Potential Treatment Effect Modifiers Research Articles

Prognostic Factors and Treatment Effect Modifiers for Physical Health, Opioid Prescription, and Health Care Utilization in Patients With Musculoskeletal Disorders in Primary Care: Exploratory Secondary Analysis of the STEMS Randomized Trial of Direct Access to Physical Therapist-Led Care.

The aims of the study were to identify prognostic factors associated with health care outcomes in patients with musculoskeletal conditions in primary care and to determine whether characteristics associated with choice of care modify treatment effects of a direct-access physical therapist-led pathway in addition to general practitioner (GP)-led care compared to GP-led care alone. A secondary analysis of a 2-parallel-arm, cluster randomized controlled trial involving general practices in the United Kingdom was conducted. Practices were randomized to continue offering GP-led care or to also offer a direct-access physical therapist-led pathway. Data from adults with musculoskeletal conditions who completed the 6-month follow-up questionnaire were analyzed. Outcomes included physical health, opioid prescription, and self-reported health care utilization over 6 months. Treatment effect modifiers were selected a priori from associations in observational studies. Multivariable regression models identified potential prognostic factors, and interaction analysis tested for potential treatment effect modifiers. Analysis of 767 participants indicated that baseline pain self-efficacy, pain severity, and having low back pain statistically predicted outcomes at 6 months. Higher pain self-efficacy scores at baseline were associated with improved physical health scores, reduced opioid prescription, and less health care utilization. Higher bodily pain at baseline and having low back pain were associated with worse physical health scores and increased opioid prescription. Main interaction analyses did not reveal that patients' age, level of education, duration of symptoms, or musculoskeletal presentation influenced response to treatment, but visual trends suggested those in the older age group proceeded to fewer opioid prescriptions and utilized less health care when offered direct access to physical therapy. Patients with musculoskeletal conditions with lower levels of pain self-efficacy, higher pain severity, and presenting with low back pain have less favorable clinical and health care outcomes in primary care. Prespecified characteristics did not modify the treatment effect of the offer of a direct-access physical therapist-led pathway compared to GP-led care. Patients with musculoskeletal conditions receiving primary care in the form of direct-access physical therapist-led or GP-led care who have lower levels of self-efficacy, higher pain severity, and low back pain are likely to have a less favorable prognosis. Age and duration of symptoms should be explored as potential patient characteristics that modify the treatment response to a direct-access physical therapist-led model of care.

PD09-05 STANDARD VERSUS EXTENDED LYMPH NODE DISSECTION AT THE TIME OF RADICAL CYSTECTOMY FOR BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023PD09-05 STANDARD VERSUS EXTENDED LYMPH NODE DISSECTION AT THE TIME OF RADICAL CYSTECTOMY FOR BLADDER CANCER Alejandro Abello, Sumedh Kaul, Aaron Fleishman, Joaquim Bellmunt, Irving Kaplan, Simon Kim, Peter Chang, Andrew Wagner, Ruslan Korets, Aria Olumi, and Boris Gershman Alejandro AbelloAlejandro Abello More articles by this author , Sumedh KaulSumedh Kaul More articles by this author , Aaron FleishmanAaron Fleishman More articles by this author , Joaquim BellmuntJoaquim Bellmunt More articles by this author , Irving KaplanIrving Kaplan More articles by this author , Simon KimSimon Kim More articles by this author , Peter ChangPeter Chang More articles by this author , Andrew WagnerAndrew Wagner More articles by this author , Ruslan KoretsRuslan Korets More articles by this author , Aria OlumiAria Olumi More articles by this author , and Boris GershmanBoris Gershman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003240.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: It is uncertain whether lymphadenectomy (LND) provides a survival benefit in patients undergoing radical cystectomy (RC). In the only completed randomized trial on this topic – LEA AUO AB 25/02 – extended LND (eLND) was associated with improved survival compared to limited/standard (sLND), although these associations did not reach statistical significance. Herein, we emulated a pragmatic clinical trial designed to resemble the LEA trial. METHODS: We identified patients in the National Cancer Database who met the following eligibility criteria based on the LEA trial: adult 40-79 years old, Charlson 0-1, underwent RC with LND for high-grade cT1/cT2-T4a cNany cM0 urothelial carcinoma of the bladder from 2006-2015, without neoadjuvant chemotherapy, at a hospital performing ≥16 RC/year. sLND and eLND were defined as removal of 4-11 and ≥12 lymph nodes based on the LEA trial. A propensity score (PS) was estimated for receipt of eLND, and the associations of LND type with overall survival (OS) were evaluated adjusting with inverse probability of treatment weights (IPW). RESULTS: A total of 2248 patients formed the study cohort, including 429 with sLND and 1813 with eLND. Baseline characteristics were well-balanced after PS adjustment. During a median follow-up of 37.5 months, eLND was associated with significantly improved 5-year OS compared to sLND (60% vs 48%; HR 0.72, 95%CI: 0.61-0.85, p<0.01; Figure 1). Effect estimates were consistent across all potential treatment effect modifiers, including cT stage, cN stage, and age (Figure 2). Results were robust in sensitivity analyses that modified the definitions for LND and relaxed the annual RC hospital volume requirement. CONCLUSIONS: In observational analyses designed to emulate a completed clinical trial, eLND was associated with improved OS compared to sLND among patients undergoing RC. Survival and effect estimates were similar to those in the LEA trial but statistically significant due to larger sample size. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e241 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alejandro Abello More articles by this author Sumedh Kaul More articles by this author Aaron Fleishman More articles by this author Joaquim Bellmunt More articles by this author Irving Kaplan More articles by this author Simon Kim More articles by this author Peter Chang More articles by this author Andrew Wagner More articles by this author Ruslan Korets More articles by this author Aria Olumi More articles by this author Boris Gershman More articles by this author Expand All Advertisement PDF downloadLoading ...

