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Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction (MARBLE)

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ClinicalTrials.gov Identifier: NCT03802396
Recruitment Status : Recruiting
First Posted : January 14, 2019
Last Update Posted : July 14, 2020
Sponsor:
Information provided by (Responsible Party):
Miles Berger, MD PhD, Duke University

Brief Summary:
This research study will evaluate the effectiveness and estimate the feasibility of administering an investigational drug called 'CN-105' (the study drug), to prevent postoperative cognitive decline, delirium (serious confusion) and underlying brain inflammatory and brain activity changes in adults 60 years and older undergoing surgery.

Condition or disease Intervention/treatment Phase
Postoperative Delirium Postoperative Cognitive Dysfunction Drug: CN-105 Drug: Placebo Phase 2

Detailed Description:

This research study will evaluate the effectiveness and estimate the feasibility of administering an investigational drug called 'CN-105' (the study drug), to prevent postoperative cognitive decline, delirium (serious confusion) and underlying brain inflammatory and brain activity changes in adults 60 years and older undergoing surgery. The word "investigational" means the study drug is still being tested in research studies and is not approved by the U.S. Food and Drug Administration (FDA).

It is hoped that CN-105 will block signaling via a gene known as ApoE4, the most common gene implicated in late life Alzheimer's disease.

Depending on when patients enroll in this study, participants will receive either a placebo or a progressively higher dose of CN-105 until the safest and best tolerated dose is reached. The study drug is given via IV (intravenous, meaning through a vein) infusion in the hospital. Study drug infusions will be given up to 4 days after surgery.

Participants will also perform memory and thinking tests, as well as complete a survey and functional assessments, both prior to surgery and again 6 weeks after surgery. Each of those research visits will last about 1 hour.

Additionally, the investigators will collect a blood sample and a cerebrospinal fluid (CSF) sample prior to the participant's surgery, 24 hours after surgery, and again 6 weeks after surgery. To obtain the CSF (cerebrospinal fluid) sample, investigators will perform a lumbar (the lower part of the spinal column) puncture. During surgery, investigators will also record participant brain waves from the scalp using an EEG (electroencephalography) monitor. An electroencephalography monitor reads the electrical activity of the brain in different places using a cap with sensors that is worn on the head.

Although previous studies have not found any associations between the study drug and any serious medical problems, investigators will monitor its effect on wound healing and postoperative infections.

Benefits of this study include the possibility of fewer problems in thinking and memory after surgery if this study drug works as hoped.

Risks of participation in this study include headache, infection/discomfort from the lumbar puncture, discomfort from the blood draw, and minor skin irritation or redness from the EEG and heart rate monitor procedures.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 201 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Investigators will enroll 201 patients total in this phase 2 escalating dose study, with escalating CN-105 doses occurring in three successive groups of 67 patients each. In each group of 67 patients, 50 will receive a given dose of CN-105 and 17 will receive placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Participants will be randomized to receive either CN-105 or placebo after they consent to participate in the trial. Participants will be enrolled in 1 of 3 dose cohorts of 67 subjects each. An independent statistician will prepare dose stratified mixed block size randomization lists in a 3 to 1 ratio to achieve the desired distribution of drug and placebo. In each block of 67 trial participants, 50 will receive CN-105 and 17 will receive placebo, in a double-blind fashion.

CN-105 and placebo will be prepared in identical bags labelled simply with the trial participant's number (1-201) to keep all trial staff and clinicians blinded to randomization. Only the investigational pharmacist will have the randomization list for each participant showing what dose of CN-105 or placebo will be administered. To minimize bias, investigators conducting the laboratory assays on the CSF and blood samples will be blinded to trial group assignment during the course of the trial.

Primary Purpose: Prevention
Official Title: Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction (MARBLE): A Phase 2 Trial to Evaluate the Efficacy and Feasibility of CN-105 in Preventing Postoperative Cognitive Dysfunction and Delirium
Actual Study Start Date : April 17, 2019
Estimated Primary Completion Date : October 17, 2022
Estimated Study Completion Date : December 17, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: CN-105

Cohort 1: 67 Patients Dose of CN-105: 0.1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17

Cohort 2: 67 Patients Dose of CN-105: 0.5 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17

Cohort 3: 67 Patients Dose of CN-105: 1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17

Drug: CN-105

Three doses of CN-105 will be used in three successive cohorts of 67 patients each (50 receiving drug and 17 receiving placebo) 0.1 mg/kg (cohort 1) 0.5 mg/kg (cohort 2)

1 mg/kg (cohort 3)

The study drug will be administered by IV every 6 hours, beginning 1 hour prior to surgery, until postoperative day 3 or hospital discharge, whichever occurs first, up to a maximum of 13 doses.


