A Safety and Efficacy Study of NicaPlant® in Aneurysmal Subarachnoid Haemorrhage Patients Undergoing Aneurysm Clipping

A Phase IIb: Randomised, Single-Blind, Safety, Tolerability, Efficacy and Pharmacokinetic Study of NicaPlant® in Aneurysmal Subarachnoid Haemorrhage Patients Undergoing Aneurysm Clipping

This study of NicaPlant® is conducted in patients who have a subarachnoid haemorrhage. Patients will be randomized in two treatment groups. Both groups will receive the standard of care and the investigational group will receive in addition NicaPlant®. NicaPlant® is tested to reduce the long-term complications of aneurysmal subarachnoid haemorrhage (aSAH).

Study Overview

• Status: Completed
• Conditions: Aneurysmal Subarachnoid Hemorrhage
• Intervention / Treatment: Drug: Nicardipine; Other: Standard of care

Detailed Description

This is a safety, tolerability, efficacy and pharmacokinetic study of NicaPlant® in subarachnoid haemorrhage patients involving two treatment groups. Both treatment groups will receive standard of care and patients randomised to the investigational group will receive in addition NicaPlant® .

NicaPlant® is a nicardipine modified-release formulation. It is presented in the form of a rod-shaped implant with a 4 mg nicardipine load. Following aneurysm clip ligation, 10 NicaPlant® implants will be placed into the basal cisterns in direct contact with the exposed cerebral blood vessel walls.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Universitätsklinik Innsbruck, Universitätsklinik für Neurochirurgie
  • Linz, Austria, 4020
    • Kepler Universitätsklinikum, Universitätsklinik für Neurochirurgie
  • Vienna, Austria, 1090
    • Medizinische Universität Wien, Universitätsklinik für Neurochirurgie
• Germany
  • Berlin, Germany, 10117
    • Charité Universitätsmedizin Berlin, Klinik für Neurochirurgie mit Arbeitsbereich pädiatrische Neurochirurgie
  • Göttingen, Germany, 37075
    • Universitätsklinikum Göttingen, Neurochirurgische Klinik
  • Munich, Germany, 81675
    • Klinikum Rechts der Isar, Neurochirurgische Klinik und Poliklinik

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Informed consent obtained according to the Country regulation.
• Male or female patients aged 18 to 75 years (inclusive).
• World Federation of Neurological Surgeons (WFNS) grade III-IV.
• Ruptured saccular aneurysm, confirmed by angiography.
• Onset of aSAH clinical symptoms within the preceding 48 hours.
• Treatment of aneurysm via surgical clip ligation within 72 hours of aSAH is achievable.
• Female patients of child-bearing potential must have a negative pregnancy test (urine or serum) at screening and must agree to use adequate birth control up to 12 weeks after implantation of the study drug. Female patients are considered to be not of child-bearing potential if they have a history of tubal ligation or hysterectomy or are post-menopausal with a minimum of 2 years without a natural menstrual cycle. Male patients must agree to use adequate birth control up to 12 weeks after implantation of the study drug.

Exclusion Criteria:

• SAH due to other causes (e.g. trauma, fusiform or mycotic aneurysm).
• World Federation of Neurosurgery (WFNS) grade I, II and V patients.
• Pregnant or Lactating Women.
• Intraventricular or intracerebral blood, in the absence of subarachnoid blood.
• Treatment of aneurysm via endovascular embolisation.
• Presence of moderate or severe vasospasm on screening angiography.
• Any known or CT /MRI evidence of previous major cerebral damage
• Evidence of a cerebral infarction with neurological deficit on pre-treatment CT/MRI.
• History of malignant disease (except for non-melanoma skin cancer) within the previous 5 years or any history of malignant brain tumours or brain metastasis.
• Patients who have received an investigational product or participated in another interventional clinical study within 30 days prior to randomisation.
• Patients with known allergy for Poly(D,L-lactide-co-glycolide) (PLGA) or nicardipine.
• Major complication during aneurysm repair such as, but not limited to, massive intraoperative haemorrhage, brain swelling, or inability to secure the ruptured aneurysm.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NicaPlant®; 10 NicaPlant® implants (total 40 mg nicardipine) will be placed after clip ligation into the basal cisterns in direct contact with the exposed cerebral blood vessel walls. In addition patients will receive standard of care for aneurysmal subarachnoid haemorrhage patients according to the treatment guidelines.	Drug: Nicardipine; 10 NicaPlant® implants releasing 4 mg nicardipine each.; Other Names: NicaPlant®; Other: Standard of care; Both arms receive the usual standard of care.
Other: Control; Standard of care for aneurysmal subarachnoid haemorrhage patients according to the treatment guidelines.	Other: Standard of care; Both arms receive the usual standard of care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of moderate to severe cerebral angiographic vasospasm assessed by digital subtraction angiography	Fishers Exact test	day 8 ± 1 after aneurysm rupture
Safety by adverse event recording	Descriptive summary	trough study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of new cerebral infarcts on computer tomography (CT) of the brain versus post-intervention CT scan	Fishers exact test	up to day 14 ± 1 after aneurysm rupture

