Feasibility of using real-world data to emulate substance use disorder clinical trials: a cross-sectional study.

INTRODUCTION: Real-world evidence is receiving considerable attention as a way to evaluate the efficacy and safety of medical products for substance use disorders (SUDs). However, the feasibility of using real-world data (RWD) to emulate clinical trials evaluating treatments for SUDs is uncertain. The aim of this study is to identify the number of clinical trials evaluating treatments for SUDs with reported results that could be feasibly emulated using observational data from contemporary insurance claims and/or electronic health record (EHR) data. METHODS: In this cross-sectional study, all phase 2-4 trials evaluating treatments for SUDs registered on ClinicalTrials.gov with reported results were identified. Each trial was evaluated to determine if the indications, interventions, at least 80% of eligibility criteria, comparators, and primary end points could be ascertained using contemporarily available administrative claims and/or structured EHR data. RESULTS: There were 272 SUD trials on ClinicalTrials.gov with reported results. Of these, when examining feasibility using contemporarily available administrative claims and/or structured EHR data, 262 (96.3%) had indications that were ascertainable; 194 (71.3%) had interventions that were ascertainable; 21 (7.7%) had at least 80% of eligibility criteria that were ascertainable; 17 (6.3%) had active comparators that were ascertainable; and 61 (22.4%) had primary end points that were ascertainable. In total, there were no trials for which all 5 characteristics were ascertainable using contemporarily available administrative claims and/or structured EHR data. When considering placebo comparators as ascertainable, there were 6 (2.2%) trials that had all 5 key characteristics classified as ascertainable from contemporarily available administrative claims and/or structured EHR data. CONCLUSIONS: No trials evaluating treatments for SUDs could be feasibly emulated using contemporarily available RWD, demonstrating a need for an increase in the resolution of data capture within a public health system to facilitate trial emulation.

CaboCombo: a prospective, phase IV study of first-line cabozantinib + nivolumab for advanced renal cell carcinoma.

Cabozantinib plus nivolumab was approved as a first-line (1L) treatment for advanced renal cell carcinoma (aRCC) following the CheckMate 9ER trial. CaboCombo (ClinicalTrials.gov identifier: NCT05361434) is a non-interventional study designed to evaluate the effectiveness and tolerability of cabozantinib plus nivolumab in a real-world setting. Overall, 311 patients with clear-cell aRCC receiving 1L cabozantinib plus nivolumab will be recruited from at least 70 centers in seven countries worldwide. The primary end point is overall survival at 18 months. Secondary end points include progression-free survival, objective response rate, safety, patterns of treatment, subsequent anticancer therapies and quality of life. CaboCombo will provide real-world evidence on the characteristics, treatment sequences, and outcomes of patients with aRCC receiving 1L cabozantinib plus nivolumab.

Renal cell carcinomas (RCC) are cancers that grow in the kidneys. Clear-cell RCC is the most common type reported in almost three quarters of patients. RCC tumors become advanced if they grow and spread to other parts of the body. In a clinical trial called CheckMate 9ER, a combination of two drugs called cabozantinib and nivolumab improved survival compared with a drug called sunitinib in patients with advanced clear-cell RCC who had not received any previous treatments. In CheckMate 9ER, cabozantinib plus nivolumab also reduced the size and slowed the spread of tumors compared with sunitinib. However, clinical trials only allow certain patients to participate under strict treatment conditions and so do not provide information on how a treatment will work in all patients. Researchers therefore carry out additional studies to gather extra information from real-world clinical practice. CaboCombo is a study that will look at how well cabozantinib plus nivolumab stops tumors from growing and spreading, the side effects of the drugs, and also how the drugs are used by doctors. It is an observational study, which means that researchers will observe all patients and doctors using the treatment but they will not intervene. The aim of the study is to gather information that will help doctors make treatment decisions for their patients. This article describes how the CaboCombo study will be carried out and the information it will give the researchers. The results will help physicians make decisions on the best treatment option for patients. Clinical Trial Registration: NCT05361434 (ClinicalTrials.gov).

Phase IV Studies: What Clinicians Need to Know!

