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

• ClinicalTrials.gov Identifier: NCT03802396
• Recruitment Status: Recruiting
• First Posted: January 14, 2019
• Last Update Posted: August 25, 2022
• Sponsor: Miles Berger, MD PhD
• Information provided by (Responsible Party): Miles Berger, MD PhD, Duke University

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.

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.

Study Design

• 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: July 15, 2018
• Estimated Primary Completion Date: March 1, 2023
• Estimated Study Completion Date: March 1, 2023

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Number of adverse events (AEs) of grade II or higher, per CTCAE criteria [ 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 of Grade II and higher 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.

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: Yanne Toulgoat-Dubois, BA; 1-919-681-9625; Yanne.t.dubois@dm.duke.edu

Contact: Miles Berger, MD, PhD; 415-694-9850; miles.berger@duke.edu

Locations

United States, North Carolina

Duke University Hospital; Recruiting

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Miles Berger, MD PhD

Investigators

• Principal Investigator: Miles Berger, MD, PhD; Duke University

More Information

• 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
• Last Update Posted: August 25, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Infectious Encephalitis; Delirium; Encephalitis; Inflammation; Postoperative Cognitive Complications; Cognitive Dysfunction; Pathologic Processes; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Postoperative Complications; Brain Diseases; Central Nervous System Diseases; Central Nervous System Infections; Infections