Cognitive Effects of Roflumilast in (a)MCI and Mild Dementia Patients (ROMEMA)

A Proof of Concept Phase II Study With the PDE4 Inhibitor Roflumilast in Patients With (Amnestic) Mild Cognitive Impairment (MCI) or Mild Dementia

The aim of the current project is to validate whether chronic intake (24 weeks) roflumilast (PDE4 inhibitor) can improve cognition in patients with (amnestic) mild cognitive impairment (MCI) and in patients with mild dementia. The project will demonstrate whether episodic memory, but also attention, information processing or executive function improves with chronic administration of roflumilast in (a)MCI and mild dementia patients.

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment; Mild Dementia; Amnestic Mild Cognitive Disorder
• Intervention / Treatment: Drug: Placebo oral tablet; Drug: Roflumilast

• Study Type: Interventional
• Enrollment (Anticipated): 81
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nina Possemis, MSc.; Phone Number: +31 (0)43 388 1022; Email: n.possemis@maastrichtuniversity.nl
• Study Contact Backup: Name: Inez Ramakers, Dr.; Email: i.ramakers@maastrichtuniversity.nl

Study Locations

• Netherlands
  • Maastricht, Netherlands
    • Recruiting
    • University of Maastricht, Faculty of Psychology and Neuropsychology
    • Contact: Nina Possemis, MSc; Email: n.possemis@maastrichtuniveristy.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 50 to 90 years of age
• Willingness (including the informal caregiver) to sign an informed consent
• Body mass index (BMI) between 18.5 and 35
• MMSE of 20 or higher
• Clinical (amnestic)MCI or mild dementia diagnosis
• Memory performance on the delayed recall in the clinically relevant 15 words VLT of 1 or more SD below the average
• Clinical dementia rating (CDR) scale total score of 0.5 or 1
• Fazekas of 2 or lower

Exclusion Criteria:

• Normal Pressure Hydrocephalus (NPH)
• Fazekas of 3 or higher
• Morbus Huntington
• Parkinson's disease
• HIV/AIDS
• Hepatitis C & B
• Recent Transient Ischemic Attack (TIA) (< 2 years)
• Cerebrovascular Accident (CVA) (< 2 years)
• TIA/CVA followed by cognitive decline (within 3 months)
• Chronic Obstructive Pulmonary Disease (COPD) gold criteria 3 or 4 and severe asthma
• History of schizophrenia, bipolar disorder or psychotic symptoms not otherwise specified or previous treatment for these diseases (lifetime)
• Current radiotherapy
• Current affective disorder (i.e. anxiety or major depression)
• Cognitive problems due to alcohol abuse, brain tumor, epilepsy, encephalitis or lack of capacity to consent to participation.
• Current treatment with (or illicit use of) cannabis, opiates, benzodiazepines, MDMA and cocaine
• Patients with moderate or major liver impairments will be excluded (e.g. Child-Pugh B and C).
• Use of medication showing strong inhibition of either CYP3A4 or CYP1A2
• Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
• Patients participating in other drug studies
• If patient does not have the possibility to be accompanied by the same informal caregiver during all test days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Placebo oral capsule, once daily for 24 weeks	Drug: Placebo oral tablet; Pill with inactive ingredients to mimic same appearance of roflumilast capsule; Other Names: Placebo
EXPERIMENTAL: Roflumilast 50ug; Roflumilast (50 microgram) oral capsule, once daily for 24 weeks	Drug: Roflumilast; chronic intervention (24 weeks): roflumilast capsule; Other Names: EU: Daxas; US: Daliresp; PDE4 inhibitor
EXPERIMENTAL: Roflumilast 100ug; Roflumilast (100 microgram) oral capsule, once daily for 24 weeks	Drug: Roflumilast; chronic intervention (24 weeks): roflumilast capsule; Other Names: EU: Daxas; US: Daliresp; PDE4 inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Verbal Learning Test (VLT) (15 words)	Change from baseline to 24 weeks of chronic intake

Secondary Outcome Measures

Outcome Measure	Time Frame
Alzheimer's disease Assessment Scale- Cognitive Sub-scale (ADAS-Cog scale)	Change from baseline to 24 weeks of chronic intake
Mini Mental State Examination (MMSE)	Change from baseline to 24 weeks of chronic intake
Pattern Separation Task	Change from baseline to 24 weeks of chronic intake
Trail-Making Test (TMT)	Change from baseline to 24 weeks of chronic intake
Letter Digit Substitution Test (LDST)	Change from baseline to 24 weeks of chronic intake
Hospital Anxiety and Depression Scale (HADS)	Change from baseline to 24 weeks of chronic intake
Alzheimer's disease co-operative study activities of daily living (ADCS-ADL) scale	Change from baseline to 24 weeks of chronic intake
Neuropsychiatric Inventory (NPI)	Change from baseline to 24 weeks of chronic intake
QoL-AD	Change from baseline to 24 weeks of chronic intake
EuroQol	Change from baseline to 24 weeks of chronic intake
Boston Naming Task	Change from baseline to 24 weeks of chronic intake

Other Outcome Measures

Outcome Measure	Time Frame
Conversion to Alzheimer's disease (AD)	24 weeks
Pharmacokinetic validation of roflumilast and its active metabolite roflumilast N-Oxide in plasma	Acute, 12 weeks chronic intake and 24 weeks chronic intake
Tau in tears	Change from baseline to 24 weeks of chronic intake

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: Inez Ramakers, Dr., Psychiatry and Neuropsychology, FHML, Maastricht University, the Netherlands.; Study Director: Frans Verhey, Prof. Dr., Psychiatry and Neuropsychology, FHML, Maastricht University, the Netherlands; Principal Investigator: Arjan Blokland, Prof. Dr., Neuropsychology & Psychopharmacology, FPN, Maastricht University, The Netherlands; Principal Investigator: Jos Prickaerts, Prof. Dr., Psychiatry and Neuropsychology, FHML, Maastricht University, the Netherlands.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 19, 2021
• Primary Completion (ANTICIPATED): October 1, 2023
• Study Completion (ANTICIPATED): October 1, 2023

Study Registration Dates

• First Submitted: August 31, 2020
• First Submitted That Met QC Criteria: December 1, 2020
• First Posted (ACTUAL): December 8, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 21, 2022
• Last Update Submitted That Met QC Criteria: April 13, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: MCI, amnestic MCI, mild dementia
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Dementia; Cognitive Dysfunction; Cognition Disorders; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 4 Inhibitors
• Other Study ID Numbers: 72476

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No