[Posted 12/Jul/2024]

AUDIENCE: Internal Medicine

KEY FINDINGS: The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting.

BACKGROUND: Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease.

DETAILS: Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi-stakeholder, multi-specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non-invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies.

Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Zannad, F., Sanyal, A. J., Butler, J., et al. (2024). MASLD and MASH At the Crossroads of Hepatology Trials and Cardiorenal Metabolic Trials. Journal of Internal Medicine. 2024; 296(1): 24-38. Published: July, 2024. DOI: 10.1111/joim.13793.

A Cohort Study of Patients From the TEMPO 3:4 Trial

[Posted 3/Sep/2024]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Visceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model independently associates with more rapid kidney growth and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity.

BACKGROUND: Body mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. Authors hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan.

DETAILS: 1,053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and at high risk of rapid disease progression. In fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of >=7% versus v5% (odds ratio [OR], 4.78 [95% CI, 3.03-7.47]). The association was stronger in women than men (interaction P < 0.01). In linear mixed models with an outcome of percent change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (3-way interaction of treatment * time * visceral adiposity, P = 0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual percent change in TKV for individuals with a normal BMI (DeLong's test z score: -2.03; P = 0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in women (fully adjusted OR, 1.06 [95% CI, 1.01-1.11] per 10 unit increase in visceral adiposity) but not men (OR, 0.98 [95% CI, 0.95-1.02]).

Copyright © Elsevier Ltd. All rights reserved.

Source: Nowak, K. L., Moretti, F., Bussola, N., et al. (2024). Visceral Adiposity and Progression of ADPKD: A Cohort Study of Patients From the TEMPO 3:4 Trial. Am J Kidney Dis. 2024; 84(3): 275-285. Published: September, 2024. DOI: XXXX.

[Posted 2/Sep/2024]

AUDIENCE: Hematology, Family Medicine

KEY FINDINGS: An alemtuzumab-based regimen successfully reduced the rate and severity of cGVHD after RIC allo-HSCT and resulted in a distinct immunomodulatory profile, which may have reduced cGVHD incidence and severity. However, increased infections and relapse resulted in a lack of survival benefit after long-term follow-up.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) remains a significant problem for patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although in vivo lymphodepletion for cGVHD prophylaxis has been explored in the myeloablative setting, its effects after reduced-intensity conditioning (RIC) are not well described.

DETAILS: Patients (N = 83) with hematologic malignancies underwent targeted lymphodepletion chemotherapy followed by a RIC allo-HSCT using peripheral blood stem cells from unrelated donors. Patients were randomized to 2 GVHD prophylaxis arms: alemtuzumab and cyclosporine (AC; n = 44) or tacrolimus, methotrexate, and sirolimus (TMS; n = 39), with the primary end point of cumulative incidence of severe cGVHD. The incidence of severe cGVHD was lower with AC vs TMS prophylaxis at 1- and 5-years (0% vs 10.3% and 4.5% vs 28.5%; overall, P = .0002), as well as any grade (P = .003) and moderate-severe (P < .0001) cGVHD. AC was associated with higher rates of grade 3 to 4 infections (P = .02) and relapse (52% vs 21%; P = .003) with no difference in 5-year GVHD-free-, relapse-free-, or overall survival. AC severely depleted naïve T-cell reconstitution, resulting in reduced T-cell receptor repertoire diversity, smaller populations of CD4Treg and CD8Tscm, but a higher ratio of Treg to naïve T-cells at 6 months.

Copyright © The American Society of Hematology. All rights reserved.

Source: Holtzman, N. G., Curtis, L. M., Salit, R. B., et al. (2024). High-Dose Alemtuzumab and Cyclosporine vs Tacrolimus, Methotrexate, and Sirolimus for Chronic Graft-Versus-Host Disease Prevention. Blood Adv.. 2024; 8(16): 4294-4310. Published: August, 2024. DOI: 10.1182/bloodadvances.2023010973.

