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MCLENA-1: A Clinical Trial for the Assessment of Lenalidomide in Amnestic MCI Patients (MCLENA-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04032626
Recruitment Status : Recruiting
First Posted : July 25, 2019
Last Update Posted : September 3, 2020
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Marwan Sabbagh, MD, The Cleveland Clinic

Brief Summary:
Accumulating evidence indicates that inflammation is prominent both in the blood and central nervous system (CNS) of Alzheimer's disease (AD) patients. These data suggest that systemic inflammation plays a crucial role in the cause and effects of AD neuropathology. Capitalizing on the experience from a previous clinical trial with thalidomide, here, the investigators hypothesize that modulating both systemic and CNS inflammation via the pleiotropic immunomodulator lenalidomide is a putative therapeutic intervention for AD if administered at a proper time window during the course of the disease.

Condition or disease Intervention/treatment Phase
Cognitive Impairment, Mild Cognitive Dysfunction Amyloid Plaque Neurodegeneration Inflammation, Brain Drug: Lenalidomide 10 mg Drug: Placebos Phase 2

Detailed Description:

There are currently no approved treatments to treat the neuroinflammatory aspects of AD. While inflammation is pervasive to many neurological disorders, no clinical trial has yet demonstrated the efficacy of anti-inflammatory agents for AD. Interestingly, chronic peripheral low-grade inflammation is associated with aging and increases the risk for disease and mortality, including AD. Accumulating evidence indicates that nuclear factor-kappa B, tumor necrosis factor alpha (TNFα), interleukins (e.g. IL-1beta, IL-2, and IL-6), and chemokines (e.g. IL-8) are found elevated both in the blood and central nervous system (CNS) of AD patients. These data confirm that inflammation plays a central role in the cause and effect of AD neuropathology.

The immunomodulator, anti-cancer agent lenalidomide is one of the very few pleiotropic agents that both lowers the expression of TNFα, IL-6, IL-8, and increases the expression of anti-inflammatory cytokines (e.g. IL-10), to modulate both innate and adaptive immune responses.

In the current project the investigators aim to test the central hypothesis that lenalidomide reduces inflammatory and AD-associated pathological biomarkers, and improves cognition. For this, the investigators designed an 18-month, Phase II, double-blind, randomized, two-armed, parallel group, placebo controlled, and proof-of-mechanism clinical study in early symptomatic AD subjects (i.e. amnestic mild cognitive impairment; aMCI). The effects of lenalidomide treatment will be assessed after 12 months of treatment and 6 months washout (month 18).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study will take place at a single site. We will enroll 30 male and female outpatients, 50-90 years of age. Lenalidomide 10 mg/day vs. placebo will be taken daily orally (ratio 1:1). The effects of lenalidomide treatment will be assessed after 12 months of treatment and 6 months washout (month 18). Participants completing the study will be involved for up to 20 months in duration, from screening to end of study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Beside the clinical pharmacologist and biostatistician, all parties involved in the present study will be blinded until all data are collected, including medical staff, patients and his/her car giver, imaging staff, and scientists collecting data from biosamples. The blinding will be lifted only after all data are acquired, and before statistical analysis.
Primary Purpose: Treatment
Official Title: MCLENA-1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients With Mild Cognitive Impairment Due to Alzheimer's Disease
Actual Study Start Date : July 22, 2020
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lenalidomide
Lenalidomide 10 mg/day taken daily orally for 12 months of treatment followed by 6 months washout. The trial will last 18 month in duration.
Drug: Lenalidomide 10 mg
Lenalid
Other Name: Lenalid

Placebo Comparator: Placebo
Placebo taken daily orally for 12 months of treatment followed by 6 months washout. The trial will last 18 month in duration.
Drug: Placebos
Placebo




Primary Outcome Measures :
  1. Change in cognition as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) total score [ Time Frame: 18 months ]
    To evaluate the effect on cognition Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) of lenalidomide 10 mg/kg titrated for up to 12 months and washed out for 6 months. ADAS is 70 points. A lower score is better

