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SOURCE CITATION: Alexander M, Harris S, Underhill C, et al. Risk-directed ambulatory thromboprophylaxis in lung and gastrointestinal cancers: the TARGET-TP randomized clinical trial. JAMA Oncol. 2023;9:1536-1545. 37733336.
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Neoplasias , Tromboembolia Venosa , Humanos , Anticoagulantes/uso terapéutico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Pacientes , Medición de Riesgo , Tromboembolia Venosa/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. METHODS: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418. FINDINGS: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. INTERPRETATION: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. FUNDING: CSL Behring.
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Angioedemas Hereditarios , Adulto , Adolescente , Humanos , Masculino , Femenino , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/prevención & control , Resultado del Tratamiento , Anticuerpos Monoclonales , Método Doble CiegoRESUMEN
BACKGROUND: Hereditary angioedema is associated with dysregulation of the kallikrein-kinin system. Factor XII (FXII) is a key initiator of the kallikrein-kinin system, which produces bradykinin, a central mediator of angioedema. Garadacimab (CSL Behring) is a first-in-class, fully human, immunoglobulin G4 monoclonal antibody targeting activated FXII, intended to prevent attacks in patients with C1-esterase inhibitor-deficient hereditary angioedema (HAE-C1-INH). We aimed to investigate garadacimab as a treatment every 4 weeks for patients with HAE-C1-INH. METHODS: In this double-blind, placebo-controlled, phase 2 study, patients with HAE-C1-INH were recruited from 12 research centres in Canada, Germany, Israel, and the USA. Eligible patients were aged 18-65 years and must have had at least four attacks of any severity over a consecutive 2-month period during the 3 months before screening or initiation of previous hereditary angioedema prophylaxis. After a run-in period of 4-8 weeks, patients were randomly assigned (1:1:1:1), using an interactive response technology via block randomisation (block sizes of 1-4), to either placebo or 75 mg, 200 mg, or 600 mg garadacimab. Patients were given an initial intravenous loading dose, and then, on day 6 and every 4 weeks for 12 weeks, they were given a subcutaneous dose of their allocated treatment. The primary endpoint was the number of monthly attacks in the intention-to-treat population (defined as all patients who underwent screening, provided consent, and were assigned to treatment) during the 12-week subcutaneous administration period assessed in the 200 mg and 600 mg garadacimab groups versus placebo. Safety was assessed in all patients who received at least one dose or partial dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03712228. FINDINGS: Between Oct 29, 2018, and Aug 28, 2019, 54 patients were screened, of whom 32 were randomly assigned to either placebo (n=8) or 75 mg (n=9), 200 mg (n=8), or 600 mg (n=7) garadacimab. The median age was 39·5 years (28·0-52·5) and 18 (56%) of 32 patients were female and 14 (34%) were male. The median number of monthly attacks during the 12-week subcutaneous treatment period was 4·6 (IQR 3·1-5·0) with placebo, 0·0 (0·0-0·4) with 75 mg garadacimab, 0·0 (0·0-0·0) with 200 mg garadacimab, and 0·3 (0·0-0·7) with 600 mg garadacimab. Compared with placebo, the rate of attacks was significantly reduced with garadacimab at 200 mg (reduced by 100% [95% CI 98-101]; p=0·0002) and 600 mg (reduced by 93% [54-110]; p=0·0003). No serious adverse events, deaths, or adverse events of special interest (anaphylaxis, thromboembolic events, and bleeding events) were observed. INTERPRETATION: Garadacimab 200 mg and 600 mg every 4 weeks significantly reduced the number of monthly attacks versus placebo and was well tolerated during the study. Garadacimab is an efficacious, subcutaneous prophylaxis in patients with HAE-C1-INH and warrants phase 3 evaluation. FUNDING: CSL Behring.
