Optimal Blood Pressure Targets with Age.

The focus of antihypertensive therapy in older adults should be on lowering the systolic blood pressure (SBP) to the patient's "optimal" benefit-based target goal. Applying benefit-based therapy to the majority of adults aged 65 years or older who are at high cardiovascular disease or cognitive impairment risk favors an SBP goal of less than 130 mm Hg, and for some, a goal of 120 mm Hg may be considered.

The effectiveness of interventions on improving body image for pregnant and postpartum women: a systematic review of randomized clinical trials.

BACKGROUND: Body image dissatisfaction, leading to a variety of negative emotions and adverse pregnancy or birth outcomes. Studies on body image interventions for pregnant and postpartum women have been reported, yielding mixed results. Existing evidence lacks a comprehensive review of the effectiveness of body image interventions for pregnant and postpartum women. OBJECTIVE: The aim of this study was to systematically review interventions which aimed at improving body image during pregnancy and postpartum in women of childbearing age, and further to explore their effectiveness. METHODS: A comprehensive literature search was conducted using electronic databases, including PubMed, Embase, Web of Science, Cochrane Library, CINAHL, SinoMed, CNKI, and Wanfang Database, to retrieve relevant studies. Body image was reported employing descriptive analysis, whereas the Cochrane Handbook tool was used to evaluate the quality and potential bias of each included study. RESULTS: Following established inclusion and exclusion criteria, 11 studies were identified from an initial 1,422 records for further analysis, involving 1290 participants. This systematic review grouped body image interventions into lifestyle interventions and psychological interventions based on their content. These interventions yielded more pronounced positive effects on improving body image in pregnant and postpartum women when compared to control groups. And, the statistical difference on psychological interventions is more significant on the whole. CONCLUSIONS: Our work offers a comprehensive overview of the effectiveness of body image interventions for pregnant and postpartum women. Psychological interventions are considered to be a suitable measure to improve body image for pregnant or postpartum women. Additional research and practical applications are recommended to enhance the mental health and well-being of perinatal women. TRIAL REGISTRATION: PROSPERO registry: CRD42024531531.

Adjuvant Therapy for High-Risk Stage II Melanoma: Current Paradigms in Management and Future Directions.

Melanoma is the fifth most common cancer in the United States and accounts for the majority of all skin cancer-related deaths, making it the most lethal cutaneous malignancy. Systemic adjuvant therapy for stage IIB-IV melanoma is now approved for patients who have undergone surgical resection, given the appreciable risk of recurrence and mortality in this patient population. Despite the lower stage, high-risk stage II melanoma (stage IIB/IIC) can often exhibit an even more aggressive course when compared to stage IIIA/IIIB disease, thus justifying consideration of adjuvant therapy in these patients. In this review, we highlight the current standard of practice for the treatment of stage IIB/C melanoma, with a focus on adjuvant therapies supported by published landmark clinical trials, including anti-PD-1 therapy. Notably, adjuvant therapies approved thus far in this patient population have demonstrated an improvement in recurrence-free survival, while their impact on overall survival is pending. Finally, this review highlights currently ongoing trials and future directions for research and treatment possibilities for high-risk clinical stage II melanoma.

Once-Weekly Insulin Icodec in Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Clinical Trials (ONWARDS Clinical Program).

