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BACKGROUND AND PURPOSE: HER-MES was the first head-to-head study of erenumab against topiramate (standard of care). This post hoc analysis of the HER-MES study evaluated the effect of erenumab versus topiramate on patient-reported outcomes at week 24. METHODS: Adult patients with episodic or chronic migraine (n = 777) were randomized (1:1) to monthly subcutaneous erenumab (n = 389) or daily oral topiramate (n = 388). Migraine-related disability, as measured by the Headache Impact Test 6 (HIT-6) and Short Form 36 Health Survey version 2 (SF-36v2), was analysed in the entire study cohort and true completers. RESULTS: In the erenumab group (vs. topiramate), significant improvements were reported in Headache Impact Test 6 total scores (composite populations, -10.88 vs. -7.72; true completers, -11.92 vs. -10.61) and a higher proportion of patients achieved a ≥5-point reduction from baseline with erenumab (composite populations, 72.2% vs. 53.9%; true completers, 79.64% vs. 71.43%). The adjusted mean change from baseline in the SF-36v2 score was greater with erenumab for both physical component summary (composite population, 5.48 vs. 3.63; true completers, 5.95 vs. 5.23) and mental component summary (composite populations, 1.00 vs. -1.18; true completers, 1.74 vs. -0.33). A higher proportion of patients on erenumab versus topiramate had a ≥5-point improvement in SF-36v2 for the physical component summary (composite populations, 47.7% vs. 37.4%; true completers, 52.1% vs. 48.9%) and mental component summary (composite populations, 25.3% vs. 16.8%; true completers, 27.3% vs. 17.7%). CONCLUSIONS: This post hoc analysis demonstrated that patients treated with erenumab had significant improvements in headache impact and quality of life as measured by patient-reported outcomes versus patients treated with topiramate.
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BACKGROUND: We compared the tolerability and efficacy of erenumab, a monoclonal antibody binding to the calcitonin gene-related peptide receptor, to topiramate for migraine prophylaxis in adults. METHODS: HER-MES was a 24-week, randomised, double-blind, double-dummy, controlled trial conducted in 82 sites in Germany. Patients with ≥4 migraine days per month and naïve to study drugs were randomly assigned (1:1) to either subcutaneous erenumab (70 or 140 mg/month) plus topiramate placebo (erenumab group) or oral topiramate at the individual dose with optimal efficacy (50-100 mg/day) plus erenumab placebo (topiramate group).The primary endpoint was medication discontinuation due to an adverse event during the double-blind phase. The proportion of patients that achieved ≥50% reduction from baseline in monthly migraine days during the last 3 months of the double-blind phase was a secondary endpoint. RESULTS: Seven hundred and seventy-seven patients were randomised (from 22 February 2019 to 29 July, 2020) and 95.1% completed the study. In the erenumab group, 10.6% discontinued medication due to adverse events compared to 38.9% in the topiramate group (odds ratio, 0.19; 95% confidence interval 0.13-0.27; p < 0.001). Significantly more patients achieved a ≥50% reduction in monthly migraine days from baseline with erenumab (55.4% vs. 31.2%; odds ratio 2.76; 95% confidence interval 2.06-3.71; p < 0.001). No new safety signals occurred. CONCLUSIONS: Erenumab demonstrated a favourable tolerability and efficacy profile compared to topiramate.Trial registration: ClinicalTrials.gov NCT03828539, URL: https://clinicaltrials.gov/ct2/show/NCT03828539.
