treatment for which a physician may prescribe a medicine, 'prescription duration', is often dispensed at the pharmacy on multiple occasions of shorter time periods, 'dispensing duration'. These durations vary significantly between and within countries. In Australia, the quantity of medication supplied at each dispensing has recently been extended from 30 to 60 days for a selection of medicines used for chronic health conditions, such as diabetes and hypertension. Dispensing durations vary between countries, with 30, 60 or 90 days being the most common-with 90 days aligning with the recommendation of the 2023 Global Report on Hypertension from the World Health Organization. The full impact of shorter vs longer prescription durations on health costs and outcomes is unknown, but current evidence suggests that 90-day dispensing could reduce costs and improve patient convenience and adherence. More rigorous research is needed.

Participants' views of ultra-low dose combination therapy for high blood pressure: a mixed-methods study from the QUARTET trial.

Single-pill combination therapy containing four quarter-dose medications for high blood pressure improves BP control compared to monotherapy, however patient-reported acceptance of the quadpill as a treatment strategy remains undescribed. We collected within-trial feedback and interviewed participants from the quadruple ultra-low-dose treatment for hypertension (QUARTET) trial to characterise patient attitudes to this intervention. All trial participants were asked about ease and preference for the quadpill and provided an opportunity to give further comments on the trial at 12 weeks (trial primary endpoint) and 52 weeks extended follow-up. Separately, we used purposive and quota sampling for the semi-structured telephone interviews, with the resultant verbatim transcripts analysed using an inductive thematic analysis approach. Themes were re-evaluated after each successive interview, and at suspected data saturation, an additional interview conducted for confirmation. At 12 weeks follow-up, 502 of 591 (85%) participants responded to acceptability questions, and 359 of 417 (86%) responded at week 52. Most reported the trial capsule easy or very easy to take. From eight sites, 16 participants were interviewed between 5 August 2020 and 19 November 2020. All described a positive experience, preferred once-daily morning dosing and found routine facilitated adherence. Participants valued individual responsibility for adherence, and involvement of the general practitioner in blood-pressure management. Most reported capsule size did not deter adherence but desired a smaller capsule. Participants described a preference for minimising number and dosage of medications, reduced capsule size, and once-daily morning dosing. These findings suggest a preference for single-pill combination therapy for blood pressure lowering.

Therapeutic Inertia With Initial Low-Dose Quadruple Combination Therapy for Hypertension: Results From the QUARTET Trial.

BACKGROUND: Low-dose combinations are a promising intervention for improving blood pressure (BP) control but their effects on therapeutic inertia are uncertain. METHODS: Analysis of 591 patients randomized to an ultra-low-dose quadruple pill or initial monotherapy. The episode of therapeutic inertia was defined as a patient visit with a BP of >140/90 mm Hg without intensification of antihypertensive treatment. We compared the frequency of therapeutic inertia episodes between Quadpill and initial monotherapy as a proportion of the total population (intention-to-treat analysis with the denominator being all participants randomized) and as a proportion of people with uncontrolled BP (with the denominator being participants with uncontrolled BP). RESULTS: Therapeutic inertia occurred in fewer participants randomized to Quadpill compared with monotherapy. For example, among the 390 participants with a 6-month follow-up, therapeutic inertia according to unattended BP was 21/192 (11%) versus 45/192 (23%), P=0.002. There were similar rates of therapeutic inertia among those with uncontrolled unattended BP in each group (all P>0.4). Consistent observations were seen with the use of attended office BP measures. The major determinants of not intensifying treatment during follow-up were BP readings that were close to target and large improvements in BP compared with the previous visit. CONCLUSIONS: Among all treated individuals, low-dose Quadpill reduced the number of therapeutic inertia episodes compared with initial monotherapy. After the first follow-up visit, most high BP values did not lead to treatment intensification in both groups. Education is needed about the importance of treatment intensification despite a significant improvement in BP or BP being close to target. REGISTRATION: URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12616001144404; Unique identifier: ACTRN12616001144404.

Ambulatory blood pressure after 12 weeks of quadruple combination of quarter doses of blood pressure medication vs. standard medication.

