Predicting Treatment Responses in Patients With Osteoarthritis: Results From Two Phase III Tanezumab Randomized Clinical Trials.

Prediction of treatment responses is essential to move forward translational science. Our question was to identify patient-based variables that predicted responses to treatments. We conducted secondary analyses on pooled data from two randomized phase III clinical trials (NCT02697773 and NCT02709486) conducted in participants with moderate to severe osteoarthritis randomized to subcutaneous placebo (n = 514) or tanezumab 2.5 mg (n = 514). We used gradient boosted regression trees to identify variables that predicted Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale scores at Week 16 and marginal plots to determine the directional relationship between each variable category and responses to placebo or tanezumab within the models. We also used Virtual Twins models to identify potential subgroups of response to the active treatment vs. placebo. We found that responses to placebo were predicted by baseline WOMAC Physical Function, baseline WOMAC Pain, the radiographic classification of the index joint, and the standard deviation of diary pain scores at baseline. In contrast, baseline WOMAC Pain along with failure of prior medications, duration of disease, and standard deviation of diary pain scores at baseline were predictive of tanezumab responses as expressed by the WOMAC Pain scores at Week 16. Those who responded to tanezumab vs. placebo were identified based on the radiographic classification of the index joint and either age or smoking status. These secondary-data analyses identified distinct and common patient-based variables to predict response to placebo or tanezumab. These findings will inform the design of future clinical trials, helping to move forward clinical pharmacology and translational science.

Real-World Adherence to Oral Methotrexate Measured Electronically in Patients With Established Rheumatoid Arthritis.

OBJECTIVE: To assess methotrexate (MTX) adherence using the Medication Event Monitoring System (MEMS) and characterize associations with adherence in patients with rheumatoid arthritis (RA). METHODS: Eligible patients participated in Forward, the National Databank for Rheumatic Diseases, and recently (12 months or sooner) initiated oral MTX. MEMS was used to compile MTX weekly dosing over 24 weeks. The Beliefs about Medicines Questionnaire (BMQ) was completed, and baseline demographics and disease characteristics obtained. MTX adherence (percentage of weeks dose taken correctly), implementation (percentage of weeks dose taken correctly from initiation until last dose), and persistence (duration from initiation to last dose) were calculated. Analyses measured associations between patient characteristics and adherence, modeled using logistic generalized estimating equations and censored Poisson regression, and persistence modeled using Cox regression. RESULTS: Overall, 60 of 119 eligible patients were included in the analysis. MTX adherence, implementation, and persistence were 75%, 80%, and 83%, respectively, at 24 weeks. Demographics and disease characteristics were generally similar between patients with 1 week or less and 2 weeks or more of missed MTX. Unemployment, less disability, higher Patient Global scores, and no prior disease-modifying antirheumatic drug (DMARD) use were associated with correct dosing. No significant differences in adherence were observed between patients receiving concomitant MTX versus MTX monotherapy, and biologic DMARD-experienced versus biologic DMARD-naïve patients. Higher scores in BMQ Specific Necessity (indicating a greater belief in the necessity of the medication) was associated with a decreased likelihood of dosing at an interval shorter than prescribed (odds ratio 0.89). CONCLUSION: Even in a participatory group over a short period, MTX adherence was suboptimal and associated with certain demographics, medication experience, and beliefs about medicines. This suggests a need for screening and alternative treatment opportunities in nonadherent MTX patients with RA.

Safety signal detection and evaluation in clinical development programs: A case study of tofacitinib.

