RESUMEN
BACKGROUND: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (TO-203, Torii, Japan/ALK, Denmark) treatment has been effective against respiratory allergic diseases in patients aged ≥12 years during European, Japanese, and North American trials. This trial was conducted to investigate the efficacy and safety of this treatment in Japanese children (5-17 years) with moderate-to-severe HDM allergic rhinitis (AR). METHODS: In this randomized, double-blind, placebo-controlled trial, 458 Japanese children were randomly assigned to a daily SQ HDM SLIT-tablet [10 000 Japanese Allergy Unit (JAU), equivalent to 6 SQ-HDM in Europe and the US] or placebo (1:1) treatment for 1 year. Inclusion required an AR symptom score of ≥7 on at least 7 days during a 14-day run-in period while symptomatic treatment was withdrawn. The primary endpoint was the total combined rhinitis score (TCRS) comprising AR symptom and medication scores during the last 8 weeks of the treatment period. RESULTS: The analysis of primary endpoint demonstrated statistically significant absolute reduction in TCRS of 1.22 with a relative difference of 23% (95% confidence interval, 14% to 31%) in the 10 000 JAU compared with placebo. Predefined stratified analyses revealed the same degree of efficacy of 1.11 (P = 0.002), 21% (8% to 32%) and 1.36 (P = 0.001), 26% (11% to 38%), respectively, in pediatric (5-11 years) and adolescent subjects (12-17 years). The treatment was well tolerated by both pediatric and adolescent subjects. CONCLUSION: This trial, for the first time, demonstrated the efficacy and safety of the HDM SLIT-tablet in pediatric patients with moderate-to-severe HDM AR (JapicCTI-152953).
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Alérgenos/administración & dosificación , Alérgenos/uso terapéutico , Dermatophagoides farinae/inmunología , Dermatophagoides pteronyssinus/inmunología , Rinitis Alérgica/terapia , Inmunoterapia Sublingual/efectos adversos , Adolescente , Animales , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Inmunoglobulina E/análisis , Inmunoglobulina G/análisis , Japón , Modelos Logísticos , Masculino , Comprimidos , Resultado del TratamientoRESUMEN
BACKGROUND: Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC). METHODS: Pooled data from the placebo groups of two phase III randomized clinical trials in patients with knee OA followed for 2 years were analyzed. Differences between individual sub-scores and pain categories of weight-bearing and non-weight bearing pain over time were assessed. Selected patient baseline characteristics were assessed for association with PPR. Association between pain categories and radiographic progression was analyzed. RESULTS: The reduction of pain in placebo-treated patients was significantly higher in the composite of questions related to weight-bearing pain compared to non-weight-bearing pain of the target knee. Baseline BMI, age and JSW were not associated with pain change. Pain reduction was higher in the Target knee, compared to the Non-Target knee at all corresponding time-points. A very weak correlation was found between weight-bearing pain and progression in the non-target knee. CONCLUSIONS: These results indicate that the reduction in pain in patients treated with placebo is significantly different between pain categories, as weight-bearing pain was significantly more reduced compared to non-weight-bearing pain. Further research in pain categories in OA is warranted. TRIAL REGISTRATION: NCT00486434 (trial 1) and NCT00704847 (trial 2).
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Artralgia/diagnóstico , Artralgia/terapia , Osteoartritis de la Rodilla/diagnóstico , Osteoartritis de la Rodilla/terapia , Dimensión del Dolor/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Artralgia/epidemiología , Ensayos Clínicos Fase III como Asunto/métodos , Humanos , Osteoartritis de la Rodilla/epidemiología , Efecto PlaceboRESUMEN
AIMS/HYPOTHESIS: The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPARγ) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the α3 chain of procollagen type VI (also called Pro-C6), is involved in both adipose tissue matrix remodelling and metabolic control. We established a serum assay for endotrophin to assess if this novel adipokine could identify type 2 diabetic patients who respond optimally to PPARγ agonists, improving the risk-to-benefit ratio. METHODS: The BALLET trial (NCT00515632) compared the glucose-lowering effects and safety of the partial PPARγ agonist balaglitazone with those of pioglitazone in individuals with type 2 diabetes on stable insulin therapy. The per protocol population (n = 297) was stratified into tertiles based on baseline endotrophin levels. Participants were followed-up after 26 weeks, after which correlational analysis was carried out between endotrophin levels and measures of glucose control. This is a secondary post hoc analysis. RESULTS: Endotrophin was significantly associated with therapeutic response to balaglitazone and pioglitazone. At week 26, only individuals in the upper two tertiles showed significant reductions in HbA1c and fasting serum glucose compared with baseline. The OR for a 1% and a 0.5% reduction in HbA1c for individuals in the upper two tertiles were 3.83 (95% CI 1.62, 9.04) p < 0.01, and 3.85 (95% CI 1.94, 7.61) p < 0.001, respectively. Endotrophin levels correlated with adipose tissue mass, insulin resistance and fatty liver index. Notably, PPARγ-associated adverse effects, such as moderate-to-severe lower extremity oedema, only occurred in the lower tertile. CONCLUSIONS/INTERPRETATION: Elevated endotrophin serum levels predict response to two insulin sensitisers and reduce the risk of associated adverse effects, thereby, identifying patients with type 2 diabetes who may profit from PPARγ agonist treatment.
