Clinical trial NCT03802396: Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Postoperative Delirium
Postoperative Cognitive Dysfunction
Keywords: Delirium
Aging
Elderly
Postoperative
Cognitive Dysfunction
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2019-01-14
Enrollment: 203
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: PREVENTION

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.

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.

Eligibility 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.

Primary outcomes:
measure: Number of Adverse Events (AEs) of Grade II or Higher Per Patient
timeFrame: up to 6-week follow-up
Secondary outcomes:
measure: Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients
timeFrame: Baseline, 24 hours, approximately 6 weeks
measure: Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients
timeFrame: Baseline, 24 hours, approximately 6 weeks
measure: Change in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients
timeFrame: Baseline, 24 hours, approximately 6 weeks
measure: Change in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients
timeFrame: Baseline, 24 hours, approximately 6 weeks
measure: Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients
timeFrame: Baseline, approximately 6 weeks
measure: Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window
timeFrame: admission to preoperative holding to hospital discharge (up to postoperative day 4)
measure: Number of Participants Who Experience Delirium
timeFrame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
measure: Peak Severity of Delirium Symptoms Between Drug vs. Placebo Treated Patients
timeFrame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
Study officials:
affiliation: Duke University
name: Miles Berger, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: