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1.
Mult Scler ; 30(7): 833-842, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38619037

RESUMEN

BACKGROUND: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension. METHODS: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension. RESULTS: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39-0.98; p = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33-0.98; p = 0.043) and 49% (RR 0.511; 95% CI 0.34-0.76; p = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23-0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group. CONCLUSION: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings.ClinicalTrials.gov: NCT02201108.


Asunto(s)
Crotonatos , Hidroxibutiratos , Esclerosis Múltiple Recurrente-Remitente , Nitrilos , Toluidinas , Humanos , Toluidinas/efectos adversos , Toluidinas/uso terapéutico , Toluidinas/administración & dosificación , Toluidinas/farmacología , Crotonatos/efectos adversos , Crotonatos/uso terapéutico , Nitrilos/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Femenino , Masculino , Método Doble Ciego , Adolescente , Niño , Resultado del Tratamiento , Imagen por Resonancia Magnética
2.
Mult Scler ; 26(9): 1083-1092, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-31172849

RESUMEN

BACKGROUND: In Phase 3 studies, teriflunomide reduced relapse rates and disability progression compared with placebo; however, decreases in lymphocyte counts were also observed. OBJECTIVE: To describe the effect of long-term teriflunomide treatment on lymphocyte counts and infection rates among patients in pooled analyses of Phase 3 core and extension studies. METHODS: Four randomized trials (TEMSO, TOWER, TENERE, and TOPIC) compared teriflunomide 7 mg or 14 mg treatment with either placebo and/or subcutaneous interferon (IFN) ß-1a 44 µg in patients with relapsing forms of multiple sclerosis (MS) (or first clinical episode suggestive of MS in TOPIC). RESULTS: In 1895, patients ever exposed to teriflunomide, mean (standard deviation) absolute lymphocyte counts declined from Week 0 (1.89 (0.59)) to Week 24 (1.67 (0.52)) and then remained stable thereafter. In the core plus extension studies (up to 10.7 years), 7.3% and 2.2% experienced Grade 1 and Grade 2 lymphopenia, respectively. Infections were reported in 56.9% of patients without lymphopenia, 60.9% with Grade 1 lymphopenia, and 54.8% with Grade 2 lymphopenia. Serious infections occurred in 3.7%, 4.3%, and 7.1%, respectively. CONCLUSION: Long-term risk of lymphopenia and infections in patients who continue to receive teriflunomide is low, demonstrating a limited impact on adaptive and innate immunity.


Asunto(s)
Crotonatos , Hidroxibutiratos , Inmunosupresores , Esclerosis Múltiple Recurrente-Remitente , Nitrilos , Toluidinas , Crotonatos/efectos adversos , Crotonatos/uso terapéutico , Femenino , Humanos , Hidroxibutiratos/uso terapéutico , Inmunosupresores/uso terapéutico , Recuento de Linfocitos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Nitrilos/uso terapéutico , Toluidinas/efectos adversos , Toluidinas/uso terapéutico
3.
Mult Scler ; 26(7): 829-836, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-30968734

RESUMEN

BACKGROUND: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. OBJECTIVES: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. METHODS: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). RESULTS: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. CONCLUSIONS: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.


Asunto(s)
Anomalías Inducidas por Medicamentos/epidemiología , Ensayos Clínicos como Asunto , Crotonatos/efectos adversos , Hidroxibutiratos/efectos adversos , Inmunosupresores/efectos adversos , Esclerosis Múltiple/tratamiento farmacológico , Nitrilos/efectos adversos , Complicaciones del Embarazo/inducido químicamente , Complicaciones del Embarazo/epidemiología , Resultado del Embarazo/epidemiología , Vigilancia de Productos Comercializados , Toluidinas/efectos adversos , Adulto , Femenino , Humanos , Recién Nacido , Embarazo , Estudios Prospectivos , Estudios Retrospectivos
4.
Mult Scler ; 24(4): 535-539, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28304217

RESUMEN

Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting multiple sclerosis (MS). The objective of this post hoc analysis of the phase 3, pooled TEMSO (NCT00134563) and TOWER (NCT00751881) dataset is to evaluate the effect of teriflunomide treatment on annualised relapse rate and disability worsening across patient subgroups defined according to prior disease-modifying therapy exposure. This analysis provides further supportive evidence for a consistent effect of teriflunomide across a broad range of patients with relapsing MS, including patients who have used and discontinued other disease-modifying therapies.