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Colágeno Tipo VI/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , PPAR gamma/agonistas , Fragmentos de Péptidos/sangre , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Anciano , Glucemia/efectos de los fármacos , Colágeno Tipo VI/metabolismo , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Masculino , Persona de Mediana Edad , Pioglitazona , Quinazolinas/uso terapéutico , Tiazolidinedionas/uso terapéuticoRESUMEN
IMPORTANCE: The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy-related asthma. OBJECTIVES: To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticosteroid (ICS) reduction period. DESIGN, SETTINGS, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products, and with HDM allergy-related rhinitis. Key exclusion criteria were FEV1 less than 70% of predicted value or hospitalization due to asthma within 3 months before randomization. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and then completely withdrawn for 3 months. INTERVENTIONS: 1:1:1 randomization to once-daily treatment with placebo (n = 277) or HDM SLIT tablet (dosage groups: 6 SQ-HDM [n = 275] or 12 SQ-HDM [n = 282]) in addition to ICS and the short-acting ß2-agonist salbutamol. MAIN OUTCOMES AND MEASURES: Primary outcome was time to first moderate or severe asthma exacerbation during the ICS reduction period. Secondary outcomes were deterioration in asthma symptoms, change in allergen-specific immunoglobulin G4 (IgG4), change in asthma control or asthma quality-of-life questionnaires, and adverse events. RESULTS: Among 834 randomized patients (mean age, 33 years [range, 17-83]; women, 48%), 693 completed the study. The 6 SQ-HDM and 12 SQ-HDM doses both significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo (hazard ratio [HR]: 0.72 [95% CI, 0.52-0.99] for the 6 SQ-HDM group, P = .045, and 0.69 [95% CI, 0.50-0.96] for the 12 SQ-HDM group, P = .03). The absolute risk differences based on the observed data (full analysis set) in the active groups vs the placebo group were 0.09 (95% CI, 0.01-0.15) for the 6 SQ-HDM group and 0.10 (95% CI, 0.02-0.16) for the 12 SQ-HDM group. There was no significant difference between the 2 active groups. Compared with placebo, there was a reduced risk of an exacerbation with deterioration in asthma symptoms (HR, 0.72 [95% CI, 0.49-1.02] for the 6 SQ-HDM group, P = .11, and 0.64 [95% CI, 0.42-0.96] for the 12 SQ-HDM group, P = .03) and a significant increase in allergen-specific IgG4. However, there was no significant difference for change in asthma control questionnaire or asthma quality-of-life questionnaire for either dose. There were no reports of severe systemic allergic reactions. The most frequent adverse events were mild to moderate oral pruritus (13% for the 6 SQ-HDM group, 20% for the 12 SQ-HDM group, and 3% for the placebo group), mouth edema, and throat irritation. CONCLUSIONS AND RELEVANCE: Among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate or severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6 months of 9 to 10 percentage points; the reduction was primarily due to an effect on moderate exacerbations. Treatment-related adverse events were common at both active doses. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2010-018621-19.
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Alérgenos/administración & dosificación , Antígenos Dermatofagoides/administración & dosificación , Asma/tratamiento farmacológico , Inmunoterapia/métodos , Pyroglyphidae/inmunología , Rinitis/tratamiento farmacológico , Administración por Inhalación , Administración Sublingual , Adolescente , Corticoesteroides/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Albuterol/uso terapéutico , Animales , Asma/inmunología , Asma/prevención & control , Progresión de la Enfermedad , Método Doble Ciego , Polvo , Femenino , Humanos , Inmunoglobulina G , Masculino , Persona de Mediana Edad , Calidad de Vida , Rinitis/inmunología , Encuestas y Cuestionarios , Comprimidos , Resultado del Tratamiento , Adulto JovenRESUMEN
IMPORTANCE: Additional therapies are needed for prevention of osteoporotic fractures. Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor. OBJECTIVE: To determine the efficacy and safety of abaloparatide, 80 µg, vs placebo for prevention of new vertebral fracture in postmenopausal women at risk of osteoporotic fracture. DESIGN, SETTING, AND PARTICIPANTS: The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) was a phase 3, double-blind, RCT (March 2011-October 2014) at 28 sites in 10 countries. Postmenopausal women with bone mineral density (BMD) T score ≤-2.5 and >-5.0 at the lumbar spine or femoral neck and radiological evidence ≥2 mild or ≥1 moderate lumbar or thoracic vertebral fracture or history of low-trauma nonvertebral fracture within the past 5 years were eligible. Postmenopausal women (>65 y) with fracture criteria and a T score ≤-2.0 and >-5.0 or without fracture criteria and a T score ≤-3.0 and >-5.0 could enroll. INTERVENTIONS: Blinded, daily subcutaneous injections of placebo (n = 821); abaloparatide, 80 µg (n = 824); or open-label teriparatide, 20 µg (n = 818) for 18 months. MAIN OUTCOMES AND MEASURES: Primary end point was percentage of participants with new vertebral fracture in the abaloparatide vs placebo groups. Sample size was set to detect a 4% difference (57% risk reduction) between treatment groups. Secondary end points included change in BMD at total hip, femoral neck, and lumbar spine in abaloparatide-treated vs placebo participants and time to first incident nonvertebral fracture. Hypercalcemia was a prespecified safety end point in abaloparatide-treated vs teriparatide participants. RESULTS: Among 2463 women (mean age, 69 years [range, 49-86]), 1901 completed the study. New morphometric vertebral fractures occurred less frequently in the active treatment groups vs placebo. The Kaplan-Meier estimated event rate for nonvertebral fracture was lower with abaloparatide vs placebo. BMD increases were greater with abaloparatide than placebo (all P < .001). Incidence of hypercalcemia was lower with abaloparatide (3.4%) vs teriparatide (6.4%) (risk difference [RD], −2.96 [95%CI, −5.12 to −0.87]; P = .006). [table: see text]. CONCLUSIONS AND RELEVANCE: Among postmenopausal women with osteoporosis, the use of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01343004.
