Montelukast Therapy on Alzheimer's Disease

Phase 2

Completed

Conditions: Alzheimer Disease

Interventions: Drug: Placebo oral tablet
Drug: Montelukast

Registration Number: NCT03991988

Lead Sponsor: Emory University

Brief Summary: This is a one-year, double-blind placebo-controlled randomized clinical trial that compares montelukast to placebo in individuals with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) dementia. The measures include cognitive function, cerebrospinal fluid (CSF) biomarkers and neuroimaging (cerebral perfusion and markers of vascular brain damage).

Participants will be treated with montelukast (escalating doses:10, 20 to 40 mg) or matched placebo.

Detailed Description: Treatment options for Alzheimer's disease (AD) remain limited, especially treatments linking neurovascular and neuroinflammatory changes with clinical manifestations of the disease. Prior research studies have documented a positive effect of cysteinyl leukotriene type 1 (cysLT-1) receptor antagonist, particularly Montelukast, on inflammatory processes in the brain and on neuronal injury, blood-brain-barrier (BBB) integrity, and amyloid-β42 (Aβ) protein accumulation. Although montelukast is currently in use for the treatment of inflammatory diseases e.g. bronchial asthma and exercise-induced bronchospasm, its effects on memory and thinking abilities and on AD biomarkers are yet to be fully understood.

This is a single site randomized controlled trial at Emory University that compares the effects of montelukast vs. placebo on memory and thinking abilities, as well as on brain imaging and markers of brain degeneration. Each participant will undergo a screening process following informed consent to determine if they meet study eligibility criteria. Participants will be enrolled in the study for 1 year.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Age: 50 years or older
MCI group will be defined based on:

(i) Subjective memory concern;

(ii) Abnormal memory function documented using the Logical Memory subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised (the maximum score is 25): [<11 for 16 or more years of education; <9 for 8-15 years of education; <6 for <7 years of education];

(iii) Montreal Cognitive Assessment (MoCA) < 26;

(iv) Clinical Dementia Rating (CDR) scale /Memory box score=0.5;

(v) General functional performance sufficiently preserved (Functional Assessment Questionnaire ≤5).
Early AD dementia group will be defined based on:

(i) Subjective memory concern;

(ii) Abnormal memory function documented using the Logical Memory subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised (the maximum score is 25): [<11 for 16 or more years of education; <9 for 8-15 years of education; <6 for <7 years of education];

(iii) Montreal Cognitive Assessment (MoCA) <26;

(iv) Clinical Dementia Rating scale/Memory box score 1 or 2;

(v) Early AD dementia defined as Functional Assessment Staging Test (FAST) of 4 or 5

Exclusion Criteria

Intolerance to Montelukast;
Current diagnosis of bronchial asthma or exercise-induced bronchospasm and currently on Montelukast or other leukotriene receptor antagonists (Zafirlukast, Pranlukast);
Liver disease (elevated liver enzymes (>2x normal): Alanine aminotransferase (ALT), AST, alkaline phosphatase, total bilirubin);
Renal disease (Creatinine >2.0 mg/dl), platelets<50,000/μl, or INR>1.9;
Diagnosis of any neurological or psychiatric disorders that affects cognition such as uncontrolled depression, schizophrenia, Parkinson's disease or use of anti-Parkinsonian therapies (unless used for essential tremor), multiple sclerosis, or other active medical condition that in the judgment of the study physicians would affect the safety of the subject or scientific integrity of the study;
Other contributing factors to cognitive impairment such as uncontrolled hypothyroidism (TSH >10 mU/l) or untreated low vitamin B12 (<250 ng/mL);
Uncontrolled congestive heart failure reflected by poor exercise tolerance and shortness of breath at rest or with some exertion;
Actively undergoing chemotherapy or radiation therapy for cancer treatment;
History of stroke in the past 3 years;
Severely impaired cognition (MoCA ≤10, FAST >5 or CDR >2);
Inability to have MRI and LP e.g. for MRI, metal implants or cardiac pacemaker or for LP, bleeding diathesis from disease states or from use of anticoagulants such as warfarin, heparin and related products, Rivaroxaban or Xarelto, Apixaban or Eliquis, Edoxaban or Savaysa, Dabigatran or Pradaxa. Subjects who can have either one lumbar puncture (LP) or MRI will be enrolled;
Inability to have cognitive assessment due to hearing, vision, or language issues or due to severe impairment;
History of increased intracranial pressure (ICP);
In those who are unable to demonstrate that they understood the details of the study using the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) instrument modified for EMERALD (i.e. lack of decisional-capacity to consent), a study partner/surrogate who can sign on their behalf will be required; otherwise, they will be excluded;
Use of phenobarbital or rifampin due to drug interaction.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Group	Placebo oral tablet	Matched placebo pill
Montelukast Group	Montelukast	Montelukast (10, 20, or 40 mg)