Do imaging findings modify the effect of non-surgical treatment in patients with knee and hip osteoarthritis? A systematic literature review

ObjectivesTo review the available evidence on diagnostic imaging findings in knee and hip osteoarthritis (OA) as treatment effect modifiers in non-surgical OA interventions.MethodsMEDLINE, Embase and The Cochrane Central Register of...

Response to fumaric acid esters for plaque type psoriasis in real-world practice is largely independent of patient characteristics at baseline – a multivariable regression analysis from the German Psoriasis Registry PsoBest

Objectives Fumaric acid esters (FAEs) are a well-established treatment option for long-term therapy of moderate to severe plaque psoriasis. This study examines effectiveness of FAEs for the treatment of plaque psoriasis in real-world practice at 12 months and if patient characteristics affect the odds of clinical response. Methods A descriptive, multivariable logistic regression analysis was conducted in a cohort drawn from the German registry PsoBest. Baseline patient characteristics were assessed as potential treatment effect modifiers. Results 444 patients (mean age 47.0 years, 39.0% female) were eligible for response analysis using nonresponder imputation at month 12. Of these, 39.6% achieved clinical response, i.e. Psoriasis Area and Severity Index (PASI) ≤ 3 or skin clearance. In logistic regression analysis (R 2 = 0.114), only baseline PASI was a significant factor: patients with PASI < 10 had a 4 times higher odds (p ≤ .001, OR 4.088), patients with PASI of 10–20 a twofold higher odds of response (p ≤ .044, OR 1.961) compared to those with PASI > 20. Neither sex, age, body weight, disease duration, comorbidity nor pretreatment had an impact on the odds of response (p > .05). Conclusions FAEs showed a favorable response at 12 months, largely independent of patient characteristics.

Tezepelumab compared with other biologics for the treatment of severe asthma: a systematic review and indirect treatment comparison

Aims To compare the efficacy of tezepelumab with other approved biologics via indirect treatment comparisons (ITCs) in patients aged ≥ 12 years with severe uncontrolled asthma. Materials and methods 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. Results 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. Limitations 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. Conclusions Findings from both ITCs (NMA and STC) support the use of tezepelumab in a broad patient population of severe uncontrolled asthma of any phenotype.

Treatment effect modifiers for individuals with acute low back pain: secondary analysis of the TARGET trial.

