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Objective: To estimate the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma (RRMM) treated with 2–4 prior lines of therapy. Methods: Matching adjusted indirect comparison (MAICs) were performed using individual patient-level data (IPD) for cilta-cel from CARTITUDE-1 and CARTITUDE-4 and published aggregated data for ide-cel from KarMMa-3. Cilta-cel patients who met inclusion criteria from KarMMa-3 were selected, and outcomes were compared against data for ide-cel using simulated IPD derived from aggregate-level data from KarMMa-3. Patient characteristics were adjusted by reweighting cilta-cel IPD to match the distribution of prognostic factors in KarMMa-3. Comparative efficacy was estimated for response outcomes using a weighted logistic regression analysis and for progression-free survival using a weighted Cox proportional hazards model. Results: Patients treated with cilta-cel were 1.2 times more likely to achieve overall response (relative response ratio [RR]: 1.18 [95% confidence interval: 1.03–1.34]; p = 0.04), 1.3 times more likely to achieve very good partial response or better (RR: 1.34 [1.15–1.57]; p = 0.003), and 1.9 times more likely to achieve complete response or better (RR: 1.91 [1.54–2.37]; p < 0.0001) versus ide-cel patients from KarMMa-3. Cilta-cel was associated with a significant 49% reduction in risk of disease progression or death versus ide-cel (hazard ratio: 0.51 [95% confidence interval: 0.31, 0.84]; p = 0.0078). Conclusion: For patients with triple-class exposed RRMM treated with 2–4 prior lines of treatment, cilta-cel was found to provide superior clinical benefit over ide-cel in terms of response and progression-free survival. [ABSTRACT FROM AUTHOR]

Nearly all patients with multiple myeloma eventually relapse or become refractory to treatment. Lenalidomide is increasingly administered in the frontline until disease progression or intolerance to therapy, resulting in the need for highly effective, lenalidomide-sparing options. In this study, carfilzomib plus daratumumab and dexamethasone were evaluated against lenalidomide-sparing, pomalidomide-containing triplets using matching-adjusted indirect comparison in the absence of head-to-head data. The analyses utilized long-term follow-up data from the CANDOR study (NCT03158688). Treatment with carfilzomib, daratumumab, and dexamethasone resulted in significantly longer progression-free survival (hazard ratio 0.60 [95% confidence interval: 0.37, 0.88])vs. pomalidomide plus bortezomib and dexamethasone, and numerically longer progression-free survival (hazard ratio 0.77 [95% confidence interval: 0.50, 1.08]) vs. daratumumab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma and previous lenalidomide exposure, the majority of whom were lenalidomide refractory. Carfilzomib plus daratumumab and dexamethasone offers a highly effective, lenalidomide-sparing treatment option for this population. [ABSTRACT FROM AUTHOR]

The SCHOLAR-2 retrospective study highlighted poor overall survival (OS) with standard of care (SOC) regimens among patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who failed a covalent Bruton tyrosine kinase inhibitor (BTKi). In the ZUMA-2 single-arm trial, brexucabtagene autoleucel (brexu-cel; autologous anti-CD19 CAR T-cell therapy) demonstrated high rates of durable responses in patients with R/R MCL who had previous BTKi exposure. Here, we compared OS in ZUMA-2 and SCHOLAR-2 using three different methods which adjusted for imbalances in prognostic factors between populations: inverse probability weighting (IPW), regression adjustment (RA), and doubly robust (DR). Brexu-cel was associated with improved OS compared to SOC across all unadjusted and adjusted comparisons. Hazard ratios (95% confidence intervals) were 0.38 (0.23, 0.61) for IPW, 0.45 (0.28, 0.74) for RA, and 0.37 (0.23, 0.59) for DR. These results suggest a substantial survival benefit with brexu-cel versus SOC in patients with R/R MCL after BTKi exposure. [ABSTRACT FROM AUTHOR]

Network meta-analysis is an extension of standard meta-analysis. It allows researchers to build a network of evidence to compare multiple interventions that may have not been compared directly in existing publications. With a Bayesian approach, network meta-analysis can be used to obtain a posterior probability distribution of all the relative treatment effects, which allows for the estimation of relative treatment effects to quantify the uncertainty of parameter estimates, and to rank all the treatments in the network. Ranking treatments using both direct and indirect evidence can provide guidance to policy makers and clinicians for making decisions. The purpose of this paper is to introduce fundamental concepts of Bayesian network meta-analysis (BNMA) to researchers in psychology and social sciences. We discuss several essential concepts of BNMA, including the assumptions of homogeneity and consistency, the fixed and random effects models, prior specification, and model fit evaluation strategies, while pointing out some issues and areas where researchers should use caution in the application of BNMA. Additionally, using an automated R package, we provide a step-by-step demonstration on how to conduct and report the findings of BNMA with a real dataset of psychological interventions extracted from PubMed. [ABSTRACT FROM AUTHOR]

Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis. Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI). Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: −5.3 [95% confidence interval (CI): −9.4, −1.2; p = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: −18.3 [95% CI: −28.6, −8.0; p < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p = 0.020]). This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy. Hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis is a rare genetic disease that runs in families, affecting about 50,000 people worldwide. This condition results in abnormal protein deposits building up, causing damage to multiple nerves (polyneuropathy) and other organs, which can shorten lifespan and have other harmful effects. Polyneuropathy symptoms include weakness, numbness, pain, dizziness, and diarrhea. Over time, everyday activities become more difficult as patients become increasingly disabled and dependent on others. Several treatments have been approved for the polyneuropathy of ATTRv amyloidosis. Many of these work in different ways to impact the disease process. An indirect treatment comparison is a well-established statistical method used by healthcare decision-makers to compare treatments when head-to-head trials are unavailable. Indirect treatment comparisons using a common approach, the Bucher method, yield similar conclusions to head-to-head studies over 90% of the time. This method was used to compare clinical trial data for tafamidis and vutrisiran, two approved treatments for ATTRv amyloidosis with polyneuropathy. The findings show that vutrisiran is more effective than tafamidis at addressing the polyneuropathy of ATTRv amyloidosis as measured by changes to sensory or motor nervous system functioning and nutritional status. Also, vutrisiran showed greater maintenance of health-related quality of life compared to tafamidis. The expected benefits of vutrisiran over tafamidis are large enough to be noticeable and clinically meaningful to a patient or clinician. This highlights the potential advantages of vutrisiran compared to tafamidis with regard to preservation of physical function and quality of life when treating ATTRv amyloidosis with polyneuropathy. [ABSTRACT FROM AUTHOR]

This study used the latest available data cuts from the CARTITUDE-1 and KarMMa clinical trials to update previously published matching-adjusted indirect treatment comparisons (MAICs) assessing the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the FDA-approved idecabtagene vicleucel (ide-cel) dose range of 300 to 450 × 106 CAR-positive T-cells in the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed). MAICs were performed with the latest available individual patient data for cilta-cel (CARTITUDE-1) and published summary-level data for ide-cel (KarMMa). The analyses included treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was assessed for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p <.0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.65 [95% CI: 2.51, 12.69; p <.0001]; RR: 2.23), DoR (hazard ratio [HR]: 0.52 [95% CI: 0.30, 0.88; p =.0152]), PFS, (HR: 0.38 [95% CI: 0.24, 0.62; p <.0001]), and OS (HR: 0.43 [95% CI: 0.22, 0.88; p =.0200]) compared with ide-cel. These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes over longer follow-up and highlight its therapeutic potential in triple-class exposed RRMM patients. [ABSTRACT FROM AUTHOR]

To assess the available clinical and economic evidence of erenumab vs onabotulinumtoxinA for chronic migraine (CM) and present de-novo indirect treatment comparisons (ITCs) based on available clinical trial data. We conducted ITCs based on results from the pivotal 295 trial (NCT02066415) of erenumab vs placebo and published aggregate data from the PREEMPT 1 (NCT00156910) and PREEMPT 2 (NCT00168428) trials of onabotulinumtoxinA vs placebo. ITCs were conducted for CM patients with and without prior administration of onabotulinumtoxinA and among CM patients with ≥3 prior preventive treatment failures. Efficacy was assessed based on responder rates of ≥50% reductions in monthly headache days (MHDs) and monthly migraine days (MMDs) as well as change from baseline in both MHDs and MMDs. Among patients with CM, 140 mg erenumab was associated with a reduction of 1.2 MHD (p =.092) and a reduction of 1.0 MMD (p =.174) compared to onabotulinumtoxinA at Week 12. Among onabotulinumtoxinA-naïve patients, erenumab was associated with a reduction of 1.8 MHD (p =.026) and 1.4 MMD (p =.080) at Week 12. Among patients that had received ≥3 prior preventive treatments, the odds ratios comparing erenumab vs onabotulinumtoxinA were 1.7 for ≥50% responder rates based on reductions in MHD (p =.155) and 1.7 for ≥50% responder rates based on reductions in MMD (p =.140). These findings suggest directional benefits (although not reaching the threshold of statistical significance) associated with erenumab vs onabotulinumtoxinA for the preventive treatment of CM. Evidence from this study may inform healthcare stakeholders in treatment selection and optimization for patients with CM. [ABSTRACT FROM AUTHOR]

