Safety and efficacy of rotigotine in patients with frontotemporal dementia: a phase 2, double-blind, randomized, placebo-controlled, multicenter trial

Abstract

Background: Frontotemporal dementia (FTD) is a common form of dementia with no approved pharmacological treatment. Clinical and experimental evidence suggest that dopaminergic transmission is impaired in FTD. Here we aimed at investigating the clinical impact of treatment with dopaminergic agonists in FTD.

Methods: This was a phase IIa 24-week randomized, double-blind, multicenter, placebo-controlled study, conducted in Italy from June 16th 2021 to April 30th 2023. Patients with a diagnosis of probable behavioral variant FTD (bvFTD) were randomly assigned in a 1:1:1 ratio to receive rotigotine transdermal patches at 4 mg/24 h, rotigotine transdermal patches at 6 mg/24 h, or placebo transdermal patches for 24 weeks. Randomization was centralized and performed using a double-blind covariate-adaptive scheme. The primary outcome was analyzed in the intention-to treat (ITT) population. The primary efficacy outcome measure was the change at 24-weeks from baseline in the Frontal Assessment Battery (FAB). The trial is completed and was registered on the clinicaltrial.gov website (NCT04937452).

Findings: A total of 128 patients were screened, of which 75 were randomized. 25 patients were randomized to receive Rotigotine 4 mg, 26 patients to Rotigotine 6 mg, and 24 patients to placebo. The mean age of patients was 66.5 ± 8 of which 31 (41%) were female. A total of 69 patients (92%) completed the study. The estimated mean change from baseline at 24 weeks in the FAB score in the ITT population was 0.18 (95% confidence interval [CI] -0.79 to 1.15) in the rotigotine 4 mg group, 0.89 (95% CI -0.09 to 1.88) in the rotigotine 6 mg group and 1.08 (95% CI 0.19-1.98) in the placebo group (rotigotine 4 mg vs placebo, -0.90; 95% CI -2.22 to 0.42; p = 0.18; rotigotine 6 mg vs placebo, -0.19; 95% CI -1.52 to 1.14; p = 0.77). No significant effect was found on secondary outcome measures. Adverse events were mild in all groups and more common in the rotigotine (4 mg: 4/25; 6 mg: 3/26) than in the placebo (1/24) group.

Interpretation: Rotigotine administration may not be a viable therapeutic option for enhancing frontal function, slowing disease progression, mitigating functional decline or ameliorating behavioral disturbances in bvFTD patients. The current findings provide data in a large sample of bvFTD that might be useful for the design of future clinical trials.

Funding: This trial was funded by a joint grant from the Alzheimer Drug Discovery Foundation (ADDF) and the Association for Frontotemporal Degeneration (AFTD) grant to GK and BB (GFTD-201902-2017958).

Keywords: Dopamine; Executive function; Frontotemporal dementia; Neurotransmission deficit; Rotigotine.

Fig. 1

Study flowchart. Randomization, trial-group assignment, and follow-up in the trial. Abbreviations: CDR-FTLD: Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Centre; FTD: Frontotemporal Dementia; PPA: Primary progressive aphasia.

Fig. 2

Clinical data results. The generalized linear mixed model estimated mean change from baseline is shown for the Frontal Assessment Battery (FAB), with higher scores indicating better frontal cognitive functions; for the Neuropsychiatric Inventory (NPI), with higher scores indicating worse behavioral symptoms; for the Frontal Behavioral Inventory (FBI), with a higher score meaning more severe behavioral disturbances; for CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Coordinating Center and Frontotemporal lobar degeneration modules–sum of boxes (CDR plus NACC FTLD), with higher scores meaning higher disease severity; for the Screening for aphasia in Neurodegeneration (SAND), with higher score meaning less severe language deficits; for Alzheimer Disease Cooperative Study Activities of Daily Living scale (ADCS-ADL), with lower scores indicating worse function; for the Mini Mental State Examination (MMSE), with higher score meaning less cognitive impairment; for the Addenbrooke's Cognitive Examination Revised (ACE-R), with higher score meaning less cognitive impairment; Baseline is plotted at week 0, which is the mean assessment time of the baseline measurement as offset from the first administration of the Rotigotine 4 mg, Rotigotine 6 mg or placebo. Cognitive evaluations were collected also at 4, 12, and 24 weeks. Error bars indicate standard errors. The y-axis of the plots has been oriented so that negative values indicate cognitive or behavioral worsening.