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

NCT ID: NCT03711903

Last Updated: 2022-12-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-24
• Study Completion Date: 2022-06-16

Brief 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.

Detailed 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)

Conditions

Intracerebral Hemorrhage

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: QUADRUPLE

Study Groups

Treatment arm

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.

Group Type: EXPERIMENTAL

Acetyl-Valine-Serine-Arginine-Arginine-Arginine-NH2 (Ac-VSRRR- NH2).

Intervention Type: DRUG

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.

Placebo arm

The Placebo arm will be given 0.9% NaCL

Group Type: PLACEBO_COMPARATOR

0.9% Sodium-chloride

Intervention Type: DRUG

normal saline

Interventions

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.

Intervention Type: DRUG

0.9% Sodium-chloride

normal saline

Intervention Type: DRUG

Other Intervention Names

CN105

Eligibility Criteria

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.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AegisCN LLC

INDUSTRY

Sponsor Role: collaborator

Singapore Clinical Research Institute

OTHER

Sponsor Role: collaborator

National Neuroscience Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

National Neuroscience Institute

Singapore, , Singapore

Countries

Singapore

References

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.

Reference Type: BACKGROUND

PMID: 23391772 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11782990 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15698624 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17033693 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16498192 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12559098 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12411654 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12223372 (View on PubMed)

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 in Healthy Adult Subjects. J Clin Pharmacol. 2017 Jun;57(6):770-776. doi: 10.1002/jcph.853. Epub 2016 Dec 19.

Reference Type: RESULT

PMID: 27990643 (View on PubMed)

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.

Reference Type: RESULT

PMID: 9184634 (View on PubMed)

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;6:34834. doi: 10.1038/srep34834.

Reference Type: RESULT

PMID: 27713572 (View on PubMed)

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.

Reference Type: RESULT

PMID: 11590206 (View on PubMed)

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 murine model. Sci Rep. 2017 Apr 21;7:46461. doi: 10.1038/srep46461.

Reference Type: RESULT

PMID: 28429734 (View on PubMed)

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.

Reference Type: RESULT

PMID: 11161595 (View on PubMed)

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.

Reference Type: RESULT

PMID: 16179504 (View on PubMed)

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.

Reference Type: RESULT

PMID: 14671250 (View on PubMed)

Other Identifiers

S-CATCH

Identifier Type: -

Identifier Source: org_study_id