To compare the efficacy and safety of abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) for the treatment of refractory neurogenic detrusor overactivity (NDO), using an indirect treatment comparison (ITC). A systematic literature review was used to identify randomized controlled trials (RCTs) that evaluated botulinum toxin type A for the treatment of refractory NDO. Treatments were compared using a Bucher ITC approach. Efficacy outcomes were reduction in number of weekly urinary incontinence (UI) episodes at 6, 12, and 24 weeks of follow-up. The safety outcome was the proportion of patients with treatment-emergent urinary tract infections (TE-UTIs) during follow-up. Subgroup/sensitivity analyses were performed to investigate the impact of heterogeneity. Fifteen studies of botulinum toxin type A were identified. Among these, onaBoNT-A 200 U was the only botulinum toxin type A considered an appropriate comparator for aboBoNT-A 600 U and 800 U. As such, six RCTs that evaluated onaBoNT-A or aboBoNT-A were included in the ITC. In base-case analyses, there were no statistically significant differences between aboBoNT-A and onaBoNT-A in terms of UI episodes or TE-UTIs. Numerically, the trend favored aboBoNT-A (either dose) for all endpoints and time points. At 12 and 24 weeks, the difference in reduction of UI episodes per week was considered clinically relevant when comparing aboBoNT-A 800 U with onaBoNT-A 200 U, but not when comparing the lower dose of aboBoNT-A (600 U) with onaBoNT-A 200 U. Results from subgroup/sensitivity analyses were consistent with the base case. Heterogeneity across studies was observed; however, strong consistency of trends across analyses suggests the impact of heterogeneity is low. There may be potential advantages of aboBoNT-A over onaBoNT-A, in terms of UI reduction, in patients with refractory NDO. More confirmatory studies are needed owing to the sparsity of current evidence. Neurogenic detrusor overactivity (NDO) is a condition in which the bladder muscle wall is overactive and does not function normally. This can lead to urinary incontinence (i.e. accidental leakage of urine). NDO may also cause urinary tract infections and upper urinary tract damage if it is left untreated or if treatment does not work (i.e. refractory NDO). Botulinum toxin is a treatment that relaxes muscles in patients with refractory NDO, so they have less chance of experiencing urinary incontinence. This study used results from clinical trials to compare two types of botulinum toxin – abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) – to see if one works better than the other. Clinical trials are experiments to assess how well treatments work by giving different treatments to different patients and observing the results. When there is no clinical trial that compares the two treatments you are interested in, it is possible to combine results from a number of different clinical trials instead. This is known as an indirect treatment comparison. We used an indirect treatment comparison to compare aboBoNT-A and onaBoNT-A for the treatment of refractory NDO. Results showed that aboBoNT-A may be more effective than onaBoNT-A in reducing the frequency of urinary incontinence episodes. On average, patients treated with aboBoNT-A had at least three fewer episodes of urinary incontinence per week than those treated with onaBoNT-A. These results suggest that patients treated with aboBoNT-A could have a better quality of life than those treated with onaBoNT-A. [ABSTRACT FROM AUTHOR]

Immunogenicity between 15-valent V114 (PCV15) and 20-valent PCV20 pneumococcal conjugate vaccines in healthy infants is compared in an indirect treatment comparison and matching-adjusted indirect comparison. Hypotheses: immunogenicity of V114 is non-inferior to PCV20 for all PCV13 serotypes, and superior to PCV20 for serotype 3 based on lower bound margins. Two phase 3 pivotal studies on 3 + 1 pediatric vaccination schedule at age 2, 4, 6, and 12–15 months compared V114 (N = 858) to PCV13 (N = 856) and PCV20 (N = 1001) to PCV13 (N = 987). Infant's age and race in V114 study were matched to those in PCV20 study. Primary endpoints were serotype-specific Immunoglobulin G (IgG) response rate difference (RRD) 30 days post-dose (PD)3; IgG geometric mean concentration (GMC) ratios 30 days PD3 and PD4. V114 was non-inferior (${\rm{margi}}{{\rm{n}}_{RRD}}$ m a r g i n R R D >-10%-point; ${\rm{margi}}{{\rm{n}}_{GMCratio}}$ m a r g i n G M C r a t i o >0.5) to PCV20 (p-value <0.001) for all endpoints. V114 was superior (${\rm{margi}}{{\rm{n}}_{RRD}}$ m a r g i n R R D >0%-point; ${\rm{margi}}{{\rm{n}}_{GMCratio}}$ m a r g i n G M C r a t i o >1.2) to PCV20 (p-value <0.001) for serotype 3: RRD was 34.5% (95%CI 27.9%-41.1%) PD3, and IgG GMC ratios were 2.39 (95%CI 2.12–2.68) PD3 and 2.15 (95%CI 1.90–2.41) PD4. Immune response to V114 administered in a 3 + 1 schedule in healthy infants was considered non-inferior to PCV20 for all 13 PCV13 serotypes and superior for serotype 3 PD3 and PD4. identifiers NCT03893448, NCT04382326 [ABSTRACT FROM AUTHOR]