Asunto(s)
Crotonatos/farmacología , Factores Inmunológicos/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Toluidinas/farmacología , Adulto , Análisis de Datos , Femenino , Humanos , Hidroxibutiratos , Masculino , Persona de Mediana Edad , Nitrilos , Recurrencia , Prevención Secundaria , Resultado del Tratamiento
5.
Mult Scler ; 20(6): 705-16, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24126064

RESUMEN

BACKGROUND: In previous studies, teriflunomide significantly reduced the annualised relapse rate (ARR) and disability progression. OBJECTIVE: This phase 3, rater-blinded study (NCT00883337) compared teriflunomide with interferon-beta-1a (IFNß-1a). METHODS: Patients with relapsing multiple sclerosis were randomised (1:1:1) to oral teriflunomide 7-or 14 mg, or subcutaneous IFNß-1a 44 µg. The primary composite endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included ARR, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised. RESULTS: Some 324 patients were randomised (IFNß-1a: 104; teriflunomide 7 mg: 109; teriflunomide 14 mg: 111). No difference in time to failure was observed. There was no difference in ARR between teriflunomide 14 mg and IFNß-1a, but ARR was significantly higher with teriflunomide 7 mg. FIS scores indicated more frequent fatigue with IFNß-1a, though differences were only significant with teriflunomide 7 mg. TSQM scores were significantly higher with teriflunomide. There were no unexpected safety findings. CONCLUSION: Effects on time to failure were comparable between teriflunomide and IFNß-1a. There was no difference between teriflunomide 14 mg and IFNß-1a on ARR, though ARR was higher with teriflunomide 7 mg. The teriflunomide safety profile was consistent with previous studies.


Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Crotonatos/uso terapéutico , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Toluidinas/uso terapéutico , Adulto , Anciano , Crotonatos/administración & dosificación , Progresión de la Enfermedad , Femenino , Humanos , Hidroxibutiratos , Interferón beta-1a , Masculino , Persona de Mediana Edad , Nitrilos , Recurrencia , Toluidinas/administración & dosificación , Resultado del Tratamiento
6.
Clin Transl Sci ; 17(1): e13690, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38010108

RESUMEN

SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor-interacting serine/threonine protein kinase 1 (RIPK1). This phase I first-in-human healthy participant study (NCT05795907) was comprised of three parts: randomized, double-blind, placebo-controlled single ascending dose (SAD; part 1a); 14-day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open-label, single-dose part 1b (PK-cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well-tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half-lives (geometric mean) ranged between 5.7-8.0 h and 7.2-8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF-to-unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166-RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough ) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547).


Asunto(s)
Encéfalo , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Adulto , Humanos , Voluntarios Sanos , Relación Dosis-Respuesta a Droga , Área Bajo la Curva , Semivida , Método Doble Ciego
7.
Lancet Neurol ; 20(12): 1001-1011, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34800398

