Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial

• Published in: The Lancet (British edition) 2017-09, Vol.390 (10102), p.1595-1602
• Main Authors: Riedl, Marc A, Grivcheva-Panovska, Vesna, Moldovan, Dumitru, Baker, James, Yang, William H, Giannetti, Bruno M, Reshef, Avner, Andrejevic, Sladjana, Lockey, Richard F, Hakl, Roman, Kivity, Shmuel, Harper, Joseph R, Relan, Anurag, Cicardi, Marco
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Androgens; Angioedema; Angioedemas, Hereditary - blood; Angioedemas, Hereditary - prevention & control; Clinical trials; Complement C1 Inhibitor Protein - adverse effects; Complement C1 Inhibitor Protein - pharmacokinetics; Complement C1 Inhibitor Protein - therapeutic use; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Double-blind studies; Drug Administration Schedule; Drug therapy; Edema; Esterase; Evidence-based medicine; FDA approval; Female; Genetic disorders; Humans; Infusions, Intravenous; Inhibitor drugs; Male; Metabolic Clearance Rate - physiology; Middle Aged; Prophylaxis; Recombinant Proteins - adverse effects; Recombinant Proteins - blood; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Treatment Outcome; Young Adult
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(17)31963-3

Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p