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NicaPlant

A randomized, single ascending dose safety, tolerability and pharmacokinetics study of NicaPlant® in aneurysmal subarachnoid hemorrhage patients undergoing clipping

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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

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 further clinical studies to investigate efficacy (EudraCT 2017-005159-10)

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 (first enrollment) to January 10, 2019 (last day-21 observation)

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 (clip ligation within 72 hours of aSAH per Table 1)

Baseline Characteristics

CharacteristicControlActive
Number of patients410
Female2 (50%)2 (20%)
Male2 (50%)8 (80%)
Mean age (years)mean 46.3 (range 30–59)cohort means 39.7–65 (patient range 29–67)
Smoker1 (25%)5 (50%)
Aneurysm location - MCA17
Aneurysm location - ACoA11
Aneurysm location - ACA1
Aneurysm location - ICA11
Fisher grade 236
Fisher grade 414
Hunt and Hess grade 103
Hunt and Hess grade 232
Hunt and Hess grade 303
Hunt and Hess grade 412
Aneurysm location - PCoA1

Arms

FieldControlNicaPlant 3 implantsNicaPlant 6 implantsNicaPlant 10 implantsNicaPlant 13 implants
InterventionOral nimodipine per institutional protocol3 NicaPlant® implants (12 mg total nicardipine) placed during aneurysm clipping; matching placebo tablets instead of oral nimodipine6 NicaPlant® implants (24 mg total nicardipine) placed during aneurysm clipping; matching placebo tablets instead of oral nimodipine10 NicaPlant® implants (40 mg total nicardipine) placed during aneurysm clipping; matching placebo tablets instead of oral nimodipine13 NicaPlant® implants (52 mg total nicardipine) placed during aneurysm clipping; matching placebo tablets instead of oral nimodipine
Duration21 days observation21 days observation21 days observation21 days observation21 days observation

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Safety and tolerability assessed by adverse events, serious adverse events, vital signs, ECG, laboratory parameters, and clinical assessments through day 21Primary2 cases of severe vasospasm; 2 SAEs (both cerebral vasoconstriction)1 case of moderate vasospasm (13 implant cohort); 11 SAEs in NicaPlant patients; 4 non-serious AEs possibly related (2 patients: bradycardia, fever); 5 serious AEs possibly/probably related (2 patients)
Incidence of moderate or severe angiographic vasospasm (≥33% diameter reduction on DSA day 8±1)Secondary2/4 patients (50%) - both severe1/10 patients (10%) - moderate
Plasma nicardipine Cmax (ng/ml)SecondaryNot applicable3 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 concentrationSecondaryNot measuredTherapeutic levels reached starting with 6 implants (measured in 6 patients with EVD)
New cerebral infarcts on CT day 14 (vs post-surgery CT)Secondary0/4 patients2/10 patients (patient 10102 in 6-implant cohort and patient 10108 in 13-implant cohort per Table 2)
Delayed ischemic neurologic deficit (DIND) / vasospasm-related deathSecondaryNo deaths due to vasospasm or DIND during 21-day observation (study-wide statement)No deaths due to vasospasm or DIND during 21-day observation (study-wide statement)
Need for anti-vasospasm rescue therapy within 21 daysSecondary3/4 patients received intra-arterial nimodipine rescue (patients 10101, 10107, 20101)2/10 patients received intra-arterial nimodipine rescue (patients 10302, 10108); additionally 1/10 (patient 20202) received 60 mg oral nimodipine once as prophylaxis
Non-serious adverse events totalAdverseCombined study total = 45 (paper does not split per-arm)Combined study total = 45; 4 assessed as possibly related to treatment in 2 NicaPlant patients (bradycardia, fever)
Serious adverse events totalAdverse2 SAEs (both cerebral vasoconstriction)11 SAEs; 5 assessed as possibly/probably related in 2 patients (combined study total = 13)
CSF culture positiveAdverse01
Cerebral hematomaAdverse02
Cerebral vasoconstrictionAdverse22
ICP increasedAdverse01 (probably related)
Partial seizuresAdverse01
Respiratory distressAdverse02
Cerebral artery occlusionAdverse02 (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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