RESUMEN

BACKGROUND: Therapeutic options for children with multiple sclerosis are scarce. Teriflunomide is approved in more than 80 countries for the treatment of adults with relapsing multiple sclerosis. The TERIKIDS study examined the safety and efficacy of teriflunomide in children with relapsing multiple sclerosis. METHODS: The TERIKIDS trial was a multicentre, phase 3, double-blind, parallel-group, randomised, placebo-controlled study conducted at 57 clinical centres in 22 countries in Asia, Europe, the Middle East, North Africa, and North America. The trial enrolled patients aged 10-17 years, diagnosed with relapsing multiple sclerosis and with at least one relapse in the year preceding screening or at least two relapses in the 2 years preceding screening. Patients were randomly assigned (2:1) to oral teriflunomide (dosage equivalent to 14 mg in adults) or matching placebo, using an interactive web and voice response system, for up to 96 weeks. Personnel in all sites and all patients were masked to study treatment in the double-blind period. Early entry into a subsequent 96-week open-label extension phase was possible before the end of the double-blind period for patients with confirmed clinical relapse or high MRI activity (at least five new or enlarged T2 lesions at week 24, followed by at least nine new or enlarged T2 lesions at week 36, or at least five new or enlarged T2 lesions at weeks 36 and 48, or at weeks 48 and 72). The primary endpoint was time to first confirmed clinical relapse by the end of the double-blind period. Key secondary imaging endpoints were number of new or enlarged T2 lesions and number of gadolinium-enhancing lesions per MRI scan. Efficacy endpoints were analysed in the intention-to-treat population, and safety was assessed in all patients randomly assigned to treatment and exposed to the double-blind study medication. This study is registered with ClinicalTrials.gov (trial number NCT02201108) and is closed to recruitment, but an additional optional open-label extension is ongoing. FINDINGS: Between July 24, 2014, and the date of last patient visit on Oct 25, 2019, 185 patients were screened for eligibility, 166 (90%) were enrolled, and 109 were randomly assigned teriflunomide and 57 were randomly assigned placebo. 102 (94%) of 109 and 53 (93%) of 57 completed the double-blind period. Switch to the ongoing open-label extension because of high MRI activity was more frequent than anticipated in the placebo group (14 [13%] of 109 patients in the teriflunomide group vs 15 [26%] of 57 in the placebo group), decreasing the power of the study. After 96 weeks, there was no difference in time to first confirmed clinical relapse with teriflunomide compared with placebo (hazard ratio 0·66, 95% CI 0·39-1·11; p=0·29). Teriflunomide reduced the number of new or enlarged T2 lesions versus placebo by 55% (relative risk 0·45, 95% CI 0·29-0·71; p=0·00061), and the number of gadolinium-enhancing lesions by 75% (relative risk 0·25, 0·13-0·51; p<0·0001). Adverse events occurred in 96 (88%) patients in the teriflunomide group and 47 (82%) patients in the placebo group; serious adverse events occurred in 12 (11%) patients in the teriflunomide group and 6 (11%) patients in the placebo group. Nasopharyngitis, upper-respiratory-tract infection, alopecia, paraesthesia, abdominal pain, and increased blood creatine phosphokinase were more frequent with teriflunomide than with placebo. During the double-blind phase, four patients in the teriflunomide group had pancreatic adverse events (two with acute pancreatitis and two with pancreatic enzyme elevation), of which three events led to treatment discontinuation. INTERPRETATION: No significant difference in time to first confirmed clinical relapse was found, possibly because more patients than expected switched from the double-blind to the open-label treatment period because of high MRI activity. Key secondary imaging analyses and a prespecified sensitivity analysis of probability of relapse or high MRI activity suggest that teriflunomide might have beneficial effects in children with relapsing multiple sclerosis by reducing the risk of focal inflammatory activity. FUNDING: Sanofi.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Pancreatitis , Enfermedad Aguda , Adolescente , Adulto , Niño , Crotonatos , Método Doble Ciego , Humanos , Hidroxibutiratos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Nitrilos , Toluidinas , Resultado del Tratamiento
8.
Eur J Nucl Med Mol Imaging ; 37(6): 1095-105, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20204358

RESUMEN

PURPOSE: Accurate staging of Hodgkin's lymphoma (HL) is necessary in selecting appropriate treatment. Bone marrow trephine biopsy (BMB) is the standard procedure for depicting bone marrow involvement. BMB is invasive and explores a limited part of the bone marrow. (18)F-FDG PET/CT is now widely used for assessing response to therapy in HL and a baseline study is obtained to improve accuracy. The aim of this retrospective analysis was to assess whether routine BMB remains necessary with concomitant (18)F-FDG PET/CT. METHODS: Data from 83 patients (newly diagnosed HL) were reviewed. All patients had received contrast-enhanced CT, BMB and (18)F-FDG PET/CT. Results of BMB were not available at the time of (18)F-FDG PET/CT imaging. RESULTS: Seven patients had lymphomatous involvement on BMB. Four patients had bone involvement on conventional CT (two with negative BMB). All patients with bone marrow and/or bone lesions at conventional staging were also diagnosed on (18)F-FDG PET/CT scan. PET/CT depicted FDG-avid bone/bone marrow foci in nine additional patients. Four of them had only one or two foci, while the other had multiple foci. However, the iliac crest, site of the BMB, was not involved on (18)F-FDG PET/CT. Osteolytic/sclerotic lesions matching FDG-avid foci were visible on the CT part of PET/CT in three patients. MRI ordered in three other patients suggested bone marrow involvement. Interim and/or end-therapy (18)F-FDG PET/CT documented response of FDG-avid bone/bone marrow foci to chemotherapy in every patient. CONCLUSION: (18)F-FDG PET/CT highly improves sensitivity for diagnosis of bone/bone marrow lesions in HL compared to conventional staging.


