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

Intracerebral Hemorrhage Clinical Trial

— S-CATCH  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03711903
• Other study ID #: S-CATCH
• Status: Completed
• Phase: Phase 2
• Start date: March 24, 2019
• Est. completion date: June 16, 2022

Study information

• Verified date: November 2022
• Source: National Neuroscience Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: June 16, 2022
• Est. primary completion date: June 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 80 Years

Eligibility

Inclusion Criteria:

1. 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).

2. Stated willingness to comply with all study procedures and availability for the duration of the study.

3. Is male or female, age 30 to 80 years, inclusive.

4. Has a confirmed diagnosis of spontaneous supratentorial ICH.

5. 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.

6. Has an interpretable and measurable diagnostic CT scan.

7. Has a GCS score = 5 on presentation

8. Has a National Institutes of Health Stroke Scale (NIHSS) score = 4

9. 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.

Related Conditions & MeSH terms

• Cerebral Hemorrhage
• Hemorrhage
• Intracerebral Hemorrhage

Intervention

Drug:
• Acetyl-Valine-Serine-Arginine-Arginine-Arginine-NH2 (Ac-VSRRR- NH2).
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.
• 0.9% Sodium-chloride
normal saline

Locations

Country	Name	City	State
Singapore	National Neuroscience Institute	Singapore

Sponsors (3)

Lead Sponsor	Collaborator
National Neuroscience Institute	AegisCN LLC, Singapore Clinical Research Institute

Country where clinical trial is conducted

Singapore, 

References & Publications (16)

Aono M, Bennett ER, Kim KS, Lynch JR, Myers J, Pearlstein RD, Warner DS, Laskowitz DT. Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures. Neuroscience. 2003;116(2):437-45. doi: 10.1016/s0306-4522(02)00709-1. — View Citation

Carhuapoma JR, Barker PB, Hanley DF, Wang P, Beauchamp NJ. Human brain hemorrhage: quantification of perihematoma edema by use of diffusion-weighted MR imaging. AJNR Am J Neuroradiol. 2002 Sep;23(8):1322-6. — View Citation

Gao J, Wang H, Sheng H, Lynch JR, Warner DS, Durham L, Vitek MP, Laskowitz DT. A novel apoE-derived therapeutic reduces vasospasm and improves outcome in a murine model of subarachnoid hemorrhage. Neurocrit Care. 2006;4(1):25-31. doi: 10.1385/NCC:4:1:025. — View Citation

Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, Spilker J, Tomsick TA, Duldner J, Broderick JP. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002 Nov;33(11):2636-41. doi: 10.1161/01.str.0000035283.34109.ea. — View Citation

Guptill JT, Raja SM, Boakye-Agyeman F, Noveck R, Ramey S, Tu TM, Laskowitz DT. Phase 1 Randomized, Double-Blind, Placebo-Controlled Study to Determine the Safety, Tolerability, and Pharmacokinetics of a Single Escalating Dose and Repeated Doses of CN-105 — View Citation

Laskowitz DT, Blessing R, Floyd J, White WD, Lynch JR. Panel of biomarkers predicts stroke. Ann N Y Acad Sci. 2005 Aug;1053:30. doi: 10.1196/annals.1344.051. No abstract available. — View Citation

Laskowitz DT, Goel S, Bennett ER, Matthew WD. Apolipoprotein E suppresses glial cell secretion of TNF alpha. J Neuroimmunol. 1997 Jun;76(1-2):70-4. doi: 10.1016/s0165-5728(97)00021-0. — View Citation

Laskowitz DT, Thekdi AD, Thekdi SD, Han SK, Myers JK, Pizzo SV, Bennett ER. Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides. Exp Neurol. 2001 Jan;167(1):74-85. doi: 10.1006/exnr.2001.7541. — View Citation

Laskowitz DT, Wang H, Chen T, Lubkin DT, Cantillana V, Tu TM, Kernagis D, Zhou G, Macy G, Kolls BJ, Dawson HN. Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury — View Citation

