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Trial record 1 of 6 for:    ACE inhibitor | lupus
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Centrally Acting ACE Inhibition in SLE

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ClinicalTrials.gov Identifier: NCT04486118
Recruitment Status : Not yet recruiting
First Posted : July 24, 2020
Last Update Posted : March 5, 2021
Sponsor:
Collaborator:
Lupus Research Alliance
Information provided by (Responsible Party):
Meggan Mackay, Northwell Health

Brief Summary:

SLE is a chronic autoimmune disease that often involves multiple systems and organs of the body. An autoimmune disease is one which your immune system attacks the cells and tissues in different parts of the body. SLE is characterized by inflammation that leads to tissue damage in many different organ systems. Lupus can cause fever, joint pains, rashes, and other symptoms. It can also affect organs such as the skin, the muscles, the kidneys, the heart, the lungs, the blood and the brain. The exact cause of SLE is not known.

Problems with memory and concentration are common in lupus; these problems are called cognitive problems. Cognitive problems can be caused by things like depression, fatigue, medication and infections. However, previous studies that have been done in animal models of lupus and in lupus patients suggest that inflammation due to lupus can affect the brain directly.

This research study is being done to test the effects of centrally-acting ACE inhibitor, named lisinopril, on resting metabolism in the brain and on cognitive function. The investigators will see if Lisinopril will decrease resting metabolism in the brain and improve cognitive function (memory and concentration) compared to a non-centrally acting ACE inhibitor called benazepril.


Condition or disease Intervention/treatment Phase
Systemic Lupus Erythematosus Drug: Lisinopril Pills Drug: Benazepril Pill Phase 2

Detailed Description:
The study is a randomized, double blind, controlled, multi-center clinical trial to test the efficacy of a CA-ACEi, lisinopril, compared to a nonCA-ACEi, benazepril, for CI in SLE as measured by improvement in regional resting brain hypermetabolism and cognitive testing. The study will also investigate the impact of CA-ACEi compared to nonCA-ACEi on microglia cell activation as measured by PBR28 binding, behavioral function, circulating inflammatory cytokines and whole blood gene expression. The target population is SLE subjects between the ages of 18 and 55 that have stable disease activity and have no history of active or prior CNS disease of any kind. If applicable, subjects must be on stable doses of corticosteroids (less than or equal to 10 mg daily of prednisone) and non-increasing doses of other immunosuppressive medications for at least 4 weeks prior to screening.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Novel Phase 2 Double-blind, Randomized, Controlled Clinical Trial to Evaluate the Efficacy of Centrally Acting, Non-toxic ACE Inhibition in Cognitive Impairment Associated With SLE
Estimated Study Start Date : May 1, 2021
Estimated Primary Completion Date : June 1, 2022
Estimated Study Completion Date : April 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: CA-ACEi

Enrolled subjects will begin treatment with a low dose of study drug (5 mg) Study drug will then be titrated up as follows, provided the increased dose is tolerated:

Day 3-15 (dosing begins after completion of FIMR Visit 1.1): 5 mg Day 29: 10 mg Day 43: 20 mg Day 57: 40 mg if tolerated Subjects will be required to achieve and maintain a minimum dose of 20 mg daily to ensure adequate dosage of the ACE inhibitor.

Drug: Lisinopril Pills
Tablets will be taken by oral administration daily, based on titration

Placebo Comparator: nonCA-ACEi

Enrolled subjects will begin treatment with a low dose of study drug (5 mg) Study drug will then be titrated up as follows, provided the increased dose is tolerated:

Day 3-15 (dosing begins after completion of FIMR Visit 1.1): 5 mg Day 29: 10 mg Day 43: 20 mg Day 57: 40 mg if tolerated Subjects will be required to achieve and maintain a minimum dose of 20 mg daily to ensure adequate dosage of the ACE inhibitor.