Asunto(s)
Médula Ósea/patología , Huesos/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Enfermedad de Hodgkin/patología , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/diagnóstico por imagen , Niño , Femenino , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/terapia , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Adulto Joven
9.
Mult Scler Relat Disord ; 46: 102438, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32911306

RESUMEN

BACKGROUND: In the phase 3 TOWER core study (NCT00751881), the efficacy and safety of teriflunomide compared with placebo were demonstrated in patients with relapsing forms of multiple sclerosis (RMS). Here, the long-term safety and efficacy outcomes from the TOWER extension study (NCT00751881) are reported. METHODS: All patients who entered the extension (N = 751) were assigned to teriflunomide 14 mg and assessed for long-term safety and efficacy. RESULTS: Of 751 patients in the TOWER extension study, 253, 265, and 233 patients received placebo/teriflunomide 14 mg, teriflunomide 7 mg/14 mg, and teriflunomide 14 mg/14 mg, respectively. Median teriflunomide exposure was 4.25 years (maximum 6.3 years). The overall frequency of adverse events (AEs) was comparable across treatment groups, but a higher proportion of patients in the teriflunomide 7 mg/14 mg (12.4%) and 14 mg/14 mg (12.4%) groups had serious AEs compared with the placebo/teriflunomide 14 mg group (6.4%). Alanine aminotransferase increase and hair thinning occurred at a higher frequency in the placebo/teriflunomide 14 mg group (11.2% and 14.3%, respectively) compared with the teriflunomide 7 mg/14 mg (3.0% and 4.5%, respectively) and 14 mg/14 mg groups (5.2% and 4.3%, respectively). The incidences of AEs of interest (hematologic and hepatic effects, peripheral neuropathy, hypertension, and malignancy) were low and comparable across treatment arms. Disability worsening and adjusted annualized relapse rates were low and stable over time, and mean Expanded Disability Status Scale scores were unchanged over time, for all treatment groups. CONCLUSION: In the TOWER extension study, the efficacy of teriflunomide 14 mg was maintained in patients with RMS. No new or unexpected AEs were observed with teriflunomide treatment, supporting a safety profile in the extension that was consistent with the core trial. These findings support the positive benefit:risk profile of teriflunomide as a long-term immunomodulatory therapy.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Crotonatos/efectos adversos , Humanos , Hidroxibutiratos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Nitrilos , Recurrencia , Toluidinas/efectos adversos
10.
J Clin Neurosci ; 59: 229-231, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30348586

RESUMEN

In the phase 3 TOWER (NCT00751881) study, teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of 12-week confirmed disability worsening (12-w CDW) vs placebo in patients with relapsing forms of MS (RMS). The TOWER population included an appreciable proportion of Asian patients. Reductions in ARR and 12-w CDW associated with teriflunomide 14 mg were comparable between the Asian and overall populations, as were the rates for adverse events and serious adverse events, with no new or unexpected safety findings. These observations provide further evidence to support the clinical benefits and safety profile of teriflunomide in a broad range of patients with RMS.


Asunto(s)
Crotonatos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Toluidinas/uso terapéutico , Adulto , Pueblo Asiatico , Método Doble Ciego , Femenino , Humanos , Hidroxibutiratos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Nitrilos , Recurrencia
11.
Mult Scler Relat Disord ; 31: 157-164, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31005729

