RESUMO
Phenylketonuria (PKU), a deficiency in the activity of the enzyme phenylalanine hydroxylase, leads to toxic levels of phenylalanine (Phe) in the blood and brain. Pegvaliase (recombinant Anabaena variabilis phenylalanine ammonia lyase conjugated with polyethylene glycol) is approved to manage PKU in patients aged greater than or equal to 18 years in the United States and in patients aged greater than or equal to 16 years in the European Union. Pharmacokinetic, pharmacodynamic, and immunogenicity results from five open-label pegvaliase trials were assessed. Studies with induction/titration/maintenance (I/T/M) dosing regimens demonstrated pharmacokinetic stabilization and sustained efficacy associated with maintenance doses (20, 40, or 60 mg/day). Immune-mediated pegvaliase clearance was high during induction/titration phases when the early immune response was peaking. The combination of low drug dosage and high drug clearance led to low drug exposure and minimal decreases in blood Phe levels during induction/titration. Higher drug exposure and substantial reductions in blood Phe levels were observed later in treatment as drug clearance was reduced due to the maturation of the immune response, which allowed for increased dosing to target levels. The incidence of hypersensitivity reactions was temporally associated with the peaking of the early antidrug immune response and decreased with time as immune response matured after the first 6 months of treatment. These results support an I/T/M dosing regimen and suggest a strategy for administration of other nonhuman biologics to achieve efficacy and improve tolerability.
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Hipersensibilidade a Drogas/epidemiologia , Fenilalanina Amônia-Liase/farmacocinética , Fenilcetonúrias/tratamento farmacológico , Adulto , Hipersensibilidade a Drogas/etiologia , Feminino , Humanos , Incidência , Masculino , Fenilalanina/sangue , Fenilalanina Amônia-Liase/administração & dosagem , Fenilalanina Amônia-Liase/efeitos adversos , Fenilcetonúrias/sangue , Fenilcetonúrias/diagnóstico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Resultado do Tratamento , Estados UnidosRESUMO
In phenylketonuria (PKU), mutations of the phenylalanine hydroxylase (PAH) gene decrease the ability of PAH to convert phenylalanine (Phe) to tyrosine (Tyr), resulting in Phe accumulation in the blood and brain and disruption of neurotransmitter (NT) biosynthesis and metabolism. The following translational study explored the relationship between pegvaliase-mediated Phe correction in plasma and the NT biosynthesis and metabolism pathway in mice and humans with PKU. Lower plasma Phe levels were associated with normalization of the NT biosynthesis pathway which correlated with an improvement in inattention symptoms in subjects with PKU.
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Encéfalo/metabolismo , Neurotransmissores/metabolismo , Fenilalanina/sangue , Fenilcetonúrias/metabolismo , Aminoácidos/metabolismo , Animais , Biomarcadores , Vias Biossintéticas , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Knockout , Mutação , Fenilalanina Amônia-Liase/administração & dosagem , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/genética , Proteínas Recombinantes/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Phenylketonuria (PKU) leads to an accumulation of phenylalanine (Phe) in the blood and subsequent neurologic, cognitive, psychiatric, and behavioral dysfunction. Many patients report social isolation and decreased quality of life. Pegvaliase is an enzyme substitution therapy that reduces blood Phe levels in patients with PKU and is associated with a risk of hypersensitivity reactions. OBJECTIVE: To define the minimum acceptable benefit (MAB) of pegvaliase, i.e., the minimum probability of achieving a blood Phe level <360⯵mol/L, which patients require to tolerate the risks of hypersensitivity associated with pegvaliase. METHODS: Adult, pegvaliase-naïve patients with blood Phe levels >600⯵mol/L participated in a patient-preference web survey using two surveys: adapted swing-weighting and thresholding. Participants were asked to make ordinal choices between varying clinical benefit and severity levels for hypersensitivity. Disease effects and treatment satisfaction were also assessed. RESULTS: Among 45 participants, the mean (standard deviation) self-reported blood Phe level was 976.9 (429.9) µmol/L; only 28.8% reported satisfaction with their current treatment. Most (84.4%) indicated difficulty in following a PKU diet; 60% reported that the PKU diet was burdensome, and 58% reported feeling socially isolated. Most (≥69%) reported their MAB to be less than the expected clinical benefit provided by pegvaliase; the mean MAB was 22.7% and 34.4% in the swing-weighting and thresholding surveys, respectively. CONCLUSION: Most participants felt the burden of PKU on their daily lives, were dissatisfied with current treatments, and were willing to accept the risks of hypersensitivity reactions to achieve recommended blood Phe levels with pegvaliase treatment.
