Evaluation of CN-105 in Subject With Acute Supratentorial Intracerebral Hemorrhage

Study Overview
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Brief Summary
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Phase 2, randomized, double-blind, placebo controlled study to evaluate the administration of CN-105 in patients with supratentorial intracerebral hemorrhage (ICH). Patients will be evaluated for eligibility within 12 hours of symptom onset. Eligible participants (30 active participants and 30 control participants) will receive CN-105 or placebo administered intravenously (IV) for a 30-minute infusion every 6 hours for up to a maximum of 3 days (13 doses) or until discharge (if earlier than 3 days). Participants will be monitored daily throughout the Treatment phase of the study (up to a maximum of 5 days) and will receive standard-of-care treatment for the duration of the study. Additional protocol assessments will be required during the Treatment phase as outlined in Section 7.5. After discharge from the hospital, participants will enter a 3-month Follow-up phase, with a clinic visit at 30 days and a follow-up telephone interview with telephone-validated mRS at 90 days after first dose of study agent.

Detailed Description
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Phase 2, randomized, double-blind, placebo controlled study to evaluate the administration of CN-105 in patients with supratentorial intracerebral hemorrhage (ICH). Patients will be evaluated for eligibility within 12 hours of symptom onset. Eligible participants (30 active participants and 30 control participants) will receive CN-105 or placebo administered intravenously (IV) for a 30-minute infusion every 6 hours for up to a maximum of 3 days (13 doses) or until discharge (if earlier than 3 days). Participants will be monitored daily throughout the Treatment phase of the study (up to a maximum of 5 days) and will receive standard-of-care treatment for the duration of the study. Additional protocol assessments will be required during the Treatment phase as outlined in Section 7.5. After discharge from the hospital, participants will enter a 3-month Follow-up phase, with a clinic visit at 30 days and a follow-up telephone interview with telephone-validated mRS at 90 days after first dose of study agent. The study is not powered to test any specific hypothesis in regard to safety and will instead use descriptive methods to describe the experience of the study cohort with respect to adverse and serious adverse events (SAEs), as well as the occurrence of several pre-specified events of interest. The secondary objective of this study will be met by comparing the modified Rankin score (mRS) at 30 days between participants treated with CN-105 with placebo controlled participants The mRS at 30 days will be compared between treated and control participants using the Wilcoxon rank sum test. Exploratory analyses include comparison of treated and control participants for radiographic cerebral edema and hematoma volume and expansion and biological markers of inflammation. Primary: To assess safety of CN-105 administration in primary ICH. Secondary: To evaluate whether the administration of CN-105 improves 30-day mortality and functional outcomes by comparing participants treated with CN-105 with placebo controlled participants. Exploratory: To investigate feasibility of Day 0, 1, 2, and 5 non-contrast head computed tomography (CT) as a radiographic surrogate to evaluate progression of perihematomal edema To investigate feasibility of using serial biochemical markers of neuroinflammation and neuronal injury as a surrogate measure of perihematomal edema and clinical outcome in the setting of spontaneous ICH.Primary: Number and severity of AEs throughout the duration of the study Number and severity of SAEs throughout the duration of the study In-hospital, 30-day, and 90-day mortality Treatment-related mortality In-hospital neurological deterioration, defined as an increase of National Institutes of Health Stroke Scale (NIHSS), > 2 from baseline and/or decrease of > 2 of Glasgow Coma Scale (GCS), persisting more than 24 hours, and unrelated to sedation Incidence of cerebritis, meningitis, ventriculitis Incidence of systemic infection Incidence of hematoma extension Secondary:. 30- and 90-day mRS Need for intracranial hypertension management NIHSS score, Glasgow Coma Scale, Montreal Cognitive Assessment, Stroke Impact Scale-16, and Barthel Index assessment at hospital discharge and 30 days after ICH Discharge disposition Exploratory: Day 0, 1, 2, 5 non-contrast head CT as a radiographic surrogate to evaluate progression of perihematomal edema Biochemical surrogates of brain injury, including plasma concentrations of S100B, glial fibrillary acidic protein, metalloproteinase-3 and -9, C-reactive protein, D-dimer, brain natriuretic peptide, interleukin-6, tumor necrosis factor-α, and vascular endothelial growth factor, assessed daily for 5 days after ICH or until discharge (concentration time area under the curve assessed for each biomarker)

Official Title
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A Phase 2, Randomized, Double Blind, Placebo , Controlled Study To Evaluate The Administration of CN-105 In Participants With Acute Supratentorial Intracerebral Hemorrhage

Conditions
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Intracerebral Hemorrhage

Intervention / Treatment
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* Drug: Acetyl-Valine-Serine-Arginine-Arginine-Arginine-NH2 (Ac-VSRRR- NH2).
