PDF: NicaPlant
(2023)Objective
To assess the safety, tolerability, and pharmacokinetics of NicaPlant® implants in preventing vasospasm after aneurysm clipping in aSAH patients
Study Summary
• Only 1 case of moderate vasospasm occurred in NicaPlant® group (10 patients) versus 2 cases of severe vasospasm in standard care group (4 patients)
• Plasma nicardipine levels remained below pharmacologically active levels, avoiding systemic side effects, while CSF levels reached therapeutic concentrations
Intervention
NicaPlant® implants (modified-release nicardipine pellets, 4 mg each) placed in proximity to cerebral blood vessels during microsurgical aneurysm clipping
Inclusion Criteria
aSAH patients Hunt and Hess grade 1-4 undergoing aneurysm clipping within 48 hours of rupture
Study Design
Arms: NicaPlant® (3, 6, 10, or 13 implants) vs Standard of Care (oral nimodipine)
Patients per Arm: 10 patients received NicaPlant® (across 4 dose cohorts), 4 patients received standard of care
Outcome
• Lower vasospasm rates in NicaPlant® groups compared to standard care
• Dose of 10 implants selected for future studies based on safety, CSF drug levels, and usability
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
Study Design
- Study Type
- Phase IIA randomized controlled single ascending dose trial
- Randomization
- Yes
- Blinding
- Single-blind (ICU personnel and assessors blinded; surgical team unblinded after randomization)
- Sample Size
- 14
- Follow-up
- 21 days
- Centers
- 4
- Countries
- Austria, Germany
Primary Outcome
Definition: Safety and tolerability assessed by adverse events, serious adverse events, vital signs, ECG, laboratory parameters, and clinical assessments through day 21
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 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) | - |
Limitations & 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
Citation
Brain and Spine 3 (2023) 102673