indirect treatment
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Ildiko Lingvay ◽  
Robert Bauer ◽  
James Baker-Knight ◽  
Jack Lawson ◽  
Richard Pratley

Abstract Aims Currently no head-to-head data are available comparing semaglutide 2.0 mg with dulaglutide 3.0 mg or 4.5 mg. We conducted an indirect treatment comparison (ITC) of their effects on glycated haemoglobin (HbA1c) and body weight in patients with type 2 diabetes (T2D). Materials and methods Multilevel network meta-regression (MLNMR) was conducted, based on a connected evidence network of published results from the AWARD-11 trial and individual patient data (IPD) from the SUSTAIN FORTE and SUSTAIN 7 trials. Results Semaglutide 2.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg and 4.5 mg, with estimated treatment differences (ETD) of –0.44%-points (95% credible interval [CrI]: –0.68, –0.19) and –0.28%-points (95% CrI: –0.52, –0.03), respectively. Semaglutide 2.0 mg also significantly reduced body weight versus dulaglutide 3.0 mg and 4.5 mg with ETDs of –3.29 kg (95% CrI: –4.62, −1.96) and –2.57 kg (95% CrI: –3.90, –1.24), respectively. Odds of achieving HbA1c <7.0% were significantly greater for semaglutide 2.0 versus dulaglutide 3.0 mg (odds ratio [OR]: 2.23 [95% CrI: 1.15, 3.90]), while this did not reach significance for semaglutide 2.0 mg versus dulaglutide 4.5 mg (OR: 1.58 [95% CrI: 0.82, 2.78]). Sensitivity analyses supported the main analysis findings. Conclusions This ITC demonstrated significantly greater reductions from baseline in HbA1c and body weight with semaglutide 2.0 mg vs dulaglutide 3.0 mg and 4.5 mg. The findings of this study provide important comparative effectiveness information until randomised head-to-head studies become available.

2021 ◽  
Vol 37 (S1) ◽  
pp. 27-28
John Scott ◽  
Moira McMurray ◽  
Rickie O'Connell ◽  
Pauline McGuire ◽  
Noreen Downes

IntroductionThe Scottish Medicines Consortium (SMC) conducts early health technology assessment (HTA) of new medicines on behalf of the National Health Service Scotland based on pharmaceutical company submissions. As the appraisals are conducted close to the point of marketing authorization, there is often a lack of direct head-to-head data. In 2019, assessment of relevant comparative efficacy was informed via indirect treatment comparisons (ITC) in 55 percent (36/66) of submissions. While the ITCs are essential to the decision-making process, they are frequently incomplete.MethodsA focus group was conducted with the clinical assessment team (n = 11) to explore problems in the submission process and to identify areas for improvement. It was agreed that providing improved guidance to companies prior to submission may prevent future inconsistencies. A working group (n = 5) was tasked with identifying and implementing potential solutions. The group reviewed the focus group findings, relevant literature, and guidance from other organizations. Draft guidance was developed that was reviewed by two pharmaceutical industry representatives (SMC subcommittee members).ResultsFindings from the focus group highlighted issues broadly related to the incomplete presentation and reporting of ITCs. The improved guidance document outlined specific requirements in a checklist format for reporting and presenting the results of different ITC data. This guidance was published in February 2020. To evaluate the impact of the updated guidance and to identify any further changes required, a follow-up focus group and survey of industry representatives is planned for March 2021.ConclusionsThe aim of the ITC guidance is to provide pharmaceutical companies with direction to improve the quality and transparency of reporting, which will in turn improve the quality of HTAs and thus strengthen the recommendations provided by the SMC. The follow-up focus groups and survey will assess the impact of the guidance. It is acknowledged that the results of this process may be limited by the small sample size and short duration of the assessment.

