Pooled Trial Research Articles

Comparing the real-world and clinical trial bleeding rates associated with oral anticoagulation treatment for atrial fibrillation

Abstract Background The prevention of stroke in patients with atrial fibrillation (AF) involves the use of oral anticoagulation, commonly in the form of direct oral anticoagulants (DOAC). However, it comes with an increased risk of bleeding and therefore, counselling patients on their individual risk is important. Although majority of patients initiated on DOAC have been represented within the clinical trials, there are some cohorts which are under-represented in whom clinicians are unable to practice evidence-based medicine. Methods Utilising the pooled clinical trial (CT) data sourced from Medidata Enterprise Data Store, 5 recent open-label industry sponsored AF trials were compared with Real-World data (RWD) was sourced from the HealthVerity Marketplace with the occurrence of bleeding events as the primary outcome of interest. Results A total of 64,421 patients were included in the analysis, with 3207 patients from the clinical DOAC trials and 61,214 patients from the RWD cohort. Overall, the patients from RWD cohort had more co-morbidities, were older (72.2 ± 11.9 vs 65.3 ±10.7 years old, p<0.001), had higher mean CHA2DS2VASc (3.98 ± 1.9 vs 2.87 ± 1.73, p<0.001) and HAD-BLED scores (2.13 ± 1.02 vs 1/04 ± 0.93, p<0.001) when compared to the trial data. When comparing the incidence of first major bleed at 12 months post treatment initiation, rates in the RWD cohort was significantly higher (10.69 vs 18.97 per 100 person-years). The impact of comorbidities such as age, CHA2DS2VASc and HAD-BLED scores were similar in both cohorts, however, there was an under-representation of older, females and more co-morbid patients within the clinical trial cohort. Conclusion DOAC treated patients have higher bleeding incidence rate in the RWD cohort as compared to clinical trials. This can be explained by the older patient age group with more complex medical histories and higher HAS-BLED scores. The under-representation of higher risk patients and lower proportion of females within clinical trials should be addressed to better translate clinical trial data into real world clinical practice.

6807 Evaluation of Tobacco Exposure and Teprotumumab Efficacy: Pooled Results from Acute TED Clinical Trials

Abstract Disclosure: S. Ugradar: Consulting Fee; Self; Acelyrin. S.T. Wester: Advisory Board Member; Self; Amgen Inc. Consulting Fee; Self; Immunovant, Lassen. Research Investigator; Self; Amgen Inc, Sling, Immunovant. R. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Q. Fu: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. G.J. Kahaly: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. Introduction: Tobacco exposure is a known risk factor for Thyroid Eye Disease (TED) development and severity. Here, we compare outcomes with teprotumumab in smokers versus non-smokers as reported in pooled clinical trials in patients with acute TED. Methods: Patients ≥18 years old from two placebo-controlled trials and an open-label extension in the US and EU (Phase 2, NCT01868997; OPTIC, NCT03298867; OPTIC-X, NCT03461211) and one placebo-controlled trial in Japan (OPTIC-J, jRCT2031210453) with Graves’ disease and recent onset (≤9 month duration) active TED (Clinical activity score, CAS≥4), were included. Patients received eight infusions of teprotumumab over 21 weeks, with the final study visit at Week 24 (three weeks after final dose). Statistical analyses were conducted to test differences in responder rates for proptosis (≥2mm, primary outcome), diplopia (Bahn-Gorman scale≥1), clinical activity score (CAS, 2-point improvement), and Overall response (proptosis + CAS), as well as proptosis mm change and Graves’ Ophthalmopathy Quality of Life (GO-QOL, range 0-100) score change. Cochran-Mantel-Haenszel tests were conducted to test the difference in responder rate for proptosis, diplopia, CAS, and Overall responder rate between smokers and non-smokers stratified by study (Phase 2, OPTIC, OPTIC-X, and OPTIC-J). Mixed Model for Repeated Measures was conducted to test the difference in the mean change in proptosis and GO-QOL. Results: Baseline characteristics and TED characteristics between teprotumumab-treated smokers (N=32, mean age 51 years, 75% female) and non-smokers (N=116), mean age 49.5 years, 68% female were similar. No significant differences were seen in proptosis (78.1% vs 83.6%, P=.585), diplopia (55.6% vs 70.2%, P=.175), CAS (73.3% vs 59.3%, P=.145), Overall (73.3% vs 76.1%, P=.814) responses and GO-QOL least squares mean (LSM) change (17.3 vs 17.0, P=.927) between smokers and non-smokers. The magnitude of LSM proptosis mm change was similar (-2.82 vs -3.23 mm, P=.19). Conclusion: In this post-hoc assessment, proptosis response rates with teprotumumab were comparable in smokers and non-smokers at Week 24. Teprotumumab produced clinically relevant decreases in proptosis, CAS, Overall response, diplopia, and improvements in quality of life over the study period of 24 weeks in both groups. These improvements were comparable to those seen in the overall teprotumumab-treated patient populations with TED. Smoking is a known risk factor for more severe TED but does not significantly affect response to teprotumumab. Public Presentation: 6/2/2024