* Drug: 0.9% Sodium-chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has given written informed consent to participate in the study in accordance with required regulations; if a participant is not capable of providing informed consent, written consent must be obtained from the participant's legally authorized representative (LAR). Stated willingness to comply with all study procedures and availability for the duration of the study. Is male or female, age 30 to 80 years, inclusive. Has a confirmed diagnosis of spontaneous supratentorial ICH. Able to receive first dose of study drug ≤ 12 hours after onset of ICH symptoms, such as alteration in level of consciousness, severe headache, nausea, vomiting, seizure, and/or focal neurological deficits, or last-known well time. Has an interpretable and measurable diagnostic CT scan. Has a GCS score ≥ 5 on presentation Has a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 Has systolic BP (SBP) < 200 mm Hg at enrollment. Exclusion Criteria: 1Known pregnancy and lactation 2.Has a temperature greater than 38.5°C at Screening. 3.ICH known to result from trauma. 4.Evidence of infratentorial hemorrhage (any involvement of the midbrain or lower brainstem as demonstrated by radiograph or complete third nerve palsy) severely limiting the recovery potential of the patient in the opinion of the investigator. 5.Evidence of primary intraventricular hemorrhage deemed to be at high risk for obstructive hydrocephalus, in the opinion of the investigator or evidence of extra-axial (i.e., subarachnoid or subdural) extension of hemorrhage severely limiting the recovery potential of the patient in the opinion of the investigator. 6.Radiographic evidence of underlying tumor. 7.Known unstable mass or active radiographic evidence and symptoms of herniation syndromes severely limiting the recovery potential of the patient in the opinion of the investigator. 8.Known ruptured aneurysm, arteriovenous malformation, or vascular anomaly. 9.Has a platelet count < 100,000/mL. 10.Has an international normalized ratio (INR) > 1.5 or irreversible coagulopathy either due to medical condition or detected before screening. 11.Is taking new oral anticoagulants (NOACS) or low molecular weight heparin at the time of ICH onset 12.In the opinion of the investigator is unstable and would benefit from supportive care rather than supportive care plus CN-105. 13. In the opinion of the investigator has any contraindication to the planned study assessments, including CT and MRI. 14.Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the study or which, in the opinion of the investigator, unacceptably increases the individual's risk by participating in the study. 15.Concomitant enrollment in another interventional study.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The treatment arm will be given CN 105 The placebo arm will be give 0/9% NaCl
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>The study drug, CN-105, will be administered at 1.0 mg/kg every 6 +/- 1 hour. The calculated volumes of study agent will be removed from the vials and transferred to 250 mL of normal saline (0.9% sodium chloride injection, USP). The recorded weight at baseline will be used to determine the appropriate amount of CN-105 drug product to administer. Estimated weight may be used if recorded weight is not available. Each dose of CN-105 or placebo will be administered as a slow IV bolus over 30 minutes. | Drug: Acetyl-Valine-Serine-Arginine-Arginine-Arginine-NH2 (Ac-VSRRR- NH2).<br>* The study drug, CN-105 is supplied in amber glass vials containing 4 mL of a concentrated 12.5-mg/mL clear-to-slightly-yellow solution.<br>* Other names: CN105;|
| Placebo Comparator: Placebo arm<br>The Placebo arm will be given 0.9% NaCL | Drug: 0.9% Sodium-chloride<br>* normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| adverse event | any untoward medical occurrence associated with the use of the drug in a participant | 0-12 hours | 
| adverse event | untoward medical occurrence associated with the use of the study drug whether considered related or not | 24 hour | 
| adverse event | untoward medical occurrence associated with the use of the study drug whether considered related or not | 48 hour | 