BACKGROUND: A combination of four ultra-low-dose blood pressure (BP) medications lowered office BP more effectively than initial monotherapy in the QUARTET trial. The effects on average ambulatory BP changes at 12 weeks have not yet been reported in detail. METHODS: Adults with hypertension who were untreated or on monotherapy were eligible for participation. Overall, 591 participants were randomized to either the quadpill (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or monotherapy control (irbesartan 150 mg). The difference in 24-h, daytime, and night-time systolic and diastolic ambulatory BP at 12 weeks along further metrics were predefined secondary outcomes. RESULTS: Of 576 participants, 289 were randomized to the quadpill group and 287 to the monotherapy group. At 12 weeks, mean 24-h ambulatory SBP and DBP were 7.7 [95% confidence interval (95% CI) 9.6-5.8] and 5.3 (95% CI: 6.5-4.1) mmHg lower in the quadpill vs. monotherapy group ( P  < 0.001 for both). Similar reductions in the quadpill group were observed for daytime (8.1/5.7 mmHg lower) and night-time (6.3/4.0 mmHg lower) BP at 12 weeks (all P  < 0.001) compared to monotherapy. The rate of BP control (24-h average BP < 130/80 mmHg) at 12 weeks was higher in the quadpill group (77 vs. 50%; P  < 0.001). The reduction in BP load was also more pronounced with the quadpill. CONCLUSION: A quadruple quarter-dose combination compared with monotherapy resulted in greater ambulatory BP lowering across the entire 24-h period with higher ambulatory BP control rates and reduced BP variability at 12 weeks. These findings further substantiate the efficacy of an ultra-low-dose quadpill-based BP lowering strategy.

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular disease.

Fixed-dose combination (FDC) therapy, also known as polypill therapy, targets risk factors for atherosclerotic cardiovascular disease (ASCVD) and has been proposed as a strategy to reduce global ASCVD burden. Here we conducted a systematic search for relevant studies from 2016-2022 to assess the effects of FDC therapy for prevention of ASCVD. The studies selected include randomized trials evaluating FDC therapy with at least one blood pressure-lowering drug and one lipid-lowering drug. The study data were independently extracted, the quality of evidence was appraised by multiple reviewers and effect estimates were pooled using a fixed-effect meta-analysis when statistical heterogeneity was low to moderate. The main outcomes of the analysis were all-cause mortality, fatal and nonfatal ASCVD events, adverse events, systolic blood pressure, low-density lipoprotein cholesterol and adherence. Among 26 trials (n = 27,317 participants, 43.2% female and mean age range 52.9-76.0), FDC therapy was associated with lower low-density lipoprotein cholesterol and systolic blood pressure, with higher rates of adherence and adverse events in both primary and mixed secondary prevention populations. For studies with a mostly primary prevention population, FDC therapy was associated with lower risk of all-cause mortality by 11% (5.6% versus 6.3%; relative risk (risk ratio) of 0.89; 95% confidence interval 0.78 to 1.00; I2 = 0%; four trials and 16,278 participants) and risk of fatal and nonfatal ASCVD events by 29% (6.1% versus 8.4%; relative risk (risk ratio) of 0.71; 95% confidence interval 0.63 to 0.79; I2 = 0%; five trials and 15,503 participants). One adequately powered trial in an exclusively secondary prevention population showed that FDC therapy reduced the risk of major adverse cardiovascular events by 24%. These findings support adoption and implementation of polypills to lower risk for all-cause mortality and ASCVD.

The contribution of sodium reduction and potassium increase to the blood pressure lowering observed in the Salt Substitute and Stroke Study.

The Salt Substitute and Stroke Study (SSaSS) demonstrated significant reductions in systolic blood pressure (SBP), and the risk of stroke, major cardiovascular events and total mortality with the use of potassium-enriched salt. The contribution of sodium reduction versus potassium increase to these effects is unknown. We identified four different data sources describing the association between sodium reduction, potassium supplementation and change in SBP. We then fitted a series of models to estimate the SBP reductions expected for the differences in sodium and potassium intake in SSaSS, derived from 24-h urine collections. The proportions of the SBP reduction separately attributable to sodium reduction and potassium supplementation were calculated. The observed SBP reduction in SSaSS was -3.3 mmHg with a corresponding mean 15.2 mmol reduction in 24-h sodium excretion and a mean 20.6 mmol increase in 24-h potassium excretion. Assuming 90% of dietary sodium intake and 70% of dietary potassium intake were excreted through urine, the models projected falls in SBP of between -1.67 (95% confidence interval: -4.06 to +0.73) mmHg and -5.33 (95% confidence interval: -8.58 to -2.08) mmHg. The estimated proportional contribution of sodium reduction to the SBP fall ranged between 12 and 39% for the different models fitted. Sensitivity analyses assuming different proportional urinary excretion of dietary sodium and potassium intake showed similar results. In every model, the majority of the SBP lowering effect in SSaSS was estimated to be attributable to the increase in dietary potassium rather than the fall in dietary sodium.

Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS).

BACKGROUND: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). METHODS: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. RESULTS: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LIMITATIONS: The study included two Cohorts with different dosing regimes. CONCLUSIONS: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.

The Prevalence of CKD in Australian Primary Care: Analysis of a National General Practice Dataset.