Treatment effect modifiers identify patient characteristics associated with treatment responses. The purpose of this secondary analysis was to identify potential treatment effect modifiers for disability from the TARGET trial that compared usual care (control) with usual care + psychologically informed physical therapy (PIPT). The sample consisted of a STarT Back tool identified high-risk patients with acute low back pain that completed Oswestry Disability Index (ODI) data at index visit and 6 months later (n = 1250). Candidate treatment effect modifiers were identified a priori and informed by the literature. Linear mixed models tested for treatment effect modification through tests of statistical interaction. All statistical interactions ( P ≤ 0.20) were stratified by modifier to inspect for specific effects ( P ≤ 0.05). Smoking was identified as a potential effect modifier (treatment * smoking interaction, P = 0.08). In participants who were smokers, the effect of PIPT was (ODI = 5.5; 95% CI: 0.6-10.4; P = 0.03) compared with usual care. In participants who were nonsmokers, the effect of PIPT was (ODI = 1.5; 95% CI: -1.4 to 4.4; P = 0.31) compared with usual care. Pain medication was also identified as a potential effect modifier (treatment × pain medication interaction, P = 0.10). In participants prescribed ≥3 pain medications, the effect of PIPT was (ODI = 7.1; 95% CI: -0.1 to 14.2; P = 0.05) compared with usual care. The PIPT effect for participants prescribed no pain medication was (ODI = 3.5; 95% CI: -0.4 to 7.4; P = 0.08) and for participants prescribed 1 to 2 pain medications was (ODI = 0.6; 95% CI: -2.5 to 3.7; P = 0.70) when compared with usual care. These findings may be used for generating hypotheses and planning future clinical trials investigating the effectiveness of tailored application of PIPT.

Exercise-based cardiac rehabilitation for coronary heart disease.

Exercise-based cardiac rehabilitation for coronary heart disease.

The effects of combined motor control and isolated extensor strengthening versus general exercise on paraspinal muscle morphology and function in patients with chronic low back pain: a randomised controlled trial protocol

BackgroundExercise is a common approach for the management of patients with chronic non-specific low back pain (LBP). However, there is no clear mechanistic evidence or consensus on what type of exercise is more effective than others. While considerable evidence suggests a link between lumbar muscle health (e.g., atrophy and fatty infiltration) with functional deficits, it is unknown whether exercises targeting the lumbar spine can lead to noticeable improvements in muscle health and functional outcomes. The primary aim of this study is to compare the effect of combined motor control and isolated strengthening lumbar exercises (MC + ILEX) versus a general exercise group (GE) on multifidus muscle morphology (size and composition). Secondary aims include assessing the effect of the interventions on overall paraspinal muscle health, pain and disability, as well as psychological factors as possible effect modifiers.MethodsA total of 50 participants with chronic non-specific LBP and moderate to severe disability, aged between 18 and 60, will be recruited from the local orthopaedic clinics and university community. Participants will be randomised (1:1) to either the MC + ILEX or GE group. Participants will undergo 24 individually supervised exercise sessions over a 12-week period. The primary outcome will be multifidus morphology (atrophy) and composition (fatty infiltration). Secondary outcomes will be muscle function (e.g., % thickness change during contraction), morphology, lumbar extension strength, pain intensity and disability. Potential treatment effect modifiers including maladaptive cognitions (fear of movement, catastrophizing), anxiety, depression, physical activity, and sleep quality will also be assessed. All measurements will be obtained at baseline, 6-week and 12-week; self-reported outcomes will also be collected at 24-week. Between-subjects repeated measure analysis of variance will be used to examine the changes in paraspinal muscle morphology over the different time points. Linear mixed models will be used to assess whether baseline scores can modify the response to the exercise therapy treatment.DiscussionThe results of this study will help clarify which of these two common interventions promote better results in terms of overall paraspinal muscle heath, back pain, disability and psychological factors in adults with chronic LBP.Trial registrationNTCT04257253, registered prospectively on February 5, 2020.

Matching-adjusted indirect treatment comparison of ozanimod versus teriflunomide for relapsing multiple sclerosis