Adverse events are anticipated during a clinical development program. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We describe here the process undertaken by Pfizer to investigate a safety signal for pancreatic cancer with tofacitinib. Potential cases of pancreatic cancer across indications from Pfizer's clinical trials and safety databases were identified and underwent in-depth case review and external expert consultation. The magnitude of the signal was quantified. The feasibility of formal signal evaluation via a hypothesis-testing study was explored. As of July 2016, 14 cases of potential pancreatic cancer were identified: eight cases in clinical development trials (psoriasis n = 6; RA n = 1; psoriatic arthritis n = 1), four cases in a postmarketing study in RA patients in Japan, and two spontaneous reports. Incidence rates (95% confidence intervals) per 100 patient-years ranged from 0 (0, 0.02) to 0.14 in RA, 0.05 (0.01, 0.15) to 0.07 (0.02, 0.16) in psoriasis, and 0.25 (0.01, 1.37) in psoriatic arthritis. The majority of patients had established risk factors for pancreatic cancer. The pharmaceutical industry's rapid and transparent response to safety signals is essential for ensuring patient safety and enabling physicians and patients to adequately assess a drug's risk:benefit. Safety signals emerging through pharmacovigilance may be true or false indicators of a causative association with drug exposure. In this example, it was determined that tofacitinib exposure was unlikely to be related to induction and promotion of pancreatic cancer; however, a relationship with pancreatic cancer promotion could not be excluded.

Natalizumab treatment in multiple sclerosis: the experience from two Brazilian MS centers.

Objective Analyze the demographics, clinical characteristics, efficacy and safety of natalizumab treatment in Brazilian patients with multiple sclerosis (MS) followed up for at least 12 months, in two tertiary MS care centers in São Paulo.Method We evaluated the effect of natalizumab treatment on annualized relapse rate and disability progression in 75 patients with MS treated with natalizumab for at least 12 months. A subgroup analysis was performed to evaluate efficacy of natalizumab treatment in patients with Expanded Disability Status Scale (EDSS) ≤ 3.0 vs patients with EDSS > 3.Results Patients treated for at least one year with natalizumab showed a 91% reduction in aRR, as well and an improvement in neurological disability. The impact of natalizumab treatment was greater in patients with EDSS < 3.0. Overall, natalizumab was safe but one patient developed progressive multifocal leukoencephalopathy.Conclusion Natalizumab as a third line therapy is safe and efficacious, especially in patients with mild neurological disability.

Regional distribution of spine and hip QCT BMD responses after one year of once-monthly ibandronate in postmenopausal osteoporosis.

In the published placebo-controlled Ibandronate Quality (IQ) study, 12 months of once-monthly oral ibandronate increased femoral and vertebral integral and trabecular bone mineral density (BMD) measured by quantitative computed tomography (QCT). Ibandronate showed significant improvements versus placebo in finite element analysis of femoral and vertebral strength. This post hoc analysis examined QCT BMD changes in novel superior and inferior vertebral volumes of interest (VOIs) and femoral and vertebral subcortical, extended cortical, and extended trabecular VOIs. Ninety-three postmenopausal women (BMD(a)T-scores< or =-2.0 at lumbar spine, total hip, or femoral neck) received ibandronate 150 mg/month (n=47) or placebo (n=46) for 12 months. QCT with Medical Imaging Analysis Framework (MIAF)-Spine and MIAF-Femur used automated segmentation and coordinate system-based identification of integral, cortical, subcortical, and trabecular VOIs and combinations (extended cortical=cortical+subcortical; extended trabecular=trabecular+subcortical). Between-group differences in mean percentage changes from baseline were determined by treatment- and center-adjusted analysis of variance. P values were post hoc, exploratory, descriptive, and unadjusted for multiple comparisons. Ibandronate increased vertebral superior and inferior trabecular and extended cortical midsection BMD (4.9%, p=0.032; 4.6%, p=0.055; 3.9%, p=0.014, respectively) versus placebo. Femoral BMD treatment differences (ibandronate versus placebo) were significant in total hip (extended trabecular 4.0%, p=0.005; extended cortical 1.5%, p=0.047; subcortical 3.7%, p=0.009), trochanter (extended trabecular 5.2%, p=0.007; extended cortical 2.4%, p=0.01), and extended trabecular femoral neck (4.0%, p=0.02). Monthly oral ibandronate for 12 months improved QCT BMD versus placebo in the vertebral periphery, subcortical total hip, and all femoral extended trabecular regions.

Efficacy and safety of monthly ibandronate in men with low bone density.