BACKGROUND: One hundred years have passed since the discovery of insulin, which is one of the most relevant events of the 20th century. This period resulted in extraordinary progress in the development of novel molecules to improve glucose control, simplify the insulin regimen, and ameliorate the quality of life. In late March 2024, the first once-weekly basal analog Icodec was approved for diabetes mellitus, generating high expectations. Our aim was to systematically review and meta-analyze the efficacy and safety of Icodec compared to once-daily insulin analogs in type 1 (T1D) and type 2 diabetes (T2D). METHODS: PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for randomized clinical trials (RCTs). Studies were included for the synthesis according to the following prespecified inclusion criteria: uncontrolled T1D or T2D, age ≥ 18 years, insulin Icodec vs. active comparators (Degludec U100, Glargine U100, Glargine U300, and Detemir), phase 3, multicenter, double-blind or open-label RCTs, and a study duration ≥ 24 weeks. RESULTS: The systematic review included 4347 patients with T1D and T2D inadequately controlled (2172 randomized to Icodec vs. 2175 randomized to once-daily basal analogs). Icodec, compared to once-daily basal analogs, slightly reduced the levels of glycated hemoglobin (HbA1c) with an estimated treatment difference (ETD) of -0.14% [95%CI -0.25; -0.03], p = 0.01, and I2 68%. Patients randomized to Icodec compared to those on once-daily basal analogs had a greater probability to achieve HbA1c < 7% without clinically relevant or severe hypoglycemic events in 12 weeks from randomization with an estimated risk ratio (ERR) of 1.17, [95%CI 1.01, 1.36], p = 0.03, and I2 66%. We did not find a difference in fasting glucose levels, time in range, and time above range between Icodec and comparators. Icodec, compared to once-daily basal analogs, resulted in a slight but statistically significant weight gain of 0.62 kg [95%CI 0.25; 0.99], p = 0.001, and I2 25%. The frequency of hypoglycemic events (ERR 1.16 [95%CI 0.95; 1.41]), adverse events (ERR 1.04 [95%CI 1.00; 1.08]), injection-site reactions (ERR 1.08 [95%CI 0.62; 1.90]), and the discontinuation of treatments were similar between the two groups. Icodec was found to work better when used in a basal-only than basal-bolus regimen with an ETD in HbA1c of -0.22%, a probability of achieving glucose control of +33%, a probability of achieving glucose control without clinically relevant or severe hypoglycemia of +28%, more time spent in target (+4.55%) and less time spent in hyperglycemia (-5.14%). The risk of clinically relevant or severe hypoglycemic events was significantly higher when background glinides and sulfonylureas were added to basal analogs (ERR 1.42 [95%CI 1.05; 1.93]). CONCLUSION: Insulin Icodec is substantially non-inferior to once-daily insulin analogs in T2D, either insulin-naïve or insulin-treated. However, Icodec works slightly better than competitors when used in a basal-only rather than basal-bolus regimen. Weight gain and hypoglycemic risk are substantially low but not negligible. Patients' education, adequate lifestyle and pharmacological interventions, and appropriate therapy adjustments are essential to minimize risks. This systematic review is registered as PROSPERO CRD42024568680.

Is "Less be More" Still a Valid Concept in Intensive Care? A Review of Critical Care Randomized Clinical Trials from the New England Journal of Medicine.

The concept of "Less is more" has been gaining increasing awareness and acceptance in Critical Care. In 2017, we attempted to systematically answer the question "Can less be more in intensive care" with empirical data. We reviewed all the critical care randomized clinical trials (RCTs) between 1 January 2008 and 5 October 2016 in the New England Journal of Medicine (NEJM). This article attempts to repeat the earlier exercise using data from 5 October 2016 to 31 December 2023. This analysis of critical care RCTs in the NEJM has shown three findings. Approximately three-quarter of RCTs in critical care in the NEJM between 2008 and 2023 failed to show benefit or harm. In the years 2008-2016, patients in the intervention cohort had a higher mortality compared to controls, but in the years 2016-2023, the difference in overall mortality in patients in the intervention and control arms was not statistically significant. Compared to the years 2008-2016, in the years from 2016 to 2023, the number of RCTs showing harm decreased and those showing benefit increased. How to cite this article: Kapadia F, Bharadwaj S, Sharma R. Is "Less be More" Still a Valid Concept in Intensive Care? A Review of Critical Care Randomized Clinical Trials from the New England Journal of Medicine. Indian J Crit Care Med 2024;28(6):533-551.

Impact of the ketogenic diet as a dietary approach on cardiovascular disease risk factors: a meta-analysis of randomized clinical trials.