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Pegvaliase is an enzyme substitution therapy developed to lower blood phenylalanine (Phe) in adults with phenylketonuria (PKU). In phase 3 clinical studies, pegvaliase substantially reduced mean blood Phe in adult subjects with PKU. The most common type of adverse event observed in the pegvaliase clinical program was hypersensitivity adverse events (HAEs), which included occurrences of arthralgia, rash, and pruritis. The most clinically relevant HAEs were acute systemic hypersensitivity reactions consistent with anaphylaxis observed in 4.6% of phase 3 patients. HAEs were more commonly observed around the time of high circulating immune complex (CIC) levels and complement activation, and the majority of subjects that experienced acute systemic hypersensitivity events were able to continue treatment, which is atypical for a classical IgE-mediated anaphylactic event, but common for type III hypersensitivity reactions. To investigate the alternative mechanism of type III hypersensitivity, serum samples collected shortly after hypersensitivity events (in phase 2 and 3 studies) were tested for anti-pegvaliase IgE using custom radioallergosorbent test and/or ImmunoCAP® (ThermoFisher Scientific, Waltham, MA) assay methods. All subjects with acute systemic hypersensitivity that were tested for anti-pegvaliase IgE at or near the time of event with one or both assays tested negative for IgE. As presented here, an investigation using selected study samples with high anti-drug antibody (ADA) titers demonstrated that presence of IgM and/or IgG ADA can interfere with measurement of a human anti-pegvaliase IgE surrogate positive control. A depletion method was therefore developed using protein A- and G-conjugated Sepharose to remove interfering IgG and IgM in serum samples to low levels (<45â¯mg/dL) before IgE testing. A final 2× concentration step brought the IgE concentration in the depleted sample to approximately the same level of the starting serum. Phase 3 study samples with sufficient volume remaining that previously tested negative for anti-pegvaliase IgE were re-tested after depletion of IgG and IgM. All samples again tested negative, confirming the original test results. Taken together, the clinical presentation, temporal association of HAEs with CIC levels and complement activation, and lack of anti-pegvaliase IgE suggest pegvaliase-associated acute systemic hypersensitivity events were not IgE-mediated. Furthermore, we describe a universal method that is broadly applicable to enzyme therapies for detection of low concentrations of drug-specific IgE in the presence of high titer anti-drug antibodies of different isotypes.
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Hipersensibilidade a Drogas/diagnóstico , Imunoensaio , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Fenilalanina Amônia-Liase/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Biomarcadores/sangue , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/imunologia , Humanos , Fenilalanina Amônia-Liase/imunologia , Valor Preditivo dos Testes , Proteínas Recombinantes/imunologia , Reprodutibilidade dos TestesRESUMO
BACKGROUND: This study assessed the immunogenicity of pegvaliase (recombinant Anabaena variabilis phenylalanine [Phe] ammonia lyase [PAL] conjugated with polyethylene glycol [PEG]) treatment in adults with phenylketonuria (PKU) and its impact on safety and efficacy. METHODS: Immunogenicity was assessed during induction, upward titration, and maintenance dosing regimens in adults with PKU (nâ¯=â¯261). Total antidrug antibodies (ADA), neutralizing antibodies, immunoglobulin (Ig) M and IgG antibodies against PAL and PEG, IgG and IgM circulating immune complex (CIC) levels, complement components 3 and 4 (C3/C4), plasma Phe, and safety were assessed at baseline and throughout the study. Pegvaliase-specific IgE levels were measured in patients after hypersensitivity adverse events (HAE). FINDINGS: All patients developed ADA against PAL, peaking by 6â¯months and then stabilizing. Most developed transient antibody responses against PEG, peaking by 3â¯months, then returning to baseline by 9â¯months. Binding of ADA to pegvaliase led to CIC formation and complement activation, which were highest during early treatment. Blood Phe decreased over time as CIC levels and complement activation declined and pegvaliase dosage increased. HAEs were most frequent during early treatment and declined over time. No patient with acute systemic hypersensitivity events tested positive for pegvaliase-specific IgE near the time of the event. Laboratory evidence was consistent with immune complex-mediated type III hypersensitivity. No evidence of pegvaliase-associated IC-mediated end organ damage was noted. INTERPRETATION: Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. FUND: BioMarin Pharmaceutical Inc.