RESUMEN

BACKGROUND: The demographics and management of patients with multiple sclerosis (MS) differ across geographical regions, but it is unclear whether/how these differences affect treatment outcomes. The aim of this post-hoc analysis was to assess teriflunomide use and patient-reported outcomes in the United States (US) and the rest of the world (ROW) in the phase 4 Teri-PRO study (NCT01895335). METHODS: In the phase 4, real-world, Teri-PRO study, patients with relapsing forms of MS received teriflunomide for 48 weeks according to local labeling. The primary endpoint was treatment satisfaction measured using the Treatment Satisfaction Questionnaire for Medication Version 1.4 (TSQM 1.4). Secondary endpoints included scores on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Performance Scale (MSPS), and Patient-Determined Disease Steps (PDDS), and occurrence of adverse events. Primary and secondary endpoints were assessed at baseline and Week 48. An exploratory subgroup analysis assessed PROs in the black patient population. RESULTS: The US and ROW groups included 545 and 455 patients, respectively. The mean age of patients in the ROW group was lower, they had a shorter mean time since first symptoms of MS, and had lower mean EDSS scores at baseline, compared with the US group (all p < 0.0001). Black patients made up 9% of US patients vs 0.2% of ROW patients. TSQM global satisfaction scores and effectiveness, side effects, and convenience subscale scores were significantly improved from baseline to Week 48 (all p < 0.0001). Disability measures were stable from baseline to Week 48 for both groups, despite different baseline level scores between the two groups. The overall proportion of patients who experienced an AE was similar across both groups. Fewer patients in the US group vs the ROW group reported hair thinning (16.1% vs 31.2%). Black patients showed comparable baseline demographics and disease characteristics and similar change over time in PROs compared with the overall US group. CONCLUSION: Patient differences observed at baseline between the US and ROW groups suggest variation in teriflunomide prescribing practices in the real-world Teri-PRO study. Improvement in treatment satisfaction and stability of disability measures were comparable between patients in the US and ROW. This suggests that teriflunomide was effective despite differences in baseline demographics and possible cultural and management differences between these geographical regions.


Asunto(s)
Crotonatos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Toluidinas/uso terapéutico , Adulto , Femenino , Humanos , Hidroxibutiratos , Masculino , Persona de Mediana Edad , Nitrilos , Medición de Resultados Informados por el Paciente , Estudios Prospectivos , Resultado del Tratamiento
12.
Mult Scler Relat Disord ; 33: 131-138, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31195337

RESUMEN

BACKGROUND: In the phase 3 TOPIC study, teriflunomide significantly reduced the risk of relapse determining conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome, versus placebo. We assessed clinical and safety outcomes associated with extended teriflunomide treatment in the TOPIC extension study. METHODS: Patients who completed the TOPIC core study (including those still on study at early termination) or converted to CDMS after at least 24 weeks in the core study were eligible to participate in the extension. The primary efficacy endpoint in the extension was time to conversion to CDMS. RESULTS: Risk of relapse determining conversion to CDMS was 47.1% lower in patients treated with teriflunomide 14 mg during the core and extension studies compared with patients treated with placebo during the core study and teriflunomide 14 mg during the extension. The incidence of adverse events was 75.8% and 81.9% for 7 and 14 mg teriflunomide, respectively. CONCLUSIONS: Reduced risk of relapse determining conversion to CDMS in patients with early MS receiving teriflunomide 14 mg in the core study remained throughout the extension supporting the benefits of early treatment. No new safety signals were observed for teriflunomide 7 or 14 mg.


Asunto(s)
Crotonatos/uso terapéutico , Enfermedades Desmielinizantes/tratamiento farmacológico , Esclerosis Múltiple/prevención & control , Toluidinas/uso terapéutico , Adulto , Método Doble Ciego , Femenino , Humanos , Hidroxibutiratos , Masculino , Nitrilos
13.
Clin Nucl Med ; 33(5): 353-5, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18431156

RESUMEN

A 51-year-old man presented with a hard subcutaneous nodule adhering to the underlying bone structures of the left eyelid in 2004. Histopathology showed a desmoplastic neurotropic melanoma (DNM) with perineural invasion. Patient presented with a first recurrence in October 2005, which was treated by surgery. In August 2006 he presented with trigeminal neuralgia of the left face in the area innervated by the first and second branches of the trigeminal nerve. A PET scan clearly shows the tumoral hypermetabolism of the subcutaneous recurrence of the neurotropic melanoma with invasion of the second or maxillary branch that follows the nerve up to the trigeminal ganglion, which was detected despite the physiological high uptake in the temporal lobe. MRI confirms the invasion and a second PET and MRI 6 months later done to evaluate resectability showed progressive disease. DNM is a rare subtype of spindle cell melanoma. It corresponds to dermal proliferation of desmoplastic cells of neural differentiation. Unlike other melanomas, however, survival for DNM may be better compared with other forms of melanoma. This rare case report presents PET imaging involving cranial nerve invasion by this uncommon melanoma subtype.