Asunto(s)
Vértebras Lumbares/lesiones , Osteoporosis Posmenopáusica , Fracturas Osteoporóticas/prevención & control , Proteína Relacionada con la Hormona Paratiroidea/uso terapéutico , Fracturas de la Columna Vertebral/prevención & control , Vértebras Torácicas/lesiones , Anciano , Anciano de 80 o más Años , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Método Doble Ciego , Femenino , Cuello Femoral/diagnóstico por imagen , Cuello Femoral/fisiología , Humanos , Hipercalcemia/inducido químicamente , Inyecciones Subcutáneas , Vértebras Lumbares/fisiopatología , Persona de Mediana Edad , Proteína Relacionada con la Hormona Paratiroidea/efectos adversos , Huesos Pélvicos/efectos de los fármacos , Huesos Pélvicos/fisiología , Placebos/uso terapéutico , Posmenopausia , Radiografía , Teriparatido/efectos adversos , Teriparatido/uso terapéuticoRESUMEN
The oral delivery of peptides and proteins has been hampered by an array of obstacles. However, several promising novel oral delivery systems have been developed. This paper reviews the most advanced oral formulation technologies, and highlights key lessons and implications from studies undertaken to date with these oral formulations. Special interest is given to oral salmon calcitonin (CT), glucagon-like peptide-1 (GLP-1), insulin, PYY-(3-36), recombinant human parathyroid hormone (rhPTH(1-31)-NH2) and PTH(1-34), by different technologies. The issues addressed include (i) interaction with water, (ii) interaction with food, (iii) diurnal variation, (iv) inter- and intra-subject variability, (v) correlation between efficacy and exposure and (vi) key deliverables of different technologies. These key lessons may aid research in the development of other oral formulations.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Fragmentos de Péptidos/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Tecnología Farmacéutica/métodos , Administración Oral , Portadores de Fármacos/química , Absorción Gastrointestinal , Humanos , Fragmentos de Péptidos/farmacocinética , Proteínas Recombinantes/farmacocinéticaRESUMEN
AIM: The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach. METHODS: We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points. RESULTS: Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P < 0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety. CONCLUSIONS: The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy.
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Ensayos Clínicos Fase III como Asunto/normas , Exactitud de los Datos , Registros Electrónicos de Salud/normas , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Calcitonina/administración & dosificación , Calcitonina/uso terapéutico , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Bases de Datos Factuales , Registros Electrónicos de Salud/estadística & datos numéricos , Femenino , Control de Formularios y Registros/métodos , Control de Formularios y Registros/normas , Control de Formularios y Registros/estadística & datos numéricos , Humanos , Osteoartritis de la Rodilla/tratamiento farmacológico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricosRESUMEN
BACKGROUND: The main aim of specific immunotherapy is sustained effect due to changes in the immune system that can be demonstrated only in long-term trials. OBJECTIVE: To investigate sustained efficacy and disease modification in a 5-year double-blind, placebo-controlled trial, including 2 years of blinded follow-up after completion of a 3-year period of treatment, with the SQ-standardized grass allergy immunotherapy tablet, Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU,(∗) ALK, Denmark) or placebo. METHODS: A randomized, double-blind, placebo-controlled, multinational, phase III trial included adults with a history of moderate-to-severe grass pollen-induced allergic rhinoconjunctivitis, with or without asthma, inadequately controlled by symptomatic medications. Two hundred thirty-eight participants completed the trial. End points included rhinoconjunctivitis symptom and medication scores, combined scores, asthma symptom and medication scores, quality of life, days with severe symptoms, immunologic end points, and safety parameters. RESULTS: The mean rhinoconjunctivitis daily symptom score was reduced by 25% to 36% (P ≤ .004) in the grass allergy immunotherapy tablet group compared with the placebo group over the 5 grass pollen seasons covered by the trial. The rhinoconjunctivitis DMS was reduced by 20% to 45% (P ≤ .022 for seasons 1-4; P = .114 for season 5), and the weighted rhinoconjunctivitis combined score was reduced by 27% to 41% (P ≤ .003) in favor of active treatment. The percentage of days with severe symptoms during the peak grass pollen exposure was in all seasons lower in the active group than in the placebo group, with relative differences of 49% to 63% (P ≤ .0001). Efficacy was supported by long-lasting significant effects on the allergen-specific antibody response. No safety issues were identified. CONCLUSION: The results confirm disease modification by SQ-standardized grass allergy immunotherapy tablet in addition to effective symptomatic treatment of allergic rhinoconjunctivitis.
