Intranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial.

Background: No treatments exist for apathy in people with frontotemporal dementia. Previously, in a randomised double-blind, placebo-controlled, dose-finding study, intranasal oxytocin administration in people with frontotemporal dementia improved apathy ratings on the Neuropsychiatric Inventory over 1 week and, in a randomised, double-blind, placebo-controlled, crossover study, a single dose of 72 IU oxytocin increased blood-oxygen-level-dependent signal in limbic brain regions. We aimed to determine whether longer treatment with oxytocin improves apathy in people with frontotemporal dementia.

Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b trial, enrolling participants from 11 expert frontotemporal dementia outpatient clinics across Canada and the USA. People aged 30-80 years with a diagnosis of probable frontotemporal dementia, a Neuropsychiatric Inventory apathy score of 2 or higher, a study partner who interacted with them for at least 3 h per day, and stable cognitive and behavioural medications for 30 days were eligible for inclusion. In stage 1, participants were randomly assigned (1:1:1:1:1:1) to one of three dose schedules (every day, every other day, and every third day) of 72 IU intranasal oxytocin or placebo and to the order they would received the intervention in the crossover; intranasal oxytocin or placebo were administered twice daily for 6 weeks, with a 6-week washout and then crossover to the other intervention. In stage 2, new participants were randomised (1:1) to the dose that had been determined as optimal in stage 1 or to placebo, with crossover as in stage 1. Randomisation used variable block sizes and was stratified by participant sex and Clinical Dementia Rating severity score. All kits of investigational product were identical and produced centrally, and all local teams, study staff, and participants were masked to treatment allocation and order. The primary outcome was difference in the change in Neuropsychiatric Inventory apathy scores for oxytocin versus placebo periods in the per-protocol population after 6 weeks of treatment. Safety was assessed at each visit via electrocardiogram, blood work, and collection of data on adverse events. This trial is registered at ClinicalTrials.gov (NCT03260920).

Findings: Between Jan 31, 2018, and Dec 11, 2020, 70 patients were screened for stage 1 and 60 (86%) were enrolled. 45 (75%) completed both treatment periods of stage 1. 72 IU oxytocin every third day was the optimal dose schedule from stage 1 based on its Bayesian posterior probability (Pr(Best)=0·478). Between June 28, 2021, and Jan 31, 2023, 42 patients were screened for stage 2, and 34 (81%) were enrolled. 28 (82%) completed both treatment periods in stage 2. 38 (40%) of 94 participants were female and 56 (60%) were male (mean age 65·9 years, SD 8·2) Treatment with oxytocin every third day resulted in an improved Neuropsychiatric Inventory apathy score, with an estimated -1·32 points (95% CI -2·43 to -0·21) relative to placebo (one sided p=0·010). Two adverse events were reported in at least 5% of participants: upper respiratory tract infection (five [6%] of 78 participants on placebo and three [5%] on every third day at all doses of oxytocin) and headache (two [3%] participants on placebo, one [7%] of 15 participants on oxytocin every day, and two [4%] of 55 participants on oxytocin every third day). No adverse events were attributed to oxytocin treatment.

Interpretation: Intranasal oxytocin given every third day was well tolerated and was associated with a small reduction in apathy in patients with frontotemporal dementia. Future trials might investigate intermittent dosing of more potent formulations than in this study, to establish whether larger effects are possible.

Funding: Canadian Institutes of Health Research and Weston Foundation.