Postoperative Cognitive Dysfunction, Postoperative Delirium
Conditions
Keywords
Delirium, Aging, Elderly, Postoperative, Cognitive Dysfunction
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.
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.
Sponsors
Miles Berger, MD PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, 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.
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.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events (AEs) of Grade II or Higher Per Patient | up to 6-week follow-up | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline, 24 hours, approximately 6 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, approximately 6 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, approximately 6 weeks | Change in CSF G-CSF cytokine levels before to after surgery between drug vs placebo treated patients. |
| Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline, 24 hours, approximately 6 weeks | Change in CSF IL-6 cytokine levels from before to after surgery between drug vs placebo treated patients. |
| Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window | admission to preoperative holding to hospital discharge (up to postoperative day 4) | 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). |
| Number of Participants Who Experience Delirium | 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). |
| Peak 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. Higher scores indicate worse delirium. |
| Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients | Baseline, approximately 6 weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CN-105 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. | 137 |
| 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. | 49 |
| Total | 186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Surgery Cancelled | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | CN-105 | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 68.4 years STANDARD_DEVIATION 5 | 68.7 years STANDARD_DEVIATION 5 | 69.5 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 135 Participants | 182 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 14 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 122 Participants | 164 Participants | 42 Participants |
| Region of Enrollment United States | 137 Participants | 186 Participants | 49 Participants |
| Sex: Female, Male Female | 51 Participants | 67 Participants | 16 Participants |
| Sex: Female, Male Male | 86 Participants | 119 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 137 | 0 / 49 |
| other Total, other adverse events | 105 / 137 | 43 / 49 |
| serious Total, serious adverse events | 11 / 137 | 11 / 49 |
Outcome results
Primary
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
Population: Participants who completed the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CN-105 | Number of Adverse Events (AEs) of Grade II or Higher Per Patient | 1 events per participant |
| Placebo | Number of Adverse Events (AEs) of Grade II or Higher Per Patient | 2 events per participant |
p-value: 0.025Wilcoxon (Mann-Whitney)
Secondary
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
Population: Participants with data collected at each timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CN-105 | Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 24 hours | 0.52 pg/mL |
| CN-105 | Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 6 weeks | -0.06 pg/mL |
| Placebo | Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 6 weeks | 0.00 pg/mL |
| Placebo | Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 24 hours | 0.91 pg/mL |
Comparison: Baseline to 24 hoursp-value: 0.116Wilcoxon (Mann-Whitney)
Comparison: Baseline to 6 weeksp-value: 0.388Wilcoxon (Mann-Whitney)
Secondary
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
Population: Participants who completed both baseline and 6-week follow-up visit and surgery on protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CN-105 | Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients | 0.08 units on a scale | Standard Deviation 0.33 |
| Placebo | Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients | 0.06 units on a scale | Standard Deviation 0.34 |
p-value: 0.803t-test, 2 sided
Secondary
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
Population: Participants who had data collected at each timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CN-105 | Change in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 24 hours | 2.46 pg/mL |
| CN-105 | Change in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 6 weeks | 0.22 pg/mL |
| Placebo | Change in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 24 hours | 3.3 pg/mL |
| Placebo | Change in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 6 weeks | -0.23 pg/mL |
Comparison: Baseline to 24 hoursp-value: 0.177Wilcoxon (Mann-Whitney)
Comparison: Baseline to 6 weeksp-value: 0.478Wilcoxon (Mann-Whitney)
Secondary
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
Population: Participants with data collected at each timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CN-105 | Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 24 hours | 130.11 pg/mL |
| CN-105 | Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 6 weeks | -2.7 pg/mL |
| Placebo | Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 24 hours | 153.43 pg/mL |
| Placebo | Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 6 weeks | 0.54 pg/mL |
Comparison: Baseline to 24 hoursp-value: 0.569Wilcoxon (Mann-Whitney)
Comparison: Baseline to 6 weeksp-value: 0.047Wilcoxon (Mann-Whitney)
Secondary
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
Population: Participants with data collected at each timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CN-105 | Change in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 24 hours | -114.39 pg/mL |
| CN-105 | Change in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 6 weeks | -17.69 pg/mL |
| Placebo | Change in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 24 hours | -116.75 pg/mL |
| Placebo | Change in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients | Baseline to 6 weeks | -4.62 pg/mL |
Comparison: Baseline to 24 hoursp-value: 0.498Wilcoxon (Mann-Whitney)
Comparison: Baseline to 6 weeksp-value: 0.745Wilcoxon (Mann-Whitney)
Secondary
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)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| CN-105 | Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window | 94.6 percentage of doses |
| Placebo | Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window | 93.8 percentage of doses |
Secondary
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
Population: Participants who completed surgery on protocol and had at least 1 postoperative CAM-3D or CAM-ICU assessment performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CN-105 | Number of Participants Who Experience Delirium | 26 Participants |
| Placebo | Number of Participants Who Experience Delirium | 13 Participants |
p-value: 0.28695% CI: [0.41, 1.3]Chi-squared
Secondary
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
Population: Subjects who completed surgery on protocol and had at least 1 postoperative CAM-3D assessment performed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CN-105 | Peak Severity of Delirium Symptoms Between Drug vs. Placebo Treated Patients | 1 score on a scale |
| Placebo | Peak Severity of Delirium Symptoms Between Drug vs. Placebo Treated Patients | 2 score on a scale |
p-value: 0.189Wilcoxon (Mann-Whitney)