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: July 14, 2020
• Sponsor: Miles Berger, MD PhD
• Information provided by (Responsible Party): Miles Berger, MD PhD, Duke University

Tracking Information

• First Submitted Date: January 10, 2019
• First Posted Date: January 14, 2019
• Last Update Posted Date: July 14, 2020
• Actual Study Start Date: April 17, 2019
• Estimated Primary Completion Date: October 17, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2020)

Number of adverse events (AEs) [ 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 in CN-105 versus placebo-treated patients.

Original Primary Outcome Measures (submitted: January 10, 2019)

Number of adverse events (AEs) [ Time Frame: 2 years ]

Number of AEs throughout the trial.

Current Secondary Outcome Measures (submitted: May 14, 2020)

• 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.
• 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
• 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
• 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.
• 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.
• 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).
• 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).
• 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.

Original Secondary Outcome Measures (submitted: January 10, 2019)

• Changes in CSF IL-6 cytokine levels [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
  Changes in cerebrospinal fluid (CSF) IL-6 cytokine levels before and after surgery
• Changes in CSF IL-8 cytokine levels [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
  Changes in cerebrospinal fluid (CSF) IL-8 cytokine levels before and after surgery
• Changes in CSF MCP-1 cytokine levels [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
  Changes in cerebrospinal fluid (CSF) MCP-1 cytokine levels before and after surgery
• Changes in CSF GCS-F cytokine levels [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
  Changes in cerebrospinal fluid (CSF) GCS-F cytokine levels before and after surgery
• Changes in CSF tau levels [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
  Changes in cerebrospinal fluid (CSF) tau levels before and after surgery
• Changes in CSF phospho-tau levels [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
  Changes in cerebrospinal fluid (CSF) phopho-tau levels before and after surgery
• Changes in CSF amyloid beta levels [ Time Frame: Baseline, 24 hours, 6 weeks +/- 3 weeks ]
  Changes in cerebrospinal fluid (CSF) amyloid beta levels before and after surgery
• Changes in cognition using the HVLT-R [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Hopkins Verbal Learning Test, Revised (HVLT-R), an auditory-verbal word-list task used to assess learning, short-term recall, long-term recall and recognition memory that is co-normed with the BVMT-R.
• Changes in cognition using the BVMT-R [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Brief Visuospatial Memory Test, Revised (BVMT-R), a visual measure of constructional praxis, spatial/figure learning, short-term recall, long-term recall and recognition memory that is co-normed with the Hopkins Verbal Learning Test, Revised (HVLT-R).
• Changes in cognition using the Digit Span subtest from the WAIS-III [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Digit Span subtest from the Wechsler Adult Intelligence Scale, 3rd Revision (WAIS-III), a test of immediate auditory-verbal recall and complex attention (i.e., working memory).
• Changes in cognition using the Digit Symbol Coding subtest from the WAIS-III [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Digit Symbol Coding subtest from the Wechsler Adult Intelligence Scale, 3rd Revision (WAIS-III) - a matching-to-sample visual scanning and visuomotor production task.
• Changes in cognition using the TMT [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Trail Making Test (TMT), Parts A & B, a test of simple visuomotor scanning and complex sequencing and set-switching executive demands.
• Changes in cognition using the COWAT [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Controlled Oral Word Association Test (COWAT), a test of lexical verbal fluency and information retrieval efficiency.
• Changes in cognition using the Grooved Pegboard Test [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Grooved Pegboard Test, a timed test of bilateral manual dexterity and motor speed.
• Changes in cognition using the WTAR [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Wechsler Test of Adult Reading (WTAR), a non-phonemic reading test used to assess crystalized pronunciation knowledge; a reliable estimate of premorbid intellectual functioning.
• Changes in cognition using the MOCA [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the Montreal Cognitive Assessment (MOCA), a test used to screen for cognitive impairment
• Changes in cognition using STOP-Bang [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in cognition as measured by the STOP-Bang brief questionnaire to assess sleep apnea risk.
• Changes in Pain Assessment using VAS [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Visual analogue scale (VAS) pain assessment
• Changes in Timed up and Go task/test [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
• Changes in Disequilibrium Assessment using Romberg Assessment [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  The Romberg test is used for the clinical assessment of patients with disequilibrium or ataxia from sensory and motor disorders
• Changes in Falls Assessment [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  A brief falls risk assessment questionnaire and questions about whether patient has fallen recently.
• Number of Postoperative Delirium Incidents [ Time Frame: Baseline, 24 hours post-surgery through patient discharge, 6 weeks +/- 3 weeks ]
  Postoperative delirium rates assessed using the CAM-ICU in intubated patients and the 3D-CAM in non-intubated patients.
• Changes in Quality of Life [ Time Frame: Baseline, 6 weeks +/- 3 weeks ]
  Changes in quality of life measured using the SF-36 instrument, a 36-item, patient-reported survey of patient health.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

Condition

• Postoperative Delirium
• Postoperative Cognitive Dysfunction

Intervention

• 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.

• 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.

Study Arms

• 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

  Intervention: Drug: CN-105
• 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

  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 10, 2019): 201
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 17, 2022
• Estimated Primary Completion Date: October 17, 2022 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Donna M Crabtree, PhD; 1-919-668-3389; donna.crabtree@duke.edu

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03802396
• Other Study ID Numbers: Pro00088855
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Miles Berger, MD PhD, Duke University
• Study Sponsor: Miles Berger, MD PhD
• Collaborators: Not Provided

Investigators

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

• PRS Account: Duke University
• Verification Date: July 2020