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of vasospasm-related morbidity/mortality	Fishers exact test	within 21 days post aneurysm rupture
Pharmacokinetic profile of NicaPlant® in plasma	AUC for multiple plasma samples	within 21 days post aneurysm rupture or within hospitalisation if shorter
Nicardipine levels in cerebrospinal fluid (CSF) (only in patients provided with an external ventricular drain (EVD) at time of CSF removal for medical reasons)	Average concentration (Cav) for single CSF samples if sufficient CSF data is obtained.	within 21 days post aneurysm rupture or within hospitalisation if shorter
Length of hospital stay	ANOVA	week 52 ± 2 after aneurysm rupture
Modified Rankin Scale	Cochran-Mantel-Haenzel (CMH) test (with modified ridits) minimum value: 0, maximum value: 6, higher scores mean a worse outcome	week 12 ± 1 after aneurysm rupture
Modified Rankin Scale	Cochran-Mantel-Haenzel (CMH) test (with modified ridits) minimum value: 0, maximum value: 6, higher scores mean a worse outcome	week 52 ± 2 after aneurysm rupture
Glasgow Outcome Scale Extended	Cochran-Mantel-Haenzel (CMH) test (with modified ridits) minimum value: 1, maximum value: 8, higher scores mean a better outcome	week 12 ± 1 after aneurysm rupture
Glasgow Outcome Scale Extended	Cochran-Mantel-Haenzel (CMH) test (with modified ridits) minimum value: 1, maximum value: 8, higher scores mean a better outcome	week 52 ± 2 after aneurysm rupture
Montreal Cognitive Assessment	ANOVA minimum value: 0, maximum value: 30, higher scores mean a better outcome	week 12 ± 1 after aneurysm rupture
Montreal Cognitive Assessment	ANOVA minimum value: 0, maximum value: 30, higher scores mean a better outcome	week 52 ± 2 after aneurysm rupture
EQ-5D-5L	ANOVA	week 12 ± 1 after aneurysm rupture
EQ-5D-5L	ANOVA	week 52 ± 2 after aneurysm rupture
SF36	ANOVA	week 12 ± 1 after aneurysm rupture
SF36	ANOVA	week 52 ± 2 after aneurysm rupture

Collaborators and Investigators

• Sponsor: BIT Pharma GmbH
• Collaborators: NeuroScios GmbH; Data Magik Limited; Pharm-Analyt Labor GmbH
• Investigators: Principal Investigator: Claudius Thomé, Prof.Dr., Universitätsklinik Innsbruck, Universitätsklinik für Neurochirurgie

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2020
• Primary Completion (Actual): May 12, 2022
• Study Completion (Actual): January 23, 2023

Study Registration Dates

• First Submitted: January 23, 2020
• First Submitted That Met QC Criteria: February 11, 2020
• First Posted (Actual): February 13, 2020

Study Record Updates

• Last Update Posted (Actual): July 12, 2023
• Last Update Submitted That Met QC Criteria: July 11, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Nicardipine; NicaPlant
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Aneurysm; Subarachnoid Hemorrhage; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Nicardipine
• Other Study ID Numbers: BIT-002; 2017-005159-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No