BACKGROUND: Cardiovascular diseases (CVD) remain the leading cause of mortality globally, and the scarcity of scientific evidence regarding the impact of ketogenic diets on CVD risk factors necessitates urgent attention and redress. OBJECTIVES: This meta-analysis evaluates the impact of the ketogenic diet on CVD risk factors compared with control diets through randomized controlled trials (RCTs). METHODS: The study was registered in advance in the PROSPERO database (CRD42023491853). A systematic search was conducted across PubMed, Web of Science, EMBASE, and Cochrane Library to identify relevant RCTs. Fixed and random effects were employed to calculate the mean differences and 95% confidence intervals (CIs) for changes in CVD risk factors pre- and postketogenic diet intervention. RESULTS: A total of 27 RCTs with 1278 participants were analyzed. The ketogenic diet intervention presented increase in total cholesterol (mean differences: 0.36 mmol/L; 95% CI: 0.15, 0.57; I2: 85.1%), low-density lipoprotein cholesterol (mean differences: 0.35 mmol/L; 95% CI: 0.20, 0.50; I2: 73.9%) and high-density lipoprotein cholesterol (mean differences: 0.16 mmol/L; 95% CI: 0.09, 0.23; I2: 86.7%) concentrations. Reductions were observed in the triglyceride (mean differences: -0.20 mmol/L; 95% CI: -0.29, -0.11; I2: 72.2%), blood glucose (mean differences: -0.18 mmol/L; 95% CI: -0.33, -0.02; I2: 76.4%), blood insulin (mean differences: -8.32 pmol/L; 95% CI: -14.52, -2.12; I2: 81.5%), diastolic blood pressure (mean differences: -1.41 mmHg; 95% CI: -2.57, -0.26; I2: 49.1%), weight (mean differences: -2.59 kg; 95% CI: -3.90, -1.28; I2: 87.4%), and body mass index (mean differences: -1.59 kg/m2; 95% CI: -2.32, -0.86; I2: 84.5%) concentrations after implementing ketogenic diets. CONCLUSIONS: Although the ketogenic diet demonstrates benefits in terms of triglyceride, blood pressure, weight, and glycemic control, its impact on CVD risk factors, especially the elevated total cholesterol and low-density lipoprotein cholesterol concentrations, warrants a cautious approach.

The Effectiveness of Dialectical Behavior Therapy Compared to Schema Therapy for Borderline Personality Disorder: A Randomized Clinical Trial.

INTRODUCTION: In the treatment of borderline personality disorder (BPD), there is empirical support for both dialectical behavior therapy (DBT) and schema therapy (ST); these treatments have never been compared directly. This study examines whether either of them is more effective than the other in treating patients with BPD. METHODS: In this randomized, parallel-group, rater-blind clinical trial, outpatients aged between 18 and 65 years with a primary diagnosis of BPD were recruited in a tertiary outpatient treatment center (Lübeck, Germany). Participants were randomized to DBT or ST with one individual and one group session per week over 1.5 years. The primary outcome was the BPD symptom severity assessed with the mean score of the Borderline Personality Disorder Severity Index at 1-year naturalistic follow-up. RESULTS: Between November 26, 2014, and December 14, 2018, we enrolled 164 patients (mean age = 33.7 [SD = 10.61] years). Of these, 81 (49.4%) were treated with ST and 83 (50.6%) with DBT, overall, 130 (79.3%) were female. Intention-to-treat analysis with generalized linear mixed models did not show a significant difference at 1-year naturalistic follow-up between DBT and ST for the BPDSI total score (mean difference 3.32 [95% CI: -0.58-7.22], p = 0.094, d = -24 [-0.69; 0.20]) with lower scores for DBT. Pre-to-follow-up effect sizes were large in both groups (DBT: d = 2.45 [1.88-3.02], ST: d = 1.78 [1.26-2.29]). CONCLUSION: Patients in both treatment groups showed substantial improvements indicating that even severely affected patients with BPD and various comorbid disorders can be treated successfully with DBT and ST. An additional non-inferiority trial is needed to show if both treatments are equally effective. The trial was retrospectively registered on the German Clinical Trials Register, DRKS00011534 without protocol changes.

Yoga as a Complementary Therapy for Cancer Patients: From Clinical Observations to Biochemical Mechanisms.

BACKGROUND: Integrative oncology combines conventional and complementary, or integrative, therapies for a holistic treatment of cancer patients. Yoga is increasingly used as a complementary therapy for cancer patients, but there is no direct evidence for its effect on cancer pathophysiology like tumor response, or patient outcome like overall survival. SUMMARY: In this narrative review, we present in detail published studies from randomized clinical trials on complementary yoga therapy for cancer patients, including details about the biochemical mechanisms involved. Medicinal hatha yoga with breathing, postures, meditation, and relaxation enhances the quality of life of cancer patients by providing both psychological and physiological health benefits, highlighting the interconnectedness of mind and body. Yoga therapy reduces stress levels improving heart rate variability, leading to changes in hormonal regulation (e.g., cortisol), reduced oxidative stress, and improved immune function with reduced inflammation. Still, the biochemical effects of yoga on the cancer disease itself are unrevealed. KEY MESSAGES: More clinical and basic research is needed for further establishment of yoga as complementary therapy in oncology.