Second-generation anaplastic lymphoma kinase (ALK) gene targeted tyrosine kinase inhibitors (TKIs) alectinib and brigatinib have shown efficacy as front-line treatments for ALK-positive non–small cell lung cancer (NSCLC). No head-to-head data are currently available for brigatinib vs alectinib in the ALK-TKI–naive population. To estimate the relative overall survival (OS) for brigatinib vs alectinib with indirect treatment comparisons (ITCs) using ALEX and ALTA-1L clinical trial data. The latest aggregate data from the ALEX trial and final patient-level data from ALTA-1L were used. ITCs were conducted with/without treatment crossover adjustments to estimate relative OS. Bucher methods, anchored matching-adjusted indirect comparisons (MAICs) and unanchored MAICs were employed in ITCs without treatment crossover adjustments. An inverse probability of censoring weight Cox model, a marginal structure model and rank-preserving structural failure time models (with/without re-censoring) within an anchored MAIC were used in ITCs with treatment crossover adjustments. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. HRs for brigatinib vs alectinib for relative OS generated from ITCs without treatment crossover adjustments ranged from 0.90 (95% CI: 0.59–1.38) in the unanchored MAIC to 1.20 (95% CI: 0.69–2.11) using the Bucher method. Methods employing treatment switching adjustments estimated HRs for relative OS ranging from 0.74 (95% CI: 0.38–1.45) to 1.11 (95% CI: 0.63–1.94). Results from all ITCs did not indicate statistically different survival profiles. Regardless of ITC methodology, OS is comparable for brigatinib vs alectinib in patients with ALK+ NSCLC previously untreated with an ALK inhibitor. [ABSTRACT FROM AUTHOR]

To perform a systematic literature review and indirect treatment comparison (ITC) to identify, summarize and quantify randomized controlled trial (RCT) evidence evaluating combination anticoagulant or P2Y12 inhibitor with low-dose aspirin versus low-dose aspirin alone for the prevention of atherothrombotic events in patients with stable coronary artery disease (CAD) and/or peripheral artery disease (PAD). We performed an updated search of CENTRAL, MEDLINE and EMBASE through 23 August 2021 to identify RCTs of adult patients with chronic CAD and/or PAD that compared combination anticoagulant or P2Y12 inhibitor with low-dose aspirin to low-dose aspirin alone. Outcomes of interest included major adverse cardiovascular events (MACEs) including cardiovascular death, stroke, or myocardial infarction (MI) and bleeding. When needed, outcomes were pooled using random-effects models to generate hazard or risk ratios (HRs or RRs) and accompanying 95% confidence intervals (CIs). Adjusted ITCs using subsequent pooled HRs/RRs were then performed. Six publications reporting the results of two unique RCTs (one evaluating clopidogrel + aspirin vs. aspirin alone and the other rivaroxaban 2.5 mg twice daily + aspirin vs. aspirin alone) were analyzed. The ITC suggested that rivaroxaban + aspirin was associated with a lower risk of MACEs compared with clopidogrel + aspirin (HR = 0.82, 95% CI = 0.68–0.98). When looking at the individual components of MACE, rivaroxaban + aspirin was associated with lower risk of cardiovascular death (HR = 0.75, 95% CI = 0.57–0.98) and stroke (RR = 0.67, 95 CI = 0.49–0.93) and similar risk of MI (RR = 0.93, 95% CI = 0.70–1.23) versus clopidogrel + aspirin. No evidence of a difference in moderate-to-severe bleeding, fatal bleeding or intracranial hemorrhage (ICH) was seen between the two treatment strategies. Compared to clopidogrel + low-dose aspirin, the use of rivaroxaban 2.5 mg twice daily + low-dose aspirin reduced the risk of MACE, CV death and stroke including ischemic stroke in patients with or at high risk for chronic CAD and/or PAD. These benefits of rivaroxaban 2.5 mg twice daily + low-dose aspirin compared to clopidogrel + low-dose aspirin appear to be achieved without significantly increasing patients' risk of moderate-to-severe bleeding, including ICH or fatal bleeding. [ABSTRACT FROM AUTHOR]

To compare the efficacy of tezepelumab with other approved biologics via indirect treatment comparisons (ITCs) in patients aged ≥ 12 years with severe uncontrolled asthma. Data from randomized controlled trials (RCTs) identified from a systematic literature review were synthesized using two different ITC approaches: network meta-analysis (NMA) and simulated treatment comparison (STC). Outcomes of interest were annualized asthma exacerbation rate (AAER) and AAER for exacerbations leading to hospitalization or emergency room visit. To address potential heterogeneity between study populations, various subgroup analyses were performed for the NMA (based on blood eosinophil count, fractional exhaled nitric oxide level, and presence of allergic asthma), and for the STC, models were adjusted for potential treatment effect modifiers. Sensitivity analyses were performed to assess the impact of study design (exclusion of non-placebo-controlled studies and non-phase 3 or 4 studies). Results were reported as rate ratios (RRs) with 95% credible/confidence intervals and ranking statistics were computed for the NMAs. Sixteen RCTs were included in at least one of the ITCs. All biologics (tezepelumab, dupilumab, benralizumab, mepolizumab, reslizumab, and omalizumab) had similar efficacy, with no statistically significant RRs for either exacerbation outcome; however, tezepelumab was favorably associated with numerically lower AAERs and was ranked first in the network for both types of exacerbation outcome. This trend was consistent in the subgroup and sensitivity analyses. As with the primary NMA, the STC results did not demonstrate any significant differences between biologics, but point estimates were favorable towards tezepelumab. Heterogeneity between trials was observed among eligibility criteria and clinically important patient characteristics; however, the impact on findings is expected to be low, based on consistency across analyses. Findings from both ITCs (NMA and STC) support the use of tezepelumab in a broad patient population of severe uncontrolled asthma of any phenotype. [ABSTRACT FROM AUTHOR]

