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1.
Immunotherapy ; 11(16): 1371-1386, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31621458

RESUMO

Aim: This prospective, Phase III study assessed the pharmacokinetics (PK), safety and tolerability of immune globulin subcutaneous, human - klhw 20% solution (IGSC-C 20%) in participants with primary humoral immunodeficiency (PI), compared with immune globulin injection (human), 10% caprylate/chromatography purified (IGIV-C 10%). Patients & methods: About 53 participants enrolled. Total 44 received IGIV-C 10% in the run-in phase and then entered the IV phase (with an additional nine who were already receiving IGIV-C 10% and entered the IV phase directly) for steady-state IV PK assessments. Total 49 entered the SC phase (weekly doses of IGSC-C 20% for ∼24 weeks). The PK profiles of IGIV-C 10% and IGSC-C 20% and their safety and tolerability parameters were compared. Results: At a dose adjustment factor of 1.37, IGSC-C 20% provided comparable (noninferior and bioequivalent) overall total immunoglobulin G exposure to IGIV-C 10% over an equal time interval. About 33 participants reported 79 adverse events during run-in + IV phases; 41 participants reported 141 adverse events during the SC phase, with most being local infusion site reactions. The majority of infusion site reactions were mild to moderate in severity. Conclusion: IGSC-C 20% was bioequivalent to IGIV-C 10% and was well tolerated, with a safety profile comparable with IGIV-C 10%, in this study. Trial registration: ClinicalTrials.gov identifier: NCT02604810.

3.
J Allergy Clin Immunol Pract ; 7(5): 1610-1618.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682573

RESUMO

BACKGROUND: Hereditary angioedema (HAE) with C1 inhibitor deficiency (C1-INH) is characterized by swelling of subcutaneous and/or submucosal tissues. OBJECTIVE: To evaluate efficacy/safety of fixed-dose subcutaneous plasma-derived C1-INH (pdC1-INH) liquid for HAE attack prevention (NCT02584959). METHODS: Eligible patients were ≥12 years with ≥2 monthly attacks prescreening or pre-long-term prophylaxis. In a partial crossover design, 80% of patients were randomized to placebo or pdC1-INH liquid for 14 weeks and crossed over from active to placebo or vice versa for another 14 weeks. The remainder were randomized to pdC1-INH liquid for 28 weeks. The primary efficacy endpoint was normalized number of attacks (NNA) versus placebo. Key additional endpoints were the proportion of patients achieving NNA reduction ≥50%, attack severity, number of attack-free days, and safety. RESULTS: Seventy-five patients were randomized and 58 (77%) completed the study. Mean age 41 years; 88% HAE type I. Least-squares means of NNA were reduced from 3.9 with placebo to 1.6 with pdC1-INH (from day 1; P < .0001). Most patients had ≥50% NNA reduction with pdC1-INH (from day 1, 78%). A total of 8.8% of placebo-treated patients were attack-free and 5.3%, 22.8%, and 63.2% had mild, moderate, and severe attacks, respectively; 37.5% of pdC1-INH-treated patients were attack-free and 8.9%, 26.8%, and 26.8% had mild, moderate, and severe attacks, respectively. Treatment-emergent adverse event rates were similar between groups (52% vs 56% for pdC1-INH crossover vs placebo, respectively). CONCLUSIONS: Fixed-dose subcutaneous pdC1-INH liquid was superior to placebo in preventing HAE attacks and demonstrated a favorable safety profile.

4.
BioDrugs ; 33(1): 33-43, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30539362

RESUMO

Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Anticorpos Monoclonais Humanizados/uso terapêutico , Calicreína Plasmática/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioedemas Hereditários/patologia , Angioedemas Hereditários/fisiopatologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/farmacologia , Ensaios Clínicos Fase I como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Pessoa de Meia-Idade , Calicreína Plasmática/efeitos dos fármacos , Adulto Jovem
5.
JAMA ; 320(20): 2108-2121, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30480729

RESUMO

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

6.
Am J Manag Care ; 24(14 Suppl): S299-S307, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30132644

RESUMO

Hereditary angioedema (HAE) is a rare genetic disease defined by recurrent attacks of edema, causing a substantial burden for patients, with morbidity, mortality, and reduced quality of life. This burden is increased by delayed diagnosis, inappropriate treatment, and suboptimal follow-up and patient education. Several novel therapeutics have recently been approved or are currently under evaluation for prevention of HAE attacks.