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Anticorpos , Complexo Antígeno-Anticorpo , Hipersensibilidade a Drogas , Fenilalanina Amônia-Liase , Fenilcetonúrias , Proteínas Recombinantes , Adulto , Anticorpos/sangue , Anticorpos/imunologia , Complexo Antígeno-Anticorpo/sangue , Complexo Antígeno-Anticorpo/imunologia , Complemento C3/imunologia , Complemento C3/metabolismo , Complemento C4/imunologia , Complemento C4/metabolismo , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Masculino , Fenilalanina/sangue , Fenilalanina/imunologia , Fenilalanina Amônia-Liase/administração & dosagem , Fenilalanina Amônia-Liase/efeitos adversos , Fenilcetonúrias/sangue , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversosRESUMO
BACKGROUND: Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. METHODS: Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600⯵mol/L were randomized 1:1 to a maintenance dose of 20â¯mg/day or 40â¯mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5â¯mg/day to 60â¯mg/day. RESULTS: Of 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12â¯months andâ¯≥â¯24â¯months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) µmol/L at baseline, 564.5 (531.2) µmol/L at 12â¯months, and 311.4 (427) µmol/L at 24â¯months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24â¯months, 68.4% of participants achieved blood Phe ≤600⯵mol/L, 60.7% of participants achieved blood Phe ≤360⯵mol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120⯵mol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6â¯months of exposure (early treatment phase) than after 6â¯months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. CONCLUSION: Results from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment.
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Fenilalanina Amônia-Liase/uso terapêutico , Fenilalanina/sangue , Fenilcetonúrias/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Fenilalanina Amônia-Liase/administração & dosagem , Fenilalanina Amônia-Liase/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Fatores de Tempo , Adulto JovemRESUMO
INTRODUCTION: Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU. METHODS: PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20â¯mg/day or 40â¯mg/day) or switch to matching placebo. RESULTS: The pooled pegvaliase group enrolled 66 participants and each placebo group enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9⯵M (504.6) in the group assigned to the 20â¯mg/day placebo group (nâ¯=â¯14), 508.2⯵M (363.7) in those assigned to the 40â¯mg/day placebo group (nâ¯=â¯14), and 503.9⯵M (520.3) in those assigned to continue pegvaliase treatment (nâ¯=â¯58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8⯵M (760.4 to 1139.1) for the 20â¯mg/day placebo group and 664.8⯵M (465.5 to 864.1) for the 40â¯mg/day placebo group in comparison to 26.5⯵M (-68.3 to 121.3) for the pooled (20â¯mg/day and 40â¯mg/day) pegvaliase group (Pâ¯<â¯0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%). CONCLUSION: Mean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had mean blood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants.