Objective: Head-to-head trials comparing siponimod with fingolimod or ofatumumab in patients with multiple sclerosis (MS) are lacking. Instead, the comparative efficacy of siponimod can be derived from indirect treatment comparisons (ITCs). We assessed the suitability of ITCs leveraging individual patient data from relevant phase III trials across different MS phenotypes.Methods: One siponimod trial in patients with secondary progressive MS (SPMS), four fingolimod trials (three in relapsing-remitting MS [RRMS], and one in primary progressive MS [PPMS]), and two ofatumumab trials in relapsing MS (RMS) were considered. The suitability of ITCs was evaluated based on trial design, patient eligibility criteria, baseline patient characteristics, placebo response, and outcome definitions for each trial. Analyses deemed feasible were conducted using one-to-one propensity score matching (PSM).Results: An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible because of insufficient overlap in key patient characteristics (e.g. disability level and relapse history) and differences in placebo response. However, a comparison between siponimod in SPMS and fingolimod in PPMS was feasible because of sufficient overlap in eligibility criteria and baseline characteristics. One-to-one PSM demonstrated siponimod was favored relative to fingolimod for time to 6- and 3-month confirmed disability progression though not significantly different (hazard ratio 0.76 [95% confidence interval 0.48-1.20; p-value = .240] and hazard ratio 0.80 [95% confidence interval 0.52-1.22; p-value = .300], respectively).Conclusions: For trials in MS, clinical phenotype is an important determinant of ITC feasibility. An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible. The only feasible comparison was between siponimod in SPMS and fingolimod in PPMS. [ABSTRACT FROM AUTHOR]

Aim: To analyse the cost-effectiveness of MEP with standard of care (SoC) versus other anti-IL-5 therapies approved for the treatment of severe eosinophilic asthma (SEA) patients, within the Spanish National Health System (NHS) perspective. Methods: A Markov model with a 4-week cycle length was used to compare MEP with BEN and RES as therapies added to SoC in the management of SEA, in terms of cost per QALY gained and incremental cost-effectiveness ratio (ICER). Costs (e2019) were obtained from public sources, while utilities and transition probabilities were retrieved from literature, e.g. network meta-analysis. Continuation criteria for biological treatment and reduction of oral corticosteroids (OCS) was set at 50% minimum reduction of exacerbation rate. Adverse events related to chronic OCS use included diabetes, osteoporosis, cataracts, acute myocardial infarct, and peptic ulcer. The analysis was performed over a 5-year time horizon from the National Healthcare System (NHCS) perspective, with a yearly discount rate of 3% applied to both costs and QALYs. Probabilistic sensitivity analysis and univariate deterministic sensitivity analysis were performed to address uncertainty around the cost-effectiveness results. Results: On top of SoC, the model indicates that MEP is dominant (lower cost, higher benefit) compared to BEN and RES: For BEN and RES, respectively, treatment with MEP had a point estimate of 0.076 and 0.075 additional QALYs, and savings of e3,173.47 and e7,772.95 per patient. The findings were robust to variation as estimated using sensitivity analysis. Conclusions: MEP is a cost-effective treatment in comparison with BEN and RES added to SoC for patients with SEA in the Spanish setting. [ABSTRACT FROM AUTHOR]

Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up. In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference. Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07–0.54; 99% CI: 0.05–0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09–1.32; 99% CI: 0.06–2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results. Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up. [ABSTRACT FROM AUTHOR]

This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the approved idecabtagene vicleucel (ide-cel) dose range of 300–460 × 106 CAR-positive T-cells for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed) using matching-adjusted indirect treatment comparisons (MAICs). MAICs were performed with individual patient data for cilta-cel (CARTITUDE-1; NCT03548207) and published summary-level data for ide-cel (KarMMa; NCT03361748). Treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa were included in the analyses. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p <.0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.49 [95% CI: 2.47, 12.21; p <.0001]; RR: 2.21), DoR (hazard ratio [HR]: 0.50 [95% CI: 0.29, 0.87; p =.0137]), and PFS (HR: 0.37 [95% CI: 0.22, 0.62; p =.0002]) when compared with ide-cel. For OS, the results were in favor of cilta-cel and clinically meaningful but with a CI overlapping one (HR: 0.55 [95% CI: 0.29, 1.05; p =.0702]). These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes, highlighting its therapeutic potential in patients with triple-class exposed RRMM. [ABSTRACT FROM AUTHOR]