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Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Trastornos Migrañosos , Adulto , Anticuerpos Monoclonales Humanizados , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Método Doble Ciego , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Topiramato/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: HER-MES was the first head-to-head, phase 4 trial to assess the tolerability and effectiveness of erenumab against standard of care treatment (topiramate). This post hoc analysis compared the efficacy of erenumab with topiramate in patients who completed the trial on study medication. METHODS: Post hoc sensitivity analysis was performed using the full analysis set. Outcomes assessed included the proportion of patients with a ≥50% reduction in monthly migraine days (MMD) from baseline (50% responder rate), over the last 3 months (months 4, 5, and 6) of the double-blind treatment phase (DBTP), the 50% responder rate during the first month of the DBTP, and change from baseline in MMD during the DBTP. Multiple imputation was done for efficacy values of patients who discontinued study treatment. RESULTS: Patients (N = 777) were randomly assigned (1:1) to either 70 or 140 mg/month erenumab (N = 389) or 50-100 mg/day topiramate (N = 388). Of these, 334 patients (85.9%) receiving erenumab, and 231 patients (59.5%) receiving topiramate completed the DBTP on study medication. Patients on study medication until the end of the DBTP received a mean dose of 119 mg/month for erenumab and 92 mg/day for topiramate. At month 1, a significantly greater proportion of patients receiving erenumab (39.2%) reported ≥50% reduction in MMD from baseline compared with those receiving topiramate (24.0%; p < 0.001). In the last 3 months, a significantly larger proportion of patients receiving erenumab (60.3%) achieved ≥50% reduction in MMD from baseline compared with those receiving topiramate (43.3%; p < 0.001). Patients receiving erenumab demonstrated significantly greater reductions in MMD during the last 3 months from baseline versus those receiving topiramate (- 6.13 vs - 4.90; 95% CI: - 1.87 to - 0.61; p < 0.001). CONCLUSIONS: This post hoc analysis demonstrated significantly superior efficacy of erenumab versus topiramate in achieving a ≥50% reduction in MMD with an early onset of efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03828539 .
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Anticuerpos Monoclonales Humanizados , Trastornos Migrañosos , Humanos , Topiramato/farmacología , Topiramato/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Método Doble Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: Forced expiratory volume in 1 second (FEV1) is the only parameter currently recognized as a surrogate endpoint in cystic fibrosis (CF) trials. However, FEV1 is relatively insensitive to changes in the small airways of patients with milder lung disease. This pilot study aimed to explore the lung clearance index (LCI) as a marker for use in efficacy trials with inhaled antibiotics in CF. METHODS: This open-label, single-arm study enrolled CF patients with Pseudomonas aeruginosa infection, who were treated with tobramycin (28-day on/off regime). FEV1, LCI and bacterial load in sputum (CFU) were assessed at baseline, after 1, 4 and 8 weeks of treatment. RESULTS: All patients (n = 17) showed elevated LCI of > 11 despite 3 patients having normal FEV1 (> 90% predicted) at baseline. Overall, LCI improved in 8 (47%) patients and FEV1 in 9 (53%) patients. At week 4, LCI improved by 0.88, FEV1 increased by 0.52%, and P. aeruginosa reduced by 30,481.3 CFU/mL. These changes were however statistically non-significant. Six adverse events occurred in 5/17 (29.4%) patients, most of which were mild-to-moderate in severity. CONCLUSIONS: Due to the low evaluable sample size, no specific trend was observed related to the changes between LCI, FEV1 and CFU. Based on the individual data from this study and from recently published literature, LCI has been shown to be a more sensitive parameter than FEV1 for lung function. LCI can be hypothesized to be an appropriate endpoint for efficacy trials in CF patients if the heterogeneity in lung function is limited by enrolling younger patients or patients with more milder lung disease and thus, limiting the ventilation inhomogeneities. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov, identifier: NCT02248922.
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Antibacterianos/administración & dosificación , Fibrosis Quística/tratamiento farmacológico , Infecciones por Pseudomonas/tratamiento farmacológico , Tobramicina/administración & dosificación , Administración por Inhalación , Adolescente , Adulto , Niño , Fibrosis Quística/fisiopatología , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Proyectos Piloto , Pseudomonas aeruginosa/efectos de los fármacos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Adulto JovenRESUMEN
In the 12-month, open-label MANDELA study, patients were randomized at month 6 after heart transplantation to (i) convert to calcineurin inhibitor (CNI)-free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI-free, n=71), or to (ii) continue reduced-exposure CNI, with EVR and steroids (EVR/redCNI, n=74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI-free patients at radomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 post-transplant post-randomization) with superiority of the CNI-free group versus EVR/redCNI : mean 64.1mL/min/1.73m2 versus 52.9mL/min/1.73m2 ; difference +11.3mL/min/1.73m2 (p<0.001). By month 18, estimated GFR had increased by ≥10mL/min/1.732 in 31.8% and 55.2% of EVR/redCNI and CNI-free patients, respectively, and by ≥25 mL/min/1.73m2 in 4.5% and 20.9%. Rates of biopsy-proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI versus the CNI-free regimen (p=0.015); 6/15 episodes in CNI-free patients occurred with EVR concentration <5ng/mL. Rates of adverse events and associated discontinuations were comparable EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One-year renal function can be improved by early conversion to EVR-based CNI-free therapy but requires close EVR monitoring. This article is protected by copyright. All rights reserved.