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Desensibilización Inmunológica/métodos , Extractos Vegetales/administración & dosificación , Rinitis Alérgica Estacional/tratamiento farmacológico , Rinitis Alérgica Estacional/inmunología , Administración Sublingual , Adolescente , Adulto , Anciano , Alérgenos/efectos adversos , Alérgenos/inmunología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina E/metabolismo , Masculino , Persona de Mediana Edad , Extractos Vegetales/efectos adversos , Poaceae , Polen/efectos adversos , Rinitis Alérgica Estacional/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Treatment of patients with perioxisome proliferator-activated receptor-γ full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-γ agonists has not been established in a clinical trial. The BALaglitazone glucose Lowering Efficacy Trial aimed to establish the glucose-lowering effects and safety parameters of the perioxisome proliferator-activated receptor-γ partial agonist balaglitazone in diabetic patients on stable insulin therapy. METHODS: Four hundred and nine subjects from three countries with type 2 diabetes on stable insulin therapy were randomized to 26 weeks of double-blind treatment with once daily doses of 10 or 20 mg balaglitazone, 45 mg pioglitazone, or matching placebo (n ≥ 99 in each group). The primary endpoint was the efficacy of balaglitazone 10 and 20 mg versus placebo on the absolute change in haemoglobin A(1c) . Secondary endpoints included levels of fasting serum glucose, and changes in body composition and bone mineral density as measured by dual energy X-ray absorptiometry, in comparison to pioglitazone 45 mg. This study is registered with Clinicaltrials.gov identifier: NCT00515632. RESULTS: In the 10- and 20-mg balaglitazone groups, and in the 45-mg pioglitazone group, significant reductions in haemoglobin A(1c) levels were observed (−0.99, −1.11, and −1.22%, respectively; p < 0.0001) versus placebo. Fasting serum glucose was similarly reduced in all treatment arms. Dual energy X-ray absorptiometry analyses showed that, while balaglitazone at 10 mg caused weight gain and fluid retention compared to placebo, the magnitude of these effects was significantly smaller than that of pioglitazone 45 mg and balaglitazone 20mg. Balaglitazone at either dose did not appear to reduce bone mineral density, while Pioglitazone showed a trend towards a reduction. CONCLUSION: Patients treated with balaglitazone at 10 mg and 20 mg and pioglitazone at 45 mg showed clinically meaningful improvements in glucose levels and HbA(1c) . With the 10 mg dose, the benefits (glucose & HgA(1c) lowering) and untoward effects (fluid and fat accumulation) were less, results that encourage further studies of this drug candidate.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , PPAR gamma/antagonistas & inhibidores , Quinazolinas/uso terapéutico , Tiazolidinedionas/uso terapéutico , Anciano , Glucemia/análisis , Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Masculino , Persona de Mediana Edad , Pioglitazona , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Tiazolidinedionas/administración & dosificación , Tiazolidinedionas/efectos adversos , Equilibrio Hidroelectrolítico/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
BACKGROUND: Sustained and disease-modifying effects of sublingual immunotherapy have never before been confirmed in a large-scale randomized, double-blind, placebo-controlled trial. OBJECTIVE: We sought to investigate sustained efficacy 1 year after a 3-year period of daily treatment with the SQ-standardized grass allergy immunotherapy tablet Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU; ALK-Abelló, Hørsholm, Denmark). METHODS: A randomized, double-blind, placebo-controlled, phase III trial including adults with a history of moderate-to-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications. The analysis set comprised 257 subjects at the follow-up. Efficacy end points were rhinoconjunctivitis symptom and medication scores, quality of life, and percentages of symptom and medication free days. Immunologic end points included grass pollen-specific serum IgG4 and IgE-blocking factor. Safety was assessed based on adverse events. RESULTS: Significant improvements in efficacy were consistently shown during 3 years' treatment. One year after treatment, the active group showed sustained reductions in mean rhinoconjunctivitis symptom scores (26%, P < .001) and medication scores (29%, P = .022) when compared with placebo. This level was similar to the efficacy observed during the 3-year treatment period. The differences in percentages of symptom- and medication-free days were significant during and 1 year after treatment. The active group also reported sustained and significant improvements in quality of life. Sustained clinical benefit was accompanied by immunologic changes. No safety issues were identified. CONCLUSION: Three years of treatment with the SQ-standardized grass allergy immunotherapy tablet resulted in consistent clinical improvement and accompanying immunologic changes that were sustained 1 year after treatment, which is indicative of disease modification and associated long-term benefits.