Asunto(s)
Fibroma Desmoplásico/complicaciones , Fibroma Desmoplásico/diagnóstico , Melanoma/complicaciones , Melanoma/diagnóstico , Neoplasias Orbitales/complicaciones , Neoplasias Orbitales/diagnóstico , Neuralgia del Trigémino/diagnóstico , Neuralgia del Trigémino/etiología , Adulto , Fluorodesoxiglucosa F18 , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Tomografía Computarizada por Rayos X/métodos
14.
Mult Scler Relat Disord ; 26: 211-218, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30273841

RESUMEN

BACKGROUND: Patient-reported outcomes (PROs) can assist clinicians in understanding the impact of disease-modifying therapy (DMT) on the daily lives of patients with multiple sclerosis (MS). With an increased number of DMTs becoming available, patients are now switching treatments more frequently in clinical practice. The effects of switching DMTs on a patient's daily life and their disease course may be reflected in PROs. The global, multicenter, open-label, phase 4 Teri-PRO study (NCT01895335), which was conducted in routine clinical practice, previously showed statistically and clinically significant increases in patient-reported treatment satisfaction in patients switching to teriflunomide from other DMTs. The impact of switching to teriflunomide from other DMTs on treatment satisfaction and a range of additional PROs was also evaluated. METHODS: Patients with relapsing forms of MS (N = 1000) received teriflunomide for 48 weeks per local labeling. Outcomes assessed in this analysis included treatment satisfaction (as measured by Treatment Satisfaction Questionnaire for Medication [Version 1.4]), disability worsening (as measured using the Expanded Disability Status Scale [EDSS] score, the Patient-Determined Disease Steps scale, and the Multiple Sclerosis Performance Scale), cognition (as measured using the Symbol Digit Modalities Test [SDMT]), treated relapses, quality of life (as measured by the Multiple Sclerosis International Quality of Life [MusiQoL] questionnaire and the Stern Leisure Activity Scale), and safety/tolerability over the course of the study in the subgroup of patients switching to teriflunomide from another DMT (n = 594). RESULTS: Patients reported significant improvements in treatment satisfaction scores following the switch to teriflunomide regardless of the reason for treating with teriflunomide (Global Satisfaction, disease worsening: baseline, 46.0, Week 48, 65.1; convenience: baseline, 57.4, Week 48, 72.4; intolerance: baseline, 50.9, Week 48, 71.1; side effects: baseline, 49.7, Week 48, 67.2; P < 0.0001 in all comparisons). These patients also showed improvement or stability in PROs evaluating disability worsening, cognition, and quality of life (EDSS: baseline, 3.1, Week 48, 3.0; SDMT: baseline, 0.975, Week 48, 0.978; MusiQoL: baseline, 67.5, Week 48, 69.5). The safety and tolerability profile of teriflunomide was consistent with that observed in other teriflunomide clinical trials. CONCLUSION: This analysis of the Teri-PRO study demonstrates the value of switching to teriflunomide from other DMTs in a real-world, clinical practice setting. The high levels of treatment satisfaction associated with teriflunomide in Teri-PRO may lead to improved adherence and thus improved outcomes.


Asunto(s)
Crotonatos/farmacología , Sustitución de Medicamentos , Factores Inmunológicos/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Toluidinas/farmacología , Adulto , Crotonatos/administración & dosificación , Crotonatos/efectos adversos , Femenino , Humanos , Hidroxibutiratos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Masculino , Persona de Mediana Edad , Nitrilos , Estudios Prospectivos , Toluidinas/administración & dosificación , Toluidinas/efectos adversos
15.
Mult Scler Relat Disord ; 17: 107-115, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29055438

RESUMEN

BACKGROUND: Patient-reported outcomes (PROs) provide clinicians with further understanding of the impact of treatment on patients' daily lives. In addition, real-world studies, which employ broader inclusion criteria than randomized trials, may help to inform prescribing decisions when selecting a disease-modifying therapy (DMT) to treat relapsing forms of MS (RMS). We sought to use PROs to determine patient treatment satisfaction and other treatment outcomes, and report safety and tolerability associated with teriflunomide, in the global, phase 4 Teri-PRO study (NCT01895335). METHODS: Patients with RMS (N = 1000) received teriflunomide for 48 weeks per local labeling. The primary endpoint was Global Satisfaction with teriflunomide treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM, V1.4). Secondary endpoints included TSQM scores at Week (W)48 vs baseline in patients switching to teriflunomide from other DMTs ('switchers'), additional PROs, and safety. RESULTS: Mean TSQM Global Satisfaction score at W48 was high (68.2). Switchers reported significant improvements across all four TSQM domains at W48 vs baseline (all p < 0.0001). Adverse events were consistent with teriflunomide clinical trials. CONCLUSION: Patients reported high treatment satisfaction with teriflunomide, with switchers also reporting improved treatment satisfaction vs baseline. High treatment satisfaction in patients with RMS may lead to improved adherence, and hence treatment outcomes.