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BACKGROUND: Palmoplantar pustular psoriasis (PPP) is a debilitating disease of the palms and/or soles that is resistant to treatment. Secukinumab, an anti-interleukin 17A monoclonal antibody, is highly efficacious in the treatment of moderate-to-severe psoriasis. OBJECTIVE: The primary objective was to determine the rate of achievement of a 75% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index (PPPASI75) with secukinumab at week 16 versus with placebo (at a 2.5% significance level). METHODS: 2PRECISE was a phase 3b multicenter, randomized, double-blind, placebo-controlled, parallel-group study comparing treatment with 300 mg of secukinumab (n = 79), 150 mg of secukinumab (n = 80), and placebo (n = 78) in subjects with moderate-to-severe PPP over a period of 52 weeks. RESULTS: The primary end point was not met. At week 16, 26.6% of subjects treated with 300 mg of secukinumab achieved PPPASI75 versus 14.1% of those who received placebo (P = .0411) (odds ratio, 2.62; 95% confidence interval, 1.04-6.60). At week 52, 41.8% of subjects treated with 300 mg of secukinumab had achieved ppPASI75. More Dermatology Life Quality Index responses of 0 or 1 were achieved with 300 mg of secukinumab (13.0%) than with placebo (4.3%) at week 16. At week 52, 43.1% of subjects receiving 300 mg of secukinumab had a Dermatology Life Quality Index response of 0 or 1. No unexpected adverse events were observed. LIMITATIONS: Small sample size and characteristics of the PPP disease course. CONCLUSION: Patients with PPP who were treated with secukinumab, 300 mg, showed benefit in terms of PPPASI75 responses over 52 weeks and improved quality of life.
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Anticuerpos Monoclonales/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Psoriasis/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Calidad de Vida , Índice de Severidad de la EnfermedadRESUMEN
Chronic pruritus is a bothersome symptom in psoriasis vulgaris and can profoundly reduce quality of life (QoL). In this exploratory analysis of the PSORITUS study, the impact of pruritus on QoL in 130 subjects with moderate-to-severe psoriasis was assessed using the ItchyQoL questionnaire. The majority of patients (n = 127) had to scratch their itchy skin regularly, which led to painful skin and frustration (mean ± standard deviation; SD ItchyQoL scores; 4.50 ± 0.56; 3.80 ± 1.09 and 4.20 ± 0.87, respectively). Changes in either temperature or season led to a worsening of itching in most of the patients (n = 126; mean ± SD ItchyQoL score; 3.80 ± 1.02). Many patients felt ashamed (n = 125) or embarrassed (n = 127) due to their itchy skin (mean ± SD ItchyQoL scores; 3.90 ± 1.26 and 3.40 ± 1.19, respectively). The results demonstrated the ItchyQoL questionnaire as a validated tool responsive to treatment for detailed insights into chronic pruritus in patients with psoriasis.
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Costo de Enfermedad , Prurito/diagnóstico , Psoriasis/diagnóstico , Calidad de Vida , Encuestas y Cuestionarios , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad Crónica , Fármacos Dermatológicos/uso terapéutico , Desconcierto , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prurito/tratamiento farmacológico , Prurito/psicología , Psoriasis/tratamiento farmacológico , Psoriasis/psicología , Reproducibilidad de los Resultados , VergüenzaAsunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Psoriasis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Placebos/efectos adversos , Psoriasis/diagnóstico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting ß2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD. METHODS: This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40â years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1â s (FEV1) ≥30% to <80% predicted) to QVA149 110/50â µg o.d. or TIO 18â µg o.d.+ FOR 12â µg twice daily (1:1) for 26â weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety. RESULTS: Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: -0.69 units; 95% CI -2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68â mL, 95% CI 37â mL to 100â mL; p<0.001) and FVC (+74â mL, 95% CI 24â mL to 125â mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%). CONCLUSIONS: QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD. TRIAL REGISTRATION NUMBER: NCT01120717.
