A proof of concept phase II study with the PDE-4 inhibitor roflumilast in patients with mild cognitive impairment or mild Alzheimer's disease dementia (ROMEMA): study protocol of a double-blind, randomized, placebo-controlled, between-subjects trial

Abstract

Background: Research into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer's disease (AD) dementia.

Methods: The study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 μg roflumilast, and 100 μg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants' performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants.

Discussion: The outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders.

Trial registration: The Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL ) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1 ) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020.

Keywords: Alzheimer; Cognitive dysfunction; Dementia; Drug intervention; Memory; Mild cognitive impairment; Phosphodiesterase 4; Randomized controlled trial; Roflumilast.

Fig. 1

Trial schedule. MMSE: Mini-Mental State Examination, 15-VLT: 15-word Verbal Learning Task, CDR: Clinical Dementia Rating, LDST: Letter Digit Substitution Task, ADAS-Cog: Alzheimer’s Disease Assessment Scale – Cognitive subscale, TMT: Trail Making Test, HADS: Hospital Anxiety Depression Scale, EQ-5D: EuroQol – 5 Dimensions, QoL-AD: Quality of Life Alzheimer’s Disease, NPI: Neuropsychiatric Inventory, ADCS-ADL: Alzheimer’s Disease Cooperative Study—Activities of Daily Living, ECG: Electrocardiogram, ROS: reactive oxygen species

Fig. 2

Schematic overview of test days