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

October 3, 2024 updated by: Miles Berger, MD PhD

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
203

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of Adverse Events (AEs) of Grade II or Higher Per Patient
Time Frame: up to 6-week follow-up
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients
Time Frame: Baseline, 24 hours, approximately 6 weeks
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
Time Frame: Baseline, 24 hours, approximately 6 weeks
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
Time Frame: Baseline, 24 hours, approximately 6 weeks
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
Time Frame: Baseline, 24 hours, approximately 6 weeks
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
Time Frame: Baseline, approximately 6 weeks
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
Time Frame: admission to preoperative holding to hospital discharge (up to postoperative day 4)
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
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).
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
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. Higher scores indicate worse delirium.
Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Miles Berger, MD PhD

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Miles Berger, MD, PhD, Duke University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 15, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 28, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 28, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 10, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 10, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 14, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 16, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 3, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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