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Conjuntivitis Alérgica/terapia , Desensibilización Inmunológica , Phleum/inmunología , Rinitis Alérgica Estacional/terapia , Administración Sublingual , Adulto , Conjuntivitis Alérgica/inmunología , Conjuntivitis Alérgica/fisiopatología , Desensibilización Inmunológica/métodos , Método Doble Ciego , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Phleum/efectos adversos , Poaceae/inmunología , Polen/inmunología , Calidad de Vida , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/fisiopatología , Comprimidos/administración & dosificación , Comprimidos/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Background: Menopause is associated with detrimental changes in turnover of bone and cartilage and a variety of symptoms with negative impact on the quality of life. Naturally occurring isoflavones from Radix Pueraria lobata, Kudzu root, may possess chondroprotective and symptom-relieving properties, but efficacy and safety of dosing and dose frequencies required for pharmacological action is unclear. Purpose: This clinical trial evaluates the efficacy on bone and cartilage turnover, menopausal symptoms, and safety of five dose regimens of Kudzu root extract administered either once, twice or three times daily in women with at least mild menopausal symptoms. Materials and Methods: Fifty postmenopausal women were randomized equally into five different dose regimen groups of Kudzu root extract in a four-week, parallel group, open-label, single-center, exploratory study design. Biomarkers CTX-I and CTX-II reflecting bone and cartilage degradation, respectively, were assessed in blood samples and 24-h urine samples. Change from baseline in the Menopause Rating Scale (MRS) and subscales was evaluated. Safety endpoints were frequency of adverse events, changes in hematology and safety chemistry data, vital signs and electrocardiogram. Results: Fifty women (Age 54.2 years, SD: 2.9) were randomized. After 4 weeks of treatment, biomarkers of bone resorption and cartilage degradation were statistically significantly reduced from baseline levels in the group receiving two capsules three times a day, serum/urine CTX-I (-18.4%, 95% CI: -8.1 to -27.5, p = 0.001/-34.2%, 95% CI: -21.6 to -44.7, p < 0.0001), urine CTX-II (-17.4% 95% CI: -2.5 to -30.0, p = 0.02). The observed effects were consistent across study groups but appeared to favour three times daily dosing. Four weeks of treatment led to statistically significant reductions in the MRS Total Score (p < 0.0001-0.03) in four out of five treatment groups. Kudzu root extract was well tolerated in all dose regimens, and no serious adverse events were reported. Conclusion: The results indicate that Kudzu extract may possess beneficial effects on bone and cartilage health and may be a promising natural alternative to existing treatments for menopausal symptoms. Kudzu root extract was well tolerated for short-term treatment of mild to severe menopausal symptoms in women in all tested doses and dose frequencies.
RESUMEN
The heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted in the field. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA). We investigated the level of blood CRPM in OA compared to RA using data from two phase III knee OA and two RA studies (N = 1591). Moreover, the association between CRPM levels and radiographic progression was investigated. The mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3-8.8] ng/mL, n = 781) compared to the RA patients (12.8 [9.5-16.0] ng/mL, n = 60); however, a significant subset of OA patients (31%) had CRPM levels (≥ 9 ng/mL) comparable to RA. Furthermore, OA patients (n = 152) with CRPM levels ≥ 9 ng/mL were more likely to develop contra-lateral knee OA assessed by X-ray over a two-year follow-up period with an odds ratio of 2.2 [1.0-4.7]. These data suggest that CRPM is a blood-based biochemical marker for early identification OA patients with an inflammatory phenotype.
Asunto(s)
Biomarcadores/sangre , Oligopéptidos/sangre , Osteoartritis de la Rodilla/sangre , Osteoartritis de la Rodilla/epidemiología , Adulto , Anciano , Artritis Reumatoide/sangre , Artritis Reumatoide/epidemiología , Artritis Reumatoide/etiología , Proteína C-Reactiva/metabolismo , Estudios de Cohortes , Susceptibilidad a Enfermedades , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Osteoartritis de la Rodilla/etiología , Osteoartritis de la Rodilla/patología , Curva ROCRESUMEN
AIMS: The aims of the study were to investigate interindividual variations in the bioavailability of salmon calcitonin (sCT) following single oral 0.8 mg doses at three different times of the day, and intraindividual variation in sCT bioavailability at each end of a 14-day treatment period. We also investigated correlations between exposure to sCT and levels of the bone resorption biomarker serum C-terminal telopeptide of collagen type I (CTX-I). METHODS: Participants were from two randomized, double-blind, placebo-controlled studies. In study I, healthy postmenopausal women received a single dose of 0.8 mg of oral sCT or placebo at 08:00 (n = 42), 17:00 (n = 20), or at 22:00 (n = 19). In study II, age-matched men or postmenopausal women with osteoarthritis received 0.8 mg oral sCT (n = 26) or placebo (n = 23) twice daily for 14 days, with dosing at 08:00 and 17:00. In both studies, drug exposure was assessed by plasma sCT concentrations, and bone resorption by CTX-I levels. RESULTS: The variability in exposure between patients, measured as coefficient of variation (CV), was as follows: 22% for the morning dose, 30% for the predinner dose, and 34% for the evening dose. In study 1, a high degree of correlation was seen between the level of exposure following a single 0.8 mg dose of sCT and suppression of serum CTX-I, with Pearson correlation coefficients of r = -0.74, -0.96, and -0.78, following doses at 08:00, 17:00, and 22:00, respectively. In study II, exposure to sCT varied widely within the same individuals between dosing days 1 and 14, with weak correlations of r = 0.40 and 0.38 at the dose times 08:00 and 17:00, respectively. As expected from this finding, the intraindividual response in serum CTX-I levels was non-significantly associated on dosing days 1 and 14 (r = 0.34 and r = 0.27 at dose times 08:00 and 17:00, respectively). CONCLUSION: Increased bioavailability of orally administered 0.8 mg sCT was highly correlated with increased suppression of the bone resorption marker serum CTX-I irrespective of the time of day. However, the high inter- and intraindividual variability in sCT exposure demonstrates the importance of determining the optimum conditions for ensuring the most beneficial sCT uptake.