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Angioedemas Hereditarios , Proteína Inhibidora del Complemento C1 , Adolescente , Adulto , Anciano , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/prevención & control , Anticuerpos Monoclonales/uso terapéutico , Proteína Inhibidora del Complemento C1/efectos adversos , Método Doble Ciego , Esterasas/uso terapéutico , Factor XIIa/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases characterized by skeletal muscle inflammation associated with cutaneous, pulmonary, and/or other visceral organ involvement. Intravenous immunoglobulin (IVIG) has been recommended as an adjunct therapy for IIM patients refractory to conventional therapy. However, IVIG has high resource needs and increased risk of adverse reactions. Subcutaneous immunoglobulin (SCIG) therapy has been used as an alternative to IVIG in primary immunodeficiencies and neuroinflammatory disorders. We assessed the satisfaction, patient preference and effectiveness in IIM patients transitioned from IVIG to SCIG. METHODS: We retrospectively reviewed consecutive 20 patients with IIM who were transitioned from IVIG to SCIG therapy for >12 months. Patient preference between IVIG vs SCIG was surveyed using a questionnaire previously used in studies with neuroinflammatory conditions. In addition, disease flares, changes in immunosuppression, cumulative prednisone doses and global disease activity were evaluated using the Myositis Intention to Treat Index (MITAX) 12-months prior to- and post-SCIG initiation. RESULTS: Most patients (78.9%) preferred SCIG over IVIG and preferred home-based therapies to hospital-based therapies. There was no significant difference in global disease activity (MITAX 3.31 vs 3.02) nor in cumulative steroid doses 12-months prior to- or post-SCIG initiation. Three patients experienced disease flares, 5 escalated in immunosuppression, while 4 patients deescalated in immunosuppressive medications. CONCLUSIONS: SCIG is preferred by most patients over IVIG without a substantial increased disease activity or need for additional corticosteroids. Future cost effectiveness studies may provide an additional rationale for utilizing SCIG over IVIG for maintenance therapy for IIM.
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A prospective study and its long-term extension examined whether weekly treatment of patients with primary immunodeficiencies (PIDs) with a 16.5% subcutaneous immunoglobulin (SCIg; cutaquig®) confers acceptable efficacy, safety, and tolerability over a follow-up of up to 238 weeks (>4 years). Seventy-five patients received 4462 infusions during up to 70 weeks of follow-up in the main study and 27 patients received 2777 infusions during up to 168 weeks of follow-up in the extension. In the main study, there were no serious bacterial infections (SBIs), and the annual rate of other infections was 3.3 (95% CI 2.4, 4.5). One SBI was recorded in the extension, for an SBI rate of 0.02 (upper 99% CI 0.19). The annual rate of all infections over the duration of the extension study was 2.2 (95% CI 1.2, 3.9). Only 15.0% (1085) of 7239 infusions were associated with infusion site reactions (ISRs), leaving 85.0% (6153) of infusions without reactions. The majority of ISRs were mild and transient. ISR incidence decreased over time, from 36.9% to 16% during the main study and from 9% to 2.3% during the extension. The incidence of related systemic adverse events was 14.7% in the main study and 7.4% in the extension. In conclusion, this prospective, long-term study with cutaquig showed maintained efficacy and low rates of local and systemic adverse reactions in PID patients over up to 238 weeks of follow-up.
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Infecciones Bacterianas , Síndromes de Inmunodeficiencia , Humanos , Estudios Prospectivos , Infusiones Subcutáneas , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Resultado del Tratamiento , Inmunoglobulinas Intravenosas/uso terapéuticoRESUMEN
Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.
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Angioedemas Hereditarios , Angioedemas Hereditarios/prevención & control , Angioedemas Hereditarios/terapia , Niño , Proteína Inhibidora del Complemento C1/genética , Proteína Inhibidora del Complemento C1/uso terapéutico , Consenso , Femenino , Humanos , EmbarazoRESUMEN
BACKGROUND & AIMS: Upregulation of hepatic delta-aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta-aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. AIMS: evaluate long-term efficacy and safety of givosiran in acute hepatic porphyria. METHODS: Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double-blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open-label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta-aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. RESULTS: Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double-blind period, 0.0 in open-label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double-blind period) and 0.0 (open-label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long-term givosiran led to sustained lowering of delta-aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double-blind period. CONCLUSIONS: Long-term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.