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Broncodilatadores/uso terapéutico , Etanolaminas/uso terapéutico , Glicopirrolato/análogos & derivados , Indanos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/uso terapéutico , Derivados de Escopolamina/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Anciano , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Método Doble Ciego , Esquema de Medicación , Combinación de Medicamentos , Etanolaminas/administración & dosificación , Etanolaminas/efectos adversos , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Fumarato de Formoterol , Glicopirrolato/administración & dosificación , Glicopirrolato/efectos adversos , Glicopirrolato/uso terapéutico , Humanos , Indanos/administración & dosificación , Indanos/efectos adversos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Derivados de Escopolamina/administración & dosificación , Derivados de Escopolamina/efectos adversos , Bromuro de Tiotropio , Resultado del Tratamiento , Capacidad Vital/efectos de los fármacosRESUMEN
Background: Radiographic axial spondyloarthritis (r-axSpA), formerly known as ankylosing spondylitis (AS), is a chronic, inflammatory rheumatic disease associated with symptoms such as inflammatory back pain, morning stiffness, and arthritis. First-line recommendations for patients with AS include treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for reducing pain and stiffness. Objectives: The objective of our study is to evaluate the efficacy and short-term NSAID-sparing effect of secukinumab in patients with AS currently treated with NSAIDs. Design: We assessed the clinical Assessment of SpondyloArthritis International Society (ASAS20) response to secukinumab and evaluated the extent to which the use of concomitant NSAID can be reduced between weeks 4 and 12 in r-axSpA patients treated with secukinumab 150 mg compared with placebo. Methods: ASTRUM was a prospective 24-week randomized controlled trial of adult patients with active r-axSpA [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ⩾4] who had a documented inadequate response to ⩾2 NSAIDs. Patients were randomized (1:1:1) to initiate treatment with subcutaneous secukinumab 150 mg from either week 0 (group 1), week 4 (group 2), or week 16 (group 3). From week 4 onward, tapering of NSAIDs was allowed in all groups. Results: This study included 211 patients (n = 71, 70, and 70 in groups 1, 2, and 3, respectively). ASAS20 response at week 12 for pooled groups 1 and 2 versus group 3 was 51.1% versus 44.3% (p = 0.35). A higher proportion of patients in groups 1 and 2 achieved ASAS40 and BASDAI50 and showed improvements in other secondary clinical outcomes as compared to group 3 at week 16. More patients in groups 1 and 2 versus group 3 stopped their NSAID intake from baseline through week 16. Conclusion: Treatment with secukinumab improved clinical outcomes and showed a short-term NSAID-sparing effect in patients with r-axSpA, even though the primary endpoint was not met. Trial registration: ClinicalTrials.gov; NCT02763046, EudraCT 2015-004575-74.
