The efficacy and safety of CABLIVI were established in a pivotal clinical study1,2,11,12
HERCULES Study Design
A pivotal, phase 3, double-blind, randomized controlled trial of 145 patients with aTTP. Patients were given PEX and immunosuppressive therapy in the form of corticosteroid treatment. Other immunosuppressive treatments such as rituximab were permitted but not required.* Patients were then randomized to receive CABLIVI (72) or placebo (73) for the duration of daily PEX and 30 days thereafter. Patients could receive extended treatment for up to 28 days if signs of underlying disease persisted, such as suppressed ADAMTS13 activity levels.1,2
Key efficacy endpoints1,2
Time to platelet count normalization§
Composite of aTTP-related events during study-drug period, including:
aTTP-related death, recurrence,‡ and ≥1 major TE event
Recurrence during overall study period‡
Key Inclusion Criteria: ≥18 years of age; clinical diagnosis of aTTP; required initiation of daily PEX and received PEX prior to randomization.2,12
Key Exclusion Criteria: Platelet count ≥100x109/L or >30x109/L if serum creatinine level >200 μmol/L; known other causes of thrombocytopenia; congenital TTP, pregnancy, or breastfeeding; clinically significant active bleeding or high risk of bleeding; known chronic treatment with anticoagulant treatment; malignant arterial hypertension; life expectancy <6 months.2,12
aTTP=acquired thrombotic thrombocytopenic purpura; PEX=plasma exchange; TE=thromboembolic; TTP=thrombotic thrombocytopenic purpura.
*2 patients in each group did not receive any immunosuppressive therapy.
† Daily PEX was variable based on platelet count normalization at ≥150,000/μL and physician discretion.12
‡ Thrombocytopenia after initial recovery of platelet count (platelet count ≥150,000/μL) that required reinitiation of daily PEX was considered a recurrence. Recurrences were termed exacerbations if they occurred within 30 days of the last PEX and relapses if they occurred more than 30 days after the last PEX.2
§ Platelet count normalization was defined as platelet count ≥150,000/μL with discontinuation of daily PEX 5 days thereafter.2
∥ Other immunosuppressive therapies include, for CABLIVI and placebo respectively: mycophenolate mofetil (6, 0), hydroxychloroquine (2, 1), bortezomib (2, 0), cyclophosphamide (1, 1), cyclosporin (1, 1).
¶ The difference between the trial groups in the percentage of patients who presented with an initial episode as compared with a recurrent episode was significant (P<0.05).2
# The normal range of ADAMTS13 activity used in the trial was 50% to 130%. As a result of the requirement for previous plasma exchange, baseline ADAMTS13 activity was higher than that measured locally at the time of admission in some cases. When available, ADAMTS13 activity levels that were locally measured at the time of admission were obtained, and the lower value of the baseline and admission values is represented.2