Assuntos
Fenilalanina Amônia-Liase/uso terapêutico , Fenilalanina/sangue , Fenilcetonúrias/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adolescente , Adulto , Proteínas Alimentares , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenilalanina Amônia-Liase/administração & dosagem , Fenilalanina Amônia-Liase/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Adulto JovemRESUMO
OBJECTIVE: To create a tool to predict probability of remission and low disease activity (LDA) in patients with RA being considered for anti-TNF treatment in clinical practice. METHODS: We analysed data from GO-MORE, an open-label, multinational, prospective study in biologic-naïve patients with active RA (DAS28-ESR ⩾3.2) despite DMARD therapy. Patients received 50 mg s.c. golimumab (GLM) once monthly for 6 months. In secondary analyses, regression models were used to determine the best set of baseline factors to predict remission (DAS28-ESR <2.6) at month 6 and LDA (DAS28-ESR ⩽3.2) at month 1. RESULTS: In 3280 efficacy-evaluable patients, of 12 factors included in initial regression models predicting remission or LDA, six were retained in final multivariable models. Greater likelihood of LDA and remission was associated with being male; younger age; lower HAQ, ESR (or CRP) and tender joint count (or swollen joint count) scores; and absence of comorbidities. In models predicting 1-, 3- and 6-month LDA or remission, area under the receiver operating curve was 0.648-0.809 (R(2) = 0.0397-0.1078). The models also predicted 6-month HAQ and EuroQoL-5-dimension scores. A series of matrices were developed to easily show predicted rates of remission and LDA. CONCLUSION: A matrix tool was developed to show predicted GLM treatment outcomes in patients with RA, based on a combination of six baseline characteristics. The tool could help provide practical guidance in selection of candidates for anti-TNF therapy.
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Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Análise de Regressão , Indução de Remissão , Resultado do TratamentoRESUMO
Abstract Adults with phenylketonuria (PKU) experience disturbances in mood. This study used qualitative and quantitative techniques to adapt the 65-item Profile of Mood States (POMS) for the assessment of key mood domains in adults with PKU. First, cognitive interviews on 58 POMS items (excluding 7 Friendliness domain items) among 15 adults and adolescents (age ≥16 years) with PKU were conducted to eliminate items poorly understood or considered irrelevant to PKU; 17 items were removed. Next, the remaining POMS items were quantitatively examined (Mokken scaling and Rasch analysis) in 115 adult patients with PKU. An additional 21 items were removed iteratively, resulting in the 20-item draft PKU-POMS. Finally, the psychometric properties of the draft PKU-POMS were examined. The instrument displayed strong psychometric properties (reliability, validity, and responsiveness) over 6 domains (Anxiety, Depression, Anger, Activity, Tiredness, and Confusion) and all items were well understood in the final cognitive interviews with 10 adults with PKU.
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Abstract Content validity of the 18-item Investigator-Rated Attention-Deficit Hyperactivity Disorder (ADHD) Rating Scale IV (I-ADHD RS-IV) with adult prompts was investigated using qualitative interviews of US clinicians who had prior experience rating adults with phenylketonuria (PKU) using the I-ADHD RS-IV. Fourteen qualitative interviews were conducted to obtain key symptom experiences of adults with PKU and assessed the relevance, clarity, and administration of the I-ADHD RS-IV. Participants (n = 13, 92.9%) endorsed the inattention symptoms as key experiences by adults with PKU and endorsed the instrument as fit for purpose for adults with PKU. Participants generally reported low frequencies of occurrence for the 9 I-ADHD RS-IV hyperactivity/impulsivity items. Despite some clinicians' concerns for the lack of patient self-awareness, the participants reported no difficulty selecting a rating on these items. This in-depth study of the content validity of the I-ADHD RS-IV provides evidence that this clinician-reported instrument captures the severity of important inattention symptoms in adults with PKU.
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OBJECTIVES: To evaluate factors influencing injection patterns and patient evaluations of an autoinjector device in biologic-naïve patients beginning golimumab (GLM) treatment. METHODS: GO-MORE was an open-label, multinational, prospective study in patients with active rheumatoid arthritis (RA) (28-joint disease activity score based on erythrocyte sedimentation rate [DAS28-ESR] ≥3.2). Patients injected 50 mg subcutaneous GLM once monthly for 6 months. Patients reported use preferences and autoinjector evaluations by questionnaire. Responses were analysed descriptively. Effects of patient variables were evaluated with chi-square tests or t-tests. RESULTS: Of 3,280 efficacy-evaluable patients, 67.7% self-injected with the autoinjector. Compared with patients who self-injected, patients who had someone else administer injections had greater baseline disease activity (e.g., DAS28-ESR 5.84 vs. 6.23, respectively), but not more tender/swollen joints in hands/wrists. Month 6 efficacy was greater for patients who self-injected. In those who self-injected, injection site (thigh [75.2%; 1,563/2,077], abdomen [17.4%; 363/2,077], upper arm [7.2%; 151/2,077]) was not associated with wrist swelling or tender/swollen joints in the hand used for injection. Autoinjector ratings were similar across injection sites, yet less pain/discomfort was associated with abdomen injection. Patient autoinjector ratings were favourable overall (e.g. ease of use, pain). Patients with baseline functional impairment had slightly less favourable ratings. CONCLUSIONS: Biologic-naïve patients who self-injected had less baseline disease activity and higher response rates than patients who did not self-inject. Although patients prefer to inject in the thigh, injection in the belly may be less painful. Most patients who self-injected had favourable autoinjector evaluations; patients with functional impairment had slightly less favourable ratings.