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BACKGROUND: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis. METHODS: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion. Participants were assigned (1:1) to receive 300 mg secukinumab or placebo subcutaneously once a week up to week 4 and every 4 weeks thereafter. In both treatment groups, prednisolone dose was tapered down to 0 mg over a 26-week period. Patients, investigator staff, and clinical trial team were masked to the treatment assignment. The primary endpoint was the median proportion (Bayesian analysis) of patients with sustained remission until week 28 in the full analysis set (ie, all patients who received at least one dose of assigned treatment, analysed according to treatment assigned at randomisation). Sustained remission rate of the placebo group from a previous trial of tocilizumab in patients with giant cell arteritis was used to derive the prior distribution of placebo sustained remission rate for the primary endpoint. The safety of secukinumab was assessed in the safety set (ie, all patients who received at least one dose of study treatment, analysed according to study treatment received). This trial is completed and is registered with ClinicalTrials.gov, NCT03765788. FINDINGS: Of the 65 patients who were assessed for eligibility, 52 patients (median age 75 years [IQR 69-79]; 35 [67%] female and 17 [33%] male, 52 [100%] White) were enrolled between Jan 30, 2019 and March 30, 2020 and were randomly assigned to receive secukinumab (n=27) or placebo (n=25). Four of 27 patients in the secukinumab group and eight of 25 patients in the placebo group discontinued treatment by week 28 of the study. On the basis of the Bayesian analysis, the median proportion of patients in sustained remission until week 28 was 70% (95% credibility interval 52-85) in the secukinumab group versus 20% (12-30) in the placebo group. The incidence of adverse events was similar in the secukinumab (27 [100%] of 27 patients had any adverse event) and placebo groups (24 [96%] of 25 patients had any adverse event); the most common adverse events were hypertension (six [22%] of 27 patients in the secukinumab group and eight [32%] of 25 patients in the placebo group) and nasopharyngitis (five [19%] of 27 patients in the secukinumab group and five [20%] of 25 patients in the placebo group). Two patients (one in each group) died during the study, neither of which was considered to be related to study treatment. INTERPRETATION: Patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, in combination with glucocorticoid taper regimen. Secukinumab was tolerated well with no new safety concerns. This proof-of-concept phase 2 study further supports the development of secukinumab as a treatment option for people with giant cell arteritis. FUNDING: Novartis Pharma.
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Anticuerpos Monoclonales Humanizados , Arteritis de Células Gigantes , Anciano , Femenino , Humanos , Masculino , Teorema de Bayes , Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides , Prednisolona , Método Doble CiegoRESUMEN
BACKGROUND: Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. METHODS: Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. RESULTS: 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23-6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8. 15.7 ± 14.3% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95%CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. C48h was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks AUC0-48h was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. CONCLUSIONS: Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.
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Anticoagulantes/administración & dosificación , Heparina de Bajo-Peso-Molecular/administración & dosificación , Diálisis Renal/métodos , Insuficiencia Renal Crónica/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/prevención & control , Femenino , Hemorragia/sangre , Hemorragia/inducido químicamente , Heparina de Bajo-Peso-Molecular/efectos adversos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/terapia , Factores de TiempoRESUMEN
BACKGROUND: A subgroup of patients with chronic spontaneous urticaria (CU) exhibits IgE antibodies directed against autoantigens, such as thyroperoxidase (TPO). We conducted this study to investigate whether such patients with CU with IgE against TPO benefit from treatment with omalizumab, a humanized anti-IgE mAb licensed for the treatment of severe persistent allergic (IgE-mediated) asthma. OBJECTIVES: We sought to assess the efficacy of omalizumab treatment in patients with CU with IgE autoantibodies against TPO. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study patients with CU (male/female, 18-70 years of age) with IgE autoantibodies against TPO who had persistent symptoms (wheals and pruritus) despite standard antihistamine therapy were randomized to receive either omalizumab (75-375 mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeks. The primary end point was the change from baseline in mean weekly urticaria activity score after 24 weeks of treatment, as calculated from patients' diaries. The safety and tolerability of omalizumab were also assessed. RESULTS: Of the 49 randomized patients (omalizumab, n = 27; placebo, n = 22), 42 completed the study. At week 24, patients demonstrated a mean reduction in the weekly urticaria activity score from baseline of 17.8 with omalizumab and 7.9 with placebo (P = .0089). Complete protection from wheal development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in the placebo group. The rate of adverse events was similar in both groups. CONCLUSIONS: The results of this study indicate that omalizumab is an effective treatment option for patients with CU with IgE autoantibodies against TPO who are refractory to conventional treatment.