BackgroundA growing number of immunomodulating disease-modifying therapies are available for treatment of relapsing multiple sclerosis (RMS). In the absence of randomized head-to-head trials, matching-adjusted indirect comparisons (MAICs) can be used to adjust for cross-trial differences and evaluate the comparative efficacy and safety of these agents. We used MAIC methodology to indirectly compare key outcomes with ozanimod (OZM) and teriflunomide (TERI) in the treatment of RMS. MethodsA systematic literature review was conducted to identify clinical trials evaluating the efficacy and safety of OZM vs TERI. Given the absence of head-to-head trials of OZM vs TERI, we used a matching-adjusted indirect comparison to adjust for potential treatment effect modifiers and prognostic factors while assessing confirmed disability progression (CDP), relapse, and safety outcomes. Individual patient data for OZM (SUNBEAM and RADIANCE Part B trials) and aggregate level data for TERI (ASCLEPIOS I/II, TOWER, OPTIMUM, and TEMSO trials) were used to evaluate the following outcomes: annualized relapse rate (ARR), proportion of patients relapsed, CDP at 3 and 6 months, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs. ResultsAfter matching, baseline patient characteristics were balanced between OZM and TERI. Compared with TERI, OZM demonstrated significant improvements in ARR (rate ratio: 0.73; 95% CI: 0.62–0.84), proportion of patients relapsed (odds ratio [OR]: 0.56; 95% CI: 0.44–0.70), overall AEs (OR: 0.35; 95% CI: 0.29–0.43), SAEs (OR: 0.53; 95% CI: 0.37–0.77), and discontinuations due to AEs (OR: 0.14; 95% CI: 0.09–0.21). OZM demonstrated statistically significant improvements in CDP at 3 months (hazard ratio [HR]: 0.78; 95% CI: 0.66–0.92) but nonsignificant differences at 6 months (HR: 0.78; 95% CI: 0.60–1.01) compared with TERI. ConclusionIn this indirect treatment comparison of patients with RMS, OZM appeared to have an improved benefit–risk profile over TERI.

Identifying potential treatment effect modifiers of the effectiveness of chiropractic care to infants with colic\xa0through prespecified secondary analyses of a randomised controlled trial

BackgroundA recent trial identified large variation in effect of chiropractic care for infantile colic. Thus, identification of possible effect modifiers could potentially enhance the clinical reasoning to select infants with excessive crying for chiropractic care. Therefore, the aim of this study is to identify potential treatment effect modifiers which might influence the effect of chiropractic care for excessive crying in infancy.MethodsDesign: Prespecified secondary analyses of data from a randomised controlled trial. The analyses are partly confirmative and partly exploratory.Setting: Four chiropractic clinics in Denmark.Participants: Infants aged 2–14 weeks with unexplained excessive crying. Of the 200 infants randomised (1:1), 103 were assigned to a chiropractic care group and 97 to a control group.Intervention: Infants in the intervention group received chiropractic care for 2 weeks, while the control group was not treated.Main analyses: The outcome was change in daily hours of crying. Fifteen baseline variables and 6 general variables were selected as potential effect modifiers, and indices based on these were constructed. Factor analyses, latent class analyses and prognosis were used to construct other potentially modifying variables. Finally, an attempt at defining a new index aiming at optimal prediction of the treatment effect was made. The predictive value for all resulting variables were examined by considering the difference in mean change in crying time between the two treatment groups, stratified by the values of the candidate variables, i.e. interaction analyses.ResultsNone of the predefined items or indices were shown to be useful in identifying colicky infants with potentially larger gain from manual therapy. However, more baseline hours of crying (p = 0.029), short duration of symptoms (p = 0.061) and young age (p = 0.089) were all associated with an increased effect on the outcome of hours of crying.ConclusionMusculoskeletal indicators were not shown to be predictive of an increased benefit for colicky infants from chiropractic treatment. However, increased benefit was associated with early treatment and a high level of baseline crying, suggesting that the most severely affected infants have the greatest potential of benefiting from manual therapy. This finding requires validation by future studies.Trial registrationClinical Trials NCT02595515, registered 2 November 2015.

PUK2 The Impact of Clinical Heterogeneity on Conducting Network Meta-Analyses for Overall Survival in Previously Untreated Intermediate- or Poor-Risk Advanced/Metastatic Renal Cell Therapies