7.
Ann Allergy Asthma Immunol ; 121(6): 673-679, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30056152

RESUMO

OBJECTIVE: To review the criteria for long-term prophylaxis therapy in patients with hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), describe how these criteria have evolved over time, and anticipate how criteria may change in the future with the availability of new C1-INH-HAE treatment options. DATA SOURCES: Treatment guidelines, consensus statements, and expert reviews. STUDY SELECTIONS: Manuscripts that described long-term prophylaxis therapy in patients with C1-INH-HAE were selected. RESULTS: Historically, patients with C1-INH-HAE were considered to be candidates for long-term prophylaxis therapy if they had at least 1 attack per month, had at least 5 days of disability per month because of C1-INH-HAE, or did not sufficiently respond to on-demand treatment. More recently, guidelines and reviews state that thresholds of number of attacks or days of disability are arbitrary and that treatment plans should be individualized to the patient's needs. Furthermore, all patients should have a comprehensive management plan that is reviewed periodically and should have at least 2 doses of on-demand treatment available. Prophylaxis therapy should be discussed as a potential treatment option for each patient; however, the decision for its use will depend on the patient's individual needs and the course of their symptoms. CONCLUSION: The criteria for long-term prophylaxis therapy in C1-INH-HAE have changed with the recognition that treatments should be individualized to the patient's needs and with the availability of new medications that have more favorable benefit-risk profiles, are easier to use, and improve patients' quality of life.

8.
Clin Exp Allergy ; 48(10): 1325-1332, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29998524

RESUMO

BACKGROUND: Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention. OBJECTIVE: To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA® ; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics. METHODS: C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated. RESULTS: C1-INH functional activity following C1-INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour-1 , respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (Ctrough ) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in Ctrough levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher Ctrough levels than IV dosing.

9.
J Allergy Clin Immunol Pract ; 6(5): 1733-1741.e3, 2018 Sep - Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29391286

RESUMO

BACKGROUND: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL). OBJECTIVE: The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks. METHODS: Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo. CONCLUSIONS: In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).

10.
Immunol Allergy Clin North Am ; 37(3): 617-628, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28687113

RESUMO

This article discusses orphan diseases, their prevalence, legislative incentives to encourage development of therapies, and the impact of treatment on health care payment systems. Specifically, the cost burden of hereditary angioedema on patients, health care systems, and society is reviewed. The impact of availability of and access to novel and specific therapies on morbidity, mortality, and overall burden of disease is explored. Changes in treatment paradigms to improve effect and reduce cost of treatment are presented.


Assuntos
Angioedemas Hereditários/epidemiologia , Angioedemas Hereditários/terapia , Doenças Raras , Efeitos Psicossociais da Doença , Descoberta de Drogas/economia , Descoberta de Drogas/legislação & jurisprudência , Farmacoeconomia , Saúde Global , Custos de Cuidados de Saúde , Humanos , Prevalência , Mecanismo de Reembolso
11.
N Engl J Med ; 376(12): 1131-1140, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28328347

RESUMO

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).


Assuntos
Proteína Inibidora do Complemento C1/administração & dosagem , Angioedema Hereditário Tipos I e II/prevenção & controle , Adulto , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Angioedema Hereditário Tipos I e II/classificação , Humanos , Injeções Subcutâneas , Masculino , Risco , Autoadministração , Índice de Gravidade de Doença
12.
J Allergy Clin Immunol Pract ; 5(2): 442-447.e1, 2017 Mar - Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27818136