Synbiotics as Treatment for Irritable Bowel Syndrome: A Review.

Irritable bowel syndrome is a persistent disturbance of the function of the gastrointestinal tract with a prevalence of about 11.2% in the population at large. While the etiology of the disorder remains unclear, there is mounting evidence that the disturbance of the gut microbiota is at least one contributing factor. This insight resulted in clinical trials investigating the therapeutic effects of products containing probiotic microorganisms. Most studies with IBS patients have evaluated the therapeutic effects of mono- and multi-strain probiotics, but only a few studies have investigated the efficacy of synbiotics (combinations of probiotic bacteria and one or more prebiotic components). This review summarizes the results from eight randomized, placebo-controlled clinical trials that investigated the efficacy of synbiotic preparations (three mono-strain and five multi-strain products) in adult IBS patients. While data remain sparse, some of the surveyed clinical trials have demonstrated interesting efficacy results in IBS patients. To allow a judgment of the role played by synbiotics in the treatment of IBS patients, more high-quality clinical trials are needed.

Medication development for AUD: A systematic review of clinical trial methodology.

Refining clinical trial methodology has become increasingly important as study design is shown to influence treatment efficacy. To maximize the efficiency of randomized clinical trials (RCTs), researchers aim to establish standardized practices. The goal of this systematic review is to describe methodological practices of clinical trials for alcohol use disorder (AUD) over the past 40 years. To achieve this goal, a PubMed search was conducted in April 2023 for RCTs on AUD medications published between July 2018 through April 2023. Resulting studies were combined with a previous search from 1985 through 2018. Inclusion criteria for the RCT studies were: (1) a randomized controlled trial, (2) double or single blinded, (3) placebo or active control condition, (4) alcohol use as the primary endpoint, (5) 4 or more weeks of treatment, and (6) 12 or more weeks of follow-up. In total, methodological data from 139 RCTs representing 19 medications and spanning the past four decades were summarized. Results indicated that the most common medications tested were naltrexone (k = 42), acamprosate (k = 24), and baclofen (k = 11). On average, participants were 74% male and consumed 226 drinks per month pre-randomization. The median length of treatment was 12 weeks (IQR = 12-16; min = 4 max = 52) and the median follow-up duration was 12.5 weeks (IQR: 12-26; min = 7 max = 104). There were two broad domains of outcomes (i.e., abstinence and heavy drinking), with most studies featuring outcomes from both domains (k = 87; 63%). Reporting practices were summarized by decade, revealing an increased enrollment of females, better reporting of race and ethnicity data, and less studies requiring pre-trial abstinence. This review summarizes the current state of the literature on randomized clinical trials for AUD including effect sizes for individual studies and summaries of key methodological features across this representative set of clinical trials.

Placebo immune-related adverse events (irAEs): A neglected phenomenon in cancer immunotherapy trials.

PURPOSE: This study aims to investigate the underexplored prevalence of placebo-reported immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) trials. METHODS: We searched public databases for randomized clinical trials (RCTs) involving ICI versus placebo treatments in patients with malignancies. Study characteristics and irAEs occurrences were extracted for meta-analyses using a random-effects model. MAIN OUTCOMES: Proportions of patients reported to experience any grade and grade 3 to 5 placebo irAEs; the risk ratio (RR) of reporting 'false' irAEs in the experiment arm (defined as 'false-irAE ratio', calculated by dividing the proportion of patients documented with irAEs in the placebo arm by that in the experimental arm). RESULTS: 47 RCTs with 30,119 patients were analyzed. The pooled proportion of patients reported to experience any grade and grade 3 to 5 irAEs among placebo participants was 22.85 % (17.33 %-29.50 %) and 3.40 % (2.35 %-4.63 %), respectively. The pooled proportion of placebo-treated patients who experienced serious irAEs was 0.67 % (0.03 %-1.91 %). Treatment discontinuation and death due to placebo irAEs occurred in 0.69 % (<0.01 %-1.30 %) and 0.12 % (<0.01 %-0.40 %) of patients, respectively. The false-irAE ratio for any grade and grade 3 to 5 irAEs were 0.49 and 0.28. The false-irAE ratio was significantly higher in RCTs with control arms of placebo plus non-immunotherapy than in those with placebo alone (any grade: 0.57 vs. 0.32, P < 0.001; grade 3 to 5: 0.36 vs. 0.12, P = 0.009). CONCLUSION: Our analyses of placebo-treated participants in ICI RCTs document the common occurrence of placebo irAEs. These findings are important for interpreting irAE profiles, avoiding inappropriate therapeutic interventions.

