Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY)

Abstract

Background: There are currently no treatments for empathy deficits in neuropsychiatric disorders. Acute administration of the hormone oxytocin has been associated with symptomatic improvements across animal models and several neuropsychiatric disorders, but results of the majority of oxytocin randomised controlled trials (RCTs) of longer duration have been negative or inconclusive. This lack of efficacy of may be due to rapid habituation to oxytocin with chronic dosing. The objective of the present study is to describe the design of a phase 2 adaptive randomised controlled crossover trial of intranasal oxytocin in frontotemporal dementia (FOXY) as an efficient model for future investigations of symptomatic treatments in neuropsychiatric and neurodegenerative disorders.

Methods: Stage 1 will identify which of three dose schedules is most promising based on change in the primary outcome measure, the Neuropsychiatric Inventory apathy/indifference domain score, over 6 weeks of treatment. In stage 2, additional patients are enrolled at the most promising dose for preliminary efficacy analysis when combined with stage 1 to determine if a phase 3 trial is warranted. Objective measures include facial expression recognition, cerebrospinal fluid (CSF) oxytocin levels, and behavioural ratings of videotaped interactions.

Results: A total of 20 patients per arm will be entered into stage 1 for a total of 60 patients. In stage 2, an additional 40 patients will be enrolled in the most promising dose arm.

Conclusions: The use of adaptive, crossover designs and inclusion of objective measures of change in CSF oxytocin levels and social behaviour will improve the efficiency and conclusiveness of RCTs of oxytocin and other symptomatic treatments in neuropsychiatric disorders.

Trial registration: ClinicalTrials.gov, NCT03260920 . Registered on August 24, 2017.

Keywords: Adaptive design; Apathy; Clinical trial; Crossover design; Empathy; Frontotemporal dementia; Oxytocin.

Conflict of interest statement

Ethics approval and consent to participate

This study has received a no objection letter from Health Canada and investigational new drug approval from the FDA. Ethics approvals will be obtained at each participating site.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Two-stage phase II adaptive crossover trial design for intranasal oxytocin for frontotemporal dementia (FOXY). In stage 1, a total of 60 patients with frontotemporal dementia (FTD) are randomized to one of three dose schedules. In the crossover design, baseline assessments are completed at the beginning of each treatment period. After baseline, participants receive twice-daily intranasal sprays of placebo or oxytocin for 6 weeks and then undergo complete outcome assessments and optional lumbar puncture. The first treatment period is followed by a washout period with no sprays given for 6 weeks. At the end of the washout period, participants are re-baselined prior to 6 weeks of twice-daily intranasal spays of the alternate drug (placebo or oxytocin). In stage 2, 20 additional patients with FTD are randomized to the most promising dose identified at the planned interim analyses at the end of stage 1, and complete procedures identical to those in stage 1 are performed