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

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

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.

Study Overview

• Status: Completed
• Conditions: Postoperative Delirium; Postoperative Cognitive Dysfunction
• Intervention / Treatment: Drug: Placebo; Drug: CN-105

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.

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CN-105; Cohort 1: 50 Patients Dose of CN-105: 0.1 mg/kg Cohort 2: 50 Patients Dose of CN-105: 0.5 mg/kg Cohort 3: 50 Patients Dose of CN-105: 1 mg/kg	Drug: CN-105; Three doses of CN-105 will be used in three successive cohorts of 50 patients each. 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: 17 Patients receiving placebo Cohort 2: 17 Patients receiving placebo Cohort 3: 17 Patients receiving placebo	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events (AEs) of Grade II or Higher Per Patient	Safety of CN-105 administration, as measured by adverse event (AE) rates of Grade II and higher in CN-105 versus placebo-treated patients.	up to 6-week follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 24 hours, approximately 6 weeks
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	Baseline, 24 hours, approximately 6 weeks
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	Baseline, 24 hours, approximately 6 weeks
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.	Baseline, 24 hours, approximately 6 weeks
Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients	To characterize cognitive function over time, while minimizing potential redundancy in the cognitive measures, a Z-score standardization was performed on the 11 cognitive test scores with mean and standard deviation derived at the baseline timepoint. We then constructed four summary scores by taking the average of the standardized cognitive test scores, which represent the following cognitive domains: verbal memory, executive function, visual memory and attention. To quantify overall cognitive function, a cognitive index was calculated as the mean of the 4 domain scores. The cognitive index score has a mean of zero, thus any positive score is above the mean, any negative score is below the mean. A continuous change score was then calculated by subtracting the baseline from the 6-week cognitive index. The resulting outcome measure is unbounded with standard deviation of 0.33. A negative change score indicating decline and a positive score indicating improvement.	Baseline, approximately 6 weeks
Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window	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).	admission to preoperative holding to hospital discharge (up to postoperative day 4)
Number of Participants Who Experience Delirium	Scores on 3D CAM (non-intubated patients) or CAM ICU (intubated patients) are used to determine whether patients have delirium (yes/no).	Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
Peak 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. Higher scores indicate worse delirium.	Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks

Collaborators and Investigators

• Sponsor: Miles Berger, MD PhD
• Investigators: Principal Investigator: Miles Berger, MD, PhD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2018
• Primary Completion (Actual): December 28, 2022
• Study Completion (Actual): December 28, 2022

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: January 10, 2019
• First Posted (Actual): January 14, 2019

Study Record Updates

• Last Update Posted (Actual): October 16, 2024
• Last Update Submitted That Met QC Criteria: October 3, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Elderly; Aging; Postoperative; Cognitive Dysfunction; Delirium
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Central Nervous System Infections; Cognition Disorders; Neuroinflammatory Diseases; Delirium; Encephalitis; Inflammation; Cognitive Dysfunction; Postoperative Cognitive Complications; Emergence Delirium; Infectious Encephalitis
• Other Study ID Numbers: Pro00088855

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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