Asunto(s)
Conservadores de la Densidad Ósea/farmacocinética , Calcitonina/farmacocinética , Administración Oral , Anciano , Disponibilidad Biológica , Biomarcadores/sangre , Conservadores de la Densidad Ósea/farmacología , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Calcitonina/farmacología , Colágeno Tipo I/efectos de los fármacos , Colágeno Tipo I/genética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , PosmenopausiaRESUMEN
This study investigated the association between body composition and risk of atrial fibrillation (AF) in postmenopausal women. In a retrospective analysis we assessed data from 5704 postmenopausal women (age 70.7 ± 6.5 yrs.) who in 1999-2001 participated in The Prospective Epidemiological Risk Factor study with body composition assessed by dual-energy X-ray absorptiometry. Outcomes were obtained from Danish Health Registries and body composition association to risk of AF was evaluated by univariable and multivariable Cox Hazard regression. 850 women developed AF after baseline. High lean body mass was associated with increased risk of AF in multivariable analyses, adjusting for body mass index (BMI), height or weight (adjusted for: BMI, hazard ratio (HR) 1.49, 95% Confidence Interval (1.22-1.80); height, HR 1.27 (1.03-1.56); weight, 1.33 (1.06-1.65)). Height and weight were associated with increased risk of AF in multivariable analyses adjusting for body composition measures. When adjusting for total lean mass, only height remained statistically significant (HR 1.34 (1.09-1.64)). In a cohort of elderly Caucasian women, high lean body mass, height and weight were associated with increased risk of AF and the variables remained significant after adjusting for age and other known risk factors of AF.
Asunto(s)
Fibrilación Atrial/epidemiología , Posmenopausia , Absorciometría de Fotón , Anciano , Estatura , Índice de Masa Corporal , Dinamarca/epidemiología , Femenino , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sistema de Registros , Estudios RetrospectivosRESUMEN
The aim of this study was to assess the bioavailability and pharmacodynamic efficacy of synthetic salmon calcitonin (ssCT) and recombinant salmon calcitonin (rsCT) in healthy postmenopausal women. The study was a single-blind, randomized study. Participants were 36 postmenopausal women 62 to 74 years old, randomly assigned to a comparison of dosing with ssCT (n = 12) or rsCT (n = 24) given in the morning at 08:00. Study parameters were plasma CT levels measured up to 2 hours postdose and changes in the bone resorption marker serum CTX-I and the cartilage degradation marker urine CTX-II measured up to 4 hours postdose. For both formulations, peak plasma concentrations were obtained 15 minutes after dosage, and no statistically significant differences in the uptake of CT were observed. Measurement of bone resorption and cartilage degradation markers displayed comparable responses, with AUCs of relative change of serum CTX-I of -250% x hours and relative change of urine CTX-II of -180% x hours during the 4-hour observation period. In conclusion, oral synthetic and recombinant calcitonin displayed comparable pharmacodynamic and kinetic properties.
