Table 1.
Summary of clinical trials of immunomodulation in ischemic stroke
| Drug | Mechanism | Trial | Design | Route of administration, time window, dose, duration | Outcome | Reference(s) |
|---|---|---|---|---|---|---|
| Minocycline | Anti-inflammatory effects: reduction of microglial activation, inhibition of MMP activity, reduced NO production, and inhibition of apoptotic cell death | Minocycline treatment in acute stroke: an open-label, evaluator-blinded study | Phase II: open-label, evaluator-blinded study of 152 patients | Route: oral Dose: 200 mg Time window: 6–24 h Duration: 5 days |
Lower NIHSS and mRS at 7 days and 30 days | [36] |
| Study of a neuroprotective drug to limit the extent of damage from an ischemic stroke (MINOS) | Phase II: dose-finding study with tiers of 3, 4.5, 6, or 10 mg/kg in a total of 60 patients, with 41 at the highest dose (10 mg/kg) and 60 % receiving concurrent tissue plasminogen activator | Route: IV Dose: 3, 4.5, 6, or 10 mg/kg Time window: 0–6 h Duration: 3 days |
Well-tolerated; compatible with TPA Half-life of approximately 24 h |
[37] | ||
| Neuroprotection with minocycline therapy for acute stroke recovery trial (NeuMAST) | Phase IV: multicenter prospective randomized open-label blinded endpoint evaluation (PROBE) pilot study of 152 patients | Route: oral Dose: 200 mg Time window: 3–48 h Duration: 5 days |
No benefit at 90 days, as measured by mRS, NIHSS or BI; terminated at interim analysis for futility | [38] | ||
| Recombinant neutrophil inhibitory factor (UK-279, 276) | Recombinant inhibitor of the CD11b/CD18 receptor, thus blocking neutrophil adhesion to endothelium and infiltration to the site of infarction | Acute stroke therapy by inhibition of neutrophils (ASTIN) | Phase II: Bayesian sequential design for double-blind, randomized, adaptive allocation of 966 patients (204 co-thrombolysed) to 1 of 16 dose tiers or placebo and early termination for efficacy or futility | Route: IV Dose: 1 of 15 doses of 10–120 mg Time window: 0–6 h Duration: single dose |
No benefit at 90 days, as measured by change in SSS adjusted for baseline; terminated at interim analysis for futility |
[50, 51] |
| Monoclonal antibody (humanized) against the neutrophil CD11/CD18 cell adhesion molecule (Hu23F2G, LeukArrest®) | Humanized monocolonal antibody against neutrophil β2 integrin CD18, thus blocking neutrophil adhesion to endothelium infiltration to the site of infarction | Phase II: dose-escalation study | Route: IV Dose: Variable Time window: 0–12 h Duration: single dose |
Concentration of 1.5 mg/kg well-tolerated; twice-daily infusion improved mRS | [6, 49] | |
| Hu23F2G phase III stroke trial (HALT) | Phase III | Terminated in interim analysis for futility; results not disclosed | [6, 49] | |||
| E-selectin | Induction of mucosal tolerance to human E-selectin to minimize inflammation and risk of further cerebral insult | E-selectin nasal spray to prevent stroke recurrence | Phase II: dose-finding study with 4 doses of intranasal recombinant human E-selectin spray, estimated enrolment of 60 people | Route: nasal spray Dose: variable Time window: 1–4 months Duration: 30 days |
Terminated; results not disclosed | [54] |
| E-Selectin nasal instillation to prevent secondary stroke | Phase I: single-center, open-label, dose-escalation trial assessing safety profile of 4 doses of intranasal recombinant human E-selectin, estimated enrolment 58 people | Route: nasal spray Dose: 0, 5, 15, or 50 μg Time window: 1–4 months Duration: 30 days |
Ongoing | [55] | ||