INTRODUCTION: Monthly oral ibandronate is indicated for the prevention and treatment of osteoporosis in postmenopausal women. The STudy Researching Osteoporosis iN Guys (STRONG) investigated the efficacy and safety of 150-mg monthly oral ibandronate in men with primary, idiopathic, or hypogonadism-related low bone density. METHODS: STRONG was a 1-year, placebo-controlled, randomized (2 ibandronate: 1 placebo), double-blind study that enrolled ambulatory men aged > or =30 years with baseline femoral neck (FN) bone mineral density (BMD) T-scores < or =-2.0 and lumbar spine (LS) BMD T-scores < or =-1.0 or LS BMD T-scores < or =-2.0, FN BMD T-scores < or =-1.0, and BMD T-scores > or =-4.0 at any site assessed by dual-energy X-ray absorptiometry. The primary endpoint was mean percent change from baseline in LS BMD at 1 year (intent-to-treat [ITT] population). Secondary endpoints included mean BMD changes from baseline at the FN, total hip (TH), and trochanter (TR) and changes in bone turnover markers (BTMs), as measured by the bone resorption marker serum C-terminal telopeptide of type 1 collagen (sCTX) and the bone formation marker bone-specific alkaline phosphatase (BSAP). All men received twice daily calcium carbonate (1000 mg/day) and vitamin D (400 IU/day). Changes in BMD for treatment groups were compared using analysis of covariance with treatment, investigative site, and baseline testosterone as factors and baseline BMD as a covariate. RESULTS: The ITT population consisted of 132 men; 47 received placebo and 85 received monthly ibandronate. Men who received ibandronate achieved greater increases in LS BMD at 12 months than those who received placebo (3.5% vs. 0.9%, respectively; difference, 2.6; p<0.001). The ibandronate group also achieved greater 12-month BMD increases than the placebo group, respectively, at the TH (1.8% vs. -0.3%; difference, 2.1; p<0.001), FN (1.2% vs. -0.2%; difference, 1.4; p=0.012), and TR (2.2% vs. 0.4%; difference, 1.7; p<0.005). In men who completed the study and adhered to the protocol (per-protocol (PP) population), percent decreases in median sCTX and BSAP levels from baseline were also greater with ibandronate versus placebo (p< or =0.001 for both comparisons). Overall, monthly ibandronate was well tolerated. CONCLUSIONS: In men with low BMD, 1 year of treatment with oral once-monthly 150-mg ibandronate significantly increased BMD at the LS and hip (TH, TR, and FN), significantly reduced BTM levels in the PP population, and was generally well tolerated.

Natalizumab treatment in multiple sclerosis: the experience from two Brazilian MS centers / Natalizumabe no tratamento da esclerose múltipla: a experiência de dois centros brasileiros

Objective Analyze the demographics, clinical characteristics, efficacy and safety of natalizumab treatment in Brazilian patients with multiple sclerosis (MS) followed up for at least 12 months, in two tertiary MS care centers in São Paulo.Method We evaluated the effect of natalizumab treatment on annualized relapse rate and disability progression in 75 patients with MS treated with natalizumab for at least 12 months. A subgroup analysis was performed to evaluate efficacy of natalizumab treatment in patients with Expanded Disability Status Scale (EDSS) ≤ 3.0 vs patients with EDSS > 3.Results Patients treated for at least one year with natalizumab showed a 91% reduction in aRR, as well and an improvement in neurological disability. The impact of natalizumab treatment was greater in patients with EDSS < 3.0. Overall, natalizumab was safe but one patient developed progressive multifocal leukoencephalopathy.Conclusion Natalizumab as a third line therapy is safe and efficacious, especially in patients with mild neurological disability.