Asunto(s)
Crotonatos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Toluidinas/uso terapéutico , Crotonatos/efectos adversos , Evaluación de la Discapacidad , Sustitución de Medicamentos , Femenino , Humanos , Hidroxibutiratos , Factores Inmunológicos/efectos adversos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/psicología , Nitrilos , Satisfacción del Paciente , Estudios Prospectivos , Calidad de Vida , Encuestas y Cuestionarios , Toluidinas/efectos adversos , Resultado del Tratamiento
16.
Neurology ; 86(10): 920-30, 2016 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-26865517

RESUMEN

OBJECTIVE: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). METHODS: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. RESULTS: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score ≤2.5; probability of 12-week disability progression ≤0.48). CONCLUSIONS: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.


Asunto(s)
Crotonatos/administración & dosificación , Internacionalidad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Toluidinas/administración & dosificación , Administración Oral , Adulto , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Crotonatos/efectos adversos , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Hidroxibutiratos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Nitrilos , Factores de Tiempo , Toluidinas/efectos adversos , Resultado del Tratamiento
17.
Mult Scler Relat Disord ; 5: 97-104, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26856952

RESUMEN

BACKGROUND: Teriflunomide, a once-daily oral immunomodulator for the treatment of relapsing-remitting multiple sclerosis, has demonstrated consistent efficacy on clinical and MRI parameters in clinical trials. OBJECTIVE: To summarize the safety and tolerability profile of teriflunomide based on data from four placebo-controlled trials. METHODS: Safety and tolerability were assessed using two teriflunomide clinical program data pools. Pool 1 contained 3044 patients randomized to teriflunomide (14 mg or 7 mg) or placebo in the core studies of one phase 2 trial and three phase 3 trials, with cumulative treatment exposure >1500 patient-years per group. Pool 2 comprised 2338 patients who received teriflunomide treatment in the above trials, including those continuing in extension studies, with a duration of treatment up to 12 years, representing >6800 patient-years. Safety assessments included adverse events, laboratory parameters, and physical examinations. RESULTS: In Pool 1, the number of patients experiencing adverse events and serious adverse events was similar in the three treatment groups. Common events occurring in ≥ 10% of patients in either teriflunomide group, and with an incidence ≥ 2% compared with placebo, were alanine aminotransferase (ALT) increase, headache, diarrhea, hair thinning, and nausea. Overall, the nature of events observed in Pool 2 was similar to Pool 1. The majority of events in both pools were of mild-to-moderate intensity, were self-limiting, and infrequently resulted in discontinuation of therapy. The most common reason for treatment discontinuation in all treatment groups was ALT elevation, reflecting the protocol requirement to discontinue treatment on confirmation of ALT > 3 × the upper limit of normal. CONCLUSIONS: No new or unexpected safety signals beyond those detected in individual trials were identified in this pooled analysis with treatment duration exceeding 12 years and a cumulative exposure to teriflunomide exceeding 6800 patient-years. Overall, both doses of teriflunomide had consistent and manageable safety profiles.


Asunto(s)
Crotonatos/efectos adversos , Factores Inmunológicos/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Toluidinas/efectos adversos , Administración Oral , Adolescente , Adulto , Crotonatos/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Hidroxibutiratos , Factores Inmunológicos/administración & dosificación , Masculino , Persona de Mediana Edad , Nitrilos , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto , Toluidinas/administración & dosificación , Resultado del Tratamiento , Adulto Joven
18.
Neurol Neuroimmunol Neuroinflamm ; 2(2): e70, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25738167