RESUMO

BACKGROUND: Hereditary angioedema (HAE) is a life-threatening disorder characterized by recurrent angioedema. Icatibant, a subcutaneous bradykinin-B2-receptor antagonist, is an effective on-demand therapy. Data outside the United States suggest that self-administration is tolerated and patient-preferred compared with administration by health care professionals at medical facilities (HCP-administration). OBJECTIVE: A prospective, multicenter study was conducted in the United States to compare icatibant self-administration and HCP-administration. METHODS: Subjects 18 years or older with type I or II HAE were recruited. The first 2 HAE attacks after enrollment were treated at medical facilities. Subjects were instructed by a health care professional on self-administration during icatibant treatment for the second HAE attack. Icatibant was self-administered for all subsequent attacks. For each treated HAE attack, efficacy, safety, and tolerability data were recorded. RESULTS: Nineteen patients with HAE received icatibant for 79 distinct HAE attacks. Mean attack duration was significantly shorter with self-administration (n = 50; 547 ± 510 minutes) than with HCP-administration (n = 29; 968 ± 717 minutes; P = .006). Mean time to treatment was significantly shorter with self-administration (143 ± 226 minutes) than with HCP-administration (361 ± 503 minutes; P < .0001). Shorter times to treatment were associated with shorter time from treatment to symptom resolution (r = 0.35; P = .02). Improvements in visual analog scale score and patient symptom score from pretreatment to 4 hours postinjection were comparable between self-administration and HCP-administration. There were no serious adverse events or discontinuations due to adverse events with self-administration or HCP-administration. CONCLUSIONS: Icatibant self-administration shortened attack duration and time to treatment, with no difference in safety or local tolerability compared with HCP-administration. These findings support icatibant as an effective on-demand option for home-based treatment.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Serviços de Assistência Domiciliar , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioedemas Hereditários/epidemiologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Bradicinina/administração & dosagem , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/administração & dosagem , Pessoal de Saúde , Humanos , Injeções Subcutâneas , Pessoa de Meia-Idade , Preferência do Paciente , Estudos Prospectivos , Autoadministração , Tempo para o Tratamento/estatística & dados numéricos , Resultado do Tratamento , Estados Unidos/epidemiologia , Escala Visual Analógica , Adulto Jovem
13.
Pediatrics ; 138(5)2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27940765

RESUMO

Hereditary angioedema (HAE) is a potentially life-threatening inherited disease characterized by attacks of skin swelling, severe abdominal pain, and upper airway swelling. Attacks typically begin in childhood, but the appropriate diagnosis is often missed. Attacks do not respond to epinephrine, antihistamines, or glucocorticoids. Recently, many effective drugs have been approved for treatment of adults with HAE, and the Medical Advisory Board of the HAE Patient's Association has developed and reported treatment recommendations for adults. Only 1 medication is approved for treatment of children <12 years of age, and there are no reported consensus recommendations for treatment of young children in the United States. The 11-member Medical Advisory Board, with extensive experience in the treatment of children, in concert with the leaders of the HAE Patient's Association, has developed these consensus recommendations to help in recognition, diagnosis, treatment of attacks, and prophylaxis of children with HAE.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Adolescente , Angioedemas Hereditários/diagnóstico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antifibrinolíticos/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Criança , Proteínas Inativadoras do Complemento 1/uso terapêutico , Proteína Inibidora do Complemento C1/uso terapêutico , Danazol/efeitos adversos , Testes Genéticos , Humanos , Equipe de Assistência ao Paciente , Educação de Pacientes como Assunto , Peptídeos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Ácido Tranexâmico/uso terapêutico
14.
Allergy Asthma Proc ; 37(6): 489-500, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27931305

RESUMO

BACKGROUND: The currently approved method of C1 inhibitor (C1 INH) administration for patients with hereditary angioedema with C1 INH deficiency (HAE) is by intravenous injection. A C1 INH subcutaneous formulation may provide an attractive mode of administration for some patients. OBJECTIVE: To evaluate efficacy and safety of two doses of subcutaneous, plasma-derived C1 INH with the dispersing agent, recombinant human hyaluronidase (rHuPH20) to prevent angioedema attacks in patients with HAE. METHODS: A randomized, double-blind, dose-ranging, crossover study, patients 12 years of age (n = 47) with a confirmed diagnosis of HAE were randomly assigned to receive subcutaneous injections of 1000 U C1 INH with 24,000 U rHuPH20 or 2000 U C1 INH with 48,000 U rHuPH20 every 3 or 4 days for 8 weeks and then crossed-over for another 8-week period. The primary efficacy end point was the number of angioedema attacks during each treatment period. RESULTS: The study was terminated early as a precaution related to non-neutralizing antibodies to rHuPH20 in 45% of patients. The mean standard deviation number of angioedema attacks during the 8-week treatment periods were 1.58 1.59 with 1000 U C1 INH and 0.97 1.26 with 2000 U. The mean (95% confidence interval [CI]) within-patient difference (2000 U-1000 U, respectively) was 0.61 (95% CI, 1.23 to 0.01) attacks per month (p = 0.0523), and 0.56 (95% CI, 1.06 to 0.05) attacks that required acute treatment, (p = 0.0315). No deaths or other serious adverse events were reported. Injection-site reaction was the most common adverse event. CONCLUSION: Despite early termination, this study demonstrated a clinically and statistically significant difference in burden of disease, which favored 2000 U C1 INH, without associated serious adverse events.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/administração & dosagem , Hialuronoglucosaminidase/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Adolescente , Adulto , Idoso , Angioedemas Hereditários/diagnóstico , Criança , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/farmacocinética , Progressão da Doença , Feminino , Humanos , Hialuronoglucosaminidase/efeitos adversos , Hialuronoglucosaminidase/farmacocinética , Injeções Subcutâneas , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Resultado do Tratamento , Adulto Jovem
15.
Int Arch Allergy Immunol ; 168(1): 44-55, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26556097