Phase IV trials, also known as postmarketing safety and efficacy studies and postmarketing surveillance (PMS) studies, occur after a drug or medical device has received regulatory approval and is available in the market. These trials are designed to collect additional information regarding the product's safety, efficacy, and prolonged effects in a larger and more diverse patient population. The foremost goal of phase IV trials is to detect any rare or long-term adverse effects that may not have been identified during the prior phases of clinical development. During phase IV trials, pharmaceutical companies, academic institutions, or other research organizations conduct studies to evaluate various aspects of the product, including its real-world effectiveness, optimal use, and any potential safety concerns. The regulatory agencies play a role in overseeing these trials to ensure that they are conducted ethically and in compliance with good clinical practice (GCP) guidelines.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Opicapone for the treatment of Parkinson's disease: a review.

Purpose: Levodopa formulations are the workhorses of the labor against motor symptoms management in Parkinson's disease (PD). Progression of PD on levodopa inevitably leads to motor fluctuations. It is important to understand the safety and efficacy of opicapone, the most recent addition to the clinician's armamentarium against these fluctuations.Materials and methods: We review the development of COMT inhibitors in the treatment of PD as well as the efficacy and safety data reported in the currently published literature of opicapone in PD. The "currently published literature" is defined as all published, PubMed indexed trials including the word "opicapone." Finally, we compare opicapone to the competitor pharmaceuticals on the market to treat symptom fluctuations in PD and share our opinion of opicapone's place in clinical practice.Results: From the reported results of phase 3 and 4 trials of opicapone in PD, it is a safe and efficacious option to combat motor fluctuations for our PD patients taking levodopa. A reduction of "off" time by up to 1 h per day can be expected, increasing "on" time with fewer dyskinesias. Opicapone is not generally hepatotoxic, and the most reported side-effects-dyskinesia, dry mouth, dizziness, diarrhea, and constipation-were seen in only 1.4% of the OPTIPARK (a large phase 4 clinical trial) study population.Conclusions: One should consider utilizing opicapone, perhaps in combination with other augmenting medications with different mechanisms of action, to help treat motor and non-motor fluctuations in PD.

A Review on Immunological Responses to SARS-CoV-2 and Various COVID-19 Vaccine Regimens.

The transmission of SARS-CoV-2 has caused serious health crises globally. So far, 7 vaccines that are already being assessed in Phase IV clinical trials are, Comirnaty/ Pfizer; Spikevax/Moderna (m RNA vaccine); Vaxzevria or Covishield; Ad26.COV2.S; Ad5-nCoV (adenoviral vector-based vaccine); CoronaVac and BBIBP-CorV (inactivated virus vaccine). Besides, there are about 280 vaccines that are undergoing preclinical and clinical trials including Sputnik-V, Covaxin or BBV152, and NVX-CoV2373. These vaccines are being studied for their immunological responses and efficiency against COVID-19, and have been reported to demonstrate effective T and B cell responses. However, the long-lasting immunity of these vaccine regimens still needs to be investigated. An in-depth understanding of the vaccine efficacy and immune control mechanism is imperative for the rational purposing and implementation of the vaccines. Hence, in this review, we have comprehensively discussed the immune response induced in COVID-19 patients, as well as in the convalescent individuals to avoid reinfection. Moreover, we have also summarized the immunological responses and prophylactic efficacy of various COVID-19 vaccine regimens. In this context, this review can give insights into the development of effective vaccines against SARS-CoV-2 and its variants in the future.

Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study.

BACKGROUND: Subclinical inflammation, including borderline lesions (BL), is very common (30-40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function. METHODS: The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression. DISCUSSION: This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL. TRIAL REGISTRATION: clinicaltrials.gov : NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1 . Protocol Version 2 of 21 January 2022. SPONSOR: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org .

Associations among cytokines, EGF and lymphocyte subpopulations in patients diagnosed with advanced lung cancer.