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Antialérgicos/uso terapéutico , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Autoanticuerpos/sangre , Autoantígenos/inmunología , Urticaria/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Autoanticuerpos/inmunología , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Omalizumab , Urticaria/sangre , Urticaria/inmunología , Adulto JovenRESUMEN
BACKGROUND: Despite the elevated risk for developing venous thromboembolic events in patients with heart failure, there are no randomized, double-blind, controlled trial data on the comparison of low-molecular-weight heparin with unfractionated heparin (UFH) in this patient population. METHODS: This was a subgroup analysis of the CERTIFY trial, which included 3,239 nonsurgical, acutely ill medical patients 70 years or older. Patients were randomized to receive 3,000-U anti-Xa certoparin once daily or 5,000-IU UFH 3 times a day. The analysis was performed on a subgroup of 542 patients diagnosed with heart failure at hospital admission. RESULTS: Patients with heart failure differed from patients without heart failure in that they were more likely using antiplatelets (67.2% vs 48.9%; P < .0001) and had a lower glomerular filtration rate (8.0% vs 5.5%; ≤ 30 mL/min per 1.73 m²; P = .0232). Thromboembolic risk was comparable except for a higher incidence of distal deep venous thrombosis (DVT) in patients with heart failure (10.80% vs 7.26%; P = .0144). Within the heart failure population, patient characteristics were comparable between randomized treatment groups. The incidence of the primary end point (proximal DVT, symptomatic nonfatal pulmonary embolism, and venous thromboembolism-related death combined) was numerically, slightly smaller with certoparin (3.78% vs 4.74% with UFH; odds ratio 0.79, 95% CI 0.32-1.94), and the incidence of major bleeding was 0.72% with certoparin versus 0.38% with UFH. CONCLUSIONS: Patients hospitalized for heart failure are at high risk for developing distal DVT and bleeding complications compared with acutely ill medical patients without heart failure. Within the heart failure population, the observed differences in prophylactic efficacy between 3,000-U anti-Xa certoparin once daily and 5,000-IU UFH 3 times a day were similar to those observed in the overall study population; this suggests that certoparin might be at least as effective as UFH also in this subgroup. There were no relevant differences in bleeding risk or frequency of adverse events.
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Anticoagulantes/uso terapéutico , Insuficiencia Cardíaca/complicaciones , Heparina de Bajo-Peso-Molecular/uso terapéutico , Heparina/uso terapéutico , Hospitalización , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Anciano , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/terapia , Humanos , MasculinoRESUMEN
BACKGROUND: Patients with cancer have an increased risk of VTE. We compared VTE rates and bleeding complications in 1) cancer patients receiving LMWH or UFH and 2) patients with or without cancer. METHODS: Acutely-ill, non-surgical patients ≥ 70 years with (n = 274) or without cancer (n = 2,965) received certoparin 3,000 UaXa o.d. or UFH 5,000 IU t.i.d. for 8-20 days. RESULTS: 1) Thromboembolic events in cancer patients (proximal DVT, symptomatic non-fatal PE and VTE-related death) occurred at 4.50% with certoparin and 6.03% with UFH (OR 0.73; 95% CI 0.23-2.39). Major bleeding was comparable and minor bleedings (0.75 vs. 5.67%) were nominally less frequent. 7.5% of certoparin and 12.8% of UFH treated patients experienced serious adverse events. 2) Thromboembolic event rates were comparable in patients with or without cancer (5.29 vs. 4.13%) as were bleeding complications. All cause death was increased in cancer (OR 2.68; 95%CI 1.22-5.86). 10.2% of patients with and 5.81% of those without cancer experienced serious adverse events (OR 1.85; 95% CI 1.21-2.81). CONCLUSIONS: Certoparin 3,000 UaXa o.d. and 5,000 IU UFH t.i.d. were equally effective and safe with respect to bleeding complications in patients with cancer. There were no statistically significant differences in the risk of thromboembolic events in patients with or without cancer receiving adequate anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov, NCT00451412.