The optimal treatment for patients with previously untreated advanced/metastatic renal cell carcinoma (aRCC) is based on the severity of disease. Recently approved novel treatments for patients with intermediate-/poor-risk disease requires indirect treatments comparisons in this patient population. This study evaluated the impact of clinical heterogeneity on the validity of a network meta-analysis (NMA) for overall survival in intermediate-/poor-risk by following the feasibility assessment framework of Cope et al. (2014) based on the ISPOR Good Practices Task Force Report. A systematic literature review was performed, after which a network of evidence, including 10 randomized clinical trials and 8 treatments of interest, was formed for the intermediate-/poor-risk population. First, heterogeneity was evaluated in terms of treatment and outcome characteristics, as well as study and patient characteristics using a pre-defined set of potential treatment effect modifiers (i.e. ECOG performance status, gender, IMDC/MSKCC risk factor, liver metastasis, number of metastatic sites, prior nephrectomy, PD-L1 status, race and region). Second, comparisons of baseline risk and observed treatment effects were evaluated for the presence of unmeasured effect modifiers. Imbalances were found in prognostic risk score (intermediate vs. poor), nephrectomy, and radiation. Furthermore, there was a lack of reporting on most of the 9 pre-specified potential treatment effect modifiers, hampering the ability to make conclusions on the presence of heterogeneity. Only one treatment comparison in the network diagram considered evidence from multiple studies, for which no significant differences were found. Due to the small number of studies included in the evidence network, using meta-regression or subgroup analyses to eliminate heterogeneity in the evidence base, caused by potential effect modifiers, was deemed infeasible. Furthermore, the presence of potential sources of heterogeneity could not be assessed for most potential treatment effect modifiers. Results of an NMA in this network should therefore be interpreted with caution.

PUK5 Systematic Identification of Potential Treatment Effect Modifiers in First-Line Advanced Renal Cell Carcinoma

Imbalance in treatment effect modifiers across studies may compromise the validity of a network meta-analysis (NMA) assessing progression- free survival (PFS) and overall survival (OS). Therefore, preceding the NMA, evaluation of differences in potential treatment effect modifiers across studies must be assessed. Following the ISPOR-AMCP-NPC Good Practice Task Force guidelines, this study aimed to identify all potential treatment effect modifiers in first-line (1L) advanced renal cell carcinoma (aRCC) by analyzing subgroup efficacy results reported in literature. A systematic literature review (SLR) identified all available randomized controlled trials in 1L aRCC up to September 18, 2019 through MEDLINE, MEDLINE-IN-PROCESS, EMBASE, and Cochrane library. The relative treatment effects (hazard ratios with confidence intervals) were extracted for progression-free survival (PFS) and overall survival (OS) within subgroups. Subgroups reported by at least three publications were selected for further investigation. The presence and direction of a statistically significant or a considerable, but not significant difference (i.e., point estimate for the HR outside the CI of the other group), in relative treatments effects between subgroups were assessed. The SLR identified 23 studies from 109 publications that reported relative treatment effects of PFS or OS, covering 25 different subgroup variables. Only two studies reported a statistically significant difference in the relative treatment effect between subgroups: one study by liver metastases (OS) and one by PD-L1 status (PFS). Considerable differences were reported for 51% (PFS) and 33% (OS) of the subgroup comparisons for ECOG performance status, gender, IMDC/MSKCC risk factor, liver metastasis, number of metastatic sites, prior nephrectomy, PD-L1 status, race, and geographic region. The review indicated that a number of factors are potential treatment effect modifiers in 1L aRCC. Clinical expert consultations are necessary to determine the clinical relevance of these potential effect modifiers.

PUK4 The Impact of Clinical Heterogeneity on Conducting Network Meta-Analyses for Progression-Free Survival of Previously Untreated Intermediate- or Poor-Risk Advanced/Metastatic Renal Cell Carcinoma Therapies

The optimal treatment for patients with previously untreated advanced/metastatic renal cell carcinoma has been based on the IMDC/MSKCC prognostic risk scores. Recently, treatments with differing mechanisms of action have been approved for patients with intermediate-/poor-risk disease, for which indirect treatment comparisons in this patient population are warranted. This study aims to evaluate the impact of clinical heterogeneity on the validity of the intermediate-/poor-risk network meta-analysis for progression-free survival by following the feasibility assessment framework of Cope et al. (2014), based on the ISPOR Good Practices Task Force Report. A systematic literature review was performed, after which a network of evidence was constructed for the intermediate-/poor-risk population including 11 randomized clinical trials and 10 treatments of interest. First, heterogeneity was analyzed in terms of treatment and outcome characteristics, as well as study and patient characteristics, using a pre-defined set of potential treatment effect modifiers: ECOG performance status, gender, IMDC/MSKCC risk factor, liver metastasis, number of metastatic sites, prior nephrectomy, PD-L1 status, race, and region. Second, direct comparisons in terms of baseline risk and observed treatment effects were evaluated for the presence of unmeasured effect modifiers. Imbalances were found in prognostic risk score (intermediate vs. poor) and their measurement (IMDC vs. MSKCC), nephrectomy, and radiation. In 2 studies, only outcomes for the intermediate-risk population were reported. Furthermore, there was a lack of reporting for most of the 9 pre-specified potential treatment effect modifiers. Only one treatment comparison in the network considered evidence from multiple studies, between which no significant differences were found. Eliminating heterogeneity in the evidence caused by prognostic risk score is advised. We recommend excluding studies reporting outcomes only for the intermediate-risk population, as well as meta-regression to adjust for imbalances across all trials, where possible.