Lei B, James ML, Liu J, Zhou G, Venkatraman TN, Lascola CD, Acheson SK, Dubois LG, Laskowitz DT, Wang H. Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage. Sci Rep. 2016 Oct 7;6 — View Citation

Li N, Liu YF, Ma L, Worthmann H, Wang YL, Wang YJ, Gao YP, Raab P, Dengler R, Weissenborn K, Zhao XQ. Association of molecular markers with perihematomal edema and clinical outcome in intracerebral hemorrhage. Stroke. 2013 Mar;44(3):658-63. doi: 10.1161/STROKEAHA.112.673590. Epub 2013 Feb 6. — View Citation

Lynch JR, Blessing R, White WD, Grocott HP, Newman MF, Laskowitz DT. Novel diagnostic test for acute stroke. Stroke. 2004 Jan;35(1):57-63. doi: 10.1161/01.STR.0000105927.62344.4C. Epub 2003 Dec 11. — View Citation

Lynch JR, Pineda JA, Morgan D, Zhang L, Warner DS, Benveniste H, Laskowitz DT. Apolipoprotein E affects the central nervous system response to injury and the development of cerebral edema. Ann Neurol. 2002 Jan;51(1):113-7. doi: 10.1002/ana.10098. — View Citation

Lynch JR, Wang H, Mace B, Leinenweber S, Warner DS, Bennett ER, Vitek MP, McKenna S, Laskowitz DT. A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury. Exp Neurol. 2005 Mar;192(1):109-16. doi: 10.1016/j.expneurol.2004.11.014. — View Citation

Misra UK, Adlakha CL, Gawdi G, McMillian MK, Pizzo SV, Laskowitz DT. Apolipoprotein E and mimetic peptide initiate a calcium-dependent signaling response in macrophages. J Leukoc Biol. 2001 Oct;70(4):677-83. — View Citation

