RESUMO
BACKGROUND: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5. METHODS: This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting. FINDINGS: 11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab. INTERPRETATION: Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab. FUNDING: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Assuntos
Enteropatias Perdedoras de Proteínas , Trombose , Criança , Humanos , Anticorpos Monoclonais , Edema , Enteropatias Perdedoras de Proteínas/tratamento farmacológico , Albumina Sérica , Resultado do Tratamento , Estudo Historicamente Controlado , Masculino , FemininoRESUMO
BACKGROUND: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. METHODS: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. RESULTS: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (P-interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P=0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding (P-interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding (P-interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P=0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (P=0.95) and postprocedural bleeding requiring intervention (P=0.93) was not significantly increased. CONCLUSIONS: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.
Assuntos
Aspirina/uso terapêutico , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/cirurgia , Rivaroxabana/uso terapêutico , Idoso , Aspirina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rivaroxabana/farmacologiaRESUMO
BACKGROUND: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described. METHODS: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization. RESULTS: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity (P for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use (P for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel (P for trend=0.06). CONCLUSIONS: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.
Assuntos
Aspirina/administração & dosagem , Clopidogrel/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Extremidade Inferior/irrigação sanguínea , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Rivaroxabana/administração & dosagem , Idoso , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND: CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) disease is ultra-rare (< 100 children or young adults worldwide) and potentially fatal. The study used mixed-methods approaches to assess how pozelimab impacts the signs and symptoms of CHAPLE disease from the patient perspective by combining within-trial interviews and clinical outcome assessments (COAs) (ClinicalTrials.gov, NCT04209634). METHODS: Interviews conducted with patients/caregivers at screening and week 24 assessed the signs and symptoms of CHAPLE disease, including those which were most bothersome, and evaluated the change. Patients/caregivers and clinicians completed the COAs; interview data contextualized the meaningfulness of change. RESULTS: Ten patients (aged 3-19 years) were enrolled; caregivers contributed to nine interviews. Abdominal pain, diarrhea, facial and peripheral edema, nausea, and vomiting are the core signs and symptoms of CHAPLE disease (≥ 90% patients experienced pre-treatment); the most bothersome signs and symptoms were abdominal pain (n = 9) and facial edema (n = 1). All core signs and symptoms were reported as resolved at week 24 interviews. Severity on global assessments changed from "mild" to "very severe" at baseline to "no signs or symptoms" at week 24. Interview results were generally consistent with sign- or symptom-specific COA scores. CONCLUSIONS: Patients with CHAPLE disease treated with pozelimab for 24 weeks experienced complete resolution of core signs and symptoms. Mixed-methods approaches can contextualize the patient experience (how patients feel and function) in rare disease trials. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04209634, registered December 24, 2019, https://classic. CLINICALTRIALS: gov/ct2/show/NCT04209634 .
Assuntos
Anticorpos Monoclonais Humanizados , Humanos , Feminino , Masculino , Adolescente , Pré-Escolar , Criança , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto Jovem , Adulto , Avaliação de Resultados em Cuidados de SaúdeRESUMO
OBJECTIVE: Assess the risk of new and worsening cancer events among participants who received the lipid-lowering therapy alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. DESIGN: Pooled post hoc analysis. SETTING: Six phase 3 or phase 4 placebo-controlled randomised trials with alirocumab. PARTICIPANTS: A total of 24,070 patients from the safety population with complete dosing data (alirocumab, n = 12,533; placebo, n = 11,537). INTERVENTION: Alirocumab 75 mg, alirocumab 150 mg, alirocumab 75 mg increasing to 150 mg if low-density lipoprotein cholesterol <50 mg/dL not achieved, or placebo, all every 2 weeks. All participants received background high-intensity or maximum-tolerated statin therapy. OUTCOMES AND MEASURES: The first new or worsening incident cancer events were assessed during the treatment-emergent adverse event period. Four outcomes were evaluated: any-neoplasm, malignant neoplasms, broad definition of hormone-sensitive cancers, and stricter definition of hormone-sensitive cancers. Sub-distribution hazard ratios and 95% confidence intervals (CIs) were estimated using a competing risk framework, with death as a competing risk. RESULTS: Considering both treatment arms in aggregate, 969 (4.03%), 779 (3.24%), 178 (0.74%) and 167 (0.69%) patients developed any neoplasm, malignant neoplasms, broad definition of hormone-sensitive cancer and strict definition of hormone-sensitive cancer events, respectively. There was no significant difference in the risk of having any neoplasm in the alirocumab versus the placebo group (sub-distribution hazards ratio [95% CI], 0.93 [0.82-1.1]; p = 0.28). A nominally lower risk of having any neoplasms with alirocumab was observed among subjects aged ≥64 years (sub-distribution hazards ratio 0.83; 95% CI, 0.70-0.99). CONCLUSIONS: Intensive low-density lipoprotein cholesterol lowering with a proprotein convertase subtilisin/kexin type 9 inhibitor combined with statin does not appear to increase the risk of new or worsening cancer events.
Assuntos
Anticorpos Monoclonais , Neoplasias , Inibidores de PCSK9 , Humanos , Anticorpos Monoclonais/uso terapêutico , LDL-Colesterol , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias/epidemiologia , Neoplasias/tratamento farmacológico , Medição de Risco , Subtilisinas , Resultado do Tratamento , Inibidores de PCSK9/efeitos adversos , Inibidores de PCSK9/uso terapêuticoRESUMO
BACKGROUND: Paclitaxel drug-coated devices (DCDs) were developed to improve lower extremity revascularization (LER) patency in peripheral artery disease (PAD) but have been associated with long-term mortality. OBJECTIVES: This study assessed DCD safety and effectiveness in LER for PAD. METHODS: VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) randomized patients with PAD who underwent LER to rivaroxaban or placebo. The primary VOYAGER PAD study efficacy and safety outcomes were composite cardiovascular and limb events and Thrombolysis In Myocardial Infarction major bleeding. For prespecified DCD analyses, primary safety and effectiveness outcomes were mortality and unplanned index limb revascularization (UILR). Major adverse limb events (MALE) were a secondary outcome. Inverse probability treatment weighting was used to account for each subject's propensity for DCD treatment. Effects of rivaroxaban were assessed with Cox proportional hazards models. RESULTS: Among 4,316 patients who underwent LER, 3,478 (80.6%) were treated for claudication, and 1,342 (31.1%) received DCDs. Median follow-up was 31 months, vital status was ascertained in 99.6% of patients, and there were 394 deaths. After weighting, DCDs were not associated with mortality (HR: 0.95; 95% CI: 0.83-1.09) or MALE (HR: 1.08; 95% CI: 0.90-1.30) but were associated with reduced UILR (3-year Kaplan-Meier: 21.5% vs 24.6%; HR: 0.84; 95% CI: 0.76-0.92). Irrespective of DCD use, consistent benefit of rivaroxaban for composite cardiovascular and limb events (Pinteraction = 0.88) and safety of rivaroxaban with respect to bleeding (Pinteraction = 0.57) were observed. CONCLUSIONS: In >4,000 patients with PAD who underwent LER, DCDs were not associated with mortality or MALE but were associated with persistent reduction in UILR. These findings provide insight into the safety and effectiveness of DCDs in PAD. (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD [VOYAGER PAD]; NCT02504216).