A proof of concept phase II study with the PDE-4 inhibitor roflumilast in patients with mild cognitive impairment (MCI)

Rationale: The current failure of drug trials in Alzheimer’s disease (AD) treatment has shifted the focus toward delaying progression from mild cognitive impairment (MCI) to dementia, which would reduce the prevalence and costs of dementia profoundly. MCI represents a transitional stage between healthy aging and dementia, and it affects 10-15% of the population over the age 65. Research on the neurobiological foundations of learning and memory has shown the cognitive enhancing effects of different types of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors are known to improve communication between neurons by selectively inhibiting the activity of PDEs, enzymes that inactivate the intracellular second messengers. In 2010, roflumilast, a PDE-4 inhibitor, was approved as an anti-inflammatory drug under the name of Daxas (European Union) for the treatment of chronic obstructive pulmonary disease exacerbations (COPD). Its favorable side effect profile allowed the first studies in healthy adults and healthy elderly. Roflumilast has been shown to improve memory in healthy adults, as well as elderly subjects with pronounced memory impairment, indicative of amnestic MCI. Accordingly, the following protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid mild cognitive impairment. Its chronic effect in clinical MCI patients above 50 years of age will be assessed using behavioral tasks, questionnaires and their informal caregiver’s input.

Objective: The objective is to validate the chronic treatment effect of roflumilast on cognitive function i.e. episodic memory in MCI patients by means of behavioral tasks. Secondary, we will assess the effects of roflumilast on other cognitive domains and its resulting possible interrelationship effect on mood.

Study design: The study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design.

Study population: 81, female and male, clinical patients with MCI due to AD (50-90 years old) will be recruited from our memory clinic at the Maastricht University Medical Center (MUMC+) and the Bio Bank-Alzheimer Center Limburg (BB-ACL) study (METC 15-4-100). Zuyderland MC will be included as a recruiting center i.e. only to draw attention to the study, not as a participating center. MCI due to AD diagnosis is characterized by a 1-2 standard deviation (SD) below the average memory performance on the delayed recall in the clinically relevant 15 words verbal learning test (VLT), and a decreased cerebrospinal fluid (CSF) A marker and/or a positive biomarker of neuronal injury i.e. magnetic resonance imaging (MRI) scan including measurements of decreased hippocampal volume or medial temporal atrophy by volumetric measures or visual rating).

Intervention: The study will consist of 3 arms (N = 27 per arm): placebo, 50 µg roflumilast and 100 μg roflumilast. The duration of treatment is 24 weeks and participants will be tested at baseline, acute intake, after 12 weeks, after completion of the treatment at 24 weeks, and two weeks thereafter (follow-up) to test if positive effects last.

Main study parameters/endpoints: Main study parameter includes the assessment of cognitive performance using a test battery in which episodic memory is the primary outcome measure, as assessed with the VLT (15 words, 5 times immediate recall, 20 min delayed recall and recognition). Secondary cognitive tests are the Alzheimer's Disease Assessment Scale-Cognitive Subscale (global cognition), Mini Mental State Examination (global cognition), Pattern Separation Memory Task (spatial memory), Letter Digit Substitution Test (information processing speed), and Trail Making Test (information processing speed and attention). Questionnaires used to assess clinically relevant effects are the Hospital Anxiety and Depression Scale, Neuropsychiatric Inventory, EuroQoL scale and QoL-AD (quality of life assessment), and the Alzheimer’s disease co-operative study activities of daily living scale (to measure instrumental and basic activities of daily living). Tau measurements in tear samples and lastly, the possible conversion to AD (yes/no), will be considered as well.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Time invested by the patient will be approximately 12 hours in total distributed over the time of 7 months (28 weeks), comprised of: filling in a medical questionnaire (30 minutes), explanation and filling in the informed consent (30 minutes), an assessment for eligibility (medical evaluation) (1 and a half hours), baseline test session (2 hours), acute test session after first single dose (3 hours), test session after 12 week chronic intake (2 hours), test session after completion of 24 week chronic intake (2 hours) and a test session two weeks post-completion for follow up (2 hours). Medical screening and test sessions are performed at the University of Maastricht. Additionally, the informal caregiver of the participant will accompany them to fill in the informed consent (30 minutes) and 2 questionnaires (per test day 30 minutes, total of 3 hours) related to daily living of the participant for each test day. The most common side-effects described for roflumilast are: weight loss, headache, nausea, diarrhoea, abdominal pain, insomnia, and dizziness. The intensity has been described as mild. Measurement that could be perceived as uncomfortable are blood samples at each test session and tear samples at baseline and the 24-week mark test session. MCI has been described as the prodromal state of AD and as of now, no treatment has been made available for MCI. Intervention at an early stage could potentially slow down or even prevent the conversion to AD because of the possible neuroprotective and anti-inflammatory effects of roflumilast.

1. Chronic treatment of 24 weeks with 50 μg roflumilast, compared to placebo, will improve episodic memory in MCI patients
2. Chronic treatment of 24 weeks with 100 μg roflumilast, compared to placebo, will improve episodic memory in MCI patients.

1. Medical screening (SCR)
2. Baseline test day (no intervention) (T0)
3. Acute intake intervention test day (T1)
4. 12-weeks of chronic intake test day (T2)
5. 24-weeks of chronic intake test day (T3)
6. Follow-up 2 weeks thereafter (T4)

Participants will be instructed to take one capsule every day for 24 weeks. The capsule can be taken with or without food.

The following dose levels will be used, as well as a placebo that only contains principal constituent lactose monohydrate.

• Roflumilast (Daxas®), 50 μg orally (N = 27)
• Roflumilast (Daxas®), 100 μg orally (N = 27)
• Placebo, orally (N = 27)