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

Sponsor

Miles Berger, MD PhD (Other)

Overall Status

Recruiting

CT.gov ID

NCT03802396

Collaborator

(none)

201

Enrollment

Location

Arms

55.5

Anticipated Duration (Months)

3.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Anticipated 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.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 :

Jul 15, 2018

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 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.

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

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

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

Change in cerebrosprinal fluid (CSF) IL-6 cytokine levels between drug vs placebo treated patients [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.
Change in CSF IL-8 cytokine levels between drug vs placebo treated patients [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
Change in CSF MCP-1 cytokine levels between drug vs placebo treated patients [Baseline, 24 hours, 6 weeks +/- 3 weeks]
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 [Baseline, 24 hours, 6 weeks +/- 3 weeks]
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 [Baseline, 6 weeks +/- 3 weeks]
Change in CCI before to after surgery between drug vs placebo treated patients.
Feasibility of drug administration within correct time windows [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).
Incidence of delirium between drug vs. placebo treated patients [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).
Severity of delirium symptoms between drug vs. placebo treated patients [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

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.