Minimal clinically important differences in six-minute walking distance in late-onset Pompe disease.

BACKGROUND: The minimal clinically important difference (MCID) is the smallest change in outcome that physicians or patients would consider meaningful and is relevant when evaluating disease progression or the efficacy of interventions. Studies of patients with late-onset Pompe disease (LOPD) have used the 6-min walk distance (6MWD) as an endpoint to assess motor function. However, an MCID for 6MWD (% predicted and meters) has yet to be established in LOPD. The objective of the study was to derive 6MWD MCID (% predicted and meters) with different analysis methods and for subgroups of different disease severity for LOPD. METHODS: Data from the PROPEL trial were used to calculate 6MWD MCID in the overall PROPEL population and subgroups of baseline severity as assessed by walking distance and body mass index (BMI), using anchor- and distribution-based approaches. RESULTS: The 6MWD MCIDs varied widely, depending on the method and subgroup, ranging from 2.27%-8.11% predicted for the overall LOPD population (23.7 m-57.2 m). For patients with baseline 6MWD < 150 m, MCIDs ranged from -0.74%-3.37% (-2.1 m-11.3 m). MCIDs increased with distance walked at baseline until a plateau was reached. For BMI subgroups, the MCIDs were generally lowest in obese patients. CONCLUSION: Our analysis shows that MCID depends on the chosen method and disease severity. The findings suggest that applying a single MCID to all patients can be misleading; consequently, a range of possible MCIDs should be considered. This may also be highly relevant for other neuromuscular diseases. This study provides a range of 6MWD MCIDs for LOPD, with lower MCIDs for more severe patients.

Assessing Quality of Life, Economic Burden, and Independence Across the Alzheimer's Disease Continuum Using Patient-Caregiver Dyad Surveys.

Background: Alzheimer's disease (AD) and mild cognitive impairment (MCI) have negative quality of life (QoL) and economic impacts on patients and their caregivers and may increase along the disease continuum from MCI to mild, moderate, and severe AD. Objective: To assess how patient and caregiver QoL, indirect and intangible costs are associated with MCI and AD severity. Methods: An on-line survey of physician-identified patient-caregiver dyads living in the United States was conducted from June-October 2022 and included questions to both patients and their caregivers. Dementia Quality of Life Proxy, the Care-related Quality of Life, Work Productivity and Activity Impairment, and Dependence scale were incorporated into the survey. Regression analyses investigated the association between disease severity and QoL and cost outcomes with adjustment for baseline characteristics. Results: One-hundred patient-caregiver dyads were assessed with the survey (MCI, n = 27; mild AD, n = 27; moderate AD, n = 25; severe AD, n = 21). Decreased QoL was found with worsening severity in patients (p < 0.01) and in unpaid (informal) caregivers (n = 79; p = 0.02). Dependence increased with disease severity (p < 0.01). Advanced disease severity was associated with higher costs to employers (p = 0.04), but not with indirect costs to caregivers. Patient and unpaid caregiver intangible costs increased with disease severity (p < 0.01). A significant trend of higher summed costs (indirect costs to caregivers, costs to employers, intangible costs to patients and caregivers) in more severe AD was observed (p < 0.01). Conclusions: Patient QoL and functional independence and unpaid caregiver QoL decrease as AD severity increases. Intangible costs to patients and summed costs increase with disease severity and are highest in severe AD.

Validation of the Patient-Reported Outcomes Measurement Information System (PROMIS®) physical function questionnaire in late-onset Pompe disease using PROPEL phase 3 data.

BACKGROUND: The construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT). METHODS: In the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers' maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients' age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods. RESULTS: 123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P < 0.0001) at baseline, between PROMIS PF20a and 6MWD (P < 0.0001), FVC (P = 0.0490), and R-PAct (P < 0.0001) when combining all measurements, and between PF20a and 6MWD (P = 0.0016) and R-PAct (P = 0.0001) when evaluating changes in scores between baseline and 52 weeks. The anchor-based and distribution-based MCID for a clinically important improvement for PROMIS PF20a were 2.4 and 4.2, respectively. CONCLUSIONS: PROMIS PF20a has validity as an instrument both to measure and to longitudinally follow physical function in patients with LOPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03729362. Registered 2 November 2018, https://www. CLINICALTRIALS: gov/search?term=NCT03729362 .

Assessing out-of-pocket expenses and indirect costs for the Alzheimer disease continuum in the United States.

