Using Data on Survival with Idiopathic Pulmonary Fibrosis to Estimate Survival with Other Types of Progressive Fibrosis Interstitial Lung Disease: A Bayesian Framework.

INTRODUCTION: Among the various types of progressive fibrosing interstitial lung diseases (PF-ILDs), substantial survival data exist for idiopathic pulmonary fibrosis (IPF) but not for other types. This hinders evidence-based decisions about treatment and management, as well as the economic modelling needed to justify research into new treatments and reimbursement approvals. Given the clinical similarities between IPF and other PF-ILDs, we reasoned that patient survival data from four major IPF trials could be used to estimate long-term survival in other PF-ILDs. METHODS: We used propensity score matching to match patients with IPF taking either nintedanib or placebo in the TOMORROW, INPULSIS-1, INPULSIS-2 and INPULSIS-ON trials to patients with PF-ILDs other than IPF in the INBUILD trial. Seven models were fitted to the survival data for the matched patients with IPF, and the three best-fitting models were used to generate informative priors in a Bayesian framework to extrapolate patient survival of the INBUILD population. RESULTS: After propensity score matching, the analysis included data from 1099 patients with IPF (640 nintedanib patients; 459 placebo patients) and 654 patients with other PF-ILDs (326 nintedanib patients; 328 placebo patients). Gamma, log-logistic and Weibull models best fit the survival of the matched patients with IPF. All three models led to consistent Bayesian estimates of survival for the matched patients with other PF-ILDs, with median rates of overall survival ranging from 6.34 to 6.50 years after starting nintedanib. The corresponding control group survival estimates were 3.42 to 3.76 years. CONCLUSION: We provide the first estimates of long-term overall survival for patients with PF-ILDs other than IPF, and our analysis suggests that nintedanib may prolong their survival. Our Bayesian approach to estimating survival of one disease based on clinical trial data from a similar disease may help inform economic modelling of rare, orphan and newly defined disorders.

Systematic literature review and network meta-analysis of sodium-glucose co-transporter inhibitors vs metformin as add-on to insulin in type 1 diabetes.

AIMS: To identify and synthesize phase 3 and phase 4 randomized controlled trials (RCTs) of sodium-glucose co-transporter (SGLT) inhibitors and metformin as adjuncts to insulin in type 1 diabetes (T1DM) using network meta-analysis (NMA). MATERIALS AND METHODS: A systematic literature review (SLR) identified relevant RCTs of ≥12 Weeks duration. MEDLINE, Embase, the Cochrane Library and grey literature were searched through October 2018. NMAs indirectly compared SGLT inhibitors and metformin for change from baseline in HbA1c, weight, total daily insulin dose and systolic blood pressure at Week 24 to 26 and Week 52. Safety outcomes were also explored. RESULTS: Nine trials (N = 6780) were included in the SLR. NMAs indicated that all therapies performed better than placebo for the efficacy outcomes at both time points. Compared with metformin at Week 24 to 26, the SGLT inhibitors dapagliflozin (5 mg), sotagliflozin (200 mg) and empagliflozin (10 mg) had larger reductions in HbA1c (mean difference [MD] = -0.24, 95% credible interval [CrI], -0.41 to -0.07, MD = -0.23, 95% CrI, -0.39 to -0.08 and MD = -0.35, 95% CrI, -0.51 to -0.19, respectively) and in weight, which were sustained in sensitivity analyses. There were few differences observed in the results of safety outcomes, such as risk of diabetic ketoacidosis (DKA), which should be interpreted cautiously because of wide CrIs. CONCLUSIONS: Adjunctive use of SGLT inhibitors in T1DM can improve glycaemic control compared with metformin while enabling weight loss, with consistent efficacy across the class. However, these results are based on indirect evidence so confirmation in a head-to-head study would be valuable.

Focused Ultrasound Thalamotomy and Other Interventions for Medication-Refractory Essential Tremor: An Indirect Comparison of Short-Term Impact on Health-Related Quality of Life.