Introduction: The prevalence of chronic kidney disease (CKD) in Australia varies substantially across reports. Using a large, nationally representative general practice data source, we determined the contemporary prevalence and staging of CKD in the Australian primary care. Methods: We performed a retrospective, community-based observational study of 2,720,529 adults with ≥1 visit to a general practice participating in the MedicineInsight program and ≥1 serum creatinine measurement (with or without a urine albumin-to-creatinine ratio [UACR] measurement) between 2011 and 2020. CKD prevalence was estimated using 3 definitions based on estimated glomerular filtration rate (eGFR) and UACR measurements with varying degrees of rigidity in terms of the number of measurements assessed to define CKD ("least", "moderate" and "most" rigid). Results: CKD prevalence in the cohort progressively increased over the 10-year study period, irrespective of the method used to define CKD. In 2020, CKD prevalence in the cohort was 8.4%, 4.7%, and 3.1% using the least, moderate, and most rigid definition, respectively. The number of patients with UACR measurements was low such that, among those with CKD in 2020, only 3.8%, 3.2%, and 1.5%, respectively, had both eGFR and UACR measurements available in the corresponding year. Patients in whom both eGFR and UACR measurements were available mostly had moderate or high risk of CKD progression (83.6%, 80.6%, and 76.2%, respectively). Conclusion: In this large, nationally representative study, we observed an increasing trend in CKD prevalence in primary care settings in Australia. Most patients with CKD were at moderate to high risk of CKD progression. These findings highlight the need for early detection and effective management to slow progression of CKD.

Rationale for a New Low-Dose Triple Single Pill Combination for the Treatment of Hypertension.

Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these 'hypertension polypills' were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.

The effect of salt substitution on frequency and severity of headache: results from the SSaSS cluster-randomised controlled trial of 20,995 participants.

BACKGROUND: Headache is one of the most common neurological symptoms. Headache disorders are associated with a high global burden of disease. Prior studies indicate that short-to-medium term sodium reduction reduces headache symptom. This study evaluated the effects of long-term reduced-sodium, added-potassium salt on headache frequency and severity in rural China. METHODS: The Salt substitute and stroke study (SSaSS) was an open-label cluster-randomised trial in rural China designed to evaluate the effect of salt substitution on mortality and cardiovascular events. Participants included adults with a history of prior stroke and those aged ≥60 years with uncontrolled high blood pressure (BP). Villages were randomly assigned in a 1:1 ratio either to intervention with salt substitute (75% sodium chloride and 25% potassium chloride by mass) or to control with continued use of regular salt (100% sodium chloride). In this pre-specified analysis, between-group differences in headache frequency and severity were evaluated. The study was registered with ClinicalTrials.gov (identifier number: NCT02092090). RESULTS: A total of 20,995 participants were included in the trial (mean age 64.3 years, 51% female, mean follow-up 4.7 years). At final follow-up at the end of the study, headache outcome data including frequency and severity of headaches was available for 16,486 (98%) of 16,823 living participants. Overall, 4454/16,486 (27%) individuals reported having headache: 27.4% in the intervention group (2301/8386) vs 26.6% in the control group (2153/8100) (RR 1.04, 95% CI: 0.93, 1.16, p = 0.48). There was no difference in headache severity between intervention and control groups (p = 0.90). CONCLUSION: Long term salt substitution did not reduce the frequency or severity of headaches in this population.

Estimating the population-level impacts of improved uptake of SGLT2 inhibitors in patients with chronic kidney disease: a cross-sectional observational study using routinely collected Australian primary care data.

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of kidney failure and death in patients with chronic kidney disease (CKD) but are underused. We evaluated the number of patients with CKD in Australia that would be eligible for treatment and estimated the number of cardiorenal and kidney failure events that could be averted with improved uptake of SGLT2 inhibitors. Methods: This cross-sectional observational study leveraged nationally representative primary care data from 392 Australian general practices (MedicineInsight) between 1 January 2020 and 31 December 2021. We identified patients that would have met inclusion criteria of key SGLT2 inhibitor trials and applied these data to age and sex-stratified estimates of CKD prevalence for the Australian population (using national census data), estimating the number of preventable events using trial event rates. Key outcomes included cardiorenal events (CKD progression, kidney failure, or death due to cardiovascular or kidney disease) and kidney failure. Findings: In MedicineInsight, 44.2% of adults with CKD would have met CKD eligibility criteria for an SGLT2 inhibitor; baseline use was 4.1%. Applying these data to the Australian population, 230,246 patients with CKD would have been eligible for treatment with an SGLT2 inhibitor. Optimal implementation of SGLT2 inhibitors (75% uptake) could reduce cardiorenal and kidney failure events annually in Australia by 3644 (95% CI 3526-3764) and 1312 (95% CI 1242-1385), respectively. Interpretation: Improved uptake of SGLT2 inhibitors for patients with CKD in Australia has the potential to prevent large numbers of patients experiencing CKD progression or dying due to cardiovascular or kidney disease. Identifying strategies to increase the uptake of SGLT2 inhibitors is critical to realising the population-level benefits of this drug class. Funding: University of New South Wales Scientia Program and Boehringer IngelheimEli Lilly Alliance.

