Alzheimer Disease
Conditions
Keywords
Alzheimer
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.
Interventions
DRUGMontelukast
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.
DRUGPlacebo oral tablet
Participants in this arm will take a matched placebo pill daily
Sponsors
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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 (CDR) 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, Dabigatran 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Montelukast Group Montelukast (10, 20, or 40 mg)
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. | 16 |
| Placebo Group Matched placebo pill
Placebo oral tablet: Participants in this arm will take a matched placebo pill daily | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Montelukast Group | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 71.3 years STANDARD_DEVIATION 8.8 | 73.9 years STANDARD_DEVIATION 7.7 | 72.6 years STANDARD_DEVIATION 8.2 |
| Dementia | 6 Participants | 7 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 16 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mild Cognitive Impairment (MCI) | 10 Participants | 9 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 16 Participants | 28 Participants |
| Region of Enrollment United States | 16 participants | 16 participants | 32 participants |
| Sex: Female, Male Female | 12 Participants | 9 Participants | 21 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 3 / 16 | 2 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
Neuropsychiatric Inventory Questionnaire (NPI-Q) Score
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).
Time frame: Baseline, 1 year
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Montelukast Group | Neuropsychiatric Inventory Questionnaire (NPI-Q) Score | Baseline | 5.00 score on a scale | Standard Error 0.97 |
| Montelukast Group | Neuropsychiatric Inventory Questionnaire (NPI-Q) Score | 1 year | 5.68 score on a scale | Standard Error 1.04 |
| Placebo Group | Neuropsychiatric Inventory Questionnaire (NPI-Q) Score | Baseline | 2.62 score on a scale | Standard Error 0.95 |
| Placebo Group | Neuropsychiatric Inventory Questionnaire (NPI-Q) Score | 1 year | 2.73 score on a scale | Standard Error 1.02 |
Primary
Number of Discontinuations From Montelukast
Number of participants that stopped taking Montelukast during follow up time
Time frame: Baseline, 1 year
Population: This outcome measured the number of participants that stopped taking Montelukast. This outcome was not assessed in the Placebo group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Montelukast Group | Number of Discontinuations From Montelukast | 0 Participants |
| Placebo Group | Number of Discontinuations From Montelukast | 0 Participants |
Primary
Number of Participants With Any Gastrointestinal (GI) Symptoms
Number of participants with any GI symptoms reported: diarrhea, nausea, vomiting
Time frame: Baseline, 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Montelukast Group | Number of Participants With Any Gastrointestinal (GI) Symptoms | 1 Participants |
| Placebo Group | Number of Participants With Any Gastrointestinal (GI) Symptoms | 1 Participants |
Primary
Number of Participants With Elevated Liver Enzymes
Number of participants with elevated liver enzymes during follow up
Time frame: Baseline, 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Montelukast Group | Number of Participants With Elevated Liver Enzymes | 0 Participants |
| Placebo Group | Number of Participants With Elevated Liver Enzymes | 0 Participants |
Primary
Number of Participants With Reported Anaphylaxis
Number of participants with reported anaphylaxis during follow up time
Time frame: Baseline, 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Montelukast Group | Number of Participants With Reported Anaphylaxis | 1 Participants |
| Placebo Group | Number of Participants With Reported Anaphylaxis | 0 Participants |
Primary
Number of Patients With Seizures
Number of participants that reported seizures during follow up time
Time frame: Baseline, 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Montelukast Group | Number of Patients With Seizures | 0 Participants |
| Placebo Group | Number of Patients With Seizures | 0 Participants |
Primary
Prothrombin Time (PT)/ International Normalized Ratio (INR)
Prothrombin time (PT)/ international normalized ratio (INR) will be measured at baseline and 1 year.
Time frame: Baseline, 1 year
Population: Data captured from participants with CSF data or who completed a lumbar puncture procedure and have available results for PT/INR.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Montelukast Group | Prothrombin Time (PT)/ International Normalized Ratio (INR) | Baseline | 1.05 ratio | Standard Error 0.02 |
| Placebo Group | Prothrombin Time (PT)/ International Normalized Ratio (INR) | Baseline | 1.02 ratio | Standard Error 0.01 |
| Placebo Group | Prothrombin Time (PT)/ International Normalized Ratio (INR) | 1 year | 1.05 ratio | Standard Error 0.05 |
Secondary
Clinical Dementia Rating (CDR) Score
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.
Time frame: Baseline, 1 year
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Montelukast Group | Clinical Dementia Rating (CDR) Score | Baseline | 0.6 score on a scale | Standard Error 0.05 |
| Montelukast Group | Clinical Dementia Rating (CDR) Score | 1 year | 0.7 score on a scale | Standard Error 0.07 |
| Placebo Group | Clinical Dementia Rating (CDR) Score | Baseline | 0.6 score on a scale | Standard Error 0.04 |
| Placebo Group | Clinical Dementia Rating (CDR) Score | 1 year | 0.7 score on a scale | Standard Error 0.07 |
Secondary
CSF Amyloid
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.
Time frame: Baseline, 1 year
Population: 22 participants with CSF amyloid data captured (11 in Montelukast group and 11 in placebo group).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Montelukast Group | CSF Amyloid | Baseline | 849.4 pg/ml | Standard Error 77.34 |
| Montelukast Group | CSF Amyloid | 1 year | 795.5 pg/ml | Standard Error 76.6 |
| Placebo Group | CSF Amyloid | Baseline | 704.6 pg/ml | Standard Error 89.48 |
| Placebo Group | CSF Amyloid | 1 year | 695.2 pg/ml | Standard Error 88.11 |
Secondary
CSF Tau Levels
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.
Time frame: Baseline, 1 year
Population: 22 participants with CSF tau data captured (11 in Montelukast group and 11 in placebo group).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Montelukast Group | CSF Tau Levels | Baseline | 20.6 pg/ml | Standard Error 2.42 |
| Montelukast Group | CSF Tau Levels | 1 year | 21.1 pg/ml | Standard Error 2.48 |
| Placebo Group | CSF Tau Levels | Baseline | 22.8 pg/ml | Standard Error 2.81 |
| Placebo Group | CSF Tau Levels | 1 year | 21.9 pg/ml | Standard Error 2.86 |
Secondary
NIH Toolbox Cognition Battery (NIHTB-CB)
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.
Time frame: Baseline, 1 year
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Montelukast Group | NIH Toolbox Cognition Battery (NIHTB-CB) | Baseline | 35.2 t-score | Standard Error 2.53 |
| Montelukast Group | NIH Toolbox Cognition Battery (NIHTB-CB) | 1 year | 33.9 t-score | Standard Error 2.89 |
| Placebo Group | NIH Toolbox Cognition Battery (NIHTB-CB) | Baseline | 35.4 t-score | Standard Error 2.93 |
| Placebo Group | NIH Toolbox Cognition Battery (NIHTB-CB) | 1 year | 37.3 t-score | Standard Error 3.41 |