Comorbidity and Disease Activity in Multiple Sclerosis

Multiple studies suggest that comorbidity worsens clinically relevant outcomes in multiple sclerosis (MS), including the severity of disability at diagnosis and rate of disability worsening after diagnosis. However, less is known regarding the association of comorbidity with measures of disease activity, such as relapse rate and magnetic resonance imaging lesion accrual, which are relevant to clinicians and clinical trialists. To evaluate the association of comorbidities with disease activity in clinical trials of disease-modifying therapies (DMTs) in populations with MS. A 2-stage meta-analytic approach was used in this cohort study of individual participant data from phase 3 clinical trials of MS DMTs that had 2 years of follow-up and were conducted from November 2001 to March 2018. Data were analyzed from February 2023 to June 2024. Comorbidity burden and individual comorbidities present at trial enrollment, including hypertension; hyperlipidemia; functional cardiovascular disease, ischemic heart, cerebrovascular, and peripheral vascular disease; diabetes; autoimmune thyroid and miscellaneous autoimmune conditions; migraine; lung and skin conditions; depression; anxiety; and other psychiatric disorders. The main outcome was evidence of disease activity (EDA) over 2 years of follow-up, defined as confirmed relapse activity, disability worsening, or any new lesions on magnetic resonance imaging. A total of 16 794 participants with MS were included from 17 clinical trials (67.2% female). Over the 2-year follow-up, 61.0% (95% CI, 56.2%-66.3%; I2 = 97.9%) of the pooled trials had EDA. After adjusting for multiple factors, the presence of 3 or more comorbidities was associated with an increased hazard of EDA (adjusted hazard ratio [AHR], 1.14; 95% CI, 1.02-1.28) compared with no comorbidity. Presence of 2 or more cardiometabolic conditions was also associated with an increased hazard of EDA (AHR, 1.21; 95% CI, 1.08-1.37) compared with no cardiometabolic comorbidity. Presence of 1 psychiatric disorder was associated with an increased hazard of EDA (AHR, 1.07; 95% CI, 1.02-1.14). In this study, a higher burden of comorbidity was associated with worse clinical outcomes in people with MS, although comorbidity could potentially be a partial mediator of other negative prognostic factors. Our findings suggest a substantial adverse association of the comorbidities investigated with MS disease activity and that prevention and management of comorbidities should be a pressing concern in clinical practice.

An exploratory graphical analysis of the Montgomery-Åsberg Depression Rating Scale pre- and post-treatment using pooled antidepressant trial secondary data

BackgroundThe 10-item Montgomery-Åsberg Depression Rating Scale (MADRS) is a commonly used measure of depression in antidepressant clinical trials. Numerous studies have adopted classical test theory perspectives to assess the psychometric properties of this scale, finding generally positive results. However, its network configural structure and stability is unexplored across different time-points and treatment groups. AimsTo assess the network structure and stability of the MADRS in clinical settings pre- and post-treatment, and to determine a configurally invariant and stable model across time-points and treatment groups (placebo and intervention). MethodIndividual participant data for 6440 participants from 14 clinical trials of major depressive disorder was obtained from the data repository Vivli.org. Exploratory Graphical Analysis (EGA) was used to identify empirical models pre-treatment (baseline) and post-treatment (8-week outcome). Bootstrapping techniques were applied to obtain optimised configurally invariant models. ResultsEmpirical models presented with performance issues at baseline and for the placebo group at outcome. An abbreviated 8-item single-community model was found to be stable and configurally invariant across time-points and treatment groups. Symptoms such as low mood and lassitude showed most centrality across all models. LimitationsMetric invariance could not be explored due to research environment limitations. ConclusionsAn 8-item one-community variant of the MADRS may provide optimal performance when conducting network analyses of antidepressant clinical trial outcomes. Findings suggest that interventions targeting low mood and lassitude might be most efficacious in treating depression among clinical trial participants. Further considerations of the potential impact on trial design and analysis should be explored.

Hypophosphatemia correction reduces ICANS incidence and duration in CAR T-cell therapy: a pooled clinical trial analysis.

A common complication of chimeric antigen receptor (CAR)-T cell therapy is immune effector cell associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR-T cell therapy across multiple clinical trials between 2015 and 2020. In addition to clinical toxicities experienced by the patients, we also interrogated the impact of serum electrolyte data and repletion of corresponding electrolyte deficiencies with ICANS incidence, severity, and duration. Hypophosphatemia was a common occurrence in CAR T-cell recipients, and the only electrolyte derangement associated with a significantly higher cumulative incidence of ICANS. Moreover, phosphorus repletion in hypophosphatemic patients was associated with significantly decreased ICANS incidence and duration. Hypophosphatemia was uniquely associated with encephalopathy neurological adverse events, which also showed the strongest positive correlation with both ICANS and CRS severity. These findings suggest that serum phosphorus could be a reliable biomarker for ICANS, and expeditious, goal-directed phosphorus repletion in response to serum hypophosphatemia could be a safe, inexpensive, and widely available intervention for such patients.

Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials

Aims/hypothesisWhether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA1c, blood glucose, blood glucose variability and weight.MethodsData from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes.ResultsThe maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced.Conclusions/interpretationThese data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance.Graphical

Validation and Application of Thresholds to Define Meaningful Change in Vasomotor Symptoms Frequency: Analysis of Pooled SKYLIGHT1 and 2 Data.

