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Venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, patients with previously untreated CLL and coexisting conditions were randomized to 12 cycles of Ven-Obi (n=216) or chlorambucil-obinutuzumab (Clb-Obi, n=216). Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS) and rates of adverse events. Patient reported outcomes (PROs) of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs 36.4 months; HR 0.40[95%CI 0.31-0.52], p<0.0001). Likewise, TTNT was longer after Ven-Obi (6-year-TTNT 65.2% vs 37.1%; HR 0.44, 95%CI 0.33-0.58, p<0.0001). In the Ven-Obi arm, presence of del(17p), unmutated-IGHV and lymph node size ≥5 cm were independent prognostic factors for shorter PFS. Five years after treatment, 17 patients (7.9% of intention-to-treat-population) in the Ven-Obi arm had uMRD (<10-4 in peripheral blood) compared to 4 (1.9%) in the Clb-Obi arm. 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69[95%CI 0.48-1.01], p=0.052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi compared to the Clb-Obi arm (median 82.1 vs 65.1 months; HR 0.70[95%CI 0.51-0.97]). Follow-up adjusted SPM incidence rates were 2.3 and 1.4/1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival, uMRD and QoL benefits support the use of one-year fixed-duration Ven-Obi in CLL. NCT02242942, EudraCT 2014-001810-24.
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Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P < 0.001). VEN + LDAC vs PBO + LDAC patients had significantly longer TTD in GHS/QoL (P = 0.011), PF (P = 0.020), and fatigue (P = 0.004), and a trend in HS-VAS (P = 0.057). Approximately 43%, 35%, 32%, and 18% of patients treated with VEN + AZA, AZA + PBO, VEN + LDAC, or LDAC + PBO, respectively, saw improvements >MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status.
Assuntos
Leucemia Mieloide Aguda , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes , Citarabina/uso terapêutico , Fadiga/etiologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , SulfonamidasRESUMO
Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least eight points at cycle three, whereas improvement was delayed until cycle eight with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Qualidade de Vida , Sulfonamidas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Medidas de Resultados Relatados pelo PacienteRESUMO
OBJECTIVE: To identify in-depth information directly from patients with diabetic foot ulcers (DFU) on DFU symptoms, impacts on functioning and effects on health-related quality of life (HRQoL). METHOD: Semi-structured, qualitative concept elicitation interviews were conducted with patients with DFUs (Wagner grade 1 or 2) until saturation was reached. Qualitative analysis (using MAXQDA, VERBI GmbH, Germany) of interview transcripts was conducted to identify concepts relevant to patients with DFUs, based on the frequency of mentions, and elucidate themes regarding impacts on HRQoL. RESULTS: Of the 18 participants, most were male (n=14; 78%) and 10 (56%) presented with a Wagner grade of 1. Frequently reported symptoms were pain/discomfort (n=15; 83%), weeping/discharge (n=10; 56%), bleeding (n=10; 56%) and swelling (n=8; 44%). Overall, patients reported more impacts than symptoms-wound care/treatment burden (n=14; 78%), limitations on exercise/physical activity (n=13; 72%), mobility limitations (n=12; 67%), and offloading (n=12; 67%) were the most frequently mentioned. Based on findings from the patient interviews, a draft conceptual model was developed outlining interrelationships between DFU symptoms, impacts, and HRQoL from the patient perspective. CONCLUSION: Qualitative interviews captured the breadth of disease-related concepts of direct importance to patients. The draft conceptual model developed from the analysis can help identify measures or instruments for use in assessing patient-reported symptoms or HRQoL in clinical practice and may have wider research applicability, including evaluation of treatment benefits in patients with DFUs.