PUK1 Synthesizing Evidence on Progression-Free Survival and Assessing the Feasibility of Network Meta-Analyses in Previously Untreated Advanced/Metastatic Renal Cell Carcinoma Therapies

When direct comparisons are unavailable, contingent on satisfying foundational assumptions, network meta-analyses (NMA) can synthesize evidence for differences in relative treatment effects. The current study investigates the validity of conducting NMA for progression-free survival (PFS) for nivolumab+cabozantinib treatment versus relevant interventions in previously untreated advanced/metastatic renal cell carcinoma (aRCC), following the feasibility assessment framework by Cope et al. (2014). A systematic literature review (SLR) identified all published randomized controlled trials (RCTs) in aRCC. Available evidence was synthesized by evaluating whether the pre-defined relevant interventions (n=10) formed a network of evidence. Clinical heterogeneity was assessed for study and population characteristics that were potential treatment effect modifiers and for outcome and treatment characteristics. Finally, baseline risk and heterogeneity (or inconsistency) in observed treatment effects were evaluated to identify inconsistencies in the results. The SLR identified 18 individual RCTs that met our inclusion criteria. Prognostic risk status was considered a treatment effect modifier, and differed across trials in terms of baseline severity, reducing the NMA validity; networks of evidence were therefore stratified by risk status. For the all-risk network, trials were excluded when only subgroups were analyzed. The all-risk network included 15 studies, the intermediate/poor-risk included 11 studies (of which, 3 only included intermediate-risk patients), and the favorable-risk network included 10 studies. Most of the a-priori defined potential treatment effect modifiers were inconsistently reported. Heterogeneity was observed in ECOG score and nephrectomy in the all-risk and intermediate/poor-risk analyses. The few direct comparisons in the network supported by multiple studies did not show significant differences in their treatment effects. The current study showed that it is feasible to perform NMAs to compare PFS in aRCC. However, imbalances in prognostic risk score across trials are present and may bias results.

Extrafine Beclometasone Dipropionate/Formoterol Fumarate vs Double Bronchodilation Therapy in Patients with COPD: A Historical Real-World Non-Inferiority Study.

PurposeThis study aimed to evaluate the non-inferiority of initiating extrafine beclometasone dipropionate/formoterol fumarate (BDP/FF) versus double bronchodilation (long-acting beta-agonists [LABA]/long-acting muscarinic antagonists [LAMA]) among patients with a history of chronic obstructive pulmonary disease (COPD) exacerbations.Patients and MethodsA historical cohort study was conducted using data from the UK’s Optimum Patient Care Research Database. Patients with COPD ≥40 years at diagnosis were included if they initiated extrafine BDP/FF or any LABA/LAMA double therapy as a step-up from no maintenance therapy or monotherapy with inhaled corticosteroids (ICS), LAMA, or LABA and a history of ≥2 moderate/severe exacerbations in the previous two years. The primary outcome was exacerbation rate from therapy initiation until a relevant therapy change or end of follow-up. Secondary outcomes included rate of acute respiratory events, acute oral corticosteroids (OCS) courses, and antibiotic prescriptions with lower respiratory indication, modified Medical Research Council score (mMRC) ≥2, and time to first pneumonia diagnosis. The non-inferiority boundary was set at a relative difference of 15% on the ratio scale. Five potential treatment effect modifiers were investigated.ResultsA total of 1735 patients initiated extrafine BDP/FF and 2450 patients initiated LABA/LAMA. The mean age was 70 years, 51% were male, 41% current smokers, and 85% had FEV1 <80% predicted. Extrafine BDP/FF showed non-inferiority to LABA/LAMA for rate of exacerbations (incidence rate ratio [IRR] = 1.01 [95% CI 0.94–1.09]), acute respiratory events (IRR = 0.98 [0.92–1.04]), acute OCS courses (IRR = 1.01 [0.91–1.11]), and antibiotic prescriptions (IRR = 0.99 [0.90–1.09]), but not for mMRC (OR = 0.93 [0.69–1.27]) or risk of pneumonia (HR = 0.50 [0.14–1.73]). None of the a priori defined effect modifier candidates affected the comparative effectiveness.ConclusionThis study found that stepping up to extrafine BDP/FF from no maintenance or monotherapy was not inferior to stepping up to double bronchodilation therapy in patients with a history of exacerbations.

