Montelukast Therapy on Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT03991988
• Recruitment Status: Recruiting
• First Posted: June 19, 2019
• Last Update Posted: October 19, 2020
• Sponsor: Emory University
• Information provided by (Responsible Party): Ihab Hajjar, Emory University

Tracking Information

• First Submitted Date: June 18, 2019
• First Posted Date: June 19, 2019
• Last Update Posted Date: October 19, 2020
• Actual Study Start Date: September 25, 2019
• Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 18, 2019)

• Number of participants with any gastrointestinal (GI) symptoms [ Time Frame: 1 year ]
  Number of participants with any GI symptoms reported: diarrhea, nausea, vomiting
• Number of participants with reported anaphylaxis [ Time Frame: 1 year ]
  Number of participants with reported anaphylaxis during follow up time
• Number of participants with elevated liver enzymes [ Time Frame: 1 year ]
  Number of participants with elevated liver enzymes during follow up
• Change in prothrombin time (PT)/ international normalized ratio (INR) [ Time Frame: Baseline, 1 year ]
• 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
• Number of patients with seizures [ Time Frame: 1 year ]
  Number of participants that reported seizures during follow up time
• Number of discontinuations from Montelukast [ Time Frame: 1 year ]
  Number of participants that stopped taking Montelukast during follow up time

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 18, 2019)

• 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.
• 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.
• 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.
• 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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Montelukast Therapy on Alzheimer's Disease
• Official Title: Effects of Montelukast Therapy on Alzheimer's Disease (EMERALD)

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.

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Alzheimer Disease

Intervention

• 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.

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

Study Arms

• Experimental: Montelukast Group
  Montelukast (10, 20, or 40 mg)
  Intervention: Drug: Montelukast
• Placebo Comparator: Placebo Group
  Matched placebo pill
  Intervention: Drug: Placebo oral tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 18, 2019): 150
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 2022
• Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03991988
• Other Study ID Numbers: IRB00111553
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Ihab Hajjar, Emory University
• Study Sponsor: Emory University
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ihab Hajjar; Emory University

• PRS Account: Emory University
• Verification Date: October 2020