Vasomotor symptoms (VMS), the characteristic symptoms of menopausal transition, are often the primary reason women seek treatment. Current treatment options for VMS include fezolinetant, a nonhormonal, selective neurokinin3 receptor antagonist. This study aimed to define a clinically meaningful threshold for reduction of moderate-to-severe VMS in postmenopausal women treated with fezolinetant and then apply it in a responder analysis of the pooled trial data. This analysis pooled data from two identical phase3, double-blind, placebo-controlled studies that randomized women with moderate-to-severe VMS to once-daily fezolinetant 30mg, 45mg, or placebo (SKYLIGHT1 and 2). The frequency of VMS was collected daily using an electronic diary. Patients completed the Patient Global Impression of Change in VMS (PGI-C VMS) instrument, which assessed changes in hot flushes/night sweats at weeks4 and 12 compared with baseline using a seven-point Likert scale. VMS frequency data were anchored to PGI-C VMS data; the anchor level for meaningful within-patient change in PGI-C VMS was "moderately better." In the pooled population (N = 1022), the mean (standard deviation) estimated thresholds for a meaningful within-patient change in moderate-to-severe VMS frequency were - 5.73 (3.47) at week4 and - 6.20 (5.18) at week12. Applying the thresholds for meaningful within-patient change to responder analyses ("missing as non-responder" imputation method) indicated a favorable clinical benefit: greater proportions of responders were observed in the fezolinetant 30-mg and 45-mg groups compared with placebo at week4 (odds ratio range 2.48-2.91; P < 0.001) and week12 (odds ratio range 1.908-2.68; P < 0.001). PGI-C VMS is sensitive to change and correlates with VMS frequency: a reduction of approximately six VMS episodes per day from baseline to week12 was meaningful at the individual patient level. Fezolinetant provides a meaningful clinical benefit for women with moderate-to-severe VMS associated with menopause and represents an important nonhormonal treatment option. NCT04003155 and NCT04003142.

Comparative effectiveness of glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes in Sweden: an emulated trial study

The comparative effectiveness of glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes mellitus (T2DM) is unknown. We conducted a sequential trial emulation from 1st January 2010 to 30th June 2020 using data from Swedish national registers. Swedish residents who were aged 65 or older, had type 2 diabetes (T2DM), and initiated GLP-1 agonists, DPP-4 inhibitors, or sulfonylureas were followed for up to 10 years to assess the risk of dementia. Participants who had dementia, used the three drug classes, or had contraindications were excluded from enrollment. The characteristics between arms were balanced through the application of propensity scores estimated from predefined covariates. Intention-to-treat effects were analysed with all enrolled participants, while the per-protocol effects were analysed with participants who adhered to the assigned treatment. The pooled trial included 88,381 participants who received prescriptions for GLP-1 agonists (n=12,351), DPP-4 inhibitors (n=43,850), or sulfonylureas (n=32,216) at baseline and were followed for an average of 4.3 years. A total of 4607 dementia cases developed during follow-up: 278 for the GLP-1 agonist initiators (incidence rate: 6.7 per 1000 person years), 1849 for DPP-4 inhibitor initiators (IR: 11.8), and 2480 for sulfonylurea initiators (IR: 13.7). In an intention-to-treat analysis, GLP-1 agonist initiation was associated with a reduced risk of dementia compared to sulfonylureas (hazard ratio: 0.69, 95% CI: 0.60-0.79, p<0.0001) and DPP-4 inhibitors (HR: 0.77, 95% CI: 0.68-0.88, p<0.0001), after adjusting for age, enrollment year, sex, socioeconomic factors, health conditions, and past medication uses. These findings were consistent in several sensitivity analyses, including a per-protocol analysis (HR for sulfonylureas: 0.41, 95% CI: 0.32-0.53, p<0.0001; HR for DPP-4 inhibitors: 0.38, 95% CI: 0.30-0.49, p<0.0001). Our research suggested that GLP-1 agonists were associated with a lower risk of dementia compared to sulfonylureas and DPP-4 inhibitors in older individuals with T2DM. Further clinical trials are needed to validate these findings. Swedish Research Council, Karolinska Institutet, the National Institute on Aging, the National Institutes of Health, and Riksbankens Jubileumsfond.

Risk factors and prediction of hypoglycaemia using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials

Aims/hypothesisThe objective of the Hypoglycaemia REdefining SOLutions for better liVES (Hypo-RESOLVE) project is to use a dataset of pooled clinical trials across pharmaceutical and device companies in people with type 1 or type 2 diabetes to examine factors associated with incident hypoglycaemia events and to quantify the prediction of these events.MethodsData from 90 trials with 46,254 participants were pooled. Analyses were done for type 1 and type 2 diabetes separately. Poisson mixed models, adjusted for age, sex, diabetes duration and trial identifier were fitted to assess the association of clinical variables with hypoglycaemia event counts. Tree-based gradient-boosting algorithms (XGBoost) were fitted using training data and their predictive performance in terms of area under the receiver operating characteristic curve (AUC) evaluated on test data. Baseline models including age, sex and diabetes duration were compared with models that further included a score of hypoglycaemia in the first 6 weeks from study entry, and full models that included further clinical variables. The relative predictive importance of each covariate was assessed using XGBoost’s importance procedure. Prediction across the entire trial duration for each trial (mean of 34.8 weeks for type 1 diabetes and 25.3 weeks for type 2 diabetes) was assessed.ResultsFor both type 1 and type 2 diabetes, variables associated with more frequent hypoglycaemia included female sex, white ethnicity, longer diabetes duration, treatment with human as opposed to analogue-only insulin, higher glucose variability, higher score for hypoglycaemia across the 6 week baseline period, lower BP, lower lipid levels and treatment with psychoactive drugs. Prediction of any hypoglycaemia event of any severity was greater than prediction of hypoglycaemia requiring assistance (level 3 hypoglycaemia), for which events were sparser. For prediction of level 1 or worse hypoglycaemia during the whole follow-up period, the AUC was 0.835 (95% CI 0.826, 0.844) in type 1 diabetes and 0.840 (95% CI 0.831, 0.848) in type 2 diabetes. For level 3 hypoglycaemia, the AUC was lower at 0.689 (95% CI 0.667, 0.712) for type 1 diabetes and 0.705 (95% CI 0.662, 0.748) for type 2 diabetes. Compared with the baseline models, almost all the improvement in prediction could be captured by the individual’s hypoglycaemia history, glucose variability and blood glucose over a 6 week baseline period.Conclusions/interpretationAlthough hypoglycaemia rates show large variation according to sociodemographic and clinical characteristics and treatment history, looking at a 6 week period of hypoglycaemia events and glucose measurements predicts future hypoglycaemia risk.Graphical