BACKGROUND: The societal costs of Alzheimer disease (AD) are considerable. Cost data stratified by cost category (direct and indirect) and AD severity in the United States are limited. OBJECTIVE: To describe out-of-pocket (OOP) expenses and indirect costs from unpaid caregiving and work impairment among patients with AD by severity and among patients with mild cognitive impairment (MCI) in a representative sample of the US population. METHODS: Data from the Health and Retirement Study (HRS) were used. HRS respondents were included if they reported an AD diagnosis or were considered as having MCI based on their cognitive performance. MCI and AD severity staging was performed using a crosswalk from results of the modified Telephone Interview of Cognitive Status to the Mini-Mental State Examination. OOP expenses were assessed along with indirect costs (costs to caregivers from providing unpaid help and costs to employers). Sensitivity analyses were performed by varying assumptions of caregiver employment, missed workdays, and early retirement. Patients with AD were stratified by nursing home status, type of insurance, and income level. All cost calculations applied sampling weights. RESULTS: A total of 18,786 patients were analyzed. Patients with MCI (n = 17,885) and AD (n = 901) were aged 67.8 ± 10.7 and 80.9 ± 9.3 years, were 55.7% and 63.3% female, and were 28.3% and 0.9% employed, respectively. OOP expenses per patient per month increased with AD severity, ranging from $420 in mild to $903 in severe AD but were higher in MCI ($554) than in mild AD. Indirect costs to employers were similar across the AD continuum ($197-$242). Costs from unpaid caregiving generally increased by disease severity, from $72 (MCI) to $1,298 (severe AD). Total OOP and indirect costs increased by disease severity, from $869 (MCI) to $2,398 (severe AD). Sensitivity analysis assuming nonworking caregivers and zero costs to employers decreased the total OOP and indirect costs by 32%-53%. OOP expenses were higher for patients with AD who had private insurance (P < 0.01), had higher incomes (P < 0.01), or were in nursing homes (P < 0.01). Indirect costs to caregivers were lower for patients with AD in nursing homes ($600 vs $1,372, P < 0.01). Total indirect costs were higher for patients with AD with lower incomes ($1,498 vs $1,136, P < 0.01) and for those not in nursing homes ($1,571 vs $799, P < 0.01). CONCLUSIONS: This study shows that OOP expenses and indirect costs increase with AD severity, OOP expenses increase with higher income, subscription of private insurance, and nursing home residency, and total indirect costs decrease with higher income and nursing home residency in the United States. DISCLOSURES This study was financially sponsored by Eisai. Drs Zhang and Tahami are employees of Eisai. Drs Chandak, Khachatryan, and Hummel are employees of Certara; Certara is a paid consultant to Eisai. The views expressed here are those of the authors and are not to be attributed to their respective affiliations. Laura De Benedetti, BSc, provided medical writing support to the manuscript; she is an employee of Certara.

Estimating Transition Probabilities Across the Alzheimer's Disease Continuum Using a Nationally Representative Real-World Database in the United States.

INTRODUCTION: Clinical Alzheimer's disease (AD) begins with mild cognitive impairment (MCI) and progresses to mild, moderate, or severe dementia, constituting a disease continuum that eventually leads to death. This study aimed to estimate the probabilities of transitions across those disease states. METHODS: We developed a mixed-effects multi-state Markov model to estimate the transition probabilities, adjusted for 5 baseline covariates, using the Health and Retirement Study (HRS) database. HRS surveys older adults in the United States bi-annually. Alzheimer states were defined using the modified Telephone Interview of Cognitive Status (TICS-m). RESULTS: A total of 11,292 AD patients were analyzed. Patients were 70.8 ± 9.0 years old, 54.9% female, and with 12.0 ± 3.3 years of education. Within 1 year from the initial state, the model estimated a higher probability of transition to the next AD state in earlier disease: 12.8% from MCI to mild AD and 5.0% from mild to moderate AD, but < 1% from moderate to severe AD. After 10 years, the probability of transition to the next state was markedly higher for all states, but still higher in earlier disease: 29.8% from MCI to mild AD, 23.5% from mild to moderate AD, and 5.7% from moderate to severe AD. Across all AD states, the probability of transition to death was < 5% after 1 year and > 15% after 10 years. Older age, fewer years of education, unemployment, and nursing home stay were associated with a higher risk of disease progression (p < 0.01). CONCLUSIONS: This analysis shows that the risk of progression is greater in earlier AD states, increases over time, and is higher in patients who are older, with fewer years of education, unemployed, or in a nursing home at baseline. The estimated transition probabilities can provide guidance for future disease management and clinical trial design optimization, and can be used to refine existing cost-effectiveness frameworks.

Long-Term Climate Treaties with a Refunding Club.