Wang J, Dore S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007 May;27(5):894-908. doi: 10.1038/sj.jcbfm.9600403. Epub 2006 Oct 11. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	biomarkers of brain injury	plasma concentrations of s100 B, glial fibrillary acidic protein, metalloproteinase -3 and 9, C-reactive protein, D-dimer, brain natriuretic peptide, interleukin -6, tumor necrosis factor, and vascular epithelial growth factor	0-12 hour
Other	biomarkers of brain injury	plasma concentrations of s100 B, glial fibrillary acidic protein, metalloproteinase -3 and 9, C-reactive protein, D-dimer, brain natriuretic peptide, interleukin -6, tumor necrosis factor, and vascular epithelial growth factor	24 hour
Other	biomarkers of brain injury	plasma concentrations of s100 B, glial fibrillary acidic protein, metalloproteinase -3 and 9, C-reactive protein, D-dimer, brain natriuretic peptide, interleukin -6, tumor necrosis factor, and vascular epithelial growth factor	48 hour
Other	biomarkers of brain injury	plasma concentrations of s100 B, glial fibrillary acidic protein, metalloproteinase -3 and 9, C-reactive protein, D-dimer, brain natriuretic peptide, interleukin -6, tumor necrosis factor, and vascular epithelial growth factor	72 hour
Other	biomarkers of brain injury	plasma concentrations of s100 B, glial fibrillary acidic protein, metalloproteinase -3 and 9, C-reactive protein, D-dimer, brain natriuretic peptide, interleukin -6, tumor necrosis factor, and vascular epithelial growth factor	96 hour
Other	biomarkers of brain injury	plasma concentrations of s100 B, glial fibrillary acidic protein, metalloproteinase -3 and 9, C-reactive protein, D-dimer, brain natriuretic peptide, interleukin -6, tumor necrosis factor, and vascular epithelial growth factor	120 hour
Primary	adverse event	any untoward medical occurrence associated with the use of the drug in a participant	0-12 hours
Primary	adverse event	untoward medical occurrence associated with the use of the study drug whether considered related or not	24 hour
Primary	adverse event	untoward medical occurrence associated with the use of the study drug whether considered related or not	48 hour
Primary	adverse event	untoward medical occurrence associated with the use of the study drug whether considered related or not	72 hour
Primary	adverse event	untoward medical occurrence associated wtth the use of study drug whether considered related or not	96 hour
Primary	adverse event	untoward medical occurrence associated wtth the use of study drug whether considered related or not	120 hour
Primary	adverse event	untoward medical occurrence associated with the use of study drug whether considered related or not	30 day
Primary	adverse event	untoward medical occurrence associated with the use of study drug whether considered related or not	90 day
Primary	GCS	score as per scale	0-12 hour
Primary	GCS	scored as per scale	24H
Primary	GCS	scored as per scale	48 hours
Primary	GCS	scored as per scale	72 Hour
Primary	GCS	scored as per scale	96 hour
Primary	GCS	scored as per scale	at 120 hour
Primary	GCS	scored as per scale	at 30 day
Primary	NIHSS	scored as per assessment	0- 12 hour
Primary	NIHSS	scored as per assessment	120 hour
Primary	NIHSS	scored as per assessment	24 hour
Primary	NIHSS	scored as per assessment	48 hour
Primary	NIHSS	scored as per assessment	72 hour
Primary	NIHSS	scored as per assessment	96 Hour
Primary	NIHSS score	score as per assessment	30 day
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	systemic infection	presence of any infection supported by clinical diagnosis, or any laboratory work up.	0-12 hour
Primary	systemic infection	presence of any infection supported by clinical diagnosis, or any laboratory work up.	24 hour
Primary	systemic infection	presence of any infection supported by clinical diagnosis, or any laboratory work up.	48 hour
Primary	systemic infection	presence of any infection supported by clinical diagnosis, or any laboratory work up.	72 hour
Primary	systemic infection	presence of any infection supported by clinical diagnosis, or any laboratory work up.	96 hours
Primary	systemic infection	presence of any infection supported by clinical diagnosis, or any laboratory work up.	120 hours
Primary	systemic infection	presence of any infection supported by clinical diagnosis, or any laboratory work up.	30 day
Primary	systemic infection	presence of any infection supported by clinical diagnosis, or any laboratory work up.	90 day
Primary	Brain CT scan	evaluate hematoma expansion	0-12 hour
Primary	Brain CT scan	evaluate hematoma expansion	24 Hour
Primary	presence of CNS infection	meningitis, cerebritis, ventriculitis	24 hour
Primary	presence of CNS infection	meningitis, cerebritis, ventriculitis	72 hours
Primary	presence of CNS infection	meningitis, cerebritis, ventriculitis	0-12 hour
Primary	presence of CNS infection	meningitis, cerebritis, ventriculitis	48 hours
Primary	presence of CNS infection	meningitis, cerebritis, ventriculitis	120 hour
Primary	presence of CNS infection	meningitis, cerebritis, ventriculitis	96 hour
Primary	presence of CNS infection	meningitis, cerebritis, ventriculitis	30 day
Primary	presence of CNS infection	meningitis, cerebritis, ventriculitis	90 day
Primary	Mortality	death related or unrelated to the study drug	0-12 hour
Primary	Mortality	death related or unrelated to the study drug	48 hour
Primary	Mortality	death related or unrelated to the study drug	72 hour
Primary	Mortality	death related or unrelated to the study drug	24 hour
Primary	Mortality	death related or unrelated to the study drug	96 hour
Primary	Mortality	death related or unrelated to the study drug	120 hour
Primary	Mortality	occurrence of death related or not related to the use of the study drug	30- day
Primary	Mortality	occurrence of death related or not related to the use of the study drug	90 -day
Secondary	outcome as assessed by mRS	MRS scoring	120 hour
Secondary	functional outcome as assessed by mRS	MRS scoring	30 Day
Secondary	outcome as assessed by mRS	MRS scoring	90Day
Secondary	cognitive assessment	Montreal cognitive assessment	120 Hour
Secondary	Discharge disposition	The place where the patient was discharge -either home, nursing home or rehabilitation care facilities	day 90
Secondary	cognitive assessment	Montreal cognitive assessment	30 day
Secondary	Barthel index	score as per assessment	120 hour
Secondary	Barthel index	score as per assessment	30 day
Secondary	Barthel index	score as per assessment	90 day