  2. Change in cognition as assessed by the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) total score [ Time Frame: 18 months ]
    To evaluate the effect on cognitionAlzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) of lenalidomide 10 mg/kg titrated for up to 12 months and washed out for 6 months. The maximum score is 30. A higher score is better

  3. Change in cognition as assessed by the Clinical Dementia Rating - Sum of Boxes (CDR-SOB) total score [ Time Frame: 18 months ]
    To evaluate the effect on cognition Clinical Dementia Rating - Sum of Boxes (CDR-SOB) of lenalidomide 10 mg/kg titrated for up to 12 months and washed out for 6 months. The SOB maximum total is 18. A lower score is better

  4. Change in cognition as assessed by the Mini Mental State Examination (MMSE) total score [ Time Frame: 18 months ]
    To evaluate the effect on cognition Mini Mental State Examination (MMSE) of lenalidomide 10 mg/kg titrated for up to 12 months and washed out for 6 months. The maximum score is 30. A higher score is better


Secondary Outcome Measures :
  1. Monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 18 months ]
    To evaluate the safety and tolerability of lenalidomide 10 mg/kg titrated for up to 12 months and washed out for 6 months. Particularly, we will monitor blood toxicities reported in oncology studies. Blood toxicity will be defined as platelets falling below 50,000/μL and/or neutrophils falling below 1,000/μL.


Other Outcome Measures:
  1. Change in brain amyoid loads [ Time Frame: 18 months ]
    To evaluate the effect on brain amyloid loads (18F-florbetapir PET imaging) of lenalidomide 10 mg/kg titrated for up to 12 months and washout for 6 months

  2. Change in neurodegeneration [ Time Frame: 18 months ]
    To evaluate the effect on neurodegeneration (hippocampal, ventricular, and whole brain volumes assessed by MRI) of lenalidomide 10 mg/kg titrated for up to 12 months and washout for 6 months

  3. Change in blood inflammatory markers [ Time Frame: 18 months ]
    To evaluate the effect on blood inflammatory markers (TNF alpha, IL-1 beta, IL-6, IL-8, and IL-10) of lenalidomide 10 mg/kg titrated for up to 12 months and washed out for 6 months



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 89 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • In order to be eligible for this study, subjects must meet the following inclusion criteria:

    1. Male or female outpatients.
    2. At least 50 years of age, but less than 90 (89 at time of screening).
    3. Females must be surgically sterile (bilateral tubal ligation, oophorectomy, or hysterectomy) or postmenopausal for 2 years (no women at risk of pregnancy will be accepted in this study).
    4. Must have been diagnosed with amnestic MCI based on the most recent NIA-AA criteria (Albert et al., 2011), i.e. at both the screening and baseline visits (visits 1 and 2) have a documented Mini Mental State Exam (MMSE) score between 22-28.
    5. CT or MRI scan of the brain obtained during the course of the dementia must be consistent with the diagnosis and show no evidence of significant focal lesions or of pathology which could contribute to dementia. If neither a CT nor an MRI scan is available from the past 12 months, a CT scan fulfilling the requirements must be obtained before randomization.
    6. Vision and hearing must be sufficient to comply with study procedures.
    7. Be able to take oral medications.
    8. Hachinski ischemic score must be ≤ 4.
    9. Geriatric depression scale must be ≤ 10.
    10. Can be on stable doses of a cholinesterase inhibitor and/or memantine as long as it is stable for at least 90 days before screening and is expected to remain on a stable dose for the remainder of the study period; or have demonstrated intolerance to or lack of efficacy from these medications.
    11. Must have a collateral informant/study partner who has significant direct contact with the patient at least 10 hours per week and who is willing to accompany the patient to all clinic visits and to be present during all telephone visits/interviews.
    12. If the patient has a legally authorized representative (LAR), the LAR must review and sign the informed consent form. If the patient does not have an LAR, the patient must appear able to provide informed consent and must review and sign the informed consent form. In addition, the patient's informant/study partner (as defined above) must sign the informed consent form. If the LAR and the patient's informant /study partner is the same individual, he/she should sign under both designations.
    13. Must reside in the community.
    14. Supervision must be available for the administration of all study medication.
    15. Patients with stable prostate cancer may be included at the discretion of the Medical Monitor.