Primary Outcome Measures

Name	Time	Method
Number of Patients With Seizures	Baseline, 1 year	Number of participants that reported seizures during follow up time
Number of Participants With Any Gastrointestinal (GI) Symptoms	Baseline, 1 year	Number of participants with any GI symptoms reported: diarrhea, nausea, vomiting
Number of Participants With Reported Anaphylaxis	Baseline, 1 year	Number of participants with reported anaphylaxis during follow up time
Neuropsychiatric Inventory Questionnaire (NPI-Q) Score	Baseline, 1 year	The NPI-Q is designed to be a self-administered questionnaire completed by informants about patients for whom they care. Each of the 12 NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Initial responses to each domain question are "Yes" (present) or "No" (absent). If the response to the domain question is "No", the informant goes to the next question. If "Yes", the informant then rates both the Severity of the symptoms present within the last month on a 3-point scale and the associated impact of the symptom manifestations on them (i.e. Caregiver Distress) using a 5-point scale. The NPI-Q provides symptom Severity and Distress ratings for each symptom reported, and total Severity and Distress scores reflecting the sum of individual domain scores. NPI-Q Severity score range: 0-36 (lower is better).
Number of Discontinuations From Montelukast	Baseline, 1 year	Number of participants that stopped taking Montelukast during follow up time
Number of Participants With Elevated Liver Enzymes	Baseline, 1 year	Number of participants with elevated liver enzymes during follow up
Prothrombin Time (PT)/ International Normalized Ratio (INR)	Baseline, 1 year	Prothrombin time (PT)/ international normalized ratio (INR) will be measured at baseline and 1 year.

Secondary Outcome Measures

Name	Time	Method
CSF Tau Levels	Baseline, 1 year	CSF tau protein (CSF-tau) is found in most patients with Alzheimer's disease. A lumbar puncture will be done at baseline and at 12 months follow up. Approximately 30-45 ml of CSF will be collected using sterile polypropylene collection tubes. Results will be reported as Phospho tau (p-tau181) in pg/ml.
CSF Amyloid	Baseline, 1 year	A lumbar puncture will be done at baseline and at 12 months follow up Approximately 30-45 ml of CSF will be collected using sterile polypropylene collection tubes. Amyloid-β42 is reported as pg/ml.
Clinical Dementia Rating (CDR) Score	Baseline, 1 year	The CDR rates each of the six general domains (or boxes) involving memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care, and a global rating is then generated, ranging from 0 to 3. A score of 0 = normal, 0.5 = very mild dementia, 1 = mild dementia, 2 = moderate dementia, and 3 = severe dementia.
NIH Toolbox Cognition Battery (NIHTB-CB)	Baseline, 1 year	The NIH Toolbox® is a computer-based comprehensive set of neuro-behavioral measurements that reliably and validly assesses neurocognitive sub-domains in clinical trials, including working memory, episodic memory, processing speed, language, attention and executive function. The fluid cognitive composite (FCC) score is derived by averaging the standard scores of each of the fluid tests (Picture Sequence Memory, List Sorting, Pattern Comparison, Flanker, and Dimensional Change Card Sort.), and then deriving standard scores based on this new distribution. The fully-adjusted FCC T-score is reported. Higher score indicates with better performance. The score ranged from a minimum of 19 (0th percentile) to a maximum of 58 (79th percentile) in this sample. The population-level T-score and percentile rank range from 23 (0.3th percentile) to 77 (99.6th percentile) with mean=50 and SD=10.

Trial Locations

Locations (4): Executive Park
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Atlanta, Georgia, United States
Wesley Woods
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Atlanta, Georgia, United States
Emory Clinic
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Atlanta, Georgia, United States
Emory University Hospital Clinical Research Network
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Atlanta, Georgia, United States