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Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Preferência do Paciente , Pacientes/psicologia , Seringas , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/psicologia , Automação , Distribuição de Qui-Quadrado , Esquema de Medicação , Desenho de Equipamento , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Injeções Subcutâneas , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Estudos Prospectivos , Autoadministração , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: Rheumatoid arthritis (RA) management involves improving clinical outcomes and quality of life (QOL). Golimumab is used as add-on therapy for patients who have failed disease-modifying antirheumatic drugs (DMARDs). This GO-MORE subanalysis investigated relationships between patient and physician expectations and outcomes. METHODS: GO-MORE was an open-label, multinational, prospective study in biologic agent-naive patients with active RA despite DMARD treatment. Patients received 50 mg subcutaneous golimumab monthly for 6 months. At baseline and month 3, patients rated treatment expectations for the following 3 months using 5-point scales (where 1 = good and 5 = poor). Outcomes were compared among expectation tertiles: most positive, intermediate, and least positive. At baseline and month 3, physicians predicted patient disease state 3 months later. RESULTS: At baseline, 3,280 efficacy-evaluable patients with moderate (21.3%) or high (78.7%) disease activity had mean ± SD disease duration of 7.6 ± 7.9 years, mean ± SD Health Assessment Questionnaire (HAQ) disability index (DI) score of 1.44 ± 0.67, and mean ± SD EuroQol 5-domain (EQ-5D) score of 0.42 ± 0.33. Patients reported high treatment expectations (mean 1.43); 95.9% expected golimumab to be better than current treatment. Patients with fewer DMARD failures, higher disease activity, shorter disease duration, younger age, and female sex reported higher expectations (P < 0.05 for all). After 6 months, patients with the most positive expectations had higher remission rates (P < 0.0001) and greater HAQ DI (P < 0.0001) and EQ-5D (P < 0.0001) score improvements. At baseline, physicians expected 29.6% and 59.2% of patients to attain remission and low disease activity, respectively, after 3 months. CONCLUSION: Patients had high expectations for golimumab treatment. Patients with more positive expectations had greater remission rates, improvements in function, and QOL.
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Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Satisfação do Paciente , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Índice de Gravidade de Doença , Fatores Sexuais , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To evaluate the efficacy and safety of subcutaneous golimumab as add-on therapy in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) treatment. To evaluate an intravenous plus subcutaneous (IV+SC) golimumab strategy in patients who had not attained remission. METHODS: GO-MORE was an open-label, multinational, prospective study in patients with active RA in typical clinical practice settings. In part 1, patients received add-on monthly 50-mg subcutaneous golimumab for 6â months. The percentage of patients with good/moderate European League Against Rheumatism (EULAR) 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) response was compared in patient subgroups with various concurrent or previous DMARD treatments. In part 2, patients with EULAR responses but not remission were randomly assigned to receive IV+SC or subcutaneous golimumab to month 12; DAS28-ESR remission was measured. RESULTS: 3366 patients were enrolled. At baseline of part 1, 3280 efficacy-evaluable patients had mean disease duration of 7.6â years and mean DAS28-ESR of 5.97 (SD=1.095). At month 6, 82.1% achieved good/moderate EULAR responses and 23.9% attained remission. When EULAR responses were analysed by the number of previously failed DMARD or the concomitant methotrexate dose, DMARD type, or corticosteroid use, no statistically significant differences were observed. Part 2 patients (N=490) who received IV+SC or subcutaneous golimumab achieved similar remission rates (â¼25%). Adverse events were consistent with previous reports of golimumab and other tumour necrosis antagonists in this population. CONCLUSIONS: Add-on monthly subcutaneous golimumab resulted in good/moderate EULAR response in most patients; 25% achieved remission after 6 more months of golimumab, but an IV+SC regimen provided no additional efficacy over the subcutaneous regimen.