To analyse the cost-effectiveness of MEP with standard of care (SoC) versus other anti-IL-5 therapies approved for the treatment of severe eosinophilic asthma (SEA) patients, within the Spanish National Health System (NHS) perspective. A Markov model with a 4-week cycle length was used to compare MEP with BEN and RES as therapies added to SoC in the management of SEA, in terms of cost per QALY gained and incremental cost-effectiveness ratio (ICER). Costs (€2019) were obtained from public sources, while utilities and transition probabilities were retrieved from literature, e.g. network meta-analysis. Continuation criteria for biological treatment and reduction of oral corticosteroids (OCS) was set at 50% minimum reduction of exacerbation rate. Adverse events related to chronic OCS use included diabetes, osteoporosis, cataracts, acute myocardial infarct, and peptic ulcer. The analysis was performed over a 5-year time horizon from the National Healthcare System (NHCS) perspective, with a yearly discount rate of 3% applied to both costs and QALYs. Probabilistic sensitivity analysis and univariate deterministic sensitivity analysis were performed to address uncertainty around the cost-effectiveness results. On top of SoC, the model indicates that MEP is dominant (lower cost, higher benefit) compared to BEN and RES: For BEN and RES, respectively, treatment with MEP had a point estimate of 0.076 and 0.075 additional QALYs, and savings of €3,173.47 and €7,772.95 per patient. The findings were robust to variation as estimated using sensitivity analysis. MEP is a cost-effective treatment in comparison with BEN and RES added to SoC for patients with SEA in the Spanish setting. [ABSTRACT FROM AUTHOR]

Background: Indirect treatment comparisons (ITCs) provide valuable evidence on comparative efficacy where head-to-head clinical trials do not exist; however, differences in patient populations may introduce bias. Therefore, it is essential to assess between-trial heterogeneity to determine the suitability of synthesizing ITC results. We provide an illustrative case study in multiple sclerosis (MS) where we assess the feasibility of conducting ITCs between siponimod and interferon beta-1b (IFN β-1b) and between siponimod and ocrelizumab.Methods: We assessed the feasibility of conducting ITCs using standard unadjusted methods (e.g. Bucher or network meta-analysis [NMA]) as well as matching-adjusted indirect comparisons (MAICs) using individual patient data (IPD) from the siponimod (EXPAND) trial, based on guidance from NICE. Time to confirmed disability progression (CDP) at 3 or 6 months was assessed.Results: Bucher ITCs and NMAs, which rely on summary-level data, were not able to account for important cross-trial differences. Comparisons between siponimod and IFN β-1b were feasible using MAIC; the HRs (95% CI) for CDP-6 and CDP-3 were 0.55 (0.33-0.91) and 0.82 (0.42-1.63), respectively. ITCs were not feasible between siponimod and ocrelizumab because study designs and patient populations were too dissimilar to conduct a reliable ITC.Conclusions: This study highlights the importance of conducting a detailed feasibility assessment before undertaking ITCs to illuminate when excessive between-trial heterogeneity would cause biased results. MAIC was performed for siponimod and IFN β-1b in the absence of a head-to-head trial and was considered a more valid approach than a traditional ITC to examine comparative effectiveness. [ABSTRACT FROM AUTHOR]

Background: Siponimod, interferon beta-1a (IFNβ-1a), IFNβ-1b and natalizumab have been evaluated as treatments for secondary progressive multiple sclerosis (SPMS) in separate randomized controlled trials (RCTs), but not head-to-head. These trials included heterogeneous patient populations, which limits the use of standard network meta-analysis (NMA) for indirect treatment comparison (ITC) of relative efficacy. Matching-adjusted indirect comparison (MAIC) aims to correct these cross-trial differences. We compared siponimod to other disease modifying treatments (DMTs) in SPMS using MAIC.Methods: Individual patient data (IPD) were available for siponimod (EXPAND), while only published summary data were available for IFNβ-1a (Nordic Study, SPECTRIMS, IMPACT), IFNβ-1b (North American Study, European Study) and natalizumab (ASCEND). MAICs were conducted between siponimod and the other DMTs by re-weighting patients in EXPAND based on logistic regression.Results: Siponimod was determined to be statistically significantly more effective for the outcome of time to 6 month confirmed disability progression (CDP) compared with 22 µg IFNβ-1a and 250 µg IFNβ-1b, and for the outcome of time to CDP-3 compared with 60 µg IFNβ-1a. Siponimod was numerically but not statistically superior for CDP in all other comparisons. For annualized relapse rate (ARR), with the exception of natalizumab, siponimod was numerically but not statistically superior to all comparators.Conclusions: EXPAND provides evidence of the efficacy of siponimod compared with placebo, and these MAICs complement this by demonstrating improved efficacy of siponimod relative to DMTs. Siponimod offers a significant therapeutic advance that may slow disease progression compared to other DMTs in an EXPAND-like population with secondary progressive disease. [ABSTRACT FROM AUTHOR]