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Porfiria Intermitente Aguda , Porfirias Hepáticas , Acetilgalactosamina/análogos & derivados , Humanos , Porfiria Intermitente Aguda/inducido químicamente , Porfiria Intermitente Aguda/tratamiento farmacológico , Porfirias Hepáticas/inducido químicamente , Porfirias Hepáticas/tratamiento farmacológico , Pirrolidinas , Calidad de VidaRESUMEN
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 .).
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Proteína Inhibidora del Complemento C1/administración & dosificación , Angioedema Hereditario Tipos I y II/prevención & control , Adulto , Proteína Inhibidora del Complemento C1/efectos adversos , Proteína Inhibidora del Complemento C1/metabolismo , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Angioedema Hereditario Tipos I y II/clasificación , Humanos , Inyecciones Subcutáneas , Masculino , Riesgo , Autoadministración , Índice de Severidad de la EnfermedadAsunto(s)
Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1 , Síndrome de Inmunodeficiencia con Hiper-IgM , Linfopenia , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM/diagnóstico , Síndrome de Inmunodeficiencia con Hiper-IgM/genética , Homocigoto , Linfopenia/diagnóstico , Linfopenia/genética , Citidina Desaminasa/genética , Inmunoglobulina MRESUMEN
Guidelines suggest restarting warfarin at known maintenance doses, although this may result in a delay to achieving therapeutic anticoagulation. As such, we compared the time to achieve an INR ≥ 2.0 between those restarting warfarin maintenance vs loading doses after transient interruption, and the impact on protein C, S and factor II levels. Patients requiring interruption of warfarin for elective procedures without hospitalization were randomized 1:1 to receive warfarin maintenance or loading doses (1.5 times the maintenance dose for 3 days followed by pre-procedural warfarin maintenance dosing). Protein C, S and Factor II were drawn at baseline (prior to warfarin interruption), 7 and 14 days after restarting warfarin. Among 19 patients randomized to maintenance and 20 to loading doses, nearly half in each group had mechanical heart valves with gastrointestinal endoscopic procedures most commonly performed (41%). The median number of days to reach an INR ≥ 2.0 was 7.8 days in the loading and 9.0 in the maintenance group (difference between medians 1.2 days, 95% CI -3.1 to 4.9; P = 0.19). Although levels of protein C, S and factor II were lower in the loading vs maintenance dose group, all remained above that of baseline. Warfarin resumption with loading doses shortened the time to achieve a therapeutic INR by a median of 1.2 days. Prompt warfarin dose escalation should be done in response to the INR. Protein C and S remained above pre-warfarin interruption levels, implying a lack of depletion with restarting warfarin.
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Procedimientos Quirúrgicos Electivos/métodos , Warfarina/administración & dosificación , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Proteína C/análisis , Proteína S/análisis , Protrombina/análisis , Factores de TiempoRESUMEN
We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) as first-line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline-based treatment due to advanced age, significant comorbidities, or pre-existing cardiac disease. The median age was 69 (21-80); 46% received FLAG for pre-existing cardiac disease and others due to age (32%), non-cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre-existing cardiac disease. Among non-transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse-free survival was 14.7 months. The median overall survival was 9.3 months with 1- and 2-yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline-based induction for Acute myeloid leukemia in those with significant comorbidities including pre-existing cardiac disease.
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Antraciclinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cardiopatías/complicaciones , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Vidarabina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Combinada , Comorbilidad , Citarabina/efectos adversos , Citarabina/uso terapéutico , Femenino , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias , Estudios Retrospectivos , Resultado del Tratamiento , Vidarabina/efectos adversos , Vidarabina/uso terapéutico , Adulto JovenRESUMEN
The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14-21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a 'bridge' to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14-21 was similar in patients treated with edoxaban and parenteral anticoagulation as a 'bridge' to warfarin (-50.1% vs -58.9%; 95% confidence interval of treatment difference, -12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens.ClinicalTrials.gov IDENTIFIER NCT01662908: INVESTIGATIONAL NEW DRUG IND APPLICATION EDOXABAN IND # 63266.