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Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To examine change in regional variations in acute care length of stay (LOS) after orthopedic surgery following expiration of the New York (NY) State exemption to the Prospective Payment System and implementation of the Medicare Short Stay Transfer Policy. METHODS: Time series analyses were conducted to evaluate change in LOS across regions after policy implementations. Small area analyses were conducted to examine residual variation in LOS. The dataset included A 100% sample of fee-for-service Medicare patients undergoing surgical repair for hip fracture or elective joint replacement surgery between 1996 and 2001. Data files from Centers for Medicare and Medicaid Services 1996-2001 Medicare Provider Analysis and Review file, 1999 Provider of Service file, and data from the 2000 United States Census were used for analysis. RESULTS: In 1996, LOS in NY after orthopedic procedures was much longer than the remainder of the country. After policy changes, LOS fell. However, significant residual variation in LOS persisted. This residual variation was likely partly explained by differences variation in regional managed care market penetration, patient management practices and unmeasured characteristics associated with the hospital location. CONCLUSIONS: NY hospitals responded to changes in reimbursement policy, reducing variation in LOS. However, even after 5 years of financial pressure to constrain costs, other factors still have a strong impact on delivery of patient care.
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OBJECTIVES: Assessment of associations between etanercept treatment and rare adverse events has been limited by the size of clinical trial populations. The authors examined the collective safety of etanercept in clinical trials across approved indications. PATIENTS AND METHODS: Forty-nine U.S. and non-U.S. trials of etanercept, involving up to 13,977 patients for approved indications, with final trial reports as of May 2006, were selected from the Amgen Inc. clinical trials database. Exposure-adjusted rates of serious infections, opportunistic infections, malignancies, and deaths were reported by trial, indication, and dosage. RESULTS: Rates of serious infections were generally similar between etanercept and controls. Overall rates of opportunistic infections and tuberculosis were low. The standardized incidence ratio (SIR) (95% CI) for malignancy was 1.00 (0.83-1.19) for all etanercept patients across all indications. The SIR for lymphoma for patients with rheumatoid arthritis was 3.45 (1.83-5.89); all other indications reported SIRs similar to those observed in the general population. The SIRs for cutaneous squamous cell carcinoma in patients with psoriasis relative to the general population with high or low sun exposure were 2.09 (1.27-3.22) and 4.96 (3.03-7.66), respectively. SIRs were less than 1.0 for all other indications regardless of sun exposure. Rates of melanoma and basal cell carcinoma were not significantly different from those in the general population. There was no increase in mortality associated with etanercept use relative to control populations. CONCLUSION: These data support the overall tolerability of etanercept across approved indications.