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4626-4626
Pranav Abraham ◽  
Xiaomeng Liao ◽  
Manoj Chevli ◽  
Sarah Smith

Abstract Introduction: Myelofibrosis (MF) is a serious and life-threatening myeloproliferative neoplasm that is characterized by stem cell-derived clonal myeloproliferation, bone marrow fibrosis, anemia and splenomegaly. The Janus kinase (JAK) pathway is the critical pathway in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor, was the first US Food and Drug Administration (FDA)-approved therapy for intermediate- and high-risk MF. However, there remains a high unmet need for alternative treatment options for patients who discontinue (41.1%-60.9% of patients discontinue after 3 months and 48.4%-73.0% after 6 months) (Fonseca E, et al. Blood 2013;122. Abstract 2833) or are no longer responding to ruxolitinib therapy (Bose P, Verstovsek S. Leuk Lymphoma 2020;61:1797-1809). The efficacy and safety of fedratinib, a JAK2 inhibitor approved by the FDA in 2019, was investigated post ruxolitinib in the single-arm trial JAKARTA-2 (NCT01523171) (Harrison CN, et al. Lancet Haematol 2017;4:e317-324; Harrison CN, et al. Am J Hematol 2020;95:594-603). New clinical evidence for treating a similar population with navitoclax plus ruxolitinib was presented at the American Society of Hematology Annual Meeting in 2020 (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50). The efficacy of fedratinib relative to navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib has not yet been evaluated. Objective: To explore the comparative efficacy of fedratinib versus navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib for the 2 binary endpoints of ≥ 35% spleen volume reduction (SVR) from baseline to the end of cycle 6 (EOC6; 24 weeks) and ≥ 50% reduction in total symptom score (TSS) from baseline to the EOC6. Methods: Evidence for fedratinib was informed by JAKARTA-2 patient-level data, and evidence for navitoclax plus ruxolitinib was informed by known reported evidence from the REFINE study (NCT03222609) (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50; Harrison CN, et al. J Clin Oncol 2019;37 (suppl 15). Abstract 7057). The suitability of these studies for indirect treatment comparison (ITC) was assessed by considering the comparability of study design, population, intervention, and outcomes. Given the lack of a common comparator in the identified studies, unanchored ITCs were performed for SVR using matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) methods. Univariable and multivariable regression models were used to identify potential prognostic factors to adjust for in the ITCs. Additionally, all reported Dynamic International Prognostic Scoring System (DIPSS)-Plus criteria were considered. Where sample size was too small, response rates (number of responders divided by total number of patients) were compared naively. Results: A subgroup of 58 JAKARTA-2 patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 and intermediate-2 or high-risk disease most closely aligned with the REFINE population was used in the analyses. Baseline mean platelet count was similar between subgroups. Across the analyses performed, results suggested fedratinib consistently increased the odds/risk of a spleen response compared with navitoclax plus ruxolitinib (Table). The MAIC, matching on ECOG PS, suggested that the odds of having an SVR for patients in the fedratinib group was 2.19 times (95% confidence interval [CI], 1.26 to 3.66) that of the navitoclax plus ruxolitinib group, and the risk of having an SVR for patients in the fedratinib group was 17.59% higher (95% CI, −2.14 to 36.97). The results from the MAIC that additionally matched on all possible DIPSS-Plus criteria (age, hemoglobin, and platelet count) were consistent. Results from the 2 methods (MAIC and STC) were also consistent. For TSS reduction, the sample size (N = 20) in REFINE was considered too small to perform a meaningful ITC; however, the absolute response rates for TSS reduction were similar across the 2 groups (29% [16/56] in the fedratinib group and 30% [6/20] in the navitoclax plus ruxolitinib group). Conclusion: In the population of patients with MF previously treated with ruxolitinib, these analyses suggest treatment with fedratinib was associated with a greater proportion of patients achieving a spleen response compared with navitoclax plus ruxolitinib. Limited data were available for comparison of TSS. Figure 1 Figure 1. Disclosures Abraham: Bristol Myers Squibb: Current Employment. Liao: BMS: Consultancy. Chevli: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Smith: Sarah Smith is an employee of BresMed. BresMed received consultancy fees from BMS/Celgene for the reasearch in this abstract. She did not receive direct payment as a result of this work outside of her normal salary payments.: Consultancy.