Aging is considered the single most significant risk factor for the majority of common malignances including lung cancer. Together immunosenescence, changes occurring with aging in the immune system, and inflammaging, characterizes by a chronic, subclinical accumulation of pro-inflammatory factors, are suggested to stand at the origin of most of the diseases of the elderly, such as cancer. The aim of this study was to determine associations among lymphocyte subpopulations, pro-inflammatory cytokines and epidermal growth factor (EGF) in patients diagnosed with non-small cell lung cancer (NSCLC). Forty-six advanced NSCLC patients were enrolled. Sixteen patients with newly diagnosed and before treatment and 30 patients after first-line platinum-based chemotherapy. Peripheral blood subpopulations were studied by flow cytometry and serum concentrations of soluble factors by ELISA. The frequency of naïve CD4+ T cells, naïve B cells and central memory CD8+ T cells were significantly lower in NSCLC patients after chemotherapy, while effector memory CD4+ T cells and terminally differentiated CD8+ T cells were significantly higher. IL-1ß and TNFα significantly correlated among them before and after platinum-based chemotherapy. Terminally differentiated T cells expressing CD57+ significantly correlated with TNFα and IL-1ß. For the first time, associations between EGF serum levels and terminally differentiated CD4+ T cells, and memory B cells were detected. This study confirms the association among terminally differentiated lymphocytes and pro-inflammatory cytokines in patients diagnosed with lung cancer, reinforcing the interconnection between terminally differentiated lymphocytes and pro-inflammatory cytokines. Clinical trial registration number: RPCEC00000205, http://registroclinico.sld.cu/.

Prevalence of control groups in cardiovascular clinical trials: An analysis of ClinicalTrials.gov from 2009 through 2019.

Clinical trials provide the foundational evidence that guide many patient-facing decisions; however, the therapeutic effect and safety of an intervention is best evaluated when compared to a control group. We used ClinicalTrials.gov to describe the proportion of registered Phase III and IV cardiovascular clinical trials that contain a control group from 2009 through 2019. Of 1,677 registered Phase III and IV cardiovascular clinical trials, 81.2% contain a control group, and the annual prevalence remained unchanged between 2009 and 2019.

Impact of biological sex on cryptococcal meningitis mortality in Uganda and South Africa.

The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunistic infections is unknown. We assessed baseline biomarkers and outcomes between 577 men and 400 women in HIV-related cryptococcal meningitis cohorts in Uganda and South Africa from 2010 to 2017. We compared 10-week mortality by sex via Cox proportional hazards models. The 10-week mortality for women was 50% (198/400) and 43% (247/577) for men. Women had higher risk of death in an unadjusted model (Hazard Ratio (HR) = 1.20; 95%CI, 1.00-1.45; P = .05). Women maintained a higher risk when adjusting for quantitative CSF culture, altered mental status, CSF pleocytosis, age, and antiretroviral status (HR = 1.31; 95%CI, 1.07-1.59; P < .01). However, after adjusting for hemoglobin, the risk of death did not differ between women and men (HR = 1.17; 95%CI, 0.94-1.45; P = .17). Moderate to severe anemia (hemoglobin < 8.5 g/dL) was present among 16% (55/355) of women and 10% (55/532) of men (P = .02). Of the 373 participants with CSF biomarkers, men had higher median pro- and anti-inflammatory, monocyte/macrophage differentiation, maturation, and migration, immune exhaustion, and cytotoxicity cytokines than women (P < .05). We identified biological sex as proxy for anemia, a potentially modifiable risk factor for cryptococcal meningitis mortality. Immune response may contribute to the multifaceted underlying mechanisms for the discrepancy in mortality based on sex. LAY SUMMARY: We examined the role of biological sex in cryptococcal meningitis mortality in a large cohort. Our findings reveal significant differences in inflammatory markers by biological sex. Women have significantly higher mortality due to cryptococcal meningitis that is attributable to anemia at baseline.

The asthma evidence base: a call for core outcomes in interventional trials.

