Application of a Novel Endpoint Staging Framework: Proof of Concept in the AMBAR Study.

Background: A theoretical endpoint staging framework was previously developed and published, aligning outcomes (i.e., memory) to the stage of Alzheimer's disease (AD) in which a given outcome is most relevant (i.e., has the greatest risk of degradation). The framework guides the selection of endpoints measuring outcomes relevant within a target AD population. Here, a proof of concept is presented via post-hoc analyses of the Alzheimer Management by Albumin Replacement (AMBAR) Phase 2b clinical trial in patients with AD (NCT01561053, 2012). Objective: To evaluate whether aligning endpoints measuring cognition, function, and quality of life to hypothesized 'target' stages of AD yields magnitudes of treatment efficacy greater than those reported in the AMBAR full analysis set (FAS). Methods: Three endpoints were tested: ADAS-Cog 12, ADCS-ADL, and QoL-AD. The magnitude of treatment efficacy was hypothesized to be maximized in the target stages of mild, mild-to-moderate, and very mild AD, respectively, compared to the full analysis set (FAS) and non-target stages. Results: For ADAS-Cog 12, the magnitude of treatment efficacy was largest in the non-target stage (-4.0, p = 0.0760) compared to target stage and FAS. For ADCS-ADL and QoL-AD, the magnitude of treatment efficacy was largest in the target stage (14.2, p = 0.0003; 2.4, p < 0.0001, respectively) compared to non-target stage and FAS. Conclusions: Findings indicated that evaluating endpoints in the most relevant AD stage can increase the magnitude of the observed treatment efficacy. Evidence provides preliminary proof of concept for the endpoint staging framework.

Toward the optimized assessment of clinical outcomes in studies of novel treatments for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is characterized by a progressive decline in cognition and daily function, leading to a greater need for caregiver support. Clinical disease is segmented into a preclinical stage, mild cognitive impairment, and mild, moderate, and severe stages of Alzheimer's dementia. Although AD trials enroll participants at various stages of illness, treatment efficacy is often assessed using endpoints based on measures of outcomes that are held fixed across disease stages. We hypothesize that matching the primary outcomes measured in the endpoint hierarchy to the stage of disease targeted by the trial will increase the likelihood of detecting true treatment benefits. AREAS COVERED: We discuss current approaches to assessing clinical outcomes in AD trials, followed by a consideration of how effect detection can be improved by linking the stage of AD to the endpoints that most likely reflect stage-specific disease progression. EXPERT OPINION: Failing to account for stage-specific relevance and sensitivity of clinical outcomes may be one factor that contributes to trial failures in AD. Given the history of failure, experts have begun to scrutinize the relevance and sensitivity of outcomes as a potentially modifiable barrier to successful trials. To this end, we present a framework for refining trial endpoint selection and evaluation.

Psychometric validation of the EORTC QLQ-HCC18 in patients with previously treated unresectable hepatocellular carcinoma.

To demonstrate the measurement properties of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18-question module (EORTC QLQ-HCC18) within a previously treated, unresectable hepatocellular carcinoma (HCC) clinical trial population that was distinct from the published QLQ-HCC18 validation population. Analyses were conducted using data from BGB-A317-208, an open label, international, clinical trial assessing efficacy and safety of the monoclonal antibody tislelizumab in adult HCC patients. The EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and QLQ-HCC18 instruments were assessed at baseline and weeks 3 and 9 follow-up visits. Per US Food and Drug Administration guidance, psychometric validation of the QLQ-HCC18 included reliability (internal consistency and test-retest), construct validity (convergent and discriminant validity and known-groups validity), ability to detect change, and meaningful within-patient change (MWPC). Known-groups validity and MWPC analyses were also stratified on several pre-defined subgroups. A total of 248 patients were included. Only the QLQ-HCC18 fatigue, nutrition, and index domains demonstrated acceptable internal consistency; acceptable test-retest reliability was found for fatigue, body image, nutrition, pain, sexual interest, and index domains. The QLQ-HCC18 fatigue domain achieved the pre-specified criterion defining acceptable convergent and discriminant validity for 13 of 16 correlations, whereas the index domain achieved the pre-specified criterion for 14 of 16 correlations. Clear differentiation of the QLQ-HCC18 change scores between improvement and maintenance anchor groups were observed for body image, fatigue, pain, and index domains, whereas differentiation between deterioration and maintenance anchor groups were observed for fever and fatigue domains. MWPC point estimates defining improvement for the QLQ-HCC18 fatigue and index domains were -7.18 and -4.07, respectively; MWPC point estimates defining deterioration were 5.34 and 3.16, respectively. The EORTC QLQ-HCC18 fatigue and index domains consistently demonstrated robust psychometric properties, supporting the use of these domains as suitable patient-reported endpoints within a previously treated, unresectable HCC patient population.

