BACKGROUND: 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. METHODS: 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. FINDINGS: 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<0·0001) and -2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported. INTERPRETATION: Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor. FUNDING: Pharming Technologies.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• hereditární angioedémy krev   prevence a kontrola   MeSH
• inhibiční protein komplementu C1 škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• intravenózní infuze MeSH
• klinické křížové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolická clearance fyziologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• rekombinantní proteiny škodlivé účinky   krev   farmakokinetika   terapeutické užití   MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• conestat alfa MeSH Prohlížeč
• inhibiční protein komplementu C1 MeSH
• rekombinantní proteiny MeSH

BACKGROUND: Hereditary angio-oedema (HAE) is manifested by repeated episodes of localised subcutaneous or sub-mucosal oedema. Symptoms are extremely variable in frequency, localisation, and severity. Atypical or mild clinical symptoms of the disease may lead to erroneous diagnosis, causing diagnostic delay. The goal of this study was to assess how diagnostic delay has changed over 33 years at a single referral centre. METHODS: We analysed diagnostic delay and first symptoms of HAE in patients who were diagnosed at an immunology department between 1980 and 2013. Patient's records were analysed. RESULTS: The median diagnostic delay in 77 HAE type 1 and 2 patients was seven (range, 0-42) years. The difference observed in diagnostic delay between probands (18 [0-42] years) and others (1 [0-37] year) was significant (p<0.001). Our data show a significant negative correlation between the length of diagnostic delay and the year of diagnosis in our group of patients (p=0.024). The median age of first symptoms among all HAE patients (N=64) was 17 (1-40) years. The first symptoms of HAE in 64 patients were analysed. Twenty-six patients had abdominal, seventeen peripheral, five facial, two urogenital, and three had laryngeal oedema as the first manifestation of the disease. The last death that was attributed to HAE was in 1977. CONCLUSIONS: Our observations demonstrate improved awareness of HAE among physicians, as documented by the significant decrease in diagnostic delay. It is believed that earlier treatment will improve patient quality of life and life expectancy.

• Klíčová slova
• Diagnostic delay, First symptoms, Hereditary angio-oedema,
• MeSH
• dítě MeSH
• dospělí MeSH
• hereditární angioedémy diagnóza   genetika   mortalita   MeSH
• inhibiční protein komplementu C1 MeSH
• kojenec MeSH
• komplement C1 - inaktivátory analýza   genetika   MeSH
• kvalita života MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nefelometrie a turbidimetrie MeSH
• opožděná diagnóza statistika a číselné údaje   MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• inhibiční protein komplementu C1 MeSH
• komplement C1 - inaktivátory MeSH
• SERPING1 protein, human MeSH Prohlížeč