Challenges of estimating treatment effects after a positive interim analysis.

BACKGROUND: This research investigates why a beneficial treatment effect reported at the first interim analysis (IA) may diminish at a subsequent analysis (SA). We examined three challenges in interpreting treatment effects from randomized clinical trials (RCTs) after the first positive IA: overestimation bias; non-proportional hazards; and heterogeneity in recruitment. We investigate how a penalized estimation method can address overestimation bias, and discuss additional factors to consider when interpreting positive IA results. METHODS: We identified oncology RCTs reporting positive results at the initial IA and a SA for event-free (EFS) and overall survival (OS). We modeled: (1) the hazard ratio at IA (HRIA) versus its timing as measured by the information fraction (IF; i.e., events at IA versus total events sought); and (2), the ratio of HRIA to HRSA (rHR) versus the IF. This was repeated for HRIA adjusted for overestimation bias. Examples of the other two challenges were sought. RESULTS: Amongst 71 RCTs, HRIA were positively associated with the IF (slope: EFS 0.83, 95 % CI 0.44-1.22; OS 0.25, 95 % CI 0.10-0.41). HRIA tended to exaggerate HRSA, and more so the lower the IF (slope rHR versus IF: EFS 0.10, 95 % CI - 0.22 to 0.42; OS 0.26, 95 % CI 0.07-0.46). Adjusted HRIA did not exaggerate HRSA (slope rHR versus IF: EFS - 0.14, 95 % CI - 0.67 to 0.39; OS 0.02, 95 % CI - 0.26 to 0.30). Examples of two other challenges are shown. CONCLUSION: Overestimation bias, non-proportional hazards, and heterogeneity in recruitment and other important treatments should be considered when communicating estimates of treatment effects from positive IAs.

Efficacy and safety of fecal microbiota transplantation for treatment of ulcerative colitis: A post-consensus systematic review and meta-analysis.

BACKGROUND: Numerous studies have assessed the efficacy and safety of fecal microbiota transplantation (FMT) as a therapy for ulcerative colitis (UC). However, the treatment processes and outcomes of these studies vary. AIM: To evaluate the efficacy and safety of FMT for treating UC by conducting a systematic meta-analysis. METHODS: The inclusion criteria involved reports of adult patients with UC treated with FMT, while studies that did not report clinical outcomes or that included patients with infection were excluded. Clinical remission (CR) and endoscopic remission (ER) were the primary and secondary outcomes, respectively. RESULTS: We included nine studies retrieved from five electronic databases. The FMT group had better CR than the control group [relative risk (RR) = 1.53; 95% confidence interval (CI): 1.19-1.94; P < 0.0008]. ER was statistically significantly different between the two groups (RR = 2.80; 95%CI: 1.93-4.05; P < 0.00001). Adverse events did not differ significantly between the two groups. CONCLUSION: FMT demonstrates favorable performance and safety; however, well-designed randomized clinical trials are still needed before the widespread use of FMT can be recommended. Furthermore, standardizing the FMT process is urgently needed for improved safety and efficacy.

The Polypill: A New Alternative in the Prevention and Treatment of Cardiovascular Disease.

Cardiovascular disease (CVD) is the primary cause of death and disability worldwide. Although age-standardized CVD mortality rates decreased globally by 14.5% between 2006 and 2016, the burden of CVD remains disproportionately higher in low- and middle-income countries compared to high-income countries. Even though proven, effective approaches based on multiple-drug intake aimed at the prevention and treatment of CVD are currently available, poor adherence, early discontinuation of treatment, and suboptimal daily execution of the prescribed therapeutic regimes give rise to shortfalls in drug exposure, leading to high variability in the responses to the prescribed medications. Wald and Law, in their landmark paper published in BMJ 2003, hypothesized that the use of a fixed-dose combination of statins, ß-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and aspirin (classic Polypill composition) may increase adherence and decrease CVD by up to 80% when prescribed as primary prevention or in substitution of traditional protocols. Since then, many clinical trials have tested this hypothesis, with comparable results. This review aims to describe the available clinical trials performed to assess the impact of fixed-dose combinations on adherence, cost-effectiveness, and the risk factors critical to the onset of CVD.