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4083-4083
Jianming He ◽  
Heather Berringer ◽  
Bart Heeg ◽  
Tobias Kampfenkel ◽  
Harikumaran R. Dwarakanathan ◽  

Abstract Introduction: The phase 3 APOLLO study demonstrated significantly better progression-free survival (PFS) and clinical responses with daratumumab, pomalidomide, and dexamethasone (D-Pd) vs pomalidomide and dexamethasone (Pd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Based on these results, D-Pd became 1 of many treatment regimens approved in this patient population. In the absence of head-to-head data, indirect comparisons can provide important information to help optimize treatment for patients with RRMM. However, indirect comparisons of aggregated clinical trial data can be subject to selection and confounding bias, thus limiting the conclusions that can be drawn from the comparison. Several statistical methodologies are available that can be used to control for baseline differences and estimate the relative treatment effect of different treatment regimens. Here, we report the results of indirect comparisons that used patient-level data to compare improvement in PFS with D-Pd vs daratumumab, bortezomib, and dexamethasone (D-Vd) and D-Pd vs Vd in patients with RRMM with prior immunomodulatory drug (IMiD) and proteasome inhibitor (PI) exposure. Methods: Data for the D-Pd cohort came from the APOLLO (NCT03180736) and EQUULEUS (NCT01998971) studies. APOLLO is a randomized, open-label, phase 3 trial in which patients with RRMM and ≥1 prior line of therapy (LOT) including lenalidomide and a PI were randomized to D-Pd (N=151) or Pd (N=153). EQULEUUS was a nonrandomized, open-label, phase 1b trial that evaluated D-Pd in 103 patients with RRMM and ≥1 prior LOT, including lenalidomide and a PI. Data for the D-Vd and Vd cohorts came from CASTOR (NCT02136134), a randomized, open-label, phase 3 trial comparing D-Vd (N=251) vs Vd (N=247) in patients with RRMM and ≥1 prior LOT. Harmonized eligibility criteria (≥1 prior LOT including an IMiD and a PI; no prior pomalidomide) were applied prior to weighting/matching. Stabilized inverse probability of treatment weighting (sIPTW), propensity score matching (PSM), and cardinality matching (CM) were explored to adjust for imbalances in patient characteristics at baseline. Propensity scores were estimated using logistic regression for sIPTW and PSM. CM is an optimization-based method to find the mathematically-guaranteed largest matched sample meeting prespecified maximum standardized mean difference criteria for matching covariates, thereby overcoming limitations of PSM associated with limited covariate overlap, which was identified in this sample. Age, sex, cytogenetic risk (high/standard/missing), Eastern Cooperative Oncology Group performance status (0, 1, or 2), International Staging System (ISS) stage (I, II, III, or missing), MM type (IgG/non-IgG/missing), prior autologous stem cell transplant (yes/no), number of prior LOT (1, 2-3, or ≥4), refractory to lenalidomide status (yes/no/not received), refractory to IMiD/PI status (IMiD only, PI only, both, neither), and years since diagnosis were considered for adjustment. The analysis focused on PFS; overall survival was not analyzed as these data are immature. Results: After harmonized eligibility criteria were applied, 253, 104, and 122 patients from the D-Pd, D-Vd, and Vd cohorts, respectively, were included for comparison. A naïve comparison of baseline characteristics identified differences between D-Pd and D-Vd/Vd cohorts. After sIPTW, PSM, and CM adjusting, some imbalances between the D-Pd and D-Vd/Vd cohorts remained. ISS stage and MM type could not be adjusted for due to the amount of missing data in EQUULEUS. The CM method yielded better balance than sIPTW. The effective sample sizes (ESS) for each method are shown in the Table. The ESS for PSM was too low for comparison of PFS. PFS hazard ratios favored D-Pd over D-Vd and Vd and were statistically significant for sIPTW and CM (Figure). Conclusions: This indirect treatment comparison showed a PFS benefit for D-Pd compared with well-established SOC regimens D-Vd and Vd in patients with RRMM with previous exposure to an IMiD and a PI. Although the low ESS of sIPTW and PSM is a limitation, these findings provide support in favor of using D-Pd in a population of patients with difficult-to-treat MM. Figure 1 Figure 1. Disclosures He: Janssen: Current Employment, Current equity holder in publicly-traded company. Heeg: Janssen: Research Funding. Kampfenkel: Janssen: Current Employment. Dwarakanathan: Janssen: Other: Data related vendor services. Johnston: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Mendes: Janssen-Cilag Farmacêutica: Current Employment. Lam: Janssen: Current Employment, Current equity holder in publicly-traded company. Bathija: Janssen: Current Employment; Parexel International: Ended employment in the past 24 months.