Abstract PO1-05-12: Pooled clinical trial data analyses comparing the biology of HER2-low vs HER2-0 breast cancer in patients with metastatic breast cancer following treatment with standard single agent chemotherapy

Abstract Background: Prior analyses of observational data suggest that for patients with metastatic breast cancer (MBC), tumor biology does not vary by HER2-low vs. HER2-0 expression given similar overall survival (OS) times after accounting for patients’ clinicopathologic features including hormone receptor (HR) status. We sought to evaluate potential differential biology by HER2-low status by (1) studying data pertaining to patients treated in historic clinical trials (i.e., data collected to measure associations between protocol defined treatments and outcomes) and (2) evaluating the endpoint of progression-free survival (PFS) in addition to OS following treatment with standard single agent chemotherapy for MBC. Methods: Pooling anonymized clinical trial data from studies within the Medidata Enterprise Data Store, we identified 142 women with HER2-negative MBC who received treatment with an NCCN recommended single agent chemotherapy in the context of a clinical trial. Using patient-level immunohistochemistry (IHC) results, we categorized patients as either HER2-low (IHC 1+/2+ and not amplified by in situ hybridization) or HER2-0 (IHC 0). We compared patients’ baseline demographic and clinicopathologic features according to HER2-low vs HER2-0 status. We used Cox proportional-hazard models stratified by HR status to estimate OS and PFS according to HER2-low vs HER2-0 classification while adjusting for patients' baseline demographic and clinicopathologic attributes. Results: Patients with HER2-low disease represented 20% (28/142) of the HER2-negative cohort. Twenty-five percent (7/28) of HER2-low patients had tumors that expressed hormone receptors compared with 17% (19/114) of HER2-0 patients (p=0.31). In this cohort, the maximum follow up time was 38.4 months. For HER2-low patients vs HER2-0 patients, the median OS was 10.7 vs. 12.7 months (p=0.37), and the median PFS was 3.5 vs. 2.9 months (log rank test, p=0.53) respectively. In Cox proportional-hazard models that adjusted for patient demographic and clinicopathologic features and were stratified by HR status, patients with HER2-low tumors had an 16% elevated (non-significant) hazard of death compared with patients with HER2-0 tumors (HR 1.16, 95% CI: 0.69-1.95) and a 22% reduced (non-significant) hazard of progression or death (HR 0.78, 95% CI: 0.45-1.35). Conclusions: Analyses of pooled historic clinical trial data pertaining to women with HER2-negative MBC who were treated with single agent chemotherapy revealed no meaningful clinical differences in either OS or PFS endpoints according to HER2-negative subtypes (i.e., HER2-low vs. HER2-0) after accounting for patient demographic and clinicopathologic features. These results support prior findings from observational research suggesting that there are no biological differences associated with HER2-negative subtypes. Table. Multivariable Cox Proportional Hazards Models for OS and PFS Stratified by Hormone Receptor Status, (N=134) Variable OS PFS HR* 95% CI HR* 95% CI Age (decade) 0.84 0.70-1.01 0.86 0.72-1.01 Race White 1.00 (referent) 1.00 (referent) Black 1.75 0.84-3.63 1.57 0.66-3.73 Asian 0.93 0.47-1.80 1.33 0.71-2.51 Other 1.69 0.45-6.38 2.10 0.62-7.15 Ethnicity Non-Hispanic or Latino 1.00 (referent) 1.00 (referent) Hispanic or Latino 2.10 0.95-4.64 1.02 0.44-2.35 HER2 Characterization HER2-0 1.00 (referent) 1.00 (referent) HER2-1+/2+ 1.16 0.69-1.95 0.78 0.45-1.35 Prior Lines of Chemotherapy for Metastatic Disease 0 1.00 (referent) 1.00 (referent) 1 0.82 0.46-1.46 1.13 0.65-1.95 2 0.69 0.35-1.36 1.00 0.52-1.93 3 0.59 0.10-3.42 2.18 0.45-10.50 ECOG Performance Status 0 1.00 (referent) 1.00 (referent) 1 1.65 1.07-2.54 1.57 1.02-2.43 Legend: OS=overall survival; PFS=progression-free survival; HR=hazard ratio; HER2=human epidermal group factor receptor 2; ECOG=Eastern Cooperative Oncology Group. *Analyses adjusted for clinical trial membership (coefficients not reported) Citation Format: Elizabeth Lamont, Emily Stein, Paolo Tarantino, Sara Tolaney, Corinne Ahlberg, Krishna Chinnathambu, Jiezhi Qi, Kala Tummagunta, Jackie Bilan, Ruthanna Davi, Lisa Ensign. Pooled clinical trial data analyses comparing the biology of HER2-low vs HER2-0 breast cancer in patients with metastatic breast cancer following treatment with standard single agent chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-12.