Placebo Comparator: Placebo

Cohort 1: 67 Patients Dose of CN-105: 0.1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17

Cohort 2: 67 Patients Dose of CN-105: 0.5 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17

Cohort 3: 67 Patients Dose of CN-105: 1 mg/kg Patients receiving drug: 50 Patients receiving placebo: 17

Drug: Placebo
Patients will receive placebo intravenously every 6 hours, beginning 1 hour prior to surgery, until postoperative day 3 or hospital discharge, whichever occurs first, up to a maximum of 13 doses, identical to those receiving the study drug.




Primary Outcome Measures :
  1. Number of adverse events (AEs) [ Time Frame: 2 years for entire study; until 6 week follow-up for individual patients ]
    safety of CN-105 administration, as measured by adverse event (AE) rates in CN-105 versus placebo-treated patients.


Secondary Outcome Measures :
  1. Change in cerebrosprinal fluid (CSF) IL-6 cytokine levels between drug vs placebo treated patients [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
    Change in CSF IL-6 cytokine levels from before to after surgery between drug vs placebo treated patients.

  2. Change in CSF IL-8 cytokine levels between drug vs placebo treated patients [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
    Change in CSF IL-8 cytokine levels from before to after surgery between drug vs placebo treated patients

  3. Change in CSF MCP-1 cytokine levels between drug vs placebo treated patients [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
    Change in CSF MCP-1 cytokine levels before to after surgery between drug vs placebo treated patients

  4. Change in CSF G-CSF cytokine levels between drug vs placebo treated patients [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
    Change in CSF G-CSF cytokine levels before to after surgery between drug vs placebo treated patients.

  5. Change in cognitive change index (CCI) between drug vs placebo treated patients [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
    Change in CCI before to after surgery between drug vs placebo treated patients.

  6. Feasibility of drug administration within correct time windows [ Time Frame: within 1 hour prior to the scheduled or actual start time of the surgery, and every 6 hours afterwards within a +/- 90 minute time window for subsequent drug doses ]
    The feasibility of perioperative CN-105 administration is assessed by tracking the percentage of doses given within the correct time window (i.e. within 1 hour prior to the scheduled or actual start time of the surgery, and within a +/- 90 minute time window for subsequent doses, which are administered every 6 hours after the start of surgery).

  7. Incidence of delirium between drug vs. placebo treated patients [ Time Frame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks ]
    Scores on 3D CAM (non-intubated patients) or CAM ICU (intubated patients) are used to determine whether patients have delirium (yes/no).

  8. Severity of delirium symptoms between drug vs. placebo treated patients [ Time Frame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks ]
    Scores on the 3D CAM (in non-intubated patients) are used to determine delirium symptom severity based on a 0 - 20 point scale of the test.



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age ≥ 60
  • Ability to speak English
  • Undergoing non-cardiac, non-neurologic surgical procedures; surgery scheduled to last > 2 hours; due to be admitted to the hospital following surgery

Exclusion Criteria:

  • Inmate of a correctional facility
  • Scheduled to receive systemic chemotherapy between the time of the two cognitive testing sessions
  • Known inability to undergo LPs due to anticoagulant use, severe anxiety, or other clinical contraindication known ahead of time.
  • Inappropriate for study inclusion based on the judgement of the principal investigator.
  • If a patient undergoes major head trauma that occurs between the times of the two cognitive testing sessions, then they will be withdrawn from the study.

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): NCT03802396


Contacts
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Contact: Donna M Crabtree, PhD 1-919-668-3389 donna.crabtree@duke.edu
Contact: Yanne Toulgoat-DuBois 1-919-681-9625 Yanne.t.dubois@dm.duke.edu

Locations
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United States, North Carolina
Duke University Hospital Recruiting
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Miles Berger, MD PhD
Investigators
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Principal Investigator: Miles Berger, MD;PhD Duke University
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Responsible Party: Miles Berger, MD PhD, Assistant Professor, Neuroanesthesiology Division, Anesthesiology Department, Duke University
ClinicalTrials.gov Identifier: NCT03802396    
Other Study ID Numbers: Pro00088855
First Posted: January 14, 2019    Key Record Dates
Last Update Posted: July 14, 2020
Last Verified: July 2020
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 Miles Berger, MD PhD, Duke University:
Delirium
Aging
Elderly
Postoperative
Cognitive Dysfunction
Additional relevant MeSH terms:
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Delirium
Encephalitis
Inflammation
Cognitive Dysfunction
Pathologic Processes
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Brain Diseases
Central Nervous System Diseases