OBJECTIVES: Biologic therapies are emerging as an option to treat a subset of patients with severe asthma, however no direct comparison between these agents has been conducted. Furthermore, heterogeneity of outcomes in clinical trials makes it difficult to compare these agents and traditional therapies. The extent to which this heterogeneity exists has major implications for evidence-based decisions and is yet to be fully reported. We conducted a literature search to examine outcomes currently being used in clinical trials for asthma. DATA SOURCES: The Cochrane Library and Clinicaltrials.gov were searched for clinical trials of asthma interventions. STUDY SELECTIONS: We limited our search to phase 2 through 4 clinical trials in adults, as early-phase trials tend to have pharmacodynamic and pharmacokinetic endpoints as primary outcomes. Interventions for acute exacerbations were excluded. RESULTS: We identified 117 studies and subsequently identified 111 outcomes. The most prevalent outcomes were asthma control and symptom severity, FEV1, and change in ACQ scale. Twenty patient-reported outcomes instruments were identified and de-facto standard asthma outcomes and PROs were under-reported in examined literature. Existing quality of life tools did not capture the day-to-day experience or the unique treatment burden from oral corticosteroids for patient with severe asthma. Compounding the absence of trials directly comparing therapies, the significant variation we identified in outcome definitions and measurement create hurdles to effectively compare traditional and biologic therapies. CONCLUSION: With the growing number of clinical trials evaluating advanced therapies such as biologics, a wide range of primary and secondary outcomes are evaluated. A core outcome set created by relevant stakeholders is needed to collectively evaluate pooled outcomes in order to allow more meaningful comparisons of asthma therapies and to incorporate the patient experience.

Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--The BRACE CORONA Trial.

Angiotensin-converting enzyme-2 (ACE2) expression may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs). Because renin-angiotensin system blockers increase levels of ACE2, a protein that facilitates coronavirus entry into cells, there is concern that these drugs could increase the risk of developing a severe and fatal form of COVID-19. The impact of discontinuing ACEI and ARBs in patients with COVID-19 remains uncertain. DESIGN: BRACE CORONA is a pragmatic, multicenter, randomized, phase IV, clinical trial that aims to enroll around 500 participants at 34 sites in Brazil. Participants will be identified from an ongoing national registry of suspected and confirmed cases of COVID-19. Eligible patients using renin-angiotensin system blockers (ACEI/ARBs) with a confirmed diagnosis of COVID-19 will be randomized to a strategy of continued ACEI/ARB treatment versus temporary discontinuation for 30 days. The primary outcome is the median days alive and out of the hospital at 30 days. Secondary outcomes include progression of COVID-19 disease, all-cause mortality, death from cardiovascular causes, myocardial infarction, stroke, transient ischemic attack, new or worsening heart failure, myocarditis, pericarditis, arrhythmias, thromboembolic events, hypertensive crisis, respiratory failure, hemodynamic decompensation, sepsis, renal failure, and troponin, B-type natriuretic peptide (BNP), N-terminal-proBNP, and D-dimer levels. SUMMARY: BRACE CORONA will evaluate whether the strategy of continued ACEI/ARB therapy compared with temporary discontinuation of these drugs impacts clinical outcomes among patients with COVID-19.