| adverse event | untoward medical occurrence associated with the use of the study drug whether considered related or not | 72 hour | 
| adverse event | untoward medical occurrence associated wtth the use of study drug whether considered related or not | 96 hour | 
| adverse event | untoward medical occurrence associated wtth the use of study drug whether considered related or not | 120 hour | 
| adverse event | untoward medical occurrence associated with the use of study drug whether considered related or not | 30 day | 
| adverse event | untoward medical occurrence associated with the use of study drug whether considered related or not | 90 day | 
| GCS | score as per scale | 0-12 hour | 
| GCS | scored as per scale | 24H | 
| GCS | scored as per scale | 48 hours | 
| GCS | scored as per scale | 72 Hour | 
| GCS | scored as per scale | 96 hour | 
| GCS | scored as per scale | at 120 hour | 
| GCS | scored as per scale | at 30 day | 
| NIHSS | scored as per assessment | 0- 12 hour | 
| NIHSS | scored as per assessment | 120 hour | 
| NIHSS | scored as per assessment | 24 hour | 
| NIHSS | scored as per assessment | 48 hour | 
| NIHSS | scored as per assessment | 72 hour | 
| NIHSS | scored as per assessment | 96 Hour | 
| NIHSS score | score as per assessment | 30 day | 
| Serious adverse event | An AE is considered serious if the investigator believes any of the following outcomes may occur: death, life threatening AE which places participants at immediate risk of death at the time of the event as it occurred, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; Congenital abnormality or birth defect ;Requires inpatient hospitalization or prolongation of existing hospitalization with the exception or preplanned (before the study) hospital admissions, planned admissions, hospitalization of less then 24 hours (after discharge from index hospitalization. | 48 hour | 
| Serious adverse event | An AE is considered serious if the investigator believes any of the following outcomes may occur: death, life threatening AE which places participants at immediate risk of death at the time of the event as it occurred, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; Congenital abnormality or birth defect ;Requires inpatient hospitalization or prolongation of existing hospitalization with the exception or preplanned (before the study) hospital admissions, planned admissions, hospitalization of less then 24 hours (after discharge from index hospitalization. | 0-12 hour | 
| Serious adverse event | An AE is considered serious if the investigator believes any of the following outcomes may occur: death, life threatening AE which places participants at immediate risk of death at the time of the event as it occurred, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; Congenital abnormality or birth defect ;Requires inpatient hospitalization or prolongation of existing hospitalization with the exception or preplanned (before the study) hospital admissions, planned admissions, hospitalization of less then 24 hours (after discharge from index hospitalization. | 72 hour | 
| Serious adverse event | An AE is considered serious if the investigator believes any of the following outcomes may occur: death, life threatening AE which places participants at immediate risk of death at the time of the event as it occurred, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; Congenital abnormality or birth defect ;Requires inpatient hospitalization or prolongation of existing hospitalization with the exception or preplanned (before the study) hospital admissions, planned admissions, hospitalization of less then 24 hours (after discharge from index hospitalization. | 96 hour | 
| Serious adverse event | An AE is considered serious if the investigator believes any of the following outcomes may occur: death, life threatening AE which places participants at immediate risk of death at the time of the event as it occurred, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; Congenital abnormality or birth defect ;Requires inpatient hospitalization or prolongation of existing hospitalization with the exception or preplanned (before the study) hospital admissions, planned admissions, hospitalization of less then 24 hours (after discharge from index hospitalization. | at 90 day | 