MPN-115: Indirect Treatment Comparisons (ITCs) of the Effect of Fedratinib Versus Ruxolitinib (RUX) on Spleen Volume for Patients with Myelofibrosis (MF) and No Prior RUX Treatment

Context: Since 2011, there have been a limited number of treatment options for patients with MF, including allogeneic stem cell transplantation and RUX, a JAK inhibitor. In 2019, another JAK inhibitor, fedratinib, was approved in the USA. As no RCTs have compared fedratinib with RUX, we performed ITCs to estimate the relative efficacy of fedratinib versus RUX in spleen volume reduction (SVR) in patients with RUX-naive MF. Objective: To explore the relative efficacy of fedratinib versus RUX for SVR in patients with RUX-naive MF. Design: A systematic literature review (SLR) originally conducted in August 2018 (and updated February 2020) examined clinical evidence published in EMBASE®, MEDLINE®, and the Cochrane Library (no time limit). RCTs investigating fedratinib or RUX in RUX-naive patients were considered for ITCs based on comparability of study design, population, intervention, comparators, and outcomes. Bucher ITCs were performed. Matching-adjusted indirect comparisons (MAICs) were explored to adjust for potential treatment effect modifiers (treatment-by-subgroup interaction term p Setting: Multicenter RCTs. Patients or other participants: Patients with RUX-naive MF. Interventions: Fedratinib versus RUX. Main outcome measures: The binary outcome of SVR ≥35% from baseline to Week 24 was investigated. Results: The SLR identified 3 studies: JAKARTA, COMFORT-I, COMFORT-II. The study control arms (placebo, best available therapy) were assumed to have equal efficacy, validated via clinician input and published literature, which enabled use of an anchored ITC. Baseline characteristics were generally comparable. A Bucher ITC indicated a numerically higher proportion of fedratinib-treated patients achieved SVR versus RUX (risk difference [95%CI] 11.0% [-1.4–23.4] comparing JAKARTA subgroup with platelet count ≥100 × 109/L; 9.4% [-2.2–20.9] comparing intention-to-treat [ITT] populations). After further accounting for baseline JAK2 mutation status (potential observed treatment effect modifier) in an MAIC, a significantly higher proportion of patients on fedratinib achieved SVR versus RUX (risk difference [95%CI] 14.7% [2.4–27.1] comparing JAKARTA subgroup with platelet count ≥100 × 109/L; 12.3% [0.6–24.0] comparing ITT populations). Scenario analyses were generally consistent. Conclusions: The MAIC analyses accounting for observable treatment effect modifiers demonstrated that a statistically significantly higher proportion of patients treated with fedratinib had SVR at Week 24 compared with RUX in RUX-naive MF.

PNS25 METHODS FOR DETECTING TREATMENT EFFECT MODIFIERS IN ANCHORED INDIRECT TREATMENT COMPARISONS: AN OVERVIEW AND SIMULATION STUDY OF MACHINE LEARNING ALGORITHMS

Anchored matching-adjusted indirect treatment comparisons (ITC) or propensity score adjustment methods (e.g. matching, reweighting) leverage individual patient data (IPD) to compare treatments across trials by anchoring through a common comparator. Since anchored ITCs adjust for imbalances in prognostic factors via the common comparator, health technology agencies (HTAs) such as NICE have recommended adjusting only for treatment effect modifiers that exhibit large imbalances between studies. Although many automated and semi-automated methods (e.g. high dimensionality propensity score, random forest, Bayesian Additive Regression Trees) for variable selection are available in open-source software packages, most practical applications of these methods have focused on detecting prognostic factors rather than treatment effect modifiers, and do not factor in imbalances between studies. This study provides a general overview of common machine-learning variable selection routines often employed for prognostic applications and explore their feasibility for identifying imbalanced treatment effect modifiers. We use Monte Carlo simulation studies to evaluate the finite sample performance of several supervised machine learning algorithms, in terms of their ability to detect true treatment effect modifiers with large imbalances, bias, and efficiency. Simulations are performed using simulated IPD that include one or more of the following characteristics: a) small samples; b) data sparsity relative to the number of potential treatment effect modifiers; and c) collinearity among variables. The findings from this overview and simulation study can inform data-driven variable selection methods for HTA and regulatory submissions involving indirect treatment comparisons which require the identification of variables that are important effect modifiers and differ between studies.