We show that an appropriately-designed "Refunding Club" can simultaneously solve both free-riding problems in mitigating climate change-participating in a coalition with an emission reduction target and enduring voluntary compliance with the target once the coalition has been formed. Countries in the Club pay an initial fee into a fund that is invested in assets. In each period, part of the fund is distributed among the Club members in relation to the emission reductions they have achieved, suitably rescaled by a weighting factor. We show that an appropriate refunding scheme can implement any feasible abatement path a Club wants to implement. The contributions to the initial fund can be used to disentangle efficiency and distributional concerns and/or to make a coalition stable. Making the grand coalition stable in the so-called "modesty approach" requires less than 0.5% of World GDP. Finally, we suggest ways to foster initial participation, to incorporate equity concerns with regard to developing countries, and ways to ease the burden to fill the initial fund.

Modelling Decline in Cognition to Decline in Function in Alzheimer's Disease.

OBJECTIVES: The study aimed to evaluate and quantify the temporal link between cognitive and functional decline, and assess the impact of the apolipoprotein E4 (APOE-e4) genotype on Alzheimer's disease (AD) progression. METHODS: A nonlinear mixed-effects Emax model was developed using longitudinal data from 659 patients with dementia due to AD sourced from the Alzheimer's disease neuroimaging initiative (ADNI) database. A cognitive decline model was first built using a cognitive subscale of the AD assessment scale (delayed word recall) as the endpoint, followed by a functional decline model, using the functional assessment questionnaire (FAQ) as the endpoint. Individual and population cognitive decline from the first model drove a functional decline in the second model. The impact of the APOE-e4 genotype status on the dynamics of AD progression was evaluated using the model. RESULTS: Mixed-effects Emax models adequately quantified population average and individual disease trajectories. The model captured a higher initial cognitive impairment and final functional impairment in APOE-e4 carriers than non-carriers. The age at cognitive decline and diagnosis of dementia due to AD was significantly lower in APOE-e4 carriers than that of non-carriers. The average [standard deviation] time shift between cognitive and functional decline, i.e. the time span between half of the maximum cognitive decline and half of the maximum functional decline, was estimated as 1.5 [1.6] years. CONCLUSION: The present analysis quantifies the temporal link between a cognitive and functional decline in AD progression at the population and individual level, and provides information about the potential benefits of pre-clinical AD treatments on both cognition and function.

Prediction of Real-World Drug Effectiveness Prelaunch: Case Study in Rheumatoid Arthritis.

BACKGROUND: Decision makers often need to assess the real-world effectiveness of new drugs prelaunch, when phase II/III randomized controlled trials (RCTs) but no other data are available. OBJECTIVE: To develop a method to predict drug effectiveness prelaunch and to apply it in a case study in rheumatoid arthritis (RA). METHODS: The approach 1) identifies a market-approved treatment ( S) currently used in a target population similar to that of the new drug ( N); 2) quantifies the impact of treatment, prognostic factors, and effect modifiers on clinical outcome; 3) determines the characteristics of patients likely to receive N in routine care; and 4) predicts treatment outcome in simulated patients with these characteristics. Sources of evidence include expert opinion, RCTs, and observational studies. The framework relies on generalized linear models. RESULTS: The case study assessed the effectiveness of tocilizumab (TCZ), a biologic disease-modifying antirheumatic drug (DMARD), combined with conventional DMARDs, compared to conventional DMARDs alone. Rituximab (RTX) combined with conventional DMARDs was identified as treatment S. Individual participant data from 2 RCTs and 2 national registries were analyzed. The model predicted the 6-month changes in the Disease Activity Score 28 (DAS28) accurately: the mean change was -2.101 (standard deviation [SD] = 1.494) in the simulated patients receiving TCZ and conventional DMARDs compared to -1.873 (SD = 1.220) in retrospectively assessed observational data. It was -0.792 (SD = 1.499) in registry patients treated with conventional DMARDs. CONCLUSION: The approach performed well in the RA case study, but further work is required to better define its strengths and limitations.

Rheumatoid arthritis patients treated in trial and real world settings: comparison of randomized trials with registries.

Objective: To investigate whether patients with RA enrolled in randomized controlled trials (RCTs) and observational studies may differ in terms of characteristics that could modify treatment effects, leading to an efficacy-effectiveness gap. Methods: We conducted systematic literature reviews to identify RCTs and observational studies with RA, treated with rituximab, tocilizumab or etanercept. We extracted baseline characteristics and compared the data of RCTs and observational studies using fixed-effects meta-analyses for the RCTs and random-effects meta-analyses for the observational studies. We also assessed whether the baseline characteristics changed over time. Results: Compared with patients enrolled in RCTs, those from observational studies were on average 3.0 years older (P < 0.001), suffered from RA for 3.1 years longer (P < 0.001), had 1.6 more prior disease modifying drugs (P = 0.001), and had a lower DAS-28 (difference -0.6, P < 0.001). CRP and ESR levels were slightly higher in RCTs. The HAQ-Disability Index (HAQ-DI) score was slightly lower in the RCT group. No differences were found in the percentages of included females or RF positivity. Over time, we found a significant decrease of - 0.08 in DAS-28 and a decrease of - 0.04 in HAQ-DI both in patients in RCTs and in patients from registries. Furthermore, ESR and CRP declined over time in RCT patients, but not in patients participating in observational studies. Conclusion: There are substantial systematic differences in patient characteristics between RCTs and registries in RA. The efficacy seen in RCTs may not reflect real-world effectiveness.