Comparing the Real-World and Clinical Trial Bleeding Rates Associated with Oral Anticoagulation Treatment for Atrial Fibrillation.

Background The prevention of stroke in patients with atrial fibrillation (AF) involves the use of oral anticoagulation, commonly in the form of direct oral anticoagulants (DOACs). However, it comes with an increased risk of bleeding, and therefore, counselling patients on their individual risks is important. Although the majority of patients initiated on DOACs have been represented within the clinical trials, some cohorts are under-represented in whom clinicians cannot practice evidence-based medicine. Methods Utilising the pooled clinical trial (CT) data sourced from Medidata Enterprise Data Store, five recent open-label industry-sponsored AF trials were compared with real-world data (RWD) sourced from the HealthVerity™ Marketplace with the occurrence of bleeding events as the primary outcome of interest. Results A total of 64,421 patients were included in the analysis, with 3207 patients from the clinical DOAC trials and 61,214 patients from the RWD cohort. Overall, the patients from the RWD cohort had more co-morbidities, were older (72.2 ± 11.9 vs. 65.3 ± 10.7 years old, p < 0.001), had higher mean CHA2DS2VASc (3.98 ± 1.9 vs. 2.87 ± 1.73, p < 0.001), and HAD-BLED scores (2.13 ± 1.02 vs. 1/04 ± 0.93, p < 0.001) when compared to the trial data. When comparing the incidence of the first major bleed at 12 months post-treatment initiation, rates in the RWD cohort were significantly higher (10.69 vs. 18.97 per 100 person-years). The impact of co-morbidities such as age, CHA2DS2VASc, and HAD-BLED scores was similar in both cohorts; however, there was an under-representation of older females and more co-morbid patients within the clinical trial cohort. Conclusions DOAC-treated patients have a higher bleeding incidence rate in the RWD cohort than in clinical trials. This can be explained by the older patient age group with more complex medical h istories and higher HAS-BLED scores. The under-representation of higher-risk patients and lower proportion of females within clinical trials should be addressed to better translate clinical trial data into real-world clinical practice.

Safety and tolerability of atogepant for the preventive treatment of migraine: a post hoc analysis of pooled data from four clinical trials

BackgroundConventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene–related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders.MethodsThis post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM).ResultsThe safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation.ConclusionsOverall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults.Trial registrationClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309).Graphical

Cost Effectiveness of Dapagliflozin for Heart Failure Across the Spectrum of Ejection Fraction: An Economic Evaluation Based on Pooled, Individual Participant Data From the DELIVER and DAPA-HF Trials.

The sodium glucose cotransporter-2 inhibitors are guideline-recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter-2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking. We conducted a US-based cost-effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3-state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality-adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (<$150 000/QALY) at a cost of <$872.58/month, of high value (<$50 000/QALY) at <$317.66/month, and cost saving at <$40.25/month. Dapagliflozin was of at least intermediate value in 92% of simulations when using the full (undiscounted) Medicare list cost in probabilistic sensitivity analyses. Cost effectiveness was most sensitive to the dapagliflozin cost and the effect on cardiovascular death. The addition of dapagliflozin to standard of care in patients with heart failure across the spectrum of ejection fraction was at least of intermediate value at the undiscounted Medicare cost and may be potentially of higher value on the basis of the level of discount, rebates, and price negotiations offered. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01035255 & NCT01920711.

Motor skill competence and moderate- and vigorous-intensity physical activity: a linear and non-linear cross-sectional analysis of eight pooled trials

BackgroundFew studies have examined the relationship between motor skill competence and device-measured physical activity in large samples and none have used non-linear modelling. This study assessed the linear and non-linear associations between motor skill competence and physical activity in children using pooled data from eight studies.MethodsCross-sectional ActiGraph accelerometer and motor skills competence data from 988 children (50.8% boys) aged 3–11 years were included. Total, object control and locomotor skill competence were assessed using the Test of Gross Motor Skill Development. Linear mixed models were fitted to examine linear associations between motor skill competence and physical activity. Then, restricted cubic splines models were used to assess potential non-linear relationships. Interactions by sex and age were assessed.ResultsThere was evidence of positive linear associations between total skill, and object control and locomotor skills, with moderate- and vigorous-intensity physical activity; however, the associations with total skill competence and object control better fitted a non-linear model. Non-linear models indicated associations were positive but relatively weak in the low to mid ranges of TGMD/object control scores but at high ranges (~ > 70 out of 100/ and ~ 35 out of 50) the association strength increased for both moderate- and vigorous-intensity physical activity. There were sex interactions for locomotor skills only, specifically for vigorous activity with boys having a stronger positive association than girls.ConclusionsThere appears to be a threshold for object control skill proficiency that children need to reach to enhance their physical activity levels which provides support for a motor skill “proficiency barrier”. This provides a tangible benchmark for children to achieve in motor competence programs.