Objective: The comparative safety and efficacy of tafamidis, patisiran and inotersen treatments for transthyretin amyloidosis with polyneuropathy (ATTR-PN) has not been evaluated in clinical trials. In the absence of head-to-head evidence, indirect treatment comparisons such as network meta-analyses (NMAs) can be performed to evaluate relative effects of treatments. This study aims to assess the feasibility of conducting an NMA of available therapies for ATTR-PN patients.Methods: Pivotal trials for three approved ATTR-PN treatments, tafamidis (Fx-005), patisiran (APOLLO) and inotersen (NEURO-TTR), were compared in terms of study design, baseline population characteristics, outcome definitions and baseline risk. These assessments of heterogeneity informed the decision to perform Bayesian NMAs.Results: Despite similar study designs, clear differences in eligibility criteria between trials were accompanied by imbalances in baseline population characteristics considered to be plausible effect modifiers, such as disease stage and previous treatment. Of the outcomes assessed, only quality of life and adverse events were similarly reported in all trials. Neuropathy outcomes were not evaluated consistently between trials.Conclusions: An NMA of ATTR-PN treatments was not feasible, given the observed cross-trial heterogeneity. This decision highlights the importance of careful consideration for clinical heterogeneity that may threaten the validity of indirect comparisons. [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy of pembrolizumab relative to other treatments used in stage III melanoma by conducting a systematic literature review (SLR) and network meta-analysis (NMA). Methods: A SLR was conducted to identify randomized clinical trials (RCTs) evaluating approved adjuvant treatments including interferon-containing regimens, BRAF-inhibitors, and PD-L1 inhibitors in stage III melanoma patients. Relative treatment effects for recurrence-free survival (RFS) were synthesized with Bayesian NMA models that allowed for hazard ratios (HRs) to vary over time. Results: Included studies formed a connected network of evidence composed of eight trials. In high-risk stage III patients, the HR for pembrolizumab vs observation decreased significantly over time with the superiority of pembrolizumab over observation becoming statistically meaningful before 3 months. By 9 months, the HR for pembrolizumab vs observation was statistically significantly lower than the HR for most other treatments vs observation, with the exception of ipilimumab and biochemotherapy due to overlapping 95% credible intervals. In BRAF + patients, pembrolizumab was statistically significantly better than observation after 3 months. The HR for both BRAF-inhibitors vs observation increased significantly over time and pembrolizumab was statistically superior to both BRAF-inhibitors after 15 months. Conclusions: Pembrolizumab results in statistically significantly improved RFS compared to all competing regimens after 9 months, except ipilimumab and biochemotherapy, for the adjuvant treatment of stage III melanoma. However, point estimate HRs vs observation for pembrolizumab are much lower than those for ipilimumab. In BRAF + patients, the advantage of pembrolizumab versus competing interventions increases over time with respect to RFS. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the comparative efficacy of cladribine tablets versus alternative disease modifying therapies (DMTs) - fingolimod, natalizumab, alemtuzumab and ocrelizumab - in adults with active relapsing-remitting multiple sclerosis (RRMS), using meta-regression to provide subpopulation-specific estimates of drug effect. Additionally, to determine the feasibility of conducting a matching-adjusted indirect comparison (MAIC) to validate the meta-regression results. Methods: A published systematic literature review (SLR) identified studies evaluating the efficacy of cladribine tablets and alternative DMTs in the management of active RRMS. A series of meta-regression models were run with adjustment for baseline risk, fitted to data from the intention-to-treat cohorts of trials identified in the SLR. A non-parametric MAIC analysis adjusted for differences between studies by reweighting patient-level data from the index trial to match the mean baseline characteristics reported for trials with only aggregate data. Results: The meta-regression analysis showed significant overlap in credible intervals for the hazard ratios of 6 month confirmed disability progression (CDP-6M) and annualized relapse rate (ARR), with no therapy statistically dominating in terms of efficacy and all therapies estimated to reduce the ARR compared to placebo in all subpopulations. In the MAIC analysis, cladribine tablets showed a reduction in CDP-6M and ARR comparable to alemtuzumab before and after matching. Conclusion: This analysis has demonstrated that cladribine tablets have comparable relative efficacy to other highly efficacious DMTs in active RRMS across all subpopulations, thus validating the comparative effectiveness results from previous network meta-analysis. The MAIC analysis showed that cladribine tablets are comparable in efficacy to alemtuzumab in the treatment of patients with RRMS. [ABSTRACT FROM AUTHOR]

Objective: Bronchial thermoplasty (BT) as an add-on therapy for uncontrolled severe asthma is an alternative to biologic therapies like omalizumab (OM). We conducted an indirect treatment comparison (ITC) to appraise comparative effectiveness of BT and OM. Methods: A systematic literature review identified relevant randomized controlled trials. The ITC followed accepted methodology. Results: The ITC comprised a sham-controlled trial of BT (AIR2) and two placebo-controlled trials of OM (INNOVATE; EXTRA). Comparing the BT post-treatment period to ongoing treatment with OM, showed no significant differences in the rate ratios (RRs) for severe exacerbations (RR of BT versus OM = 0.91 [95% CI: 0.64, 1.30]; p = 0.62) or hospitalizations (RR = 0.57 [95% CI: 0.17, 1.86]; p = 0.53); emergency department visits were significantly reduced by 75% with BT (RR=0.25 [95% CI: 0.07, 0.91]; p=0.04); the proportions of patients with clinically meaningful response on the asthma quality-of-life questionnaire were comparable (RR = 1.06 [95% CI: 0.86, 1.34]; p = 0.59). The RR for exacerbations statistically favours OM over the total study period in AIR2 (RR = 1.50 [95% CI: 1.11, 2.02]; p = 0.009) likely reflecting a transient increase in events during the BT peri-treatment period. Conclusions: The ITC should be interpreted cautiously considering the differences between patient populations in the included trials. However, based on the analysis, BT compares well with a potentially more costly pharmacotherapy for asthma. Clinicians evaluating the relative merits of using these treatments should consider the totality of evidence and patient preferences to make an informed decision. [ABSTRACT FROM AUTHOR]

