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

Primary Purpose

Postoperative Delirium, Postoperative Cognitive Dysfunction

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
CN-105
Placebo
Sponsored by
Miles Berger, MD PhD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Postoperative Delirium focused on measuring Delirium, Aging, Elderly, Postoperative, Cognitive Dysfunction

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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undergoes major head trauma that occurs between the times of the two cognitive testing sessions, then they will be withdrawn from the study.

Sites / Locations

  • Duke University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

CN-105

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Number of adverse events (AEs) of grade II or higher, per CTCAE criteria
safety of CN-105 administration, as measured by adverse event (AE) rates of Grade II and higher in CN-105 versus placebo-treated patients.

Secondary Outcome Measures

Change in cerebrospinal fluid (CSF) IL-6 cytokine levels between drug vs placebo treated patients
Change in CSF IL-6 cytokine levels from before to after surgery between drug vs placebo treated patients.
Change in CSF IL-8 cytokine levels between drug vs placebo treated patients
Change in CSF IL-8 cytokine levels from before to after surgery between drug vs placebo treated patients
Change in CSF MCP-1 cytokine levels between drug vs placebo treated patients
Change in CSF MCP-1 cytokine levels before to after surgery between drug vs placebo treated patients
Change in CSF G-CSF cytokine levels between drug vs placebo treated patients
Change in CSF G-CSF cytokine levels before to after surgery between drug vs placebo treated patients.
Change in cognitive change index (CCI) between drug vs placebo treated patients
Change in CCI before to after surgery between drug vs placebo treated patients.
Feasibility of drug administration within correct time windows
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).
Incidence of delirium between drug vs. placebo treated patients
Scores on 3D CAM (non-intubated patients) or CAM ICU (intubated patients) are used to determine whether patients have delirium (yes/no).
Severity of delirium symptoms between drug vs. placebo treated patients
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.

Full Information

First Posted
January 10, 2019
Last Updated
October 2, 2023
Sponsor
Miles Berger, MD PhD
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1. Study Identification

Unique Protocol Identification Number
NCT03802396
Brief Title
Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction
Acronym
MARBLE
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Completed
Study Start Date
July 15, 2018 (Actual)
Primary Completion Date
December 28, 2022 (Actual)
Study Completion Date
December 28, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Miles Berger, MD PhD

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Postoperative Delirium, Postoperative Cognitive Dysfunction
Keywords
Delirium, Aging, Elderly, Postoperative, Cognitive Dysfunction

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
203 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CN-105
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
CN-105
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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 Measure Information:
Title
Number of adverse events (AEs) of grade II or higher, per CTCAE criteria
Description
safety of CN-105 administration, as measured by adverse event (AE) rates of Grade II and higher in CN-105 versus placebo-treated patients.
Time Frame
2 years for entire study; until 6 week follow-up for individual patients
Secondary Outcome Measure Information:
Title
Change in cerebrospinal fluid (CSF) IL-6 cytokine levels between drug vs placebo treated patients
Description
Change in CSF IL-6 cytokine levels from before to after surgery between drug vs placebo treated patients.
Time Frame
Baseline, 24 hours, 6 weeks +/- 3 weeks
Title
Change in CSF IL-8 cytokine levels between drug vs placebo treated patients
Description
Change in CSF IL-8 cytokine levels from before to after surgery between drug vs placebo treated patients
Time Frame
Baseline, 24 hours, 6 weeks +/- 3 weeks
Title
Change in CSF MCP-1 cytokine levels between drug vs placebo treated patients
Description
Change in CSF MCP-1 cytokine levels before to after surgery between drug vs placebo treated patients
Time Frame
Baseline, 24 hours, 6 weeks +/- 3 weeks
Title
Change in CSF G-CSF cytokine levels between drug vs placebo treated patients
Description
Change in CSF G-CSF cytokine levels before to after surgery between drug vs placebo treated patients.
Time Frame
Baseline, 24 hours, 6 weeks +/- 3 weeks
Title
Change in cognitive change index (CCI) between drug vs placebo treated patients
Description
Change in CCI before to after surgery between drug vs placebo treated patients.
Time Frame
Baseline, 6 weeks +/- 3 weeks
Title
Feasibility of drug administration within correct time windows
Description
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).
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
Title
Incidence of delirium between drug vs. placebo treated patients
Description
Scores on 3D CAM (non-intubated patients) or CAM ICU (intubated patients) are used to determine whether patients have delirium (yes/no).
Time Frame
Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
Title
Severity of delirium symptoms between drug vs. placebo treated patients
Description
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.
Time Frame
Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Miles Berger, MD, PhD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Hospital
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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