A Phenomapping Tool and Clinical Score to Identify Low Diuretic Efficiency in Acute Decompensated Heart Failure

BackgroundIndividuals with acute decompensated heart failure (ADHF) have a varying response to diuretic therapy. Strategies for the early identification of low diuretic efficiency to inform decongestion therapies are lacking. ObjectivesThe authors sought to develop and externally validate a machine learning–based phenomapping approach and integer-based diuresis score to identify patients with low diuretic efficiency. MethodsParticipants with ADHF from ROSE-AHF, CARRESS-HF, and ATHENA-HF were pooled in the derivation cohort (n = 794). Multivariable finite-mixture model-based phenomapping was performed to identify phenogroups based on diuretic efficiency (urine output over the first 72 hours per total intravenous furosemide equivalent loop diuretic dose). Phenogroups were externally validated in other pooled ADHF trials (DOSE/ESCAPE). An integer-based diuresis score (BAN-ADHF score: blood urea nitrogen, creatinine, natriuretic peptide levels, atrial fibrillation, diastolic blood pressure, hypertension and home diuretic, and heart failure hospitalization) was developed and validated based on predictors of the diuretic efficiency phenogroups to estimate the probability of low diuretic efficiency using the pooled ADHF trials described earlier. The associations of the BAN-ADHF score with markers and symptoms of congestion, length of stay, in-hospital mortality, and global well-being were assessed using adjusted regression models. ResultsClustering identified 3 phenogroups based on diuretic efficiency: phenogroup 1 (n = 370; 47%) had lower diuretic efficiency (median: 13.1 mL/mg; Q1-Q3: 7.7-19.4 mL/mg) than phenogroups 2 (n = 290; 37%) and 3 (n = 134; 17%) (median: 17.8 mL/mg; Q1-Q3: 10.8-26.1 mL/mg and median: 35.3 mL/mg; Q1-Q3: 17.5-49.0 mL/mg, respectively) (P < 0.001). The median urine output difference in response to 80 mg intravenous twice-daily furosemide between the lowest and highest diuretic efficiency group (phenogroup 1 vs 3) was 3,520 mL/d. The BAN-ADHF score demonstrated good model performance for predicting the lowest diuretic efficiency phenogroup membership (C-index: 0.92 in DOSE/ESCAPE validation cohort) that was superior to measures of kidney function (creatinine or blood urea nitrogen), natriuretic peptide levels, or home diuretic dose (DeLong P < 0.001 for all). Net urine output in response to 80 mg intravenous twice-daily furosemide among patients with a low vs high (5 vs 20) BAN-ADHF score was 2,650 vs 660 mL per 24 hours, respectively. Participants with higher BAN-ADHF scores had significantly lower global well-being, higher natriuretic peptide levels on discharge, a longer in-hospital stay, and a higher risk of in-hospital mortality in both derivation and validation cohorts. ConclusionsThe authors developed and validated a phenomapping strategy and diuresis score for individuals with ADHF and differential response to diuretic therapy, which was associated with length of stay and mortality.

OP88 Translating Patient Reported Measure Score Into Specific Outcomes From The Patient Perspective–Example Using Health Assessment Questionnaire-Disability Index

IntroductionTo facilitate communication of clinical study results among patients, clinicians, and payers, this post-hoc analysis examined the association between achieving the Health Assessment Questionnaire-Disability Index (HAQ-DI) clinical meaningful improvement (CMI) and normalization of individual daily activities using pooled clinical trial data of patients with moderate-severe psoriatic arthritis (PsA).MethodsPatients with active PsA (n=1,120) who participated in two Phase III trials were administered the HAQ-DI at baseline and weeks (W) 24 and 52. The HAQ-DI is a patient-reported instrument measuring functional status that is validated for rheumatological diseases including PsA. It contains 20-items assessing activities of daily living using a 0-3 Likert scale [0=able to perform activity without difficulty (normalization) through to 3=unable to perform activity]; 0.35 or more improvement in total HAQ-DI represents the CMI in PsA patients. Study participants with baseline item-specific scores more than zero (indicating some level of impairment) who experienced both 0.35 or more improvement in total HAQ-DI and item-specific score equal to zero, were compared over time.ResultsThe proportion of patients with compromised ability to perform individual activities at baseline ranged from 42.3 percent (Difficulty Turning Faucet) to 84.1 percent (Difficulty Doing Chores). Fourteen of 20 activities with 60 percent or more of patients reporting impairment at baseline decreased to one of 20 activities in patients reaching the CMI at W24. Fourteen of 20 activities with 50 percent or more of patients reporting no impairment at W24 increased to 18 of 20 activities at W52. Notably, the proportion of patients reporting impairment for the two outlier activities at W52 (Reach-Get Down 5lb Item/Doing Chores) decreased during the follow-up period by 28 percent and 30 percent, respectively, despite presenting as very challenging at baseline.ConclusionsPsA patients achieving a clinically meaningful change in total HAQ-DI over time were more likely to achieve normalization of individual daily activities. Translating changes in patient-reported outcome scores to specific symptom or functional improvements are meaningful to help patients understand clinical trial results, as well as to communicate with payers the value of accessing treatment for specific health conditions.

The Validity of a Synthetic Control Arm Derived from Historical Multiple Myeloma Clinical Trials

