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CompletedNCT03802396MARBLEUpdated Oct 16, 2024Results posted

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

A Phase 2 interventional study of CN-105 and Placebo in Postoperative Delirium and Postoperative Cognitive Dysfunction, sponsored by Miles Berger, MD PhD. Completed at 1 site in United States. Open to participants aged 60 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-10-16.

Sponsored by Miles Berger, MD PhD · Phase 2, Interventional, and Prevention

Phase
Phase 2
Study type
Interventional
Enrollment
203
Allocation
Randomized
Ages
60 Years and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Postoperative Delirium
  • Postoperative Cognitive Dysfunction

Keywords

  • Delirium
  • Aging
  • Elderly
  • Postoperative
  • Cognitive Dysfunction
03

Who can participate

Ages eligible
60 Years and older
Sexes eligible
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

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.
04

Study design

Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
203 participants (actual)

Study arms

  • Experimental
    CN-105

    Cohort 1: 50 Patients Dose of CN-105: 0.1 mg/kg Cohort 2: 50 Patients Dose of CN-105: 0.5 mg/kg Cohort 3: 50 Patients Dose of CN-105: 1 mg/kg

    Drug: CN-105

  • Placebo comparator
    Placebo

    Cohort 1: 17 Patients receiving placebo Cohort 2: 17 Patients receiving placebo Cohort 3: 17 Patients receiving placebo

    Drug: Placebo

Interventions

  • DrugCN-105

    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.

  • DrugPlacebo

    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.

05

What researchers measure

Primary outcomes

  1. Number of Adverse Events (AEs) of Grade II or Higher Per Patient

    Safety of CN-105 administration, as measured by adverse event (AE) rates of Grade II and higher in CN-105 versus placebo-treated patients.

    Time frame: up to 6-week follow-up

Secondary outcomes

  1. Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients

    Change in CSF IL-6 cytokine levels from before to after surgery between drug vs placebo treated patients.

    Time frame: Baseline, 24 hours, approximately 6 weeks

  2. Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients

    Change in CSF IL-8 cytokine levels from before to after surgery between drug vs placebo treated patients

    Time frame: Baseline, 24 hours, approximately 6 weeks

  3. Change in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients

    Change in CSF MCP-1 cytokine levels before to after surgery between drug vs placebo treated patients

    Time frame: Baseline, 24 hours, approximately 6 weeks

  4. Change in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients

    Change in CSF G-CSF cytokine levels before to after surgery between drug vs placebo treated patients.

    Time frame: Baseline, 24 hours, approximately 6 weeks

  5. Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients

    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.

    Time frame: Baseline, approximately 6 weeks

  6. Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window

    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).

    Time frame: admission to preoperative holding to hospital discharge (up to postoperative day 4)

  7. Number of Participants Who Experience Delirium

    Scores on 3D CAM (non-intubated patients) or CAM ICU (intubated patients) are used to determine whether patients have delirium (yes/no).

    Time frame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks

  8. Peak Severity of Delirium Symptoms Between Drug vs. Placebo Treated Patients

    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.

    Time frame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks

06

Results

Posted Sep 4, 2024

Participant flow

Participant flow — Overall Study
MilestoneCN-105Placebo
Started14049
Completed13749
Not completed30
Withdrew: Withdrawal by subject20
Withdrew: Surgery cancelled10

Outcome measures

PrimaryNumber of Adverse Events (AEs) of Grade II or Higher Per Patient

Safety of CN-105 administration, as measured by adverse event (AE) rates of Grade II and higher in CN-105 versus placebo-treated patients.

Time frame:
up to 6-week follow-up
Reported as:
Median · events per participant
Number of Adverse Events (AEs) of Grade II or Higher Per Patient
events per participantCN-105Placebo
Number of Adverse Events (AEs) of Grade II or Higher Per Patient1 (1 to 3)2 (1 to 5)
Statistical analysis
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.025
SecondaryChange in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients

Change in CSF IL-6 cytokine levels from before to after surgery between drug vs placebo treated patients.

Time frame:
Baseline, 24 hours, approximately 6 weeks
Reported as:
Median · pg/mL
Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients
pg/mLCN-105Placebo
Baseline to 24 hours0.52 (-0.08 to 1.35)0.91 (0.30 to 1.63)
Baseline to 6 weeks-0.06 (-0.40 to 0.17)0.00 (-0.20 to 0.12)
Statistical analysis
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.116
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.388
SecondaryChange in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients

Change in CSF IL-8 cytokine levels from before to after surgery between drug vs placebo treated patients

Time frame:
Baseline, 24 hours, approximately 6 weeks
Reported as:
Median · pg/mL
Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients
pg/mLCN-105Placebo
Baseline to 24 hours130.11 (69.11 to 227.90)153.43 (67.44 to 268.26)
Baseline to 6 weeks-2.7 (-8.06 to 0.32)0.54 (-4.23 to 4.08)
Statistical analysis
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.569
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.047
SecondaryChange in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients

Change in CSF MCP-1 cytokine levels before to after surgery between drug vs placebo treated patients

Time frame:
Baseline, 24 hours, approximately 6 weeks
Reported as:
Median · pg/mL
Change in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients
pg/mLCN-105Placebo
Baseline to 24 hours-114.39 (-177.58 to -22.06)-116.75 (-195.11 to -26.95)
Baseline to 6 weeks-17.69 (-58.01 to 21.33)-4.62 (-32.16 to 6.32)
Statistical analysis
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.498
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.745
SecondaryChange in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients

Change in CSF G-CSF cytokine levels before to after surgery between drug vs placebo treated patients.