Objetivo Analisar as características clínicas e demográficas, assim como a eficácia e segurança do tratamento com natalizumabe (usado em terceira linha), por no mínimo 12 meses, em pacientes brasileiros acompanhados em dois centros de tratamento de esclerose múltipla, na cidade de São Paulo.Método Avaliamos o efeito do tratamento com natalizumabe na taxa anualizada de surto (aRR) e progressão de incapacidade (medida por Expanded Disability Status Scale (EDSS)) em 75 pacientes tratados por, no mínimo 12 meses. Realizamos uma análise de subgrupo em pacientes com EDSS ≤ 3,0 e com EDSS > 3, para avaliar o impacto no tratamento, considerando-se o grau de incapacidade neurológica.Resultados O tratamento com natalizumabe, por pelo menos um ano, reduziu a aRR em 91%, assim como melhorou a incapacidade neurológica. Em pacientes com EDSS ≤ 3,0 observamos um impacto maior do tratamento na incapacidade neurológica, reduzindo sua progressão em 51%, durante o período do estudo. O tratamento com natalizumabe é seguro, porém um paciente desenvolveu leucoencefalopatia multifocal progressiva.Conclusão O tratamento com natalizumabe, em terceira linha terapêutica é seguro e eficaz especialmente, em pacientes com incapacidade neurológica leve (EDSS ≤ 3.0).

Nebulized fluticasone propionate vs. budesonide as adjunctive treatment in children with asthma exacerbation.

OBJECTIVES: To compare the effects of nebulized fluticasone propionate (FP) and nebulized budesonide (BUD) in addition to inhaled salbutamol in children with mild asthma exacerbation. METHODS: The study was a multicenter, randomized, single-blind, parallel group design. One hundred and sixty-eight children, aged 4-15 years, were randomly allocated to receive either nebulized FP (250 mcg) or nebulized BUD (500 mcg) twice daily for 10 days. On presentation, at the end of treatment, and after a 7-day follow-up, clinical assessment and pulmonary function measurements were performed. Daytime and nighttime asthma symptom scores, the use of rescue salbutamol, and morning/evening peak expiratory flow (PEF) values were recorded at home during the treatment period. Morning cortisol concentration (51 children) and overnight urinary cortisol excretion (30 children) were also measured in six centers at the start and at the end of the treatment. RESULTS: Improvement of morning PEF was significantly higher in patients treated with FP (p=0.032). The percentage of symptom-free nights was significantly higher in the BUD group (p=0.006), but no difference was found in symptom-free days. No intergroup difference was detected in the percentage of days/nights free from rescue medication and in pulmonary function tests performed in outpatient settings. There was no evidence of hypothalamo-pituitary-adrenal axis suppression. CONCLUSIONS: A short course of nebulized FP has the same effects as a double dose of nebulized BUD, when either drug is added to bronchodilator therapy in children with mild asthma exacerbation

Immune parameters in hemorrhagic fever with renal syndrome during the incubation and acute disease: case report.

We describe immune parameters in a Croatian soldier who presented with mild flu-like symptoms and interstitial inflammatory infiltrate in the lungs on an X-ray during the incubation phase of hemorrhagic fever with renal syndrome (HFRS). Enzyme-linked immunosorbent assay (ELISA) IgM and polymerase chain reaction (PCR) were negative. Two weeks later, he developed HFRS caused by the Puumala virus. We performed two-color immunofluorescence cytometry with monoclonal antibodies identifying the activation markers on T cells. Serum samples were also examined by enzyme immunoassay (EIA) for the presence of interleukins IL-2 and IL-6 and their soluble receptors (sR). The analysis of early and late activation markers during the period of incubation revealed a small increase in the percentage of helper (CD4+CD25+) T cells and no significant increase in total activated (HLA-DR+TCR+) and cytotoxic (CD8+CD71+) T cells as compared with healthy controls. In the serum, only the concentration of soluble IL-6 receptor was increased. However, when the patient developed HFRS, all activation markers on T cells increased. Concentrations of sIL-2Ralpha and IL-6 remained increased two and six days after HFRS onset, respectively, whereas sIL-6R increased six days after HFRS onset. IL-2 concentration did not change. Our case indicates that rapid, modern diagnostic tools are necessary in the diagnosis of infectious diseases and their differential diagnosis. Immunological tests, which provide information on the patient immune status and especially on early changes in immune parameters, may contribute to the improvement of the diagnosis, prognosis, and therapy of HFRS.