Asunto(s)
Conservadores de la Densidad Ósea/administración & dosificación , Resorción Ósea/tratamiento farmacológico , Calcitonina/administración & dosificación , Posmenopausia , Administración Oral , Anciano , Área Bajo la Curva , Disponibilidad Biológica , Biomarcadores/sangre , Biomarcadores/orina , Conservadores de la Densidad Ósea/farmacocinética , Conservadores de la Densidad Ósea/farmacología , Calcitonina/farmacocinética , Calcitonina/farmacología , Colágeno Tipo I/sangre , Colágeno Tipo I/efectos de los fármacos , Colágeno Tipo II/efectos de los fármacos , Colágeno Tipo II/orina , Femenino , Humanos , Persona de Mediana Edad , Péptidos/sangre , Péptidos/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacología , Método Simple CiegoRESUMEN
AIMS: To investigate the influence of food intake on the bioavailability and pharmacodynamic effects of salmon calcitonin (sCT). METHODS: A single-blind, randomized, partly placebo-controlled study was conducted in 36 healthy postmenopausal female volunteers aged 62-74 years. The influence of food intake on oral dosing with 0.8 mg of sCT at 22.00 h was evaluated for a (i) predose meal at 18.00 h, (ii) predose meal at 20.00 h, (iii) predose meal at 21.00 h, (iv) postdose meal at 22.10 h, (v) no meal, and (vi) meal at 20.00 h and placebo at 22.00 h. Study biomarkers were plasma sCT levels and changes in the bone resorption marker CTX-I (C-terminal telopeptide of collagen type I). RESULTS: The predose meal at 18.00 and 21.00 h significantly decreased relative oral bioavailability of sCT to 26% [95% confidence interval (CI) 0.09, 0.73 and 0.09, 0.75, P= 0.009 and P= 0.01]. The meal consumed 10 min after dosing decreased the oral bioavailability of sCT to 59% (95% CI 0.21, 1.68), although nonsignificant (P= 0.48). This decreased bioavailability led to lower relative suppression of serum CTX-I, with an AUC of the 4-h efficacy response of -91%-x-hours for those receiving a meal at 18.00 h, compared with -238%-x-hours for fasting subjects. The Dunnett-adjusted difference between these two treatment sequences was 147%-x-hours (95% CI 68, 225) (P= 0.0003). The AUC was comparable among fasting subjects and those consuming a meal 10 min after dosing. CONCLUSIONS: Postprandial dosing may limit the bioavailability of orally administered sCT. Maximal benefit can be achieved by dosing at least 10 min prior to meal time.
Asunto(s)
Conservadores de la Densidad Ósea/farmacocinética , Densidad Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Calcitonina/farmacocinética , Colágeno Tipo I/efectos de los fármacos , Ingestión de Alimentos/fisiología , Administración Oral , Anciano , Área Bajo la Curva , Disponibilidad Biológica , Biomarcadores/sangre , Conservadores de la Densidad Ósea/administración & dosificación , Calcitonina/administración & dosificación , Ayuno/fisiología , Femenino , Humanos , Persona de Mediana Edad , Método Simple Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: This is an interim analysis of a randomized, double-blind, placebo-controlled phase III trial with 3 years of daily treatment with grass tablet immunotherapy (GRAZAX; ALK-Abelló A/S, Hørsholm, Denmark) or placebo, followed by 2 years of follow-up to assess the persistent efficacy. OBJECTIVE: We sought to evaluate the efficacy and safety of specific immunotherapy with grass allergen tablets compared with placebo after treatment covering 2 consecutive grass pollen seasons. METHODS: The interim analyses included 351 adult participants with moderate-to-severe allergic rhinoconjunctivitis caused by grass pollen. Participants were treated with active (n = 189) or placebo (n = 162) tablets for an average of 22 months. All participants were allowed to use symptomatic rescue medication. RESULTS: The primary efficacy analysis showed highly significant mean reductions of 36% in rhinoconjunctivitis symptom score (P < .0001; median reduction, 44%) and 46% in rhinoconjunctivitis medication score (P < .0001; median reduction, 73%) in the active group relative to the placebo group. Mean rhinoconjunctivitis quality of life was 33% better (P < .0001; median, 40%). Clinical improvements were paralleled by significant changes in allergen-specific immunoglobulins. The treatment was well tolerated, and adverse events led to withdrawal in less than 1% of participants. There were no serious adverse events related to treatment. CONCLUSION: Grass allergen tablet immunotherapy showed progressive immunologic changes and highly significant efficacy over 2 years of continued treatment.
Asunto(s)
Antígenos de Plantas/administración & dosificación , Conjuntivitis/tratamiento farmacológico , Desensibilización Inmunológica/métodos , Hipersensibilidad/complicaciones , Poaceae/inmunología , Rinitis/tratamiento farmacológico , Administración Sublingual , Adulto , Antígenos de Plantas/efectos adversos , Antígenos de Plantas/uso terapéutico , Conjuntivitis/etiología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Rinitis/etiología , Comprimidos , Resultado del TratamientoRESUMEN
BACKGROUND: Excessive cartilage degradation is a known characteristic of osteoarthritis (OA). Biochemical markers, such as uCTX-II, have been shown to be associated with disease severity, yet the tissue origin of CTX-II has been disputed. This analysis investigates the association between OA knee joints at different radiographic stages and pain categories with levels of uCTX-II and biomarkers of bone resorption and formation. METHODS: Baseline data of two randomised clinical trials (NCT00486434 and NCT00704847) in patients with radiographic OA and presence of pain were analysed post hoc. A subgroup with available urine samples and evaluable radiographs for both knees (N = 1241) was analysed. Urine CTX-I, urine CTX-II and serum osteocalcin were analysed for associations with combined Kellgren-Lawrence (KL) scores, gender and pain for both knees to assess the contribution of joints at different stages. RESULTS: Pain, BMI, age, gender and KL grade were all significantly associated with uCTX-II. The association between pain and CTX-II appeared to be driven by weight-bearing pain. The level of uCTX-II incrementally increased with higher radiographic severity of each knee. Levels of bone markers CTX-I and osteocalcin were both significantly associated with BMI and gender, but neither were associated with radiographic severity. Biomarker levels between male or female groups of identical KL scores were found to be higher in females compared to males in some but not all KL score groups. CONCLUSIONS: These results indicate that levels of uCTX-II are independently associated with radiographic severity of OA and pain intensity. CTX-II was associated with weight-bearing pain, but not non-weight-bearing pain, independent of co-variates. Bilateral OA knee joints appear to contribute to uCTX-II levels in an incremental manner according to radiographic severity of single joints. The data suggest that biomarker differences between genders should be taken into account when evaluating these markers in the context of structural features of OA.