Introduction While randomized phase III clinical trials (RCTs) are the gold-standard for establishing drug efficacy in the United States, external control arms (ECAs) may be valuable for both early and late phase drug development. An ECA is a collection of patients with the disease of interest who were treated outside of a clinical trial of interest (ie, target trial) and whose outcomes are compared to those of the target trial patients' to evaluate comparative drug efficacy and/or safety. ECAs created through rigorous statistical non-experimental methods such as matching patient-level characteristics may provide early estimates of comparative efficacy in advance of RCTs and offset prospective enrollment of control patients in randomized studies. We evaluate the validity of using a matched ECA to estimate the comparative efficacy of an experimental drug in relapsed refractory multiple myeloma (r/r MM). Methods From the anonymized Medidata Enterprise Data Store (MEDS), we identified historic RCTs in r/r MM containing patients exposed to an experimental drug as well as an active control drug (ie, a corticosteroid). Arbitrarily, we selected one trial to serve as the “target trial”. For the remaining trials, we collapsed all corticosteroid control patients into a single pool to construct an ECA. Using propensity score (PS) optimal full matching, we identified corticosteroid ECA patients by selecting from the candidate patients those whose baseline demographic and clinical attributes were similar to patients receiving the experimental drug in the target trial. Using the Kaplan-Meier (KM) estimator and a Cox proportional hazards regression, we first compared overall survival time (OS) of patients in the experimental drug arm vs control arm in the target trial. We then compared the OS in the experimental drug arm vs the ECA. Results We found fewer than five historic clinical trials from MEDS which were open-label RCTs conducted from 2010-2017. They enrolled r/r MM patients aged ≥18 years who had received more than two prior lines of therapy, one of which was lenalidomide and bortezomib. The target trial contained 300 patients in the investigational drug arm and 152 patients in the control arm. Using the PS matching, we identified 183 patients from the control arms in pooled trials that were matched with 290 patients in the investigational drug arm in the target trial (i.e., ECA). These ECA patients were then upweighted to be matched with 290 patients in the investigational drug arm in the target trial. Full matching successfully attenuated baseline differences between the investigational drug and ECA arms. Figure 2 shows the KM curves of OS (investigational vs control) in the target trial. Median OS was 13.25 months vs. 8.52 months (log-rank p&amp;lt;0.01) and the investigational drug was associated with a 36% reduction in the hazard of death (HR 0.74, 95% CI: 0.60-0.92). Figure 2 shows the KM curves of OS, after full matching, using the ECA. Median OS was 13.51 months vs. 8.75 months (log-rank p&amp;lt;0.01) and the investigational drug was associated with a 36% reduction in the hazard of death (HR 0.74, 95% CI: 0.58-0.94). Conclusions In this methodologic validation study, we have demonstrated that it is possible to produce an ECA from historical clinical trials data using propensity score methods which replicates the comparative efficacy estimate from a target without introducing bias. That is, the ECA, which was well balanced with the investigational arm with respect to baseline patient attributes, returned nearly identical estimates of comparative efficacy as assessed by OS of both target trial control arm and ECA against the target trial experimental arm. This work illustrates that it is possible to create a valid ECA even when historical data size is limited and to do so without excessive exclusion of non-matched patients. That the treatment effect on OS estimated in comparison to the randomized control was very closely matched by that of the ECA suggests this approach to ECAs may be used to (1) estimate comparative efficacy of therapies that have only been studied in single arm settings and/or (2) augment or replace a randomized control arm in future trials when ethically or practically challenging. Figure 1A. Kaplan-Meier OS estimates of target trial experimental (N=300) vs. control arm (N=152) Figure 1B. Kaplan-Meier OS estimates of target trial experimental (N=290) vs. ECA (N=290)

Machine Learning-Based Decision Tree for Identifying and Grading Severity of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Based on Neurological Adverse Events in Patients Treated with CD19 CAR-T

Introduction One of the major challenges associated with Chimeric Antigen Receptor T-cell (CAR-T) therapy is the development of immune effector cell-associated neurotoxicity syndrome (ICANS), which can vary in severity and requires prompt intervention. This study proposes using machine learning in combination with clinical insight to build a decision tree that accurately identifies and grades ICANS severity in patients treated with CD19 CAR-T based on the neurological adverse events (NAEs). Methods We conducted a retrospective analysis of 384 patients that exhibited NAEs after being treated with CD19-targeted CART-cell therapy in the pooled clinical trial data from the Medidata Enterprise Data Store. Of note, this dataset excludes patients without NAEs; these patients were assumed to not experience clinical ICANS. Patient NAEs were reviewed and the highest ICANS grade was assigned by a neuroimmunologist, resulting in the following patient counts: grade 0 (n=61), 1 (n=69), 2 (n=166), 3 (n=75), 4 (n=13). The clinical expert graded each patient based on the NAEs recorded in the first 28 days post infusion during the clinical trial, their CTCAE toxicity and symptom onset day. To process NAEs, we first mapped each of the 219 verbatim terms to the MedDRA hierarchy using a proprietary Medidata coding algorithm. We then aggregated the NAEs to the High Level Group Term (HLGT) level except for the MedDRA term “Neurological Disorders NEC” which was broken down to the High Level Term (HLT) level due to the large size of this group (73 out of 219 terms).The mapping of NAEs to MedDRA groups was reviewed together with the neuroimmunologist. The final dataset included the CTCAE severity of the NAEs mapped to MedDRA groups as features and the expert-labeled ICANS grades as the target variable. The data was then split into train (70%) and test (30%) sets stratifying by study and ICANS grade. We fit a decision tree while performing 5-fold hyperparameter grid search on the train set. The tree with the highest area under the Receiver Operating Characteristic curve one-vs-one (ROCAUC OVO) was selected and evaluated on the test set using an array of classification performance metrics. The model output was evaluated at the ICANS grade and severity (no/moderate/severe) level. The confusion matrices for the test set and the full decision tree were plotted. Results When binning the ICANS grade prediction by severity (grade 0 = no ICANS, grade 1-2 = moderate, grade 3-4 = severe), the model achieves a strong out-of-sample accuracy of 83.6% and ROCAUC OVO of 0.935. Regarding the individual ICANS grade prediction, the model yielded lower out-of-sample accuracy of 54.3%, with the majority of errors between grades 1 and 2. In spite of this, there was still reasonable discrimination based on the out-of-sample ROCAUC OVO values of 0.863. The training algorithm selected six MedDRA groups of NAEs to make predictions with: Headaches, Seizures (incl subtypes), Encephalopathies, Cortical dysfunction NEC, Disturbances in consciousness NEC, and Movement disorders (incl parkinsonism). We observe that patients with only headaches (a separate feature in our dataset) are all labeled as having no ICANS while those with seizures of grade 2 and higher are classified as grade 4. Refer to Figure 1 for the full decision tree. Comparing the neurologist-assigned versus predicted ICANS grades in the out-of-sample patient group (Figure 2) revealed that the majority of errors were bound to +/- one grade. Only three out of 116 patients were mislabeled by two grades. Crucially, none of the grade 1+ patients were predicted by the model to have grade 0. Conclusion Our machine learning-based decision tree accurately predicts the severity and grade of ICANS in CD19 CAR-T treated patients, aiding in clinical decision-making as well as retrospective analyses of ICANS patients. This type of clinical decision support tool has the potential to be a powerful aid to physicians by providing them with earlier physiological insights and data-driven assessments to help them triage patients accordingly. The model's performance highlights its potential clinical utility in improving patient care and outcomes. Further validation across multiple neurologists and prospective studies are warranted to assess its generalizability and refine its predictive capabilities. Acknowledgments We thank the developers of Scikit-learn and Dtreeviz Python packages for open-sourcing their code.