BACKGROUND: Up to 50% of essential tremor patients are refractory to medication and require alternative treatment to achieve tremor relief. This study aimed to identify and analyze evidence supporting the use of the emerging magnetic resonance-guided focused ultrasound (MRgFUS) compared to alternative stimulatory and ablative interventions for the treatment of medication-refractory essential tremor: radiofrequency thalamotomy, unilateral deep brain stimulation (DBS), and stereotactic radiosurgery. METHODS: A systematic literature review was conducted to identify clinical, health-related quality of life (HRQoL), and economic evidence for each intervention. Because of the lack of comparative evidence captured, a feasibility assessment was performed to determine possible comparisons between interventions, and newly established matching-adjusted indirect comparison and simulated treatment comparison techniques were used to conduct a comparison between unilateral DBS aggregate data and MRgFUS individual patient data. RESULTS: The systematic literature review identified 1,559 records, and screening yielded 46 relevant articles. The captured studies demonstrated that radiofrequency thalamotomy, DBS, stereotactic radiosurgery, and MRgFUS all exhibit clinical efficacy, with variation in onset and duration of tremor relief, and are each associated with a unique safety profile. The matching-adjusted indirect comparison and simulated treatment comparison results demonstrated no evidence of a difference in efficacy (measured by Clinical Rating Scale for Tremor Total) and HRQoL (measured by Clinical Rating Scale for Tremor Part C) outcomes between MRgFUS and unilateral DBS in the short term (≤12 months). CONCLUSIONS: This study provides preliminary evidence that MRgFUS could elicit similar short-term tremor- and HRQoL-related benefits to DBS, the current standard of care, and allowed for the first robust statistical comparison between these interventions.

Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features.

BACKGROUND: Alkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduce symptoms and progression. The All Alkaptonuria Severity Score Index (AKUSSI) measures disease severity in clinical, joint and spine domains, with 57 subcomponent feature scores. Our primary aim was to assess tools for validating scores such as the AKUSSI by detecting relationships between features both before and during nitisinone treatment. METHODS: AKUSSI measurements from nitisinone-treated patients visiting the National AKU Centre between 01-Jun-2012 and 31-May-2016 were analysed pre-treatment, at first treatment and annually to Year 3 post-treatment. Principal component analysis (PCA) and redundancy analysis assessed whether any AKUSSI features contributed little information to the overall score. RESULTS: 65 AKU patients were included: 17 with a pre-treatment AKUSSI measurement (10 later received nitisinone) and 48 with a first measurement at their first treatment visit. In PCA, the first four principal components (PC1-PC4) explained ≥50% of AKUSSI variance at all visits (54.1-87.3%). Some features regularly dominated their domain's PC1: ears, aortic sclerosis, and nasal/temporal eye scores (clinical), pain-related scores (joint) and cervical, lumbar and thoracic spine scores (spine). Only the right-hand/wrist score was consistently redundant. Right eye (nasal) and left ear scores were redundant pre-treatment, potentially correlating with other dominant clinical PC1 features. CONCLUSIONS: PCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics.

Evidence in support of hyperkalaemia management strategies: A systematic literature review.

BACKGROUND: Hyperkalaemia is a potentially life-threatening condition that can be managed with pharmacological and non-pharmacological approaches. With the recent development of new hyperkalaemia treatments, new information on safe and effective management of hyperkalaemia has emerged. OBJECTIVES: This systematic literature review (SLR) aimed to identify all relevant comparative and non-comparative clinical data on management of hyperkalaemia in adults. Our secondary aim was to assess the feasibility of quantitatively comparing randomised controlled trial (RCT) data on the novel treatment sodium zirconium cyclosilicate (ZS) and established pharmacological treatments for the non-emergency management of hyperkalaemia, such as the cation-exchangers sodium/calcium polystyrene sulphonate (SPS/CPS). METHODS: MEDLINE, Embase and the Cochrane Library were searched on 3rd April 2017, with additional hand-searches of key congresses and previous SLRs. Articles were screened by two independent reviewers. Eligible records reported interventional or observational studies of pharmacological or non-pharmacological management of hyperkalaemia in adults. RESULTS: Database searches identified 2,073 unique records. Two hundred and one publications were included, reporting 30 RCTs, 29 interventional non-RCTs and 43 observational studies. Interventions investigated in RCTs included ZS (3), SPS/CPS (3), patiromer (4) and combinations of temporising agents (6 RCTs). A robust and meaningful indirect treatment comparison between ZS and long-established cation-binding agents (SPS/CPS) was infeasible because of heterogeneity between studies (including time points and dosing) and small sample size in SPS/CPS studies. CONCLUSIONS: Despite hyperkalaemia being associated with several chronic diseases, there is a paucity of high-quality randomised evidence on long-established treatment options (SPS and CPS) and a limited evidence base for hyperkalaemia management with these agents.