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Imunoglobulina G/efeitos adversos , Fatores Imunológicos/efeitos adversos , Infecções/epidemiologia , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Artrite Juvenil/tratamento farmacológico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Progressão da Doença , Relação Dose-Resposta a Droga , Etanercepte , Humanos , Imunoglobulina G/uso terapêutico , Fatores Imunológicos/uso terapêutico , Neoplasias/epidemiologia , Neoplasias/mortalidade , Infecções Oportunistas/epidemiologia , Psoríase/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Psoriasis adversely affects health-related quality of life (HRQoL) in adults; however, little information exists about its impact on children and adolescents. OBJECTIVE: The effect of etanercept therapy on HRQoL compared with placebo was evaluated in children and adolescents with moderate to severe plaque psoriasis. METHODS: HRQoL data were collected from patients 4 to 17 years of age in a randomized, double-blind, placebo-controlled, North American, phase III study of etanercept. Instruments for assessing HRQoL included the Children's Dermatology Life Quality Index (CDLQI), Pediatric Quality of Life Inventory (PedsQL), Stein Impact on Family Scale, and Harter Self-Perception Profile for Children. RESULTS: Baseline CDLQI and PedsQL scores revealed reduced HRQoL in patients with psoriasis relative to comparative populations. Patients treated with etanercept demonstrated significantly higher mean percentage improvement in total CDLQI scores from baseline to week 12 compared with those treated with placebo (52.3% etanercept vs 17.5% placebo [P = .0001]). At week 12, patients who achieved 75% improvement in their Psoriasis Area and Severity Index score had higher percentage improvements from baseline in total CDLQI scores than those who did not have 75% improvement in Psoriasis Area and Severity Index score. LIMITATIONS: The PedsQL, Stein scale, and Harter profile demonstrated limited improvement in patients' HRQoL, suggesting that these scales may not be sensitive to issues that are relevant to children with psoriasis and their families. CONCLUSION: Etanercept therapy had a clinically and statistically meaningful impact on disease-specific quality of life (CDLQI) and a clinically meaningful impact on general quality of life (PedsQL) in children and adolescents with moderate to severe plaque psoriasis.
Assuntos
Fármacos Dermatológicos/uso terapêutico , Imunoglobulina G/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/psicologia , Qualidade de Vida , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Etanercepte , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Satisfação do Paciente , Psoríase/diagnóstico , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Direct correlation of assessments of a validated composite measure such as the Asthma Control Questionnaire (ACQ) and risk of exacerbation has not been previously demonstrated in a randomized controlled trial. OBJECTIVE: To evaluate the ability of the ACQ score over time to predict risk of a future asthma exacerbation. METHODS: This analysis included data from a 12-week placebo-controlled trial (N = 292) of AMG 317, an IL-4 receptor α antagonist, in patients with moderate to severe atopic asthma. At baseline, patients had an ACQ score ≥1.5. Exacerbations were defined as requirement for systemic corticosteroids. A Cox proportional hazards model was used, with ACQ score as the time-dependent covariate. The analysis was repeated for individual components of the ACQ. RESULTS: Each 1-point increase in ACQ was associated with a 50% increased risk of exacerbation (hazard ratio, 1.50; 95% CI, 1.03-2.20) for the following 2-week period. Evaluation of individual ACQ components also demonstrated a similar trend, though each to a lesser degree than the full composite ACQ. CONCLUSION: Although based on a retrospective analysis, with small number of exacerbations, these findings support the utility of the composite ACQ score measurement to predict risk of future exacerbation in clinical trials and clinical practice. The composite ACQ score measurement was found to be a better predictor of future risk than individual ACQ components.
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Asma/diagnóstico , Inquéritos e Questionários , Adulto , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Masculino , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos RetrospectivosRESUMO
OBJECTIVE: To investigate the correlation between the Disease Activity Score using a 28-joint count (DAS28) based on physician-derived joint counts and the DAS28 based on patient-derived joint counts (Pt-DAS28) in rheumatoid arthritis (RA). METHODS: Data from a multicenter, open-label study investigating the immunogenicity of etanercept (ETN) were analyzed. ETN-naive patients with active RA received ETN 50 mg once weekly alone or with methotrexate (MTX). Joint counts were performed at baseline, Week 12, and Week 24 by the physician and patient independently. Patients received instruction in performing joint assessments. RESULTS: Of 447 patients enrolled (ETN, n = 218; ETN + MTX, n = 229), most were women (79%) and the mean age was 54.5 years. Correlation coefficients between DAS28 and Pt-DAS28 were > or = 0.57 at baseline, Week 12, and Week 24. At Week 24, 48%, 39%, and 12% of patients could be classified as having low, moderate, or high disease activity, respectively, using DAS28. Using Pt-DAS28, 43%, 39%, and 18% were similarly classified. Agreement in the category of disease activity classification occurred in 72% of patients (kappa = 0.55). At Week 24, 78% of patients using DAS28 and 72% of patients using Pt-DAS28 were classified as moderate or good European League Against Rheumatism responders. CONCLUSION: These results support the possible use of patient-derived tender and swollen joint counts to aid in the assessment of disease activity and clinical response in patients with RA.