Development and validation of the DOAC Score: a novel bleeding risk prediction tool for patients with atrial fibrillation

Abstract Background Clinicians and patients must balance the ischemic benefits and bleeding risks when deciding to anticoagulate patients with atrial fibrillation (AF). Current clinical decision tools for assessing bleeding risk have limited performance and were developed for individuals anticoagulated with warfarin. Purpose This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with AF taking direct-acting oral anticoagulants (DOACs). Methods Among individuals taking dabigatran 150mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial, a risk score was developed to determine the probability for bleeding, based on covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. We then refined the model in the GARFIELD-AF registry, with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACS, the risk prediction model was validated in the COMBINE-AF pooled clinical trial cohort and the RAMQ administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared to the HAS-BLED score. Results Of the 5684 patients in RE-LY, 386 experienced a major bleeding event, within a median follow-up of 1.74-years. The prediction model was well-calibrated (goodness-of-fit P = 0.57) and had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping. The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, non-steroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI: 38.9%-59.3%, P&amp;lt;0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C Statistic: 0.73 vs 0.60, P for difference &amp;lt;0.001) and among 12,296 individuals in GARFIELD-AF (C statistic: 0.71 vs 0.66, P for Difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25,586 individuals in COMBINE-AF (C statistic: 0.67 vs 0.63, P for Difference &amp;lt;0.001) and 11,945 individuals in RAMQ (C statistic: 0.65 vs 0.58, P for Difference &amp;lt;0.001). Conclusion In individuals with AF on DOAC therapy, the DOAC Score can help stratify patients based on expected bleeding risk.

Abstract 14354: The Impact of Riociguat in Pulmonary Arterial Hypertension Patients With Comorbidities Included in Interventional Clinical Trials

Background: The number of pulmonary arterial hypertension (PAH) patients with comorbidities is increasing, however, there are few published data from these patients in PAH therapy clinical trials meaning that evidence-based treatment recommendations have not been made. Aim: This post-hoc analysis of pooled riociguat clinical trial data assessed the impact of riociguat in patients with PAH and comorbidities. Methods: All interventional studies of riociguat in patients with PAH (PATENT-1, PATENT PLUS, RESPITE, MOTION, REPLACE, and the Phase II study) were included in the pooled analysis. The safety of riociguat and placebo was assessed in patients with ≥3 comorbidities vs &lt;3 comorbidities. Safety was assessed by adverse events (AEs) and serious AEs (SAEs). Comorbidities included: age ≥65 years, body mass index ≥30 kg/m 2 , history of essential hypertension, diabetes mellitus, history of significant coronary artery disease, and atrial fibrillation. Results: The 609 patients who received riociguat and 132 patients who received placebo in the main phase clinical trials of riociguat were included in the analysis. Of these, 113 patients (19%) in the riociguat group and 21 patients (16%) in the placebo group had ≥3 comorbidities. In both treatment groups, AE rates were higher in patients with ≥3 comorbidities vs &lt;3 comorbidities (riociguat 93% vs 86%; placebo 95% vs 84%); with most AEs being mild or moderate. Study drug-related AE rates were similar in both treatment groups and in patients with ≥3 comorbidities vs &lt;3 comorbidities (riociguat 54% vs 56%; placebo 52% vs 52%). SAE rates were higher in riociguat-treated patients with ≥3 comorbidities vs &lt;3 comorbidities (25% vs 12%); of these, 4% and 3% were study drug-related, respectively. In patients with ≥3 comorbidities, study drug-related SAE rates were higher in those receiving placebo vs riociguat (10% vs 4%). AE rates leading to study drug discontinuation were higher in patients with ≥3 comorbidities vs &lt;3 comorbidities (riociguat 6% vs 4%; placebo 10% vs 6%), whereas AE rates leading to death were similar in both groups (riociguat 2% vs 1%; placebo 0% vs 4%). Conclusion: These data suggest that riociguat had an acceptable tolerability profile in PAH patients with comorbidities with most AEs being mild or moderate.