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Anticoagulantes/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Inhibidores del Factor Xa/administración & dosificación , Heparina/administración & dosificación , Angiografía por Resonancia Magnética , Flebografía/métodos , Piridinas/administración & dosificación , Tiazoles/administración & dosificación , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/tratamiento farmacológico , Warfarina/administración & dosificación , Administración Intravenosa , Administración Oral , Adulto , Anciano , Anticoagulantes/efectos adversos , Quimioterapia Combinada , Inhibidores del Factor Xa/efectos adversos , Estudios de Factibilidad , Femenino , Heparina/efectos adversos , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Piridinas/efectos adversos , Tiazoles/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Warfarina/efectos adversosRESUMEN
We outline a case whereby RBCX was successfully provided over disparate geographical areas and time zones in Canada and overcame the logistical challenges of coordinating care across four different health care systems with the application of modern telecommunication technologies. We present this case as a model for other SCD providers and patients.
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Anemia de Células Falciformes/terapia , Atención a la Salud , Transfusión de Eritrocitos , Recambio Total de Sangre , Adulto , Canadá , Humanos , MasculinoRESUMEN
Background: Hereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased quality of life. Long-term prophylaxis (LTP) to prevent angioedema episodes is a key component of disease management. Berotralstat, an oral, once-daily plasma kallikrein inhibitor, was approved for LTP by Health Canada in 2022. Methods: We conducted a retrospective, real-world study investigating the effectiveness and adverse effects of berotralstat. Data on angioedema frequency, disease control, and adverse events were tabulated. Patient satisfaction with treatment was scored on a 5-point Likert scale, with 1 representing very unsatisfied and 5 representing very satisfied with therapy. Results: From June, 2022 and May, 2023, 8 patients with HAE type 1 or type 2 received berotralstat. Effectiveness data were available for 7 patients who continued the drug for at least 3 months, 4 of whom switched to berotralstat from plasma-derived C1 inhibitor LTP. In these 7 patients, the average number of attacks per month decreased from 3.3 to 1.6 (p<0.05), representing a ~52% reduction in attack frequency. Median angioedema control test score numerically improved from 8 to 13 (p=0.0781). Of the 8 patients who received berotralstat, 3 reported no adverse effects and 5 experienced gastrointestinal side effects, which were mild and transient in 3 and led to discontinuation in 1. Average treatment satisfaction was between satisfied and very satisfied at 4.3. Conclusion: Berotralstat is an effective agent for long-term prophylaxis in HAE. Most patients experienced no adverse effects or mild, transient gastrointestinal symptoms.
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Angioedema , Angioedemas Hereditarios , Pirazoles , Humanos , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/diagnóstico , Calidad de Vida , Estudios Retrospectivos , CanadáRESUMEN
Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare inborn error of immunity that presents with episodic swelling. Management is multifaceted and includes on-demand treatment of swelling episodes, short-term prophylaxis to prevent swelling episodes from procedures, and long-term prophylaxis (LTP) to prevent angioedema on an ongoing basis. All approved on-demand therapies are parenteral, necessitating patient training for home administration, particularly intravenous C1 inhibitor. These complexities can result in care gaps for rural HAE patients. We conducted a cross-sectional study at our Angioedema Center of Reference and Excellence to assess the care provided to urban and rural patients. The proportion of patients receiving LTP, proportion of patients diagnosed as children, and disease control measured using the Angioedema Control Test (AECT) were collected. Logistic and Poisson regression models adjusted for age and sex were used to compare the two groups. The proportion using LTP was similar at 62% and 61% in urban and rural patients, respectively (odds ratio [OR] 1.01 (CI 95% 0.34-2.99)). Among urban patients, 52% were diagnosed as children compared to 60% among rural residents (1.43 (0.37-5.56)). The mean (IQR) AECT score was 14.0 (8.5-15.5) in urban patients and 13.0 (10.0-14.0) in rural patients (Poisson ß -0.001 (-0.23-0.23). These data indicate that rural patients received similar high-quality care. We attribute these findings to the centralized care model employed in which HAE patients in the region are seen at a single comprehensive care clinic.