GetReal in mathematical modelling: a review of studies predicting drug effectiveness in the real world.

The performance of a drug in a clinical trial setting often does not reflect its effect in daily clinical practice. In this third of three reviews, we examine the applications that have been used in the literature to predict real-world effectiveness from randomized controlled trial efficacy data. We searched MEDLINE, EMBASE from inception to March 2014, the Cochrane Methodology Register, and websites of key journals and organisations and reference lists. We extracted data on the type of model and predictions, data sources, validation and sensitivity analyses, disease area and software. We identified 12 articles in which four approaches were used: multi-state models, discrete event simulation models, physiology-based models and survival and generalized linear models. Studies predicted outcomes over longer time periods in different patient populations, including patients with lower levels of adherence or persistence to treatment or examined doses not tested in trials. Eight studies included individual patient data. Seven examined cardiovascular and metabolic diseases and three neurological conditions. Most studies included sensitivity analyses, but external validation was performed in only three studies. We conclude that mathematical modelling to predict real-world effectiveness of drug interventions is not widely used at present and not well validated. © 2016 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd.

Get real in individual participant data (IPD) meta-analysis: a review of the methodology.

Individual participant data (IPD) meta-analysis is an increasingly used approach for synthesizing and investigating treatment effect estimates. Over the past few years, numerous methods for conducting an IPD meta-analysis (IPD-MA) have been proposed, often making different assumptions and modeling choices while addressing a similar research question. We conducted a literature review to provide an overview of methods for performing an IPD-MA using evidence from clinical trials or non-randomized studies when investigating treatment efficacy. With this review, we aim to assist researchers in choosing the appropriate methods and provide recommendations on their implementation when planning and conducting an IPD-MA.

Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers.

BACKGROUND: Empagliflozin is a potent, oral, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The goal of these studies was to investigate potential drug-drug interactions between empagliflozin and gemfibrozil (an organic anion-transporting polypeptide 1B1 [OATP1B1]/1B3 and organic anion transporter 3 [OAT3] inhibitor), rifampicin (an OATP1B1/1B3 inhibitor), or probenecid (an OAT3 and uridine diphosphate glucuronosyltransferase inhibitor). METHODS: Two open-label, randomized, crossover studies were undertaken in healthy subjects. In the first study, 18 subjects received the following in 1 of 2 randomized treatment sequences: a single dose of empagliflozin 25 mg alone and gemfibrozil 600 mg BID for 5 days with a single dose of empagliflozin 25 mg on the third day. In the second study, 18 subjects received a single dose of empagliflozin 10 mg, a single dose of empagliflozin 10 mg coadministered with a single dose of rifampicin 600 mg, and probenecid 500 mg BID for 4 days with a single dose of empagliflozin 10 mg on the second day in 1 of 6 randomized treatment sequences. RESULTS: In the gemfibrozil study, 11 subjects were male, mean age was 35.1 years and mean body mass index (BMI) was 23.47 kg/m(2). In the rifampicin/probenecid study, 10 subjects were male, mean age was 32.7 years and mean BMI was 23.03 kg/m(2). Exposure to empagliflozin was increased by coadministration with gemfibrozil (AUC0-∞: geometric mean ratio [GMR], 158.50% [90% CI, 151.77-165.53]; Cmax: GMR, 115.00% [90% CI, 106.15-124.59]), rifampicin (AUC0-∞: GMR, 135.20% [90% CI, 129.58-141.06]; Cmax: GMR, 175.14% [90% CI, 160.14-191.56]), and probenecid (AUC0-∞: GMR, 153.47% [90% CI, 146.41-160.88]; Cmax: GMR, 125.60% [90% CI, 113.67-138.78]). All treatments were well tolerated. CONCLUSIONS: Increases in empagliflozin exposure were <2-fold, indicating that the inhibition of the OATP1B1/1B3, OAT3 transporter, and uridine diphosphate glucuronosyltransferases did not have a clinically relevant effect on empagliflozin exposure. No dose adjustments of empagliflozin were necessary when it was coadministered with gemfibrozil, rifampicin, or probenecid. ClinicalTrials.gov identifiers: NCT01301742 and NCT01634100.