Drug: Benazepril Pill
Tablets will be taken by oral administration daily, based on titration




Primary Outcome Measures :
  1. Brain Metabolism [ Time Frame: 3 years ]
    The primary outcome measure for evaluation of the primary objective will be the change in regional metabolism between baseline and 12 months in the posterior putamen/GP/thalamus on FDG-PET imaging.


Secondary Outcome Measures :
  1. PBR28 [ Time Frame: 3 years ]
    PBR28 Imaging: Normality of the imaging data will be tested with the Shapiro-Wilkes Test. If normally distributed, the two-sample Student's t-test and the MMRMA will be used to compare the [11C]-PBR28 Standardized Uptake Value Ratios (SUVR; primary imaging endpoint for microglial cell activation) in the regions of interest between the CA-ACEi and nonCA-ACEi treated groups at baseline and over time, respectively. The regions of interest include the posterior putamen/GP/thalamus, hippocampus, temporal lobes, orbitofrontal cortex, sensorimotor cortex and occipital lobes. If the data are found to be non-normally distributed, corresponding non-parametric tests will be used for statistical analyses.

  2. Automated Neuropsychological Assessment Metrics (ANAM) [ Time Frame: 3 years ]
    Changes in cognitive testing from baseline to 6 and 12 months as measured by Automated Neuropsychological Assessment Metrics (ANAM) subtest

  3. 2x2 spatial memory task [ Time Frame: 3 years ]
    Changes in cognitive testing from baseline to 6 and 12 months as measured by 2x2 spatial memory task

  4. Spatial Navigation Task [ Time Frame: 3 years ]
    Changes in cognitive testing from baseline to 6 and 12 months as measured by Spatial Navigation Task

  5. Mood Assessments [ Time Frame: 3 years ]
    Changes in mood from baseline to 6 and 12 months as measured by the Beck Depression Inventory and the ANAM Mood Assessments

  6. Patient Reported Outcomes [ Time Frame: 3 years ]
    Changes in patient reported outcomes; the PROMIS-Cognitive Function, LFA-REAL Patient Report, LupusPRO and the patient global assessment, between baseline, 6 and 12 months

  7. Disease Activity [ Time Frame: 3 years ]
    Changes in disease activity between baseline and 12 months as measured by the SLEDAI-2K, the SELENA SLEDAI Flare Index, LFA-REAL Clinician Report and physician global assessment

  8. Microglial Cell Activation [ Time Frame: 3 years ]
    Changes in microglial cell activation from baseline to 12 months as measured by changes in regional volume of distribution of PBR28 tracer binding

  9. Inflammatory Cytokines [ Time Frame: 3 years ]
    Changes in levels of circulating inflammatory cytokines between baseline and 6 and 12 months measured by proteomics on serum using Meso Scale Discovery platform

  10. RNA-Seq [ Time Frame: 3 years ]
    Changes in RNA-Seq transcriptome profiles of whole blood between baseline and 6 and 12 months collected in PAXgene blood RNA tubes.



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:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Must be able to understand and provide informed consent. 2. Must be ≥18 and ≤55 years of age: subjects with age > 55 will be excluded to avoid confounding effects of age on cognitive testing.

3. Must fulfill the 1997 American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE or the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) Criteria for SLE.

4. Must have stable disease activity and medication doses for 4 weeks prior to screening. Stable disease activity is defined as no increase in disease activity requiring an increase or change in medications.

5. Must be on a corticosteroid dose that is ≤ prednisone 10 mg daily, or equivalent.

6. Must have increased resting metabolism in the posterior putamen/GP/thalamus on the screening FDG-PET scan that is

  • > 1.647 for non-Black SLE subjects and
  • > 1.699 for Black SLE subjects.