A Critical Examination of Existing Knowledge

[Posted 29/Aug/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: This review highlights the need for additional research because of the lack of standardized reporting of clinical effects in the studies under scrutiny. A deeper exploration of the pathophysiology focusing on dietary modifications and their potential associations with HS severity is essential. Furthermore, it is crucial to recognize that patients' willingness to experiment with new diets makes them vulnerable to fraudulent interventions, highlighting the importance of evidence-based dietary guidance.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic condition that can overwhelm patients, and the effectiveness of supplementary dietary treatments remains uncertain. The primary aim of this review is to explore the connection between diet and HS progression. However, it is imperative to note that the evidence supporting a substantial role of the diet in HS remains weak. Dietary alterations alone should not be considered independent solutions for managing HS.

DETAILS: Medical therapy continues to be indispensable for adequate treatment. Research indicates that the Mediterranean lifestyle and diet may provide cost-effective and beneficial adjustments when combined with traditional therapies. Conversely, foods with a high glycemic index and dairy could worsen HS symptoms, conceivably through mechanisms linked to insulin resistance and inflammation. Zinc, known for its antioxidant properties, shows promise as an adjunct therapy. Moreover, evidence suggests a connection between vitamin D deficiency and HS severity, although the findings are inconclusive. Brewer's yeast-free diet, B12 supplementation, intermittent fasting, and reducing the intake of refined sugar and dairy merit further investigation.

Copyright © John Wiley & Sons Ltd. All rights reserved.

Source: Vural, S., Baskurt, D., Yildirici, S., et al. (2024). Evaluating Dietary Considerations in Hidradenitis Suppurativa: A Critical Examination of Existing Knowledge. International Journal of Dermatology. 2024; 63(8): 987-998. Published: July, 2024. DOI: XX10.1111/ijd.17101XX.

A Phase 2C, Open-Label, Multicentre, Partially Randomised Controlled Trial

[Posted 27/Aug/2024]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments.

BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB.

DETAILS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2.93 (95% CI 2.17-3.96; p<0.0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]).

Copyright © The Author(s). Published by Elsevier Ltd. All rights reserved.

Source: Cevik, M., Thompson, L. C., Upton, C., et al. (2024). Bedaquiline-Pretomanid-Moxifloxacin-Pyrazinamide for Drug-Sensitive and Drug-Resistant Pulmonary Tuberculosis Treatment: A Phase 2C, Open-Label, Multicentre, Partially Randomised Controlled Trial. The Lancet Infectious Diseases. 2024; 24(9): 1003-1014. Published: September, 2024. DOI: 10.1016/S1473-3099(24)00223-8.

A Target Trial Emulation Study

[Posted 25/Aug/2024]

AUDIENCE: Internal Medicine

KEY FINDINGS: Older adults starting dialysis when their eGFR fell below 12 mL/min/1.73 mm² who were not referred for transplant had modest gains in life expectancy and less time at home.

BACKGROUND: Aim of the study is to compare survival and home time between older adults who started dialysis at an estimated glomerular filtration rate (eGFR) less than 12 mL/min/1.73 m² and those who continued medical management.

DETAILS: Participants were adults aged 65 years or older with chronic kidney failure and eGFR below 12 mL/min/1.73 m² who were not referred for transplant. Among 20,440 adults (mean age, 77.9 years [SD, 8.8]), the median time to dialysis start was 8.0 days in the group starting dialysis and 3.0 years in the group continuing medical management. Over a 3-year horizon, the group starting dialysis survived 770 days and the group continuing medical management survived 761 days (difference, 9.3 days [95% CI, -17.4 to 30.1 days]). Compared with the group continuing medical management, the group starting dialysis had 13.6 fewer days at home (CI, 7.7 to 20.5 fewer days at home). Compared with the group continuing medical management and forgoing dialysis completely, the group starting dialysis had longer survival by 77.6 days (CI, 62.8 to 91.1 days) and 14.7 fewer days at home (CI, 11.2 to 16.5 fewer days at home).

Copyright © American College of Physicians. All Rights Reserved.

Source: Montez-Rath, M. E., Thomas, I., Charu, V., et al. (2024). Effect of Starting Dialysis Versus Continuing Medical Management on Survival and Home Time in Older Adults With Kidney Failure: A Target Trial Emulation Study. Ann Intern Med.. 2024; Epub. Published: August 20, 2024. DOI: 10.7326/M23-302.