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Heparina de Bajo-Peso-Molecular/uso terapéutico , Heparina/uso terapéutico , Neoplasias/complicaciones , Tromboembolia/prevención & control , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Método Doble Ciego , Femenino , Hemorragia/complicaciones , Hemorragia/prevención & control , Heparina/análogos & derivados , Humanos , Modelos Logísticos , Masculino , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Tromboembolia/complicaciones , Resultado del Tratamiento , Trombosis de la Vena/prevención & controlRESUMEN
BACKGROUND: One key pathological finding in giant cell arteritis (GCA) is the presence of interferon-gamma and interleukin (IL)-17 producing T helper (Th) 1 and Th17 cells in affected arteries. There is anecdotal evidence of successful induction and maintenance of remission with the monoclonal anti-IL-17A antibody secukinumab. Inhibition of IL-17A could therefore represent a potential new therapeutic option for the treatment of GCA. METHODS: This is a randomized, parallel-group, double-blind, placebo-controlled, multi-center, phase II study in which patients, treating physicians, and the associated clinical staff as well as the sponsor clinical team are blinded. It is designed to evaluate efficacy and safety of secukinumab compared to placebo in combination with an open-label prednisolone taper regimen. Patients included are naïve to biological therapy and have newly diagnosed or relapsing GCA. Fifty patients are randomly assigned in a 1:1 ratio to receive either 300 mg secukinumab or placebo subcutaneously at baseline, weeks 1, 2 and 3, and every 4 weeks from week 4. Patients in both treatment arms receive a 26-week prednisolone taper regimen. The study consists of a maximum 6-week screening period, a 52-week treatment period (including the 26-week tapering), and an 8-week safety follow-up, with primary and secondary endpoint assessments at week 28. Patients who do not achieve remission by week 12 experience a flare after remission or cannot adhere to the prednisolone tapering will enter the escape arm and receive prednisolone at a dose determined by the investigator's clinical judgment. The blinded treatment is continued. Two optional imaging sub-studies are included (ultrasound and contrast-media enhanced magnetic resonance angiography [MRA]) to assess vessel wall inflammation and occlusion before and after treatment. The primary endpoint is the proportion of patients in sustained remission until week 28 in the secukinumab group compared to the proportion of patients in the placebo group. A Bayesian approach is applied. DISCUSSION: The trial design allows the first placebo-controlled data collection on the efficacy and safety of secukinumab in patients with GCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT03765788 . Registration on 5 December 2018, prospective registration, EudraCT number 2018-002610-12; clinical trial protocol number CAIN457ADE11C.
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Arteritis de Células Gigantes , Anticuerpos Monoclonales Humanizados , Teorema de Bayes , Ensayos Clínicos Fase II como Asunto , Método Doble Ciego , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Humanos , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
AIMS: ACTIVITY-HF was a randomized, double-blind, active-controlled study, which assessed the short-term effect of sacubitril/valsartan compared with the active comparator enalapril on improving maximal exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 201 ambulatory patients with HFrEF (left ventricular ejection fraction ≤ 40%, New York Heart Association class III) across 34 centres in Germany were randomized (1:1) to receive sacubitril/valsartan 97/103 mg bid (n = 103) or enalapril 10 mg bid (n = 98). The primary endpoint of the study was the change from baseline in peak oxygen consumption (VO2 ; adjusted to body weight) after 12 weeks, and the key secondary endpoint was change from baseline in peak VO2 after 6 weeks. The study population was predominantly male (81.1%) with a mean age of 66.9 years and a body mass index of 29.4 kg/m2 . Change in peak VO2 from baseline to Week 12 was similar between sacubitril/valsartan and enalapril groups [least squares mean difference: 0.32 mL/min/kg; 95% confidence interval (CI) -0.21, 0.85; P = 0.2327]. Similarly, no significant differences were observed between the two treatment groups in minute ventilation to carbon dioxide production slope, exercise capacity at first ventilatory threshold or Borg scale at either Week 6 or Week 12. Change in heart rate at first ventilatory threshold was lower in the sacubitril/valsartan group compared with the enalapril group at Week 12 (mean -3.75 bpm; 95% CI -7.03, -0.48; P = 0.0248). The safety of sacubitril/valsartan was comparable to enalapril. CONCLUSION: In patients with HFrEF, short-term treatment with sacubitril/valsartan for 12 weeks did not result in significant benefits on peak VO2 when compared with enalapril.