| Serious adverse event | An AE is considered serious if the investigator believes any of the following outcomes may occur: death, life threatening AE which places participants at immediate risk of death at the time of the event as it occurred, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; Congenital abnormality or birth defect ;Requires inpatient hospitalization or prolongation of existing hospitalization with the exception or preplanned (before the study) hospital admissions, planned admissions, hospitalization of less then 24 hours (after discharge from index hospitalization. | at 120 hour | 
| Serious adverse event | An AE is considered serious if the investigator believes any of the following outcomes may occur: death, life threatening AE which places participants at immediate risk of death at the time of the event as it occurred, persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; Congenital abnormality or birth defect ;Requires inpatient hospitalization or prolongation of existing hospitalization with the exception or preplanned (before the study) hospital admissions, planned admissions, hospitalization of less then 24 hours (after discharge from index hospitalization. | at 30 day | 
| systemic infection | presence of any infection supported by clinical diagnosis, or any laboratory work up. | 0-12 hour | 
| systemic infection | presence of any infection supported by clinical diagnosis, or any laboratory work up. | 24 hour | 
| systemic infection | presence of any infection supported by clinical diagnosis, or any laboratory work up. | 48 hour | 
| systemic infection | presence of any infection supported by clinical diagnosis, or any laboratory work up. | 72 hour | 
| systemic infection | presence of any infection supported by clinical diagnosis, or any laboratory work up. | 96 hours | 
| systemic infection | presence of any infection supported by clinical diagnosis, or any laboratory work up. | 120 hours | 
| systemic infection | presence of any infection supported by clinical diagnosis, or any laboratory work up. | 30 day | 
| systemic infection | presence of any infection supported by clinical diagnosis, or any laboratory work up. | 90 day | 
| Brain CT scan | evaluate hematoma expansion | 0-12 hour | 
| Brain CT scan | evaluate hematoma expansion | 24 Hour | 
| presence of CNS infection | meningitis, cerebritis, ventriculitis | 24 hour | 
| presence of CNS infection | meningitis, cerebritis, ventriculitis | 72 hours | 
| presence of CNS infection | meningitis, cerebritis, ventriculitis | 0-12 hour | 
| presence of CNS infection | meningitis, cerebritis, ventriculitis | 48 hours | 
| presence of CNS infection | meningitis, cerebritis, ventriculitis | 120 hour | 
| presence of CNS infection | meningitis, cerebritis, ventriculitis | 96 hour | 
| presence of CNS infection | meningitis, cerebritis, ventriculitis | 30 day | 
| presence of CNS infection | meningitis, cerebritis, ventriculitis | 90 day | 
| Mortality | death related or unrelated to the study drug | 0-12 hour | 
| Mortality | death related or unrelated to the study drug | 48 hour | 
| Mortality | death related or unrelated to the study drug | 72 hour | 
| Mortality | death related or unrelated to the study drug | 24 hour | 
| Mortality | death related or unrelated to the study drug | 96 hour | 
| Mortality | death related or unrelated to the study drug | 120 hour | 
| Mortality | occurrence of death related or not related to the use of the study drug | 30- day | 
| Mortality | occurrence of death related or not related to the use of the study drug | 90 -day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| outcome as assessed by mRS | MRS scoring | 120 hour | 
| functional outcome as assessed by mRS | MRS scoring | 30 Day | 
| outcome as assessed by mRS | MRS scoring | 90Day | 
| cognitive assessment | Montreal cognitive assessment | 120 Hour | 
| Discharge disposition | The place where the patient was discharge -either home, nursing home or rehabilitation care facilities | day 90 | 
| cognitive assessment | Montreal cognitive assessment | 30 day | 
| Barthel index | score as per assessment | 120 hour | 
| Barthel index | score as per assessment | 30 day | 
| Barthel index | score as per assessment | 90 day |