    1. Inability or unwillingness to give written informed consent or comply with study protocol
    2. History of neurological diseases including, but not limited to, severe head injury or history of brain surgery, stroke, seizure, toxic exposure, mental retardation, multiple sclerosis, dementia
    3. History of documented transient ischemic attacks within 6 months of screening.
    4. Limited fluency with English that in the opinion of the investigator would limit the subject's performance on the written assessments.
    5. History of illicit drug or alcohol dependence/abuse within the past 12 months.
    6. Current use of anxiolytic, anticonvulsant, antidepressant or antipsychotic medications.
    7. Current and/or chronic use of narcotic analgesia for > 3 weeks within the last 3 months.
    8. Increased disease activity within 4 weeks of screening defined by an increase in SLEDAI by 3 points or more, exclusive of points from serologies, which prompts an increase in or new addition of SLE medications.
    9. History of a diagnosis of a primary psychiatric disorder preceding SLE diagnosis.
    10. Current active acute infections requiring antibiotics within 2 weeks of screening and chronic known infections (eg. hepatitis B, C, and/or HIV).
    11. Co-existing other autoimmune disease(s) other than autoimmune thyroid disease and secondary Sjogren's Syndrome.
    12. Pregnant and/or lactating women and/or women unwilling to use an acceptable form of contraception.
    13. The presence of uncontrolled, severe hypertension, diabetes or heart disease.
    14. History of hereditary or idiopathic angioedema.
    15. Impaired renal function with an eGFR< 60%.
    16. Current use of aliskiren in diabetic patients.
    17. Current use of naltrexone or chronic minocycline use; both are agents also known to alter microglia activation.
    18. Current use of an ACE inhibitor or angiotensin receptor blocker or use for more than 4 weeks within the past 1 year.
    19. Known intolerance to ACE inhibitors.
    20. Presence of any active medical condition that in the opinion of the investigator may contribute to cognitive and/or behavioral disturbances.
    21. Use of investigational drugs within 30 days or 5 half-lives before Visit 1 (Day 1), whichever is longer.
    22. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
    23. A systolic blood pressure less than 100 mmHg at screening. If the investigator feels that the patient is insufficiently hydrated, the patient may be re-evaluated for blood pressure during the screening period.
    24. A severe lupus flare within the 6 months prior to screening defined as increased disease activity requiring an increased or added dose of corticosteroids greater than 0.5 mg/kg and/or the addition of a new immunosuppressive drug to control the increased disease activity.
    25. The presence of suicidal ideation on the Beck Depression Inventory at screening or sufficient depressive symptoms to warrant intervention with pharmacologic therapy and/or referral for treatment.

Exclusion Criteria:

  1. The participant elects to withdraw consent from all future study activities, including follow-up.
  2. The participant is "lost to follow-up" (i.e., no further follow-up is possible because attempts to reestablish contact with the participant have failed).
  3. The participant dies.
  4. The Investigator no longer believes participation is in the best interest of the participant.
  5. The participant is unable to titrate up to and tolerate the minimum ACE inhibitor dose of 20 mg daily for any reason.
  6. The participant is unable to demonstrate a minimum compliance rate of 75% (based on the returned pill count) at Visits 2.0, 2.1 and 3.0 in order to titrate up to the next dose level of study drug.
  7. The participant experiences a disease flare necessitating increased doses of corticosteroids and/or changes in immunosuppressive medications between Screening and the FIMR Visit 1.1.

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): NCT04486118


Contacts
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Contact: Andrew Shaw 516-562-2591 anshaw@northwell.edu
Contact: Meggan Mackay, MD 516-562-3838 mmackay@northwell.edu

Sponsors and Collaborators
Northwell Health
Lupus Research Alliance
Investigators
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Principal Investigator: Meggan Mackay, MD The Feinstein Institute for Medical Research
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Responsible Party: Meggan Mackay, Principal Investigator, Northwell Health
ClinicalTrials.gov Identifier: NCT04486118    
Other Study ID Numbers: ACE-2020
First Posted: July 24, 2020    Key Record Dates
Last Update Posted: March 5, 2021
Last Verified: March 2021
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
Additional relevant MeSH terms:
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Lupus Erythematosus, Systemic
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Lisinopril
Benazepril
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Cardiotonic Agents
Protective Agents
Physiological Effects of Drugs