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Aminobutiratos , Compuestos de Bifenilo , Enalapril , Insuficiencia Cardíaca , Valsartán , Anciano , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Combinación de Medicamentos , Enalapril/uso terapéutico , Femenino , Humanos , Masculino , Consumo de Oxígeno , Volumen Sistólico , Tetrazoles/uso terapéutico , Valsartán/uso terapéutico , Función Ventricular IzquierdaRESUMEN
A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Hidroxiurea/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Factores de Edad , Anciano , Antineoplásicos Alquilantes/efectos adversos , Benzamidas , Terapia Combinada , Dacarbazina/efectos adversos , Dacarbazina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Temozolomida , Resultado del Tratamiento , Adulto JovenRESUMEN
Psoriasis increases the risk of cardiovascular (CV) disease. Secukinumab, a fully human monoclonal antibody against IL-17A, shows significant efficacy in psoriasis, but effects on CV markers are unknown. CARIMA (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab) was a 52-week, randomized, double-blind, placebo-controlled, exploratory trial in patients with moderate to severe plaque psoriasis without clinical CV disease. Patients were randomly assigned to receive 300 mg or 150 mg secukinumab until week 52 or to receive placebo until week 12 and then 300 mg or 150 mg secukinumab until week 52. The primary outcome was endothelial function measured by flow-mediated dilation (FMD). Baseline FMD was significantly lower in psoriasis patients than healthy volunteers (4.4 ± 3.9% vs. 6.1 ± 3.3%, P = 0.01). At week 12, baseline-adjusted mean FMD was numerically higher in patients receiving secukinumab versus those receiving placebo, but this difference (300-mg group, +1.2%; 150-mg group, +0.76%; P = 0.223 and P = 0.403 by analysis of covariance) did not reach significance. At week 52, FMD increased across groups. FMD was significantly higher than baseline in patients receiving the label dose of 300 mg secukinumab for 52 weeks (+2.1%, 95% confidence interval = 0.8-3.3; P = 0.0022). Other relevant CV markers were unchanged. CARIMA indicates that secukinumab might have a beneficial effect on CV risk by improving the endothelial function of patients with plaque psoriasis.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Psoriasis/tratamiento farmacológico , Psoriasis/epidemiología , Adulto , Biomarcadores/sangre , Enfermedades Cardiovasculares/prevención & control , Comorbilidad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Endotelio Vascular/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Psoriasis/diagnóstico , Valores de Referencia , Flujo Sanguíneo Regional/efectos de los fármacos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVES: Microalbuminuria is known as an independent predictor for stroke, myocardial infarction, and death. The purpose of the VALERIA trial was a comparison of the efficacy and safety of combination therapy of valsartan and lisinopril with valsartan and lisinopril high-dose monotherapy in patients with hypertension and microalbuminuria. METHODS: This was a randomized, double-blind, interventional, parallel-group study. After a washout/placebo-run-in phase of 3 weeks, 133 patients were randomized to treatment (1: 1:1) with either lisinopril 40 mg, valsartan 320 mg, or a combination of valsartan/lisinopril 320/20 mg for 30 weeks. RESULTS: At baseline, the urine albumin creatinine ratio was similar for the three treatment groups (geometric means, lisinopril 9.6 mg/mmol, valsartan 9.1 mg/mmol, and valsartan/lisinopril 9.5 mg/mmol). After 30 weeks of treatment, the geometric mean urine albumin creatinine ratio had decreased in all three groups by 41, 51, and 62% to 5.7 mg/mmol (lisinopril), 4.5 mg/mmol (valsartan), and 3.6 mg/mmol (valsartan/lisinopril). The decrease for valsartan/lisinopril was statistically significantly greater compared with lisinopril [adjusted ratio 60%, confidence interval (38-94%), P = 0.029]. Normalization of microalbuminuria was greatest with valsartan and valsartan/lisinopril (lisinopril 17%, valsartan 31%, and valsartan/lisinopril 38% of patients) and was statistically significant for lisinopril in contrast with valsartan/lisinopril (P = 0.034). Differences in blood pressure reduction between the groups were not statistically significant. All treatments were safe and well tolerated. CONCLUSION: The combination of valsartan and lisinopril provided a significantly better reduction of urine albumin creatinine ratio and more than doubled the rate of patients with normalized urine albumin creatinine ratio compared with lisinopril alone. All treatments were safe and well tolerated.