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Artrite Reumatoide/fisiopatologia , Nível de Saúde , Articulações/fisiopatologia , Participação do Paciente/métodos , Sinovite/fisiopatologia , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/terapia , Avaliação da Deficiência , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Medição da Dor , Satisfação do Paciente , Exame Físico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Índice de Gravidade de Doença , Inquéritos e Questionários , Sinovite/terapia , Resultado do TratamentoRESUMO
RATIONALE: IL-4 and IL-13 share many biological functions important in the development of allergic airway inflammation and are implicated in the pathogenesis of asthma. AMG 317 is a fully human monoclonal antibody to IL-4Ralpha that blocks both IL-4 and IL-13 pathways. OBJECTIVES: To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma. METHODS: In this phase 2, randomized, double-blind, placebo-controlled study, patients received weekly subcutaneous injections of placebo or AMG 317 (75-300 mg) for 12 weeks, followed by a 4-week follow-up period. The primary endpoint was change from baseline at Week 12 in Asthma Control Questionnaire (ACQ) symptom score. MEASUREMENTS AND MAIN RESULTS: Mean ACQ change (SE) was -0.49 (0.09) in placebo (n = 74), and -0.43 (0.11), -0.58 (0.12), and -0.70 (0.09) in the AMG 317 75 mg (n = 73), 150 mg (n = 73), and 300 mg (n = 74) groups, respectively (treatment effect P = 0.25). No statistically significant differences were observed in the secondary endpoints. Numerical decreases in number of and time to exacerbations were noted in patients receiving AMG 317 150 mg and 300 mg. Preplanned analyses by tertile of baseline ACQ revealed that patients with higher baseline ACQ scores (>or=2.86) were more likely to respond to AMG 317. Serious adverse events were reported in three patients, each noted as not related to study drug. CONCLUSIONS: AMG 317 did not demonstrate clinical efficacy across the overall group of patients. Clinically significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores. AMG 317 was safe and well tolerated in this study population. Clinical trial registered with www.clinicaltrials.gov (NCT 00436670).
Assuntos
Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Colelitíase/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/induzido quimicamente , Receptores de Interleucina-13/efeitos dos fármacos , Receptores de Interleucina-4/efeitos dos fármacos , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To evaluate responses by time to initiation of nonbiologic disease-modifying antirheumatic drugs (DMARD) in a DMARD-naive cohort of patients with early seropositive rheumatoid arthritis (RA). METHODS: Subjects were categorized by the time from symptom onset to the first DMARD use (median 5.7 months, range 0.6-15.9). Subjects who started their first DMARD within 5 months of symptom onset were compared to subjects who started after 5 months. Disease Activity Scores (DAS-44) and total Sharp Score (TSS) progression rates were analyzed using Wilcoxon rank-sum and chi-square tests; multiple linear regression analysis adjusted for potential covariates. The slope of the least-squares regression line was calculated to estimate the annualized TSS progression rates. RESULTS: Of 233 RA patients, 76% were female and mean age was 50 (SD 13) years. At DMARD start, DAS-44 was similar in all subsets within the 0.6 to 15 months' duration between symptom onset and DMARD initiation. Erosion scores tended to be higher in those who started DMARD later, but Health Assessment Questionnaire-Disability Index (HAQ-DI) scores were higher in those who started DMARD earlier. During the 2 years after DMARD initiation, improvements in HAQ-DI and DAS-44 were similar in the various duration subsets, with about 25% ever achieving DAS remission (DAS < 1.6). Radiographic progression tended to be numerically but not statistically more rapid in the earlier subsets. CONCLUSION: Following initiation of nonbiologic DMARD therapy at various times within 15 months of symptom onset, improvements of DAS-44, HAQ-DI, remission rate, and radiographic progression rate were similar, although higher baseline erosion scores were present in those with later initiation of DMARD.