RESUMO

BACKGROUND: In randomized, controlled, double-blind, multicenter phase 3 studies, one icatibant injection was efficacious and generally well tolerated in patients with a single hereditary angioedema (HAE) attack. Here, the efficacy and safety of icatibant for multiple HAE attacks was evaluated across the controlled and open-label extension phases of the For Angioedema Subcutaneous Treatment (FAST)-3 study (NCT00912093). METHODS: In the controlled phase, adults with HAE type I or II were randomized (1:1) to receive a single subcutaneous injection of icatibant 30 mg or placebo within 6 h of an attack becoming mild (laryngeal) or moderate (cutaneous/abdominal). Open-label icatibant was administered for severe laryngeal symptoms. In the open-label extension phase, patients could receive up to three icatibant injections per attack. Efficacy and safety were analyzed for the first five icatibant-treated attacks at any location (prospective analysis) and laryngeal attacks (post hoc analysis) across both phases. Efficacy outcomes were based on patient-reported symptom severity (visual analog scale). RESULTS: In groups of patients with one to five icatibant-treated attacks at any location (n = 88), the median times to onset of symptom relief, onset of primary symptom relief and almost complete symptom relief were 1.9-2.1, 1.5-2.0 and 3.5-19.7 h, respectively. The same outcomes for laryngeal attacks (n = 25) were 1.0-2.0, 1.0-2.0 and 1.5-8.1 h, respectively. The most frequently reported adverse events were a worsening or recurrence of HAE attack, headache and nasopharyngitis. Two serious adverse events (arrhythmia and noncardiac chest pain) were considered to be related to icatibant. CONCLUSIONS: Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Adulto , Bradicinina/efeitos adversos , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas/métodos , Masculino , Estudos Prospectivos , Recidiva , Resultado do Tratamento
16.
Allergy Asthma Proc ; 36(3): 206-12, 2015 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25803135

RESUMO

Hereditary angioedema (HAE) is a rare autosomal-dominant disease characterized by recurring attacks of nonpruritic, nonpitting edema caused by an inherited deficiency or dysfunction of C1 esterase inhibitor (C1 INH). Symptoms can present years before an accurate diagnosis is made. The objective of this study, the Angioedema Clinical Epidemiology Testing Initiative for the Study of Hereditary Angioedema, was to determine the prevalence and clinical manifestations of HAE in untested first-degree blood relatives of known patients with HAE. Patients with a confirmed diagnosis of HAE recruited first-degree relatives who had not been evaluated for HAE. Enrolled subjects underwent complement testing (C4, C1 INH antigen, and functional C1 INH). If the lab tests were abnormal, the enrolled subjects returned to the site for a follow-up visit and questionnaire. Overall, 31 patients with HAE and 46 first-degree relatives enrolled in the study. Of 46 enrolled relatives, 30 (65%) had lab test results that ruled out a diagnosis of HAE, two (4%) were categorized as "HAE not ruled out," and 14 (30%) were newly diagnosed with HAE. Of 14 newly diagnosed subjects, nine (64%) reported having experienced symptoms that may have been related to HAE, such as swelling in the throat, face, or extremities or abdominal pain. When reported, median age of symptom onset in these 14 subjects was nine years whereas newly diagnosed asymptomatic subjects had a median chronological age of six years. These 14 subjects reported a historic mean standard deviation rate of 2.51 (5.59) swelling episodes per month with a mean standard deviation duration of 1.6 (0.74) days. This study's findings reinforce the importance of testing family members of patients with HAE to detect this hereditary condition.