Effect of vitamin D supplementation on pain and physical function in patients with knee osteoarthritis (OA): an OA Trial Bank protocol for a systematic review and individual patient data (IPD) meta-analysis

IntroductionObservational data suggest that vitamin D deficiency is associated with the onset and progression of knee osteoarthritis (OA). However, randomised controlled trials (RCTs) to date investigating the efficacy of vitamin...

Potential treatment effect modifiers for manipulative therapy for children complaining of spinal pain.Secondary analyses of a randomised controlled trial

BackgroundIn children, spinal pain is transitory for most, but up to 20% experience recurrent and bothersome complaints. It is generally acknowledged that interventions may be more effective for subgroups of those affected with low back pain. In this secondary analysis of data from a randomized clinical trial, we tested whether five indicators of a potential increased need for treatment might act as effect modifiers for manipulative therapy in the treatment of spinal pain in children. We hypothesized that the most severely affected children would benefit more from manipulative therapy.MethodThis study was a secondary analysis of data from a randomised controlled trial comparing advice, exercises and soft tissue treatment with and without the addition of manipulative therapy in 238 Danish school children aged 9–15 years complaining of spinal pain. A text message system (SMS) and clinical examinations were used for data collection (February 2012 to April 2014).Five pre-specified potential effect modifiers were explored: Number of weeks with spinal pain 6 months prior to inclusion, number of weeks with co-occurring musculoskeletal pain 6 months prior to inclusion, expectations of the clinical course, pain intensity, and quality of life.Outcomes were number of recurrences of spinal pain, number of weeks with pain, length of episodes, global perceived effect, and change in pain intensity. To explore potential effect modification, various types of regression models were used depending on the type of outcome, including interaction tests.ResultsWe found that children with long duration of spinal pain or co-occurring musculoskeletal pain prior to inclusion as well as low quality of life at baseline tended to benefit from manipulative therapy over non-manipulative therapy, whereas the opposite was seen for children reporting high intensity of pain. However, most results were statistically insignificant.ConclusionsThis secondary analysis indicates that children more effected by certain baseline characteristics, but not pain intensity, have a greater chance to benefit from treatment that include manipulative therapy. However, these analyses were both secondary and underpowered, and therefore merely exploratory. The results underline the need for a careful choice of inclusion criteria in future investigations of manipulative therapy in children.Trial registrationNCT01504698; results

Comparative effectiveness of triple therapy versus dual bronchodilation in COPD.

This real-world study compared the effectiveness of triple therapy (TT; long-acting muscarinic antagonists (LAMAs)/long-acting inhaled β-agonists (LABAs)/inhaled corticosteroids (ICSs)) versus dual bronchodilation (DB; LAMAs/LABAs) among patients with frequently exacerbating COPD. A matched historical cohort study was conducted using United Kingdom primary care data. Patients with COPD aged ≥40 years with a history of smoking were included if they initiated TT or DB from no maintenance/LAMA therapy and had two or more exacerbations in the preceding year. The primary outcome was time to first COPD exacerbation. Secondary outcomes included time to treatment failure, first acute respiratory event, and first acute oral corticosteroid (OCS) course. Potential treatment effect modifiers were investigated. In 1647 matched patients, initiation of TT reduced exacerbation risk (adjusted hazard ratio (HR) 0.87, 95% CI 0.76–0.99), risk of acute respiratory event (HR 0.74, 95% CI 0.66–0.84) and treatment failure (HR 0.83, 95% CI 0.73–0.95) compared with DB. Risk reduction for acute respiratory events was greater for patients with higher rates of previous exacerbations. At baseline blood eosinophil counts (BECs) ≥ 0.35×109 cells·L−1, TT was associated with lower risk of OCS prescriptions than DB. This study provides real-life evidence of TT being more effective in reducing exacerbation risk than DB, which became more accentuated with increasing BEC and previous exacerbation rate.