Asunto(s)
Huesos/metabolismo , Proteína de la Matriz Oligomérica del Cartílago/metabolismo , Cartílago Articular/metabolismo , Colágeno Tipo II/metabolismo , Colágeno Tipo I/metabolismo , Osteoartritis de la Rodilla/metabolismo , Péptidos/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Huesos/diagnóstico por imagen , Estudios Transversales , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/diagnóstico , Radiografía , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: To investigate the influence of water intake and dose timing on the pharmacokinetic and pharmacodynamic parameters of an oral formulation of salmon calcitonin (sCT). METHODS: The study was a randomized, partially-blind, placebo-controlled, single dose, exploratory crossover phase I study. 56 healthy postmenopausal women were randomly assigned to receive five treatments. The treatments comprised a combination of study medication (SMC021 (0.8 mg sCT + 200 mg 5-CNAC), SMC021 placebo, or 200 IU Miacalcic NS nasal spray), water volume given with the tablet (50 or 200 ml water), and time between dosing and meal (10, 30, or 60 minutes pre-meal). Plasma sCT levels and changes in the bone resorption (C-terminal telopeptide of collagen type I) was investigated. Trial regristration. RESULTS: Oral delivery of 0.8 mg of sCT with 50 ml of water compared to that with 200 ml water resulted in a two-fold increase in maximum concentration (Cmax and AUC0-4) of plasma sCT but comparable time to reach maximum concentration (Tmax). The sCT AUC0-4 with 50 ml of water was 4-fold higher than that obtained with nasal calcitonin. The increased absorption of sCT resulted in increased efficacy demonstrated by AUC of the relative change of serum CTX-I measured in the 6 hours post dosing. CONCLUSION: 0.8 mg sCT with 50 ml of water taken 30 and 60 minutes prior to meal time resulted in optimal pharmacodynamic and pharmacokinetic parameters. The data suggest that this novel oral formulation may have improved absorption and reduction of bone resorption compared to that of the nasal form.
Asunto(s)
Conservadores de la Densidad Ósea/farmacocinética , Calcitonina/farmacocinética , Ingestión de Líquidos , Administración Oral , Adulto , Anciano , Área Bajo la Curva , Disponibilidad Biológica , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/farmacología , Huesos/efectos de los fármacos , Huesos/metabolismo , Calcitonina/administración & dosificación , Calcitonina/farmacología , Estudios Cruzados , Ingestión de Alimentos , Femenino , Humanos , Absorción Intestinal , Persona de Mediana Edad , Factores de TiempoRESUMEN
Mutations in the CSA and CSB genes cause Cockayne syndrome, a rare inherited disorder characterized by UV sensitivity, severe neurological abnormalities, and progeriod symptoms. Both gene products function in the transcription-coupled repair (TCR) subpathway of nucleotide excision repair (NER), providing the cell with a mechanism to remove transcription-blocking lesions from the transcribed strands of actively transcribed genes. Besides a function in TCR of NER lesions, a role of CSB in (transcription-coupled) repair of oxidative DNA damage has been suggested. In this study we used mouse models to compare the effect of a CSA or a CSB defect on oxidative DNA damage sensitivity at the levels of the cell and the intact organism. In contrast to CSB(-/-) mouse embryonic fibroblasts (MEFs), CSA(-/-) MEFs are not hypersensitive to gamma-ray or paraquat treatment. Similar results were obtained for keratinocytes. In contrast, both CSB(-/-) and CSA(-/-) embryonic stem cells show slight gamma-ray sensitivity. Finally, CSB(-/-) but not CSA(-/-) mice fed with food containing di(2-ethylhexyl)phthalate (causing elevated levels of oxidative DNA damage in the liver) show weight reduction. These findings not only uncover a clear difference in oxidative DNA damage sensitivity between CSA- and CSB-deficient cell lines and mice but also show that sensitivity to oxidative DNA damage is not a uniform characteristic of Cockayne syndrome. This difference in the DNA damage response between CSA- and CSB-deficient cells is unexpected, since until now no consistent differences between CSA and CSB patients have been reported. We suggest that the CSA and CSB proteins in part perform separate roles in different DNA damage response pathways.