Assuntos
Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/epidemiologia , Família , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Proteínas do Sistema Complemento/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto Jovem
17.
J Allergy Clin Immunol Pract ; 3(2): 206-212.e4, 2015 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25609335

RESUMO

BACKGROUND: Ecallantide is a human plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema for patients 12 years of age and older. Ecallantide is produced in Pichia pastoris yeast cells by recombinant DNA technology. Use of ecallantide has been associated with a risk of hypersensitivity reactions, including anaphylaxis. OBJECTIVE: The objective of this detailed retrospective data review was to characterize anaphylaxis cases within the ecallantide clinical trials database. METHODS: Potential cases of hypersensitivity reactions in the ecallantide clinical development program were identified by examining reported adverse events. The National Institute of Allergy and Infectious Disease criteria were used to identify those events that were consistent with anaphylaxis; these cases were then reviewed in detail. Results from investigational antibody testing also were examined. RESULTS: Among patients who received subcutaneous ecallantide (n = 230 patients; 1045 doses of 30 mg ecallantide), 8 patients (3.5%) had reactions that met the National Institute of Allergy and Infectious Disease criteria for anaphylaxis; none occurred on first exposure to the drug. All 8 reactions had symptom onset within 1 hour of exposure and cutaneous manifestations commonly observed in type I hypersensitivity reactions. All the reactions responded to standard management of type I hypersensitivity reactions and resolved without fatal outcomes. IgE antibody testing to ecallantide or P pastoris was not consistently positive in patients who experienced apparent type I hypersensitivity reactions. CONCLUSION: Anaphylaxis episodes after subcutaneous ecallantide exposure have clinical features suggestive of type I hypersensitivity reactions. However, anti-ecallantide or anti-P pastoris IgE antibody status was not found to be reliably associated with anaphylaxis.


Assuntos
Anafilaxia/induzido quimicamente , Angioedemas Hereditários/tratamento farmacológico , Hipersensibilidade a Drogas/etiologia , Peptídeos/efeitos adversos , Adolescente , Adulto , Idoso , Anafilaxia/sangue , Anafilaxia/diagnóstico , Anafilaxia/imunologia , Criança , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Imunoglobulinas/sangue , Injeções Intravenosas , Injeções Subcutâneas , Calicreínas/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Testes Cutâneos , Adulto Jovem
18.
J Allergy Clin Immunol Pract ; 3(2): 200-5, 2015 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25609336

RESUMO

INTRODUCTION: Measuring functional C1 inhibitor (C1 INH) with chromogenic or ELISA methods can confirm a diagnosis of hereditary angioedema (HAE) due to C1 INH deficiency. Previous studies found differences in the agreement of these assays. OBJECTIVE: To evaluate the agreement between chromogenic or ELISA methods in the context of an observational study. METHODS: Patients with previously confirmed HAE underwent functional C1 INH testing. These patients contacted first-degree relatives (parents, siblings, or offspring) not previously evaluated for HAE, who underwent a panel of complement testing, including for functional C1 INH. RESULTS: Overall, 31 patients with HAE and 46 untested relatives enrolled. Of 46 relatives, 14 (30.4%) were newly diagnosed with HAE based on their laboratory results. Among the 31 patients previously confirmed with HAE, all had low functional C1 INH according to the chromogenic method, whereas 22 (71.0%) had low, 7 (22.6%) had equivocal, and 2 (6.5%) had normal functional C1 INH according to the ELISA method. In the 14 newly diagnosed relatives, all had low functional C1 INH according to the chromogenic method, whereas 11 (78.5%) had low and 3 (21.4%) had equivocal results according to the ELISA method. CONCLUSION: Despite the apparent discordance in the ELISA and chromogenic assays in a small number of patients, both were useful in measuring functional C1 INH. To establish the diagnosis of HAE due to C1 INH deficiency, functional C1 INH results should be interpreted in combination with family and clinical history, and with other complement tests.