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Angioedemas Hereditarios , Población Rural , Humanos , Masculino , Femenino , Estudios Transversales , Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/terapia , Niño , Adulto , Adolescente , Preescolar , Población Urbana , Adulto Joven , Proteína Inhibidora del Complemento C1/uso terapéutico , Persona de Mediana EdadRESUMEN
BACKGROUND: Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long-term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema. METHODS: This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double-blind, placebo-controlled) and a treatment period 2 (TP2: ≥44-week open-label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open-label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long-term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed. FINDINGS: Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open-label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 39·0 years (IQR 27·0-53·0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87·9 weeks (IQR 50·0-106·6) in the garadacimab 200 mg group and 44·1 weeks (24·1-56·1) in the garadacimab 600 mg group. Median monthly attack rates were 0·0 (IQR 0·0-0·1) in the garadacimab 200 mg group and 0·1 (0·0-0·4) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run-in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths. INTERPRETATION: Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long-term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema. FUNDING: CSL Behring.
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Angioedemas Hereditarios , Anticuerpos Monoclonales Humanizados , Calidad de Vida , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Angioedemas Hereditarios/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Método Doble Ciego , Resultado del Tratamiento , Adulto Joven , Adolescente , AncianoRESUMEN
Introduction: Short-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15-20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection. While imaging studies have identified multi-organ injury patterns in patients with recovered COVID-19, their respective contributions to the disability and morbidity of long COVID is unclear. Methods: A multicenter, observational study of 215 vaccine-naïve patients with clinically recovered COVID-19, studied at 3-6 months following infection, and 133 healthy volunteers without prior SARS-CoV-2 infection. Patients with recovered COVID-19 were screened for long COVID related symptoms and their impact on daily living. Multi-organ, multi-parametric magnetic resonance imaging (MRI) and circulating biomarkers were acquired to document sub-clinical organ pathology. All participants underwent pulmonary function, aerobic endurance (6 min walk test), cognition testing and olfaction assessment. Clinical outcomes were collected up to 1 year from infection. The primary objective of this study is to identify associations between organ injury and disability in patients with long-COVID symptoms in comparison to controls. As a secondary objective, imaging and circulating biomarkers with the potential to exacerbate cardiovascular health were characterized. Discussion: Long-term sequelae of COVID-19 are common and can result in significant disability and cardiometabolic disease. The overall goal of this project is to identify novel targets for the treatment of long COVID including mitigating the risk of incident cardiovascular disease. Study registration: clinicaltrials.gov (MOIST late cross-sectional study; NCT04525404).
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BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)
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Angioedemas Hereditarios/tratamiento farmacológico , Antagonistas del Receptor de Bradiquinina B2 , Bradiquinina/análogos & derivados , Enfermedad Aguda , Adulto , Bradiquinina/administración & dosificación , Bradiquinina/efectos adversos , Bradiquinina/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Análisis de Intención de Tratar , Masculino , Estadísticas no Paramétricas , Ácido Tranexámico/uso terapéuticoRESUMEN
We report an approximately 80% reduction in angioedema attacks with lanadelumab, a mAb targeting plasma kallikrein, in a case of hereditary angioedema with normal C1 inhibitor levels. This finding supports a central pathophysiologic role for kallikrein in hereditary angioedema with normal C1 levels and supports the need for prospective studies of lanadelumab use with this condition.
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BACKGROUND: X-linked agammaglobulinemia (XLA) is the most common form of agammaglobulinemia and is caused by mutations in Btk, which encodes Bruton tyrosine kinase (BTK). CASE DESCRIPTION: We describe a 36-year-old male who presented as an infant with hypogammaglobulinemia and sinopulmonary infections and was initially diagnosed with common variable immunodeficiency. Genetic testing showed he was hemizygous for Btk c.240G > A. This synonymous variant affecting the last nucleotide of exon 3 leads to aberrant splicing of most but not all mRNA transcripts. CONCLUSION: We demonstrated reduced BTK protein expression confirming the pathogenicity of the variant and related our findings to genotype-phenotype relationship studies ina XLA caused by synonymous mutations.