Aim: To review and compare methods for indirect comparison of aflibercept and ranibizumab in patients with diabetic macular edema.Methods: Post-stratification, inverse probability weighting based on simulated data, weight optimization, and regression model techniques were used to compare pooled individual patient-level data from the RESTORE and RESPOND (ranibizumab 0.5 mg as needed after 3 initial monthly doses) studies with summary-level data from the VIVID and VISTA (aflibercept 2.0 mg every 8 weeks after 5 initial monthly doses, 2q8) studies. The impact of adjusting for up to two baseline characteristics was assessed.Results: All methods provided similar results. After adjustment for baseline best-corrected visual acuity and central retinal thickness, no statistically significant difference in average gain in baseline best-corrected visual acuity from baseline at month 12 was found between ranibizumab 0.5 mg and aflibercept 2q8.Conclusions: Weight optimization and regression methods are useful options to adjust for more than one baseline characteristic. [ABSTRACT FROM AUTHOR]

Objective: End-stage renal disease is the final and irreversible stage in chronic kidney disease, leading to patient mortality, unless managed by dialysis or transplantation (the treatment of choice). This study aimed to compare a currently recommended immunosuppressive treatment, tacrolimus, against a newer treatment, belatacept, using indirect treatment comparison (ITC) techniques since no head-to-head randomized controlled trials (RCTs) comparing tacrolimus against belatacept currently exist.Methods: ITC was employed to calculate estimates for the relative risks and mean difference of tacrolimus against belatacept. The choice of the Bucher ITC model was driven by the available data and the simple indirect treatment comparison involving three treatments was considered appropriate.Results: The results of the indirect analysis showed no significant differences between belatacept and tacrolimus treatments for mortality and graft loss. The acute rejection rate was significantly lower with tacrolimus (Prograf* and Advagraf (*) ) compared with belatacept (0.22 [0.13, 0.39] to 0.44 [0.20, 0.99]).Conclusions: The results of this systematic review and meta-analysis suggests that tacrolimus is significantly superior to belatacept in terms of acute rejection outcomes but comparable for graft and patient survival. Further research should include a properly designed clinical trial comparing tacrolimus against belatacept directly.Limitations: These include variations in terms of clinical and design differences among the trials, weaknesses in the Bucher method and the lack of long-term clinical trial data with tacrolimus to compare with the recent long-term (7 years) belatacept trial data. [ABSTRACT FROM AUTHOR]

Objectives: To assess the relative efficacy and tolerability of vortioxetine against different antidepressant monotherapies in patients with major depressive disorder (MDD) with inadequate response to selective serotonin reuptake inhibitor (SSRI) or serotonin–norepinephrine reuptake inhibitor (SNRI) therapy. Methods: A systematic search was conducted for monotherapy studies in patients with MDD with inadequate response to first-line therapy. Treatments included SSRIs, SNRIs, and other antidepressants. Identified studies underwent a three-stage screening/data extraction process and critical appraisal. Adjusted indirect treatment comparisons (ITCs) on systematic literature review outputs were made using Bucher’s method, comparing remission rates and withdrawal rates due to adverse events (AEs). Results: Of 27 studies meeting the inclusion criteria, a few studies were of high quality according to the National Institute of Health and Care Excellence checklist. Three studies contributed to an evidence network for quantitative assessment comparing vortioxetine with agomelatine, sertraline, venlafaxine XR, and bupropion SR. Vortioxetine had a statistically significantly higher remission rate than agomelatine (risk difference [RD]: −11.0% [95% CI: −19.4; −2.6]), and numerically higher remission rates than sertraline (RD: −14.4% [95% CI: −29.9; 1.1]), venlafaxine (RD: −7.20% [95% CI: −24.3; 9.9]), and bupropion (RD: −10.70% [95% CI: −27.8; 6.4]). Withdrawal rates due to AEs were statistically significantly lower for vortioxetine than sertraline (RD: 12.1% [95% CI: 3.1; 21.1]), venlafaxine XR (RD: 12.3% [95% CI: 0.8; 23.8]), and bupropion SR (RD: 18.3% [95% CI: 6.4; 30.1]). Conclusions: The current systematic literature review found a few high quality switch studies assessing monotherapies in patients with MDD with inadequate response to SSRI/SNRIs. ITCs indicated that switching to vortioxetine leads to numerically higher remission rates compared with other antidepressants. Vortioxetine is a well tolerated treatment, showing statistically lower withdrawal rates due to AEs compared with other antidepressants. Vortioxetine is a relevant therapeutic alternative in patients experiencing inadequate response to prior SSRI or SNRI therapy. [ABSTRACT FROM PUBLISHER]