Assuntos
Angioedemas Hereditários/diagnóstico , Proteína Inibidora do Complemento C1/análise , Adolescente , Adulto , Idoso , Angioedemas Hereditários/sangue , Angioedemas Hereditários/epidemiologia , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Allergy Asthma Proc ; 35(5): 371-6, 2014 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25295804

RESUMO

Patients with hereditary angioedema (HAE) have impaired health-related quality of life (HRQoL), but the effect of preventative treatment strategies on HRQoL has not been evaluated. This study was designed to evaluate the effect of routine prevention therapy with nanofiltered C1 inhibitor (C1 INH-nf; human) on the HRQoL of patients with HAE. Thiry-six-item Short Form (SF-36) Version 1.0 questionnaires were administered at the beginning and end of two 12-week treatment periods in this multicenter, randomized, placebo-controlled, crossover study. Patients (n = 22) received intravenous injections of 1000 U of C1 INH-nf or placebo every 3-4 days for 12 weeks and then crossed over to the other treatment arm for a second 12-week period. Patients could receive open-label C1 INH-nf (1000 U) for the acute treatment of angioedema attacks in either arm of the study. Sixteen patients had evaluable SF-36 data. Mean physical component summary scores (PCSs) were 36.41 at baseline, 37.06 at the end of the placebo period, and 43.92 at the end of the C1 INH-nf period. Mean mental component summary scores (MCSs) were 49.90, 44.98, and 54.00, respectively. Least square mean differences (95% confidence intervals) between C1 INH-nf and placebo in norm-based SF-36 scores at the end of each treatment period were 6.55 (1.48, 11.62; p = 0.015) for PCS and 8.70 (1.67, 15.72; p = 0.019) for MCS. In a clinical trial setting, patients with HAE had significantly better HRQoL after 12 weeks of C1 INH-nf for routine prevention compared with acute treatment of individual angioedema attacks in the absence of routine prevention while on placebo. This study was a part of the clinical trial NCT01005888 registered in www.clinicaltrials.gov.


Assuntos
Angioedemas Hereditários/epidemiologia , Angioedemas Hereditários/prevenção & controle , Proteína Inibidora do Complemento C1/uso terapêutico , Pré-Medicação , Qualidade de Vida , Adulto , Estudos Cross-Over , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do Tratamento
20.
Allergy Asthma Proc ; 35(5): 377-81, 2014 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25198193

RESUMO

Icatibant was efficacious and generally well tolerated for type I or II hereditary angioedema (HAE) attacks in adults in the phase III, randomized, placebo-controlled For Angioedema Subcutaneous Treatment (FAST)-3 trial. The Icatibant Outcome Survey (IOS) is an international, observational study assessing icatibant treatment of HAE attacks. We conducted a posthoc analysis to compare for the first time the treatment of HAE type I or II attacks in patients prescribed icatibant in real-world (IOS) versus controlled trial settings (FAST-3). In FAST-3, patients received icatibant administered by health care professionals (HCPs). In IOS, patients self-administered icatibant or were treated by HCPs. Median time to treatment, time to resolution (almost complete resolution [FAST-3] or complete resolution [IOS]), and attack duration in patients who were treated by an HCP were compared between IOS and FAST-3. Descriptive statistical methods compared nonlaryngeal attacks treated less than 12 hours from attack onset. Analysis included 102 patients (376 attacks) from IOS and 43 patients (43 attacks) from FAST-3 (controlled phase). All endpoints were significantly longer for patients in FAST-3 (HCP administration) versus IOS (HCP administration) (p < .001; all comparisons). For FAST-3 (HCP administered) versus IOS (HCP administered), median time from attack onset to treatment was 6.5 versus 2.0 hours, median time to symptom resolution was 8.0 versus 3.5 hours, and median attack duration was 16.9 versus 7.3 hours, respectively. For combined HCP and self-administration in IOS, these endpoints were 1.6, 4.4, and 7.8 hours, respectively. This posthoc analysis showed for the first time that type I and II HAE attacks were treated earlier with icatibant in a real-world versus a phase III setting, with a shortened time to symptom resolution and attack duration. ClinicalTrials.gov NCT00912093 (FAST-3); NCT01034969 (IOS).


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Antagonistas de Receptor B2 da Bradicinina/uso terapêutico , Bradicinina/análogos & derivados , Adolescente , Adulto , Angioedemas Hereditários/diagnóstico , Bradicinina/administração & dosagem , Bradicinina/uso terapêutico , Antagonistas de Receptor B2 da Bradicinina/administração & dosagem , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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