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Montelukast Therapy on Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT03991988
Recruitment Status : Recruiting
First Posted : June 19, 2019
Last Update Posted : September 30, 2019
Sponsor:
Information provided by (Responsible Party):
Ihab M. Hajjar, 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, 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.


Condition or disease Intervention/treatment Phase
Alzheimer Disease Drug: Montelukast Drug: Placebo oral tablet Phase 2

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 and will be compensated for their participation.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Effects of Montelukast Therapy on Alzheimer's Disease (EMERALD)
Actual Study Start Date : September 25, 2019
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Montelukast

Arm Intervention/treatment
Experimental: Montelukast Group
Montelukast (10, 20, or 40 mg)
Drug: Montelukast

Participants in this arm will take a pill of Montelukast daily on escalating doses: 10, 20 to 40 mg.

All participants will be initiated on 10 mg. The dose will be increased in 2-week increments to 20 mg and 40 mg as long as participants report no intolerable symptoms or adverse events.


Placebo Comparator: Placebo Group
Matched placebo pill
Drug: Placebo oral tablet
Participants in this arm will take a matched placebo pill daily




Primary Outcome Measures :
  1. Number of participants with any gastrointestinal (GI) symptoms [ Time Frame: 1 year ]
    Number of participants with any GI symptoms reported: diarrhea, nausea, vomiting

  2. Number of participants with reported anaphylaxis [ Time Frame: 1 year ]
    Number of participants with reported anaphylaxis during follow up time

  3. Number of participants with elevated liver enzymes [ Time Frame: 1 year ]
    Number of participants with elevated liver enzymes during follow up

  4. Change in prothrombin time (PT)/ international normalized ratio (INR) [ Time Frame: Baseline, 1 year ]
  5. Change in Neuropsychiatric Inventory Questionnaire (NPI-Q) [ Time Frame: 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

  6. Number of patients with seizures [ Time Frame: 1 year ]
    Number of participants that reported seizures during follow up time

  7. Number of discontinuations from Montelukast [ Time Frame: 1 year ]
    Number of participants that stopped taking Montelukast during follow up time


Secondary Outcome Measures :
  1. Change in CSF amyloid [ Time Frame: 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.

  2. Change in CSF tau [ Time Frame: 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.

  3. Change in Clinical Dementia Rating (CDR) [ Time Frame: 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-no impairment to 3-severe impairment.

    A study informant or study partner will be questioned either by phone or in person to assist with the CDR.


  4. Change in NIH Toolbox Cognition battery (NIHTB-CB) [ Time Frame: Baseline, 1 year ]

    The NIH Toolbox® is a comprehensive set of neuro-behavioral measurements that quickly assess cognitive, emotional, sensory, and motor functions from the convenience of an iPad.

    It is a computer-based test battery that reliably and validly assesses neurocognitive sub-domains in clinical trials, including working memory, episodic memory, processing speed, language, attention and executive function.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age: 50 years or older
  2. 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 scale /Memory box score=0.5;

    (v) General functional performance sufficiently preserved (Functional Assessment Questionnaire ≤5).

  3. 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:

  1. Intolerance to Montelukast;
  2. Current diagnosis of bronchial asthma or exercise-induced bronchospasm and currently on Montelukast or other leukotriene receptor antagonists (Zafirlukast, Pranlukast);
  3. Liver disease (elevated liver enzymes (>2x normal): Alanine aminotransferase (ALT), AST, alkaline phosphatase, total bilirubin);
  4. Renal disease (Creatinine >2.0 mg/dl), platelets<50,000/μl, or INR>1.9;
  5. 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;
  6. Other contributing factors to cognitive impairment such as uncontrolled hypothyroidism (TSH >10 mU/l) or untreated low vitamin B12 (<250 ng/mL);
  7. Uncontrolled congestive heart failure reflected by poor exercise tolerance and shortness of breath at rest or with some exertion;
  8. Actively undergoing chemotherapy or radiation therapy for cancer treatment;
  9. History of stroke in the past 3 years;
  10. Severely impaired cognition (MoCA ≤10, FAST >5 or CDR >2);
  11. 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, Dabigatraban or Pradaxa. Subjects who can have either one lumbar puncture (LP) or MRI will be enrolled;
  12. Inability to have cognitive assessment due to hearing, vision, or language issues or due to severe impairment;
  13. History of increased intracranial pressure (ICP);
  14. 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;
  15. Use of phenobarbital or rifampin due to drug interaction.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03991988


Contacts
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Contact: Ihab Hajjar, MD 4047121763 ihajjar@emory.edu

Locations
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United States, Georgia
Emory Clinic Recruiting
Atlanta, Georgia, United States, 30322
Contact: Ihab Hajjar, MD    404-712-1763    ihajjar@emory.edu   
Principal Investigator: Ihab Hajjar, MD         
Emory University Hospital Clinical Research Network Recruiting
Atlanta, Georgia, United States, 30322
Contact: Ihab Hajjar, MD    404-712-1763    ihajjar@emory.edu   
Principal Investigator: ihab Hajjar, MD         
Executive Park Recruiting
Atlanta, Georgia, United States, 30329
Contact: Ihab Hajjar, MD    404-712-1763    ihajjar@emory.edu   
Principal Investigator: Ihab Hajjar, MD         
Wesley Woods Recruiting
Atlanta, Georgia, United States, 30329
Contact: Ihab Hajjar, MD    404-712-1763    ihajjar@emory.edu   
Principal Investigator: Ihab Hajjar, MD         
Sponsors and Collaborators
Emory University
Investigators
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Principal Investigator: Ihab Hajjar Emory University

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Responsible Party: Ihab M. Hajjar, Associate Professor, Emory University
ClinicalTrials.gov Identifier: NCT03991988     History of Changes
Other Study ID Numbers: IRB00111553
First Posted: June 19, 2019    Key Record Dates
Last Update Posted: September 30, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Ihab M. Hajjar, Emory University:
Alzheimer
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Montelukast
Anti-Asthmatic Agents
Respiratory System Agents
Leukotriene Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP1A2 Inducers
Cytochrome P-450 Enzyme Inducers
Molecular Mechanisms of Pharmacological Action