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Atividades Cotidianas , Pé Diabético/fisiopatologia , Edema/fisiopatologia , Exercício Físico , Hemorragia/fisiopatologia , Limitação da Mobilidade , Dor/fisiopatologia , Qualidade de Vida , Adulto , Idoso , Efeitos Psicossociais da Doença , Pé Diabético/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Índice de Gravidade de Doença , Suporte de CargaRESUMO
BACKGROUND: In diseases where there is a large subjective component, such as celiac disease (CD), patient reported-outcomes (PRO) endpoints are highly relevant. However, there is a gap in knowledge about which PRO endpoints and instruments should be used for clinical trials for treatment of celiac disease. OBJECTIVES: To identify patient-centered symptom, impact, and health-related quality of life (HRQoL) concepts in CD and relevant PRO instruments, and to gather expert input on concepts and instruments to inform selection of PRO endpoints for use in clinical trials of new CD treatments. METHODS: A targeted literature review was conducted to identify symptom, impact, and HRQoL concepts, including those captured in PROs further reviewed against U.S. Food and Drug Administration standards for development and validation as endpoints. US and European clinicians, payers, and a patient advocate (n = 21) were interviewed to assess the identified concepts' relative importance in measuring treatment benefit and to gauge the value of potential PROs as endpoints for market access/reimbursement. RESULTS: Thirty-four published studies were identified: 27 elucidated patient-centered concepts and 7 detailed the development or validation of PRO instruments. The Celiac Disease Symptom Diary and Celiac Disease Patient Reported Outcome instrument were deemed most appropriate for use as endpoints; however, each had limitations related to conceptual coverage, evidence for measurement properties, and feasibility for use in clinical trials. Experts reported gastrointestinal symptoms as most important to treat, with extra-intestinal symptoms burdensome from the patient perspective as well. Payers emphasized measuring both frequency and severity of symptoms and targeting patients nonresponsive to the gluten-free diet for treatment. CONCLUSIONS: With emerging treatment options for CD, further work is needed to operationalize PRO symptom endpoints that are meaningful to patients, valued by payers, and acceptable to regulators in demonstrating efficacy.
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Doença Celíaca/terapia , Dieta Livre de Glúten , Medidas de Resultados Relatados pelo Paciente , Doença Celíaca/diagnóstico , Doença Celíaca/economia , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Dieta Livre de Glúten/efeitos adversos , Dieta Livre de Glúten/economia , Custos de Cuidados de Saúde , Nível de Saúde , Humanos , Qualidade de Vida , Índice de Gravidade de Doença , Participação dos Interessados , Resultado do TratamentoRESUMO
BACKGROUND: Individuals with Parkinson's disease often experience periods of off time when their motor symptoms are poorly controlled, significantly impacting their lives. OBJECTIVES: To identify the consequences of motor fluctuations on day-to-day activities and areas of unmet treatment priority among individuals with moderate to advanced Parkinson's disease, to assess whether existing patient-reported outcome instruments adequately capture these consequences and priorities, and based on these evaluations, to adapt an existing or develop a new instrument. METHODS: The research was conducted in 2 stages: concept exploration and content confirmation. Concept exploration included direct input from individuals with Parkinson's disease representing the intended context of use via concept elicitation interviews. Content confirmation and item refinement was achieved through 5 rounds of cognitive debriefing. Final rounds of cognitive debriefing also included usability testing of the draft instrument for electronic data capture. RESULTS: Concept elicitation interviews were conducted among 29 individuals with Parkinson's disease (55% male; mean age 60.8 years). Concept saturation was achieved quickly with more than 90% of concepts identified by the end of the 16th interview. None of the existing outcome instruments were found to be fit for purpose in the intended context of use; therefore, a new instrument was developed. After 5 rounds, cognitive debriefing participants indicated clear and consistent interpretation of the items. CONCLUSIONS: Evidence from this study supports the content validity of the Parkinson's Disease Activities of Daily Living, Interference and Dependence Instrument as the basis of a clinical trial endpoint for capturing priority treatment benefit outcomes to individuals with moderate to advanced Parkinson's disease experiencing motor fluctuations.
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OBJECTIVE: This study investigated the suitability of the Montgomery-Asberg Depression Rating Scale (MADRS), with a 24-hour recall period (MADRS-24hr), to assess the rapid onset of the antidepressant effect of a treatment in patients with treatment-resistant depression (TRD). Psychometric properties of the MADRS-24hr were assessed together with qualitative assessment of content validity. METHODS: Content validity was assessed using semistructured interviews conducted from November 2013 to December 2013 in patients (18-64 years old) with TRD who met DSM-IV diagnostic criteria and health care professionals (HCPs) experienced in treating major depressive disorder and familiar with using the MADRS. The psychometric properties of MADRS-24hr were evaluated using data from 2 randomized clinical studies involving patients with TRD. RESULTS: A total of 23 patients (15 [65%] women) with TRD (mean age = 45 years) and 11 HCPs were interviewed. With the exception of reduced sleep, the majority of patients and HCPs reported that the items captured in the MADRS can fluctuate in a 24-hour period. The majority of participants also reported that a meaningful change in depression symptoms could be assessed in a 24-hour recall period, except for reduced sleep and appetite. Assessment of the psychometric properties of the MADRS-24hr showed that this instrument had high internal consistency reliability (Cronbach α of 0.84 and 0.91) and test-retest reliability (intraclass correlation coefficients of 0.96 and 0.91), had construct validity, and was responsive to change following an intervention. CONCLUSIONS: Overall, results suggest that MADRS-24hr can be used to assess the rapid onset of antidepressant efficacy of a treatment in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01627782 and NCT01640080.