NicaPlant
A randomized, single ascending dose safety, tolerability and pharmacokinetics study of NicaPlant® in aneurysmal subarachnoid hemorrhage patients undergoing clipping
Year of Publication: 2023
Authors: Johannes Kerschbaumer, Christian Franz Freyschlag, Ondra Petr, ..., Claudius Thomé
Journal: Brain and Spine
Citation: Brain and Spine 3 (2023) 102673
Link: https://doi.org/10.1016/j.bas.2023.102673
PDF: https://www.researchgate.net/publication...eurysm_Clipping
PDF: Clinical Question
Is NicaPlant®, a modified-release nicardipine implant placed during aneurysm clipping, safe and tolerable for preventing vasospasm in aSAH patients?
Bottom Line
Placement of NicaPlant® implants during aneurysm clipping raised no safety concerns. The dose of 10 implants was selected for further clinical efficacy studies based on favorable CSF drug concentrations, safety profile, and usability.
Major Points
- First-in-human phase IIA randomized controlled trial of NicaPlant® implants in aSAH patients undergoing clipping
- Single ascending dose design with 4 cohorts: 3, 6, 10, or 13 implants (4 mg nicardipine each)
- Plasma nicardipine levels remained below pharmacologically active thresholds, avoiding systemic side effects
- CSF levels reached therapeutic concentrations starting with 6 implants
- Only 1 case of moderate vasospasm in NicaPlant® groups (n=10) versus 2 cases of severe vasospasm in standard care group (n=4)
- 45 non-serious and 13 serious adverse events reported; 5 serious AEs assessed as possibly related to treatment
- Independent Data Safety Monitoring Board found no safety concerns
- 10 implant dose selected for future phase IIB efficacy trial
Design
Study Type: Phase IIA randomized controlled single ascending dose trial
Randomization: 1
Blinding: Single-blind (ICU personnel and assessors blinded; surgical team unblinded after randomization)
Enrollment Period: April 25, 2018 to January 10, 2019
Follow-up Duration: 21 days
Centers: 4
Countries: Austria, Germany
Sample Size: 14
Analysis: SAS v9.4; Non-compartmental pharmacokinetic analysis; Independent neuroradiologist performed blinded angiogram and CT analysis
Inclusion Criteria
- Aneurysmal subarachnoid hemorrhage (aSAH)
- Hunt and Hess grade 1 to 4
- Undergoing aneurysm clipping
- Randomization within 48 hours of aneurysm rupture
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Number of patients | 4 | 10 |
| Female | 2 (50%) | 8 (varied by cohort) |
| Male | 2 (50%) | 6 (varied by cohort) |
| Mean age (years) | 46.3-59 | 39.7-65 |
| Smoker | 1 (25%) | 5 (50%) |
| Aneurysm location - MCA | 2 | 6 |
| Aneurysm location - ACoA | 1 | |
| Aneurysm location - ACA | 1 | |
| Fisher grade 2 | 3 | 7 |
| Fisher grade 4 | 1 | 3 |
| Hunt and Hess grade 1 | 0 | 2 |
| Hunt and Hess grade 2 | 3 | 4 |
| Hunt and Hess grade 3 | 0 | 2 |
| Hunt and Hess grade 4 | 1 | 2 |
| Aneurysm location - ACoA/ACA | 2 | |
| Aneurysm location - ICA | 1 | |
| Aneurysm location - PCoA | 1 |
Arms
| Field | Control | NicaPlant 3 implants | NicaPlant 6 implants | NicaPlant 10 implants | NicaPlant 13 implants |
|---|---|---|---|---|---|
| Intervention | Oral nimodipine per institutional protocol | 3 NicaPlant® implants (12 mg total nicardipine) placed during aneurysm clipping; matching placebo tablets instead of oral nimodipine | 6 NicaPlant® implants (24 mg total nicardipine) placed during aneurysm clipping; matching placebo tablets instead of oral nimodipine | 10 NicaPlant® implants (40 mg total nicardipine) placed during aneurysm clipping; matching placebo tablets instead of oral nimodipine | 13 NicaPlant® implants (52 mg total nicardipine) placed during aneurysm clipping; matching placebo tablets instead of oral nimodipine |
| Duration | 21 days observation | 21 days observation | 21 days observation | 21 days observation | 21 days observation |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Safety and tolerability assessed by adverse events, serious adverse events, vital signs, ECG, laboratory parameters, and clinical assessments through day 21 | Primary | 2 cases of severe vasospasm; 13 total SAEs in all patients | 1 case of moderate vasospasm (13 implant cohort); 4 non-serious AEs possibly related (2 patients); 5 serious AEs possibly related (2 patients) | ||
| Incidence of moderate or severe angiographic vasospasm (≥33% diameter reduction on DSA day 8±1) | Secondary | 2/4 patients (50%) - both severe | 1/10 patients (10%) - moderate | ||
| Plasma nicardipine Cmax (ng/ml) | Secondary | Not applicable | 3 implants: 0.849, 0.383; 6 implants: 1.38, 1.19; 10 implants: 1.39, 2.41, 1.91; 13 implants: 0.867, 2.67, 3.56 | ||
| CSF nicardipine concentration | Secondary | Not measured | Therapeutic levels reached starting with 6 implants (measured in 6 patients with EVD) | ||
| New cerebral infarcts on CT day 14 | Secondary | Not explicitly quantified | Not explicitly quantified | ||
| Delayed ischemic neurologic deficit (DIND) | Secondary | Not explicitly quantified | No deaths due to vasospasm or DIND | ||
| Non-serious adverse events total | Adverse | Included in 45 total | 45 total; 4 possibly related to treatment (2 patients: bradycardia, fever) | ||
| Serious adverse events total | Adverse | Included in 13 total | 13 total; 5 possibly/probably related in 2 patients | ||
| CSF culture positive | Adverse | 0 | 1 | ||
| Cerebral hematoma | Adverse | 0 | 2 | ||
| Cerebral vasoconstriction | Adverse | 2 | 2 | ||
| ICP increased | Adverse | 0 | 1 (probably related) | ||
| Partial seizures | Adverse | 0 | 1 | ||
| Respiratory distress | Adverse | 0 | 2 | ||
| Cerebral artery occlusion | Adverse | 0 | 2 (1 probably related - M2 branch re-occlusion) |
Subgroup Analysis
Dose-escalation analysis across 4 cohorts (3, 6, 10, 13 implants). CSF pharmacokinetics analyzed in 6 patients with EVD. 10 implant dose demonstrated optimal balance of therapeutic CSF levels, safety, and surgical feasibility.
Criticisms
- Small sample size (14 patients total) limits statistical power for efficacy conclusions
- Not powered to detect differences in vasospasm rates or clinical outcomes
- Unbalanced randomization (10 treatment vs 4 control patients)
- Single-blind design (surgical team aware of treatment allocation)
- No placebo implants in control group for ethical reasons
- Short 21-day follow-up period
- One patient with 13 implants had low CSF nicardipine levels possibly due to hematoma evacuation surgery
- Heterogeneous patient population (Hunt and Hess grades 1-4)
- Multiple dose cohorts with very small numbers per cohort (2-3 patients)
- Causality of some serious adverse events to treatment uncertain
Funding
Partially supported by Austrian research promotion agency project 860144. BIT Pharma GmbH (manufacturer) involvement in trial conduct.
Based on: NicaPlant (Brain and Spine, 2023)
Authors: Johannes Kerschbaumer, Christian Franz Freyschlag, Ondra Petr, ..., Claudius Thomé
Citation: Brain and Spine 3 (2023) 102673
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