Ensuring the affordable becomes accessible-lessons from ketamine, a new treatment for severe depression.

In this paper, the case study of ketamine as a new treatment for severe depression is used to outline the challenges of repurposing established medicines and we suggest potential solutions. The antidepressant effects of generic racemic ketamine were identified over 20 years ago, but there were insufficient incentives for commercial entities to pursue its registration, or support for non-commercial entities to fill this gap. As a result, the evaluation of generic ketamine was delayed, piecemeal, uncoordinated, and insufficient to gain approval. Meanwhile, substantial commercial investment enabled the widespread registration of a patented, intranasal s-enantiomeric ketamine formulation (Spravato®) for depression. However, Spravato is priced at $600-$900/dose compared to ~$5/dose for generic ketamine, and the ~AUD$100 million annual government investment requested in Australia (to cover drug costs alone) has been rejected twice, leaving this treatment largely inaccessible for Australian patients 2 years after Therapeutic Goods Administration approval. Moreover, emerging evidence indicates that generic racemic ketamine is at least as effective as Spravato, but no comparative trials were required for regulatory approval and have not been conducted. Without action, this story will repeat regularly in the next decade with a new wave of psychedelic-assisted psychotherapy treatments, for which the original off-patent molecules could be available at low-cost and reduce the overall cost of treatment. Several systemic reforms are required to ensure that affordable, effective options become accessible; these include commercial incentives, public and public-private funding schemes, reduced regulatory barriers and more coordinated international public funding schemes to support translational research.

Standardized treatment protocols for hypertension: global availability, characteristics, and alignment with the hypertension guideline recommendations.

BACKGROUND: Hypertension control is suboptimal globally. Implementing evidence-based, simple, standardized treatment protocols (STPs) has been instrumental in effectively and efficiently improving treatment and control of hypertension. We aimed to identify, characterize, and critically appraise hypertension STPs. METHODS: We defined STP as a series of steps for the pharmacological treatment of primary hypertension, with information on target population, BP threshold for treatment initiation, target BP, specific drugs/classes/doses, and follow-up frequency. STPs for adult patients were identified from the websites of relevant health organizations, Google search, and through expert consultations (until July 2023). STPs for secondary, gestational, or malignant hypertension or those that were templates/samples were excluded. Included STPs were critically appraised using HEARTS in the Americas Checklist for hypertension management in primary care and compared with the 2021 WHO hypertension management guideline recommendations. RESULTS: Fifty STPs were identified. All STPs had a stepwise treatment approach, involved guideline-recommended first-line drugs, and 98% consisted of at least four steps. Majority (54%) recommended monotherapy with calcium channel blockers as first-line treatment. Only 44% STPs recommended treatment initiation with combination therapy, and 16% recommended single-pill combinations. Most (62%) had dose-intensification as the second step. Most (74%) STPs did not provide complete dosing information. Only one STP mentioned a target time for achieving BP control. On average, STPs scored a performance of 68% on the HEARTS Checklist. CONCLUSION: Several STPs are available globally; however, most of them have enormous scope for improvement through interventions aimed at alignment with the latest evidence-based guidelines and multistakeholder engagement.

Randomised controlled trial of neurostimulation for symptoms of anorexia nervosa (TRENA study): study protocol.

BACKGROUND: Anorexia nervosa (AN) has amongst the highest mortality rates and the highest treatment costs of any psychiatric disorder. Recently, interest in non-invasive brain stimulation as a novel treatment for AN has grown. These include repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). METHODS: This double-blind, randomised sham-controlled trial will compare the relative acceptability and efficacy of tDCS and rTMS in people with AN. 70 participants will be randomised to active or sham tDCS, or active or sham rTMS treatment (2:1:2:1 ratio) over an 8-week treatment period. Participants will receive treatment as usual across the study duration. The primary outcomes are change on the Eating Disorder Examination Questionnaire and treatment acceptability. Secondary outcomes will include change in weight, cognition, mood, interpersonal functioning, and quality of life. Following the 8-week assessment, all participants will have the option of receiving an additional 12 weeks of at-home tDCS. A follow-up assessment will be conducted at 20 weeks post treatment. DISCUSSION: Research into non-invasive brain stimulation as treatments for AN has potential to improve clinical outcomes for patients by comparing the relative efficacy and acceptability of both treatment modalities in the inpatient and at-home setting (i.e., for at-home tDCS) results from this study will provide important information for informing future larger clinical trials of these treatments for AN. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05788042.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.