| IL-1 receptor antagonist (rhIL-1Ra, Anakinra) | IL-1 receptor blockade to reduce cerebral inflammation | A randomized phase II study of IL-1 receptor antagonist in patients with acute stroke | Phase II: randomized, double-blind, placebo-controlled trial in 34 patients | Route: IV Time window: 0–6 h Dose: 100 mg loading followed by a 2 mg/kg/h infusion over 72 h Duration: 3 days |
No adverse events attributed to treatment; greater reduction in NIHSS at 3 months; more patients with mRS 0–1 at 3 months |
[46] |
| SC-IL STROKE study | Phase II: randomized, controlled trial with planned sample size of 120 (80 stroke patients and 40 healthy volunteers) | Route: SC Time window: 0–6 h Dose: 100 mg twice daily for 72 h Duration: 3 days |
Ongoing | [47] | ||
| Murine anti-ICAM-1 (Enlimomab) | Murine monoclonal antibody against intercellular adhesion molecule ICAM-1 to block leukocyte attachment and migration through the cerebral endothelium |
Safety, pharmacokinetics, and biological activity of enlimomab (anti-ICAM-1 antibody) | Phase II: open-label, dose-escalation study in 32 patients hospitalized for acute stroke (ischemic or hemorrhagic) | Route: IV Time window: 0–24 h Dose: 140–480 mg Duration: 5 days |
Between 140 and 480 mg of Enlimomab administered over 5 days was safe at 30 days; a loading dose of 160 mg followed by 4 daily maintenance doses of 40 mg suggested suitable for further study | [57] |
| Enlimomab acute stroke trial (EAST) | Phase III: double-blind, randomized, placebo-controlled, parallel-group, 90-day follow-up trial of 625 patients | Route: IV Time window: 0–6 h Dose: 160 mg (day 1), and 40 mg daily (days 2–5) Duration: 5 days |
Mortality higher in enlimomab-treated patients; significantly more adverse events with Enlimomab; terminated | [58] | ||
| The sphingosine-1-phosphate receptor (S1PR) regulator Fingolimod (FTY720) | Reduced egress of T cells, B cells, NK cells, and other S1PR-expressing cells from the lymph nodes | Efficacy and safety of FTY720 for acute stroke | Phase II: randomized, open-label, evaluator-blinded, parallel-group clinical pilot trial of 22 patients |
Route: oral Time window: 4.5–72 h Dose: 0.5 mg Duration: 3 days |
Well-tolerated; no increase in infections; milder neurological deficit at 7 days; limited lesion enlargement at 7 days; decreased microvascular permeability at 7 days |
[67] |
| Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke: A Pilot Trial | Phase II: randomized, open-label, parallel-group, 90-day follow up trial of 47 patients | Route: oral Time window: 0–4.5 h Dose: 0.5 mg Duration: 3 days |
Well-tolerated; attenuated reperfusion; improved clinical outcomes |
[68] | ||
| Natalizumab | Blockade of the α4-β1 integrin | Effect of Natalizumab on Infarct Volume in Acute Ischemic Stroke (ACTION) | Phase II: randomized, double-blinded, parallel-assignment clinical trial of 161 patients | Route: IV Time window: 0–9 h Dose: 300 mg Duration: single dose |
No reduction in focal infarct growth from day 1 to day 5; functional outcome improvement sustained over 90 days | [62, 63] |
| Safety and Efficacy of Intravenous Natalizumab in Acute Ischemic Stroke (ACTION II) | Phase II: randomized, double-blinded, parallel-assignment clinical trial with estimated enrolment of 240 patients | Route: IV Time window: 0–9 h Dose: 300 mg Duration: single dose |
Ongoing | [64] |
MMP = matrix metalloproteinase; NO = nitric oxide; IV = intravenous; NIHSS = National Institutes of Health Stroke Scale; mRS = modified Rankin Score; TPA = tissue plasminogen activator; BI = Barthel index; SSS = Scandinavian Stroke Scale; IL = interleukin; SC = subcutaneous; ICAM-1 = intercellular adhesion molecule 1; NK = natural killer