Survival after acute episodes of immune-mediated thrombotic thrombocytopenic purpura (iTTP) - cognitive functioning and health-related quality of life impact: a descriptive cross-sectional survey of adults living with iTTP in the United Kingdom.

OBJECTIVES: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare life-threatening thrombotic microangiopathy affecting adults with unpredictable disease onset and acute presentation. This study aimed to describe the health-related quality of life (HRQoL), cognitive functioning and work productivity of survivors following acute episode(s) of iTTP in the United Kingdom (UK). METHODS: An online survey was developed in collaboration with the TTP Network. Descriptive statistics were calculated for the health questionnaire Short Form Survey-36 Version 2 (SF-36v2), the Hospital Anxiety and Depression Score (HADS), the PROMIS Cognitive Function Abilities Subset - Short Form 6a (PROMIS CFAS - SF6a), and the Work Productivity and Activity Index: Specific Health Problem (WPAI-SHP), along with several iTTP-specific bespoke questions. RESULTS: Fifty participants were recruited between July-November 2019. The mean (standard deviation [SD]) standardized SF-36v2 physical and mental component scores were 42.16 (9.59) and 33.61 (12.34), lower than population norms. The mean (SD) standardized PROMIS CFAS - SF6a score was 39.69 (7.86), lower than population norms. HADS mean (SD) scores of 12.18 (3.14) and 11.78 (2.36) indicated moderate levels of anxiety and depression, respectively. Of those employed (58%), approximately 42.73% of participants reported work productivity loss due to their iTTP. Participants also reported experiencing flashbacks, fatigue interference in family, social and intimate life, and fears of relapse. DISCUSSION AND CONCLUSION: Regardless of recency of the last acute episode, participant scores signified impairments in all domains. Remission from an acute episode of disease does not signify the conclusion of care, but rather the requirement for long-term healthcare particularly focused on psychological support.

Pre-post changes in main outcomes of medical rehabilitation in Germany: protocol of a systematic review and meta-analysis of individual participant and aggregated data.

INTRODUCTION: Multidisciplinary, complex rehabilitation interventions are an important part of the treatment of chronic diseases. However, little is known about the effectiveness of routine rehabilitation interventions within the German healthcare system. Due to the nature of the social insurance system in Germany, randomised controlled trials examining the effects of rehabilitation interventions are challenging to implement and scarcely accessible. Consequently, alternative pre-post designs can be employed to assess pre-post effects of medical rehabilitation programmes. We present a protocol of systematic review and meta-analysis methods to assess the pre-post effects of rehabilitation interventions in Germany. METHODS AND ANALYSIS: The respective study will be conducted within the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A systematic literature review will be conducted to identify studies reporting the pre-post effects (start of intervention vs end of intervention or later) in German healthcare. Studies investigating the following disease groups will be included: orthopaedics, rheumatology, oncology, pulmonology, cardiology, endocrinology, gastroenterology and psychosomatics. The primary outcomes of interest are physical/mental quality of life, physical functioning and social participation for all disease groups as well as pain (orthopaedic and rheumatologic patients only), blood pressure (cardiac patients only), asthma control (patients with asthma only), dyspnoea (patients with chronic obstructive pulmonary disease only) and depression/anxiety (psychosomatic patients only). We will invite the principal investigators of the identified studies to provide additional individual patient data. We aim to perform the meta-analyses using individual patient data as well as aggregate data. We will examine the effects of both study-level and patient-level moderators by using a meta-regression method. ETHICS AND DISSEMINATION: Only studies that have received institutional approval from an ethics committee and present anonymised individual patient data will be included in the meta-analysis. The results will be presented in a peer-reviewed publication and at research conferences. A declaration of no objection by the ethics committee of the University of Würzburg is available (number 20180411 01). TRIAL REGISTRATION NUMBER: CRD42018080316.