Time frame:
Baseline, 24 hours, approximately 6 weeks
Reported as:
Median · pg/mL
Change in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients
pg/mLCN-105Placebo
Baseline to 24 hours2.46 (0.75 to 6.36)3.3 (1.89 to 10.18)
Baseline to 6 weeks0.22 (-1.10 to 1.13)-0.23 (-0.96 to 0.77)
Statistical analysis
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.177
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.478
SecondaryChange in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients

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.

Time frame:
Baseline, approximately 6 weeks
Reported as:
Mean · units on a scale
Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients
units on a scaleCN-105Placebo
Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients0.08 ± 0.330.06 ± 0.34
Statistical analysis
  • CN-105 vs Placebo · t-test, 2 sided · p = 0.803
SecondaryFeasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window

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).

Time frame:
admission to preoperative holding to hospital discharge (up to postoperative day 4)
Reported as:
Mean · percentage of doses
Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window
percentage of dosesCN-105Placebo
Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window94.6 (92.9 to 96.0)93.8 (90.8 to 96.0)
SecondaryNumber of Participants Who Experience Delirium

Scores on 3D CAM (non-intubated patients) or CAM ICU (intubated patients) are used to determine whether patients have delirium (yes/no).

Time frame:
Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
Reported as:
Count of participants · Participants
Number of Participants Who Experience Delirium
ParticipantsCN-105Placebo
Number of Participants Who Experience Delirium2613
Statistical analysis
  • CN-105 vs Placebo · Chi-squared · p = 0.286 · Risk ratio (rr): 0.73 · 95% CI 0.41 to 1.30
SecondaryPeak Severity of Delirium Symptoms Between Drug vs. Placebo Treated Patients

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.

Time frame:
Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
Reported as:
Median · score on a scale
Peak Severity of Delirium Symptoms Between Drug vs. Placebo Treated Patients
score on a scaleCN-105Placebo
Peak Severity of Delirium Symptoms Between Drug vs. Placebo Treated Patients1 (1 to 2)2 (1 to 2)
Statistical analysis
  • CN-105 vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.189

Adverse events

Collected over Surgery to 6-week follow-up visit. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
CN-1050/137 (0%)11/137 (8%)105/137 (76.6%)
Placebo0/49 (0%)11/49 (22.4%)43/49 (87.8%)
Most frequent serious events
Showing 10 of 29
Most frequent serious events
EventCN-105Placebo
ANEMIABlood and lymphatic system disorders1/1373/49
HYPOTENSIONVascular disorders1/1373/49
HYPOXIARespiratory, thoracic and mediastinal disorders0/1372/49
CONSTIPATIONGastrointestinal disorders0/1371/49
CYSTOSCOPY FOR REMOVAL OF URINARY CATHETERSurgical and medical procedures0/1371/49
FATIGUEGeneral disorders0/1371/49
GASTRIC STENOSISGastrointestinal disorders0/1371/49
HEMORRHAGEInjury, poisoning and procedural complications0/1371/49
HYPERTENSIONVascular disorders0/1371/49
HYPOXEMIARespiratory, thoracic and mediastinal disorders0/1371/49
Most frequent other events
Showing 10 of 109
Most frequent other events
EventCN-105Placebo
HYPERTENSIONVascular disorders61/13722/49
DECREASED LYMPHOCYTE COUNTInvestigations27/13715/49
ANEMIABlood and lymphatic system disorders30/1379/49
INFECTIONInfections and infestations17/1376/49
HYPERGLYCEMIAMetabolism and nutrition disorders4/1376/49
DIZZINESSNervous system disorders3/1375/49
VOMITINGGastrointestinal disorders5/1375/49
HYPOTENSIONVascular disorders12/1373/49
HYPOALBUMINEMIAMetabolism and nutrition disorders11/1374/49
NAUSEAGastrointestinal disorders6/1374/49

Baseline characteristics

Participants who completed the study.

Age, Continuous
Age, Continuous(years)CN-105PlaceboTotal
Mean68.4 ± 5.069.5 ± 6.068.7 ± 5.0
Sex: Female, Male
Sex: Female, Male(Participants)CN-105PlaceboTotal
Female511667
Male8633119
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)CN-105PlaceboTotal
Hispanic or Latino213
Not Hispanic or Latino13547182
Unknown or Not Reported011
Race (NIH/OMB)
Race (NIH/OMB)(Participants)CN-105PlaceboTotal
American Indian or Alaska Native202
Asian303
Native Hawaiian or Other Pacific Islander000
Black or African American9514
White12242164
More than one race000
Unknown or Not Reported123
Region of Enrollment
Region of Enrollment(Participants)CN-105PlaceboTotal
United States13749186
07

Study locations

1 site
  • Duke University Hospital
    Durham, North Carolina 27710, United States
08

References and documents

Study documents

  • Protocol and statistical analysis plan · May 25, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT03802396
Lead sponsor
Miles Berger, MD PhD
Responsible party
Miles Berger, MD PhD (Assistant Professor, Neuroanesthesiology Division, Anesthesiology Department, Duke University) — Sponsor-investigator
First posted
Jan 14, 2019
Start date
Jul 15, 2018
Primary completion
Dec 28, 2022
Completion
Dec 28, 2022
Results posted
Sep 4, 2024
Last update
Oct 16, 2024

Study contacts

Miles Berger, MD, PhD
principal investigator · Duke University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
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