      Exclusion Criteria:

  • Subjects will be excluded if they have any of the condition listed below:

    1. Current evidence or history within the last 3 years of a neurological or psychiatric illness that could contribute to dementia, including (but not limited to) epilepsy, focal brain lesion, Parkinson's disease, seizure disorder, head injury with loss of consciousness
    2. DSM IV criteria for any major psychiatric disorder including psychosis, major depression and bipolar disorder.
    3. Known history or self-reported alcohol or substance abuse.
    4. Living alone.
    5. Poorly controlled hypertension.
    6. History of myocardial infarction or signs or symptoms of unstable coronary artery disease within the last year (including revascularization procedure/angioplasty).
    7. Severe pulmonary disease (including chronic obstructive pulmonary disease) requiring more than 2 hospitalizations within the past year.
    8. Requirement for home oxygen use or sleep apnea.
    9. Any thyroid disease (unless euthyroid on treatment for at least 6 months prior to screening).
    10. Active neoplastic disease (except for skin tumors other than melanoma) within five years.
    11. History of multiple myeloma.
    12. Absolute neutropenia of <750/mm3, or a history of neutropenia.
    13. History of or current thromboembolism (including deep venous thrombosis).
    14. Any clinically significant hepatic or renal disease (including presence of Hepatitis B or C antigen/antibody or an elevated transaminase levels of greater than two times the upper limit of normal (ULN) or creatinine greater than 1.5 x ULN).
    15. Clinically significant hematologic or coagulation disorder including any unexplained anemia or a platelet count less than 100,000/μL at screening.
    16. Use of any investigational drug within 30 days or within five half-lives of the investigational agent, whichever is longer.
    17. Use any investigational medical device within two weeks before screening or after end of the present study.
    18. Females who are at risk of pregnancy or are of child bearing age.
    19. Unwilling or unable to undergo MRI and PET imaging.
    20. Cardiac pacemaker or defibrillator or other implanted device.

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): NCT04032626


Contacts
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Contact: Marwan N Sabbagh, M.D. 702-483-6000 sabbagm@ccf.org

Locations
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United States, Nevada
Cleveland Clinic Lou Ruvo Center for Brain health Recruiting
Las Vegas, Nevada, United States, 89103
Sponsors and Collaborators
The Cleveland Clinic
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Marwan N Sabbagh, M.D. The Cleveland Clinic
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Responsible Party: Marwan Sabbagh, MD, Director, Lou Ruvo Center for Brain Health, Cleveland Clinic, Nevada, The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT04032626    
Other Study ID Numbers: 19-658
R01AG059008 ( U.S. NIH Grant/Contract )
K01AG047279 ( U.S. NIH Grant/Contract )
First Posted: July 25, 2019    Key Record Dates
Last Update Posted: September 3, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The protocol used and data collected in the course of this study will be shared with other researchers. The protocol will be published in a scientific journal and presented as posters in scientific meetings. Data and remaining biosamples, after deidentification, will be made available to the community 6 months after publication of the results of the study in peer-reviewed articles.
Supporting Materials: Study Protocol
Time Frame: Published in a scientific paper (accessible online in 2020) Posters presented at scientific meetings (e.g. AAIC 2019)
Access Criteria:
  • Papers will be accessible online
  • Data and biosamples can be requested from the principal investigator 6 months after publication of the results of the study in peer-reviewed articles

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Marwan Sabbagh, MD, The Cleveland Clinic:
Alzheimer's disease
Biomarkers
Brain Amyloid
Brain Imaging
Cognition
Immunomodulation
Additional relevant MeSH terms:
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Encephalitis
Amyloidosis
Inflammation
Nerve Degeneration
Plaque, Amyloid
Cognitive Dysfunction
Pathologic Processes
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Proteostasis Deficiencies
Metabolic Diseases
Pathological Conditions, Anatomical
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Lenalidomide
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents