Postoperative DeliriumPhase 2MARBLENCT03802396
Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction
A Phase 2 study testing CN-105 in people with Postoperative Delirium and Postoperative Cognitive Dysfunction, run by Miles Berger, MD PhD at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 60 years and olderHealthy volunteers can take part
- Conditions the study is for
- Postoperative Delirium, Postoperative Cognitive Dysfunction
- What is being tested?
- CN-105
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 203 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Jul 2018to 28 Dec 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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undergoes major head trauma that occurs between the times of the two cognitive testing sessions, then they will be withdrawn from the study.
Trial locations and contacts
1 site in 1 country.
United States1 site
Duke University Hospital
Durham, North Carolina, 27710
About this study
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
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.
- Being tested
- CN-105, Placebo
- Keywords
- Delirium, Aging, Elderly, Postoperative, Cognitive Dysfunction
- Medical subject headings
- Emergence Delirium, Postoperative Cognitive Complications, Delirium, Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CN-105Drug
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.
PlaceboDrug
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 group | Role | What they receive |
|---|---|---|
| CN-105 | Experimental | 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 Receives: Drug: CN-105 |
| Placebo | Placebo comparator | Cohort 1: 17 Patients receiving placebo
Cohort 2: 17 Patients receiving placebo
Cohort 3: 17 Patients receiving placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: up to 6-week follow-up
Secondary outcomes (8)
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.
Measured: Baseline, 24 hours, approximately 6 weeks
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
Measured: Baseline, 24 hours, approximately 6 weeks
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
Measured: Baseline, 24 hours, approximately 6 weeks
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.
Measured: Baseline, 24 hours, approximately 6 weeks
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.
Measured: Baseline, approximately 6 weeks
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).
Measured: admission to preoperative holding to hospital discharge (up to postoperative day 4)
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).
Measured: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
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.
Measured: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jan 2019
- Study start15 Jul 2018
- Primary completion28 Dec 2022
- Study completion28 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Postoperative DeliriumStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 203 participants (actual)
Sponsor and investigators
- Lead sponsor
- Miles Berger, MD PhD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Miles Berger, MD PhD, Duke University
- Investigators
- Miles Berger, MD, PhD, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03802396
- Sponsor's protocol ID
- Pro00088855
- Acronym
- MARBLE
- Status last verified
- Oct 2024
- First submitted
- 10 Jan 2019
- Last updated
- 16 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Timko NJ, Cooter Wright M, Smith MR, Boykin PC, Emerson JM, Woldorff MG, Eleswarpu S, Herbert JT, Moretti EW, Devinney MJ, Ayoub CM, Rockhold FW, Ryu D, Syed A, VanDusen KW, Bunning T, Hsia BJ, Bolognesi MP, Jiranek WA, Zetterberg H, Blennow K, Huebner JL, Li Z, Reekes TH, Browndyke JN, Laskowitz DT, Berger M; MARBLE Study Investigators. Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients: The Phase 2 MARBLE Randomized Clinical Trial. JAMA Netw Open. 2026 Apr 1;9(4):e262289. doi: 10.1001/jamanetworkopen.2026.2289.
PubMed 41931297
Study at a glance
From the registry record, last updated by the sponsor on 16 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03802396
- Acronym / sponsor ID
- MARBLE / Pro00088855
- Keywords
- Delirium, Aging, Elderly, Postoperative, Cognitive Dysfunction
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 203 participants (actual)
- Lead sponsor
- Miles Berger, MD PhDUniversity, hospital or other
- Study start
- 15 Jul 2018 (actual)
- Primary completion
- 28 Dec 2022 (actual)
- Study completion
- 28 Dec 2022 (actual)
- First posted
- 14 Jan 2019 (actual)
- Results
- Posted 4 Sep 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| CN-105 | Experimental | Drug: CN-105Cohort 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 |
| Placebo | Placebo comparator | Drug: PlaceboCohort 1: 17 Patients receiving placebo Cohort 2: 17 Patients receiving placebo Cohort 3: 17 Patients receiving placebo |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CN-105Three 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. | Drug | CN-105 |
| PlaceboPatients 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. | Drug | Placebo |
Primary outcome
Number of Adverse Events (AEs) of Grade II or Higher Per Patient
Time frame: 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.
8 secondary outcomes
Change in Cerebrospinal Fluid (CSF) IL-6 Cytokine Levels Between Drug vs Placebo Treated Patients
Time frame: Baseline, 24 hours, approximately 6 weeks
Change in CSF IL-8 Cytokine Levels Between Drug vs Placebo Treated Patients
Time frame: Baseline, 24 hours, approximately 6 weeks
Change in CSF MCP-1 Cytokine Levels Between Drug vs Placebo Treated Patients
Time frame: Baseline, 24 hours, approximately 6 weeks
Change in CSF G-CSF Cytokine Levels Between Drug vs Placebo Treated Patients
Time frame: Baseline, 24 hours, approximately 6 weeks
Change in Cognitive Change Index (CCI) Between Drug vs Placebo Treated Patients
Time frame: Baseline, approximately 6 weeks
Feasibility of Drug Administration as Measured by the Percentage of Doses Given Within the Correct Time Window
Time frame: admission to preoperative holding to hospital discharge (up to postoperative day 4)
Number of Participants Who Experience Delirium
Time frame: Baseline, day of surgery (twice), post-operative days 1 - 5 (twice), 6 weeks +/- 3 weeks
Peak 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41931297Timko NJ, Cooter Wright M, Smith MR, Boykin PC, Emerson JM, Woldorff MG, Eleswarpu S, Herbert JT, Moretti EW, Devinney MJ, Ayoub CM, Rockhold FW, Ryu D, Syed A, VanDusen KW, Bunning T, Hsia BJ, Bolognesi MP, Jiranek WA, Zetterberg H, Blennow K, Huebner JL, Li Z, Reekes TH, Browndyke JN, Laskowitz DT, Berger M; MARBLE Study Investigators. Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients: The Phase 2 MARBLE Randomized Clinical Trial. JAMA Netw Open. 2026 Apr 1;9(4):e262289. doi: 10.1001/jamanetworkopen.2026.2289.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Miles Berger, MD, PhD principal investigator
Duke University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing CN-105 in people with Postoperative Delirium and Postoperative Cognitive Dysfunction, run by Miles Berger, MD PhD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Adverse Events (AEs) of Grade II or Higher Per Patient (time frame: up to 6-week follow-up). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03802396, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2024.