RESUMEN

OBJECTIVE: To evaluate immune responses to neoantigen and recall antigens in healthy subjects treated with teriflunomide. METHODS: This was a randomized, double-blind, placebo-controlled study. Subjects received oral teriflunomide (70 mg once daily for 5 days followed by 14 mg once daily for 25 days) or placebo for 30 days. Antibody responses were evaluated following rabies vaccination (neoantigen) applied at days 5, 12, and 31 of the treatment period. Occurrence of delayed-type hypersensitivity (DTH) to Candida albicans, Trichophyton, and tuberculin (recall antigens) was assessed before and at the end of treatment to investigate cellular memory response. Safety and pharmacokinetics were evaluated. RESULTS: Forty-six randomized subjects were treated (teriflunomide, n = 23; placebo, n = 23) and completed the rabies vaccination. Geometric mean titers for rabies antibodies were lower with teriflunomide at days 31 and 38 than with placebo. However, all subjects achieved sufficient seroprotection following rabies vaccination (titers well above the 0.5 IU/mL threshold). Overall, the DTH response to recall antigens in the teriflunomide group did not notably differ from responses in the placebo group. CONCLUSIONS: Following vaccination, geometric mean titers for rabies antibodies were lower with teriflunomide than with placebo. However, teriflunomide did not limit the ability to achieve seroprotective titers against this neoantigen. Evaluation of DTH showed that teriflunomide had no adverse impact on the cellular memory response to recall antigens. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in normal subjects treated with teriflunomide, antibody titer responses to rabies vaccination are lower than with placebo but sufficient for seroprotection.

19.
Clin Nucl Med ; 28(5): 375-8, 2003 May.
Artículo en Inglés | MEDLINE | ID: mdl-12702932

RESUMEN

A 28-year-old woman underwent mammary lymphoscintigraphy for evaluation of the sentinel node status of a small infiltrating ductal carcinoma in the central, lower, and outer quadrant of the left breast confirmed by biopsy. The patient was scheduled for lumpectomy and sentinel node biopsy. Lymphoscintigraphy showed increased uptake at two sites of the peritumorally injected tracer (60 MBq; 1.6 mCi rhenium sulfur nanocolloid) in internal mammary nodes, two of which were located most proximal to the tumor and related to the tumor by two distinct lymphatic ducts. An axillary lymph node was also detected. At surgery, the gamma probe confirmed the location of all the hot spots, and four nodes were harvested: one axillary, two first internal mammary nodes in the third intercostal space, and one internal mammary node in the second intercostal space. Histologic analysis revealed that the axillary sentinel node was free of disease, but the two first intramuscular sentinel nodes were metastatic. The second-echelon internal mammary node above the sentinel nodes (second intercostal space) was free of disease. This case shows the benefit of imaging all the drainage pathways of a breast tumor and retrieving nonaxillary lymph nodes, which may be the only positive nodes. As a result of the findings, the patient's prognosis may be altered and the subsequent therapeutic approach may be modified. Although exclusive involvement of the internal mammary chain is well established and relatively rare (occurring in approximately 5% of cases), it is important to remember that the axillary status of a breast tumor is not the only major prognostic factor.


Asunto(s)
Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/secundario , Neoplasias de la Mama/diagnóstico por imagen , Ganglios Linfáticos/diagnóstico por imagen , Renio , Compuestos de Tecnecio , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adulto , Axila , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Metástasis Linfática , Cintigrafía , Radiofármacos/farmacocinética , Renio/farmacocinética , Biopsia del Ganglio Linfático Centinela/métodos , Compuestos de Tecnecio/farmacocinética , Distribución Tisular
20.
Neurol Ther ; 3(2): 133-8, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26000229

RESUMEN

INTRODUCTION: Teriflunomide, indicated for the treatment of relapsing-remitting multiple sclerosis, is contraindicated in pregnancy based on signs of developmental toxicity in the offspring of rats and rabbits; developmental toxicity has also been observed in preclinical studies of other disease-modifying therapies. Despite the requirement to use reliable contraception in clinical trials evaluating the safety and efficacy of teriflunomide, a number of pregnancies have been reported. This work reports pregnancy outcomes in teriflunomide clinical trials. METHODS: Pregnancy outcomes were evaluated in a retrospective analysis of the global pharmacovigilance database. The following information was collected from the pharmacovigilance database or individual patient files: treatment allocation, pregnancy outcome, teriflunomide exposure, and use of the accelerated elimination procedure. RESULTS: At data cut-off, 83 pregnancies were reported in female patients and 22 pregnancies were documented in partners of male patients. All newborns were healthy and did not have any structural or functional abnormalities at birth. CONCLUSION: Available data do not indicate any teratogenic signals in patients treated with teriflunomide.

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