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NCT Number: NCT03802396

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

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.

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Key information

Conditions

Postoperative Delirium Cognition Disorders Cognitive Dysfunction Confusion Delirium Emergence Delirium Mental Disorders Nervous System Diseases Neurobehavioral Manifestations Neurocognitive Disorders Neurologic Manifestations Pathologic Processes Pathological Conditions, Signs and Symptoms Postoperative Cognitive Complications Postoperative Cognitive Dysfunction Postoperative Complications Signs and Symptoms

Age range

60 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Duke University Hospital

Durham, North Carolina, 27710, United States

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

CN-105

Drug

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

Drug

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 outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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).

  7. 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).

  8. 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.

Sponsors and collaborators

Lead sponsor

Miles Berger, MD PhD

Other

Registry information

Official study 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

Acronym: MARBLE

Important dates

Study start
2018
Primary completion
2022
Study completion
2022
First posted
Jan 14, 2019
Registry last updated
Oct 16, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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