Enhancing glycaemic control and promoting cardiovascular health: the therapeutic potential of Trigonella foenumgraecum in diabetic patients - a systematic review and meta-analysis.

Background: The antidiabetic potential of fenugreek has been highlighted in past literature, and various in-vitro and in-vivo studies have validated its glucose-lowering effects; however, very limited data are available on its effects on diabetic patients. Objective: An updated systematic review and meta-analysis of randomized control trials that assessed patients who were administered fenugreek. Methods: The PRISMA guidelines (Supplemental Digital Content 1, http://links.lww.com/MS9/A361) were followed when conducting this meta-analysis. PubMed, Scopus, Google Scholar and MEDLINE were searched from inception until June 2023, for randomized control trials that compared fenugreek with control in patients with type 2 diabetes mellitus (DM) and reported the following outcomes of interest: fasting blood glucose, glycated haemoglobin A1c (HbA1c) and postprandial glucose levels. The findings were presented as mean difference (MD) with 95% confidence intervals (CIs) and were pooled using a random effects model. Results: Fenugreek significantly (P<0.001) reduced the fasting blood sugar (FBS), HbA1c levels and postprandial glucose levels in diabetic patients when compared to the control. Conclusion: Among patients with type 2 DM, our comparisons demonstrated a reduction in FBS, HbA1c levels and postprandial glucose levels with the administration of fenugreek seed at 2-5 mg dose in powder form.

Design of randomized clinical trials with a binary endpoint: Conditional versus unconditional analyses of a two-by-two table.

When designing a randomized clinical trial to compare two treatments, the sample size required to have desired power with a specified type 1 error depends on the hypothesis testing procedure. With a binary endpoint (e.g., response), the trial results can be displayed in a 2 × 2 table. If one does the analysis conditional on the number of positive responses, then using Fisher's exact test has an actual type 1 error less than or equal to the specified nominal type 1 error. Alternatively, one can use one of many unconditional "exact" tests that also preserve the type 1 error and are less conservative than Fisher's exact test. In particular, the unconditional test of Boschloo is always at least as powerful as Fisher's exact test, leading to smaller required sample sizes for clinical trials. However, many statisticians have argued over the years that the conditional analysis with Fisher's exact test is the only appropriate procedure. Since having smaller clinical trials is an extremely important consideration, we review the general arguments given for the conditional analysis of a 2 × 2 table in the context of a randomized clinical trial. We find the arguments not relevant in this context, or, if relevant, not completely convincing, suggesting the sample-size advantage of the unconditional tests should lead to their recommended use. We also briefly suggest that since designers of clinical trials practically always have target null and alternative response rates, there is the possibility of using this information to improve the power of the unconditional tests.

Quantifying proportion of treatment effect by surrogate endpoint under heterogeneity.

When the primary endpoints in randomized clinical trials require long term follow-up or are costly to measure, it is often desirable to assess treatment effects on surrogate instead of clinical endpoints. Prior to adopting a surrogate endpoint for such purposes, the extent of its surrogacy on the primary endpoint must be assessed. There is a rich statistical literature on assessing surrogacy in the overall population, much of which is based on quantifying the proportion of treatment effect on the primary endpoint that is explained by the treatment effect on the surrogate endpoint. However, the surrogacy of an endpoint may vary across different patient subgroups according to baseline demographic characteristics, and limited methods are currently available to assess overall surrogacy in the presence of potential surrogacy heterogeneity. In this paper, we propose methods that incorporate covariates for baseline information, such as age, to improve overall surrogacy assessment. We use flexible semi-non-parametric modeling strategies to adjust for covariate effects and derive a robust estimate for the proportion of treatment effect of the covariate-adjusted surrogate endpoint. Simulation results suggest that the adjusted surrogate endpoint has greater proportion of treatment effect compared to the unadjusted surrogate endpoint. We apply the proposed method to data from a clinical trial of infliximab and assess the adequacy of the surrogate endpoint in the presence of age heterogeneity.