2021 ◽  
Vol 19 (1) ◽  
Hongbing Lin ◽  
Huishan Chen ◽  
Xuetao Zhao ◽  
Zhen Chen ◽  
Peipei Zhang ◽  

AbstractPeriodontitis is a chronic inflammatory disease that leads to the destruction of both soft and hard periodontal tissues. Complete periodontal regeneration in clinics using the currently available treatment approaches is still a challenge. Mesenchymal stem cells (MSCs) have shown promising potential to regenerate periodontal tissue in various preclinical and clinical studies. The poor survival rate of MSCs during in vivo transplantation and host immunogenic reaction towards MSCs are the main drawbacks of direct use of MSCs in periodontal tissue regeneration. Autologous MSCs have limited sources and possess patient morbidity during harvesting. Direct use of allogenic MSCs could induce host immune reaction. Therefore, the MSC-based indirect treatment approach could be beneficial for periodontal regeneration in clinics. MSC culture conditioned medium (CM) contains secretomes that had shown immunomodulatory and tissue regenerative potential in pre-clinical and clinical studies. MSC-CM contains a cocktail of growth factors, cytokines, chemokines, enzymes, and exosomes, extracellular vesicles, etc. MSC-CM-based indirect treatment has the potential to eliminate the drawbacks of direct use of MSCs for periodontal tissue regeneration. MSC-CM holds the tremendous potential of bench-to-bed translation in periodontal regeneration applications. This review focuses on the accumulating evidence indicating the therapeutic potential of the MSC-CM in periodontal regeneration-related pre-clinical and clinical studies. Recent advances on MSC-CM-based periodontal regeneration, existing challenges, and prospects are well summarized as guidance to improve the effectiveness of MSC-CM on periodontal regeneration in clinics.

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S529-S529
Sonya J Snedecor ◽  
Melanie Schroeder ◽  
Nicolas Van de Velde

Abstract Background Switching to cabotegravir long-acting + rilpivirine long-acting (CAB LA + RPV LA) administered every month (Q1M) has demonstrated non-inferiority in viral suppression versus a range of standard of care (SoC) antiretroviral regimens, including tenofovir alafenamide based regimens, in two pivotal phase 3 clinical trials (ATLAS [NCT02951052] and FLAIR [NCT02938520]). Furthermore, CAB LA + RPV LA every 2 months (Q2M) has demonstrated non-inferiority in maintaining viral suppression compared with CAB LA + RPV LA Q1M in a phase 3b study (ATLAS-2M [NCT03299049]). As bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) was not widely used at study initiation, the regimen was not present in the SoC arms of ATLAS and FLAIR. The objective was to compare efficacy and safety of CAB LA + RPV LA Q2M to BIC/FTC/TAF using indirect treatment comparison. Methods Two switch studies appropriate for facilitating indirect comparison to BIC/FTC/TAF were identified via systematic literature review (Molina et al. 2018 [NCT02603120] and Sax et al. 2020 [NCT03110380]). Indirect comparison using a generalisation of Bucher’s methodology to calculate relative risk, odds ratio, and risk differences in efficacy (Week 48 HIV RNA < 50 c/mL and ≥50 c/mL per FDA Snapshot approach and CD4+ cell change from baseline) and safety (discontinuation due to adverse events [AEs] and overall and serious AEs excluding injection site reactions [ISRs]) was conducted. Results for CAB LA + RPV LA Q2M in ATLAS-2M participants with prior integrase inhibitor (INI) exposure, but without prior CAB exposure, were indirectly compared to those with prior INI use in ATLAS and FLAIR via the common CAB LA + RPV LA Q1M comparator and were then indirectly compared to BIC/FTC/TAF via the INI comparator (Figure 1). Results No statistically significant differences in virologic failure, virologic suppression, CD4+ cell change, discontinuations due to AEs, and non-ISR serious/non-serious AEs were found between CAB LA + RPV LA Q2M and BIC/FTC/TAF (Table 1). Conclusion Indirect treatment comparison indicated efficacy and safety of CAB LA + RPV LA Q2M is not different from BIC/FTC/TAF. These regimens will be further compared in a randomized head-to-head non-inferiority trial (SOLAR, NCT04542070). Disclosures Sonya J. Snedecor, PhD, ViiV Healthcare (Other Financial or Material Support, Author’s employer, OPEN Health received funding to execute this study) Melanie Schroeder, MSc, ViiV Healthcare (Employee) Nicolas Van de Velde, PhD, ViiV Healthcare (Employee)

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