Renal Effects of Dapagliflozin in People with and without Diabetes with Moderate or Severe Renal Dysfunction: Prospective Modeling of an Ongoing Clinical Trial.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular events and onset and progression of renal disease by mechanisms that remain incompletely understood but may include clearance of interstitial congestion and reduced glomerular hydrostatic pressure. The ongoing DAPASALT mechanistic clinical study will evaluate natriuretic, diuretic, plasma/extracellular volume, and blood pressure responses to dapagliflozin in people with type 2 diabetes with normal or impaired renal function (D-PRF and D-IRF, respectively) and in normoglycemic individuals with renal impairment (N-IRF). In this study, a mathematical model of renal physiology, pathophysiology, and pharmacology was used to prospectively predict changes in sodium excretion, blood and interstitial fluid volume (IFV), blood pressure, glomerular filtration rate, and albuminuria in DAPASALT. After validating the model with previous diabetic nephropathy trials, virtual patients were matched to DAPASALT inclusion/exclusion criteria, and the DAPASALT protocol was simulated. Predicted changes in glycosuria, blood pressure, glomerular filtration rate, and albuminuria were consistent with other recent studies in similar populations. Predicted albuminuria reductions were 46% in D-PRF, 34.8% in D-IRF, and 14.2% in N-IRF. The model predicts a similarly large IFV reduction between D-PRF and D-IRF and less, but still substantial, IFV reduction in N-IRF, even though glycosuria is attenuated in groups with impaired renal function. When DAPASALT results become available, comparison with these simulations will provide a basis for evaluating how well we understand the cardiorenal mechanism(s) of SGLT2i. Meanwhile, these simulations link dapagliflozin's renal mechanisms to changes in IFV and renal biomarkers, suggesting that these benefits may extend to those with impaired renal function and individuals without diabetes. SIGNIFICANCE STATEMENT: Mechanisms of SGLT2 inhibitors' cardiorenal benefits remain incompletely understood. We used a mathematical model of renal physiology/pharmacology to prospectively predict responses to dapagliflozin in the ongoing DAPASALT study. Key predictions include similarly large interstitial fluid volume (IFV) reductions between subjects with normal and impaired renal function and less, but still substantial, IFV reduction in those without diabetes, even though glycosuria is attenuated in these groups. Comparing prospective simulations and study results will assess how well we understand the cardiorenal mechanism(s) of SGLT2 inhibitors.

Blood eosinophils as a biomarker of future COPD exacerbation risk: pooled data from 11 clinical trials.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation and chronic inflammation. Predicting exacerbations of COPD, which contribute to disease progression, is important to guide preventative treatment and improve outcomes. Blood eosinophils are a biomarker for patient responsiveness to inhaled corticosteroids (ICS); however, their effectiveness as a predictive biomarker for COPD exacerbations is unclear. METHODS: This post hoc analysis pooled data from 11 Boehringer Ingelheim-sponsored Phase III and IV randomised COPD studies with similar methodologies. Exacerbation data were collected from these studies, excluding patients from the ICS withdrawal arm of the WISDOM® study. Patients were grouped according to their baseline blood eosinophil count, baseline ICS use and number of exacerbations in the year prior to each study. RESULTS: Exacerbation rate data and baseline eosinophil count were available for 22,125 patients; 45.6% presented with a baseline blood eosinophil count of ≤ 150 cells/µL, 34.3% with 150-300 cells/µL and 20.1% with > 300 cells/µL. The lowest exacerbation rates were observed in patients with ≤ 150 cells/µL, with small increases in exacerbation rate observed with increasing eosinophil count. When stratified by exacerbation history, the annual rate of exacerbations for patients with 0 exacerbations in the previous year increased in line with increasing eosinophil counts (0.38 for ≤ 150 cells/µL, 0.39 for 150-300 cells/µL and 0.44 for > 300 cells/µL respectively). A similar trend was identified for patients with one exacerbation in the previous year, 0.62, 0.66 and 0.67 respectively. For patients with ≥ 2 exacerbations, exacerbation rates fluctuated between 1.02 (≤ 150 cells/µL) to 1.10 (150-300 cells/µL) and 1.07 (> 300 cells/µL). Higher exacerbation rates were noted in patients treated with ICS at baseline (range 0.75 to 0.82 with increasing eosinophil count) compared with patients not on ICS (range 0.45 to 0.49). CONCLUSION: We found no clinically important relationship between baseline blood eosinophil count and exacerbation rate. Hence, the current analysis does not support the use of blood eosinophils to predict exacerbation risk; however, previous exacerbation history was found to be a more reliable predictor of future exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00168844 , NCT00168831 , NCT00387088 , NCT00782210 , NCT00782509 , NCT00793624 , NCT00796653 , NCT01431274 , NCT01431287 , NCT02296138 and NCT00975195 .

Improving the evaluation of COPD exacerbation treatment effects by accounting for early treatment discontinuations: a post-hoc analysis of randomized clinical trials.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned. METHODS: The association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model - allowing for the simultaneous analysis of multiple types of correlated events - to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data. RESULTS: A statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that - with such an association - models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10-15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms. CONCLUSIONS: We have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.