Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

Background: ‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. / Methods: Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. / Findings: Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation. / Interpretation: Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. / Funding: Axcella Therapeutics

Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin : The Randomized, Controlled EMPA-VISION Trial

Acknowledgments The authors express their gratitude toward the Oxford cardiovascular magnetic resonance nursing team, specifically Judith DeLos Santos, Catherine Krasopoulos, Marion Galley, and Claudia Nunes; and the diabetes trials unit team, particularly Irene Kennedy, for her organization skills. The authors also thank the team of the computed tomography suite at the Manor Hospital Oxford as well as all patients who participated in this trial. Drs Holman and Neubauer are Emeritus National Institute for Health Research senior investigators. The views expressed are those of the author(s) and not necessarily those of the National Health Service, National Institute for Health and Care Research, or Department of Health. Sources of Funding Boehringer Ingelheim is the sponsor of the EMPA-VISION study and was involved in early stages of its study design. Boehringer Ingelheim employees (Drs Lee and Massey) also supported preparation of this manuscript. Dr Neubauer acknowledges support from the Oxford British Heart Foundation Centre of Research Excellence. Drs Holman and Neubauer were supported by the Oxford National Institute for Health Research Biomedical Research Centre. Drs Rodgers and Valkovič are funded by Sir Henry Dale Fellowships from the Wellcome Trust and the Royal Society [098436/Z/12/B and 221805/Z/20/Z, respectively]. Dr Valkovič also gratefully acknowledges support of the Slovak Grant Agencies VEGA (Vedecká grantová agentúra) [2/0003/20] and APVV (Slovak Research and Development Agency) [No. 19–0032]. Dr Miller acknowledges support from the Novo Foundation (NNF21OC0068683).Peer reviewedPublisher PD

Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy.

Aims Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM. Methods The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I–III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. Conclusion TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM

In-vivo 31P-MRS of skeletal muscle and liver: A way for non-invasive assessment of their metabolism

In addition to direct assessment of high energy phosphorus containing metabolite content within tissues, phosphorus magnetic resonance spectroscopy (31P-MRS) provides options to measure phospholipid metabolites and cellular pH, as well as the kinetics of chemical reactions of energy metabolism in vivo. Even though the great potential of 31P-MR was recognized over 30 years ago, modern MR systems, as well as new, dedicated hardware and measurement techniques provide further opportunities for research of human biochemistry. This paper presents a methodological overview of the 31P-MR techniques that can be used for basic, physiological, or clinical research of human skeletal muscle and liver in vivo. Practical issues of 31P-MRS experiments and examples of potential applications are also provided. As signal localization is essential for liver 31P-MRS and is important for dynamic muscle examinations as well, typical localization strategies for 31P-MR are also described

In-vivo 31P-MRS of skeletal muscle and liver: A way for non-invasive assessment of their metabolism

In addition to direct assessment of high energy phosphorus containing metabolite content within tissues, phosphorus magnetic resonance spectroscopy (31P-MRS) provides options to measure phospholipid metabolites and cellular pH, as well as the kinetics of chemical reactions of energy metabolism in vivo. Even though the great potential of 31P-MR was recognized over 30 years ago, modern MR systems, as well as new, dedicated hardware and measurement techniques provide further opportunities for research of human biochemistry. This paper presents a methodological overview of the 31P-MR techniques that can be used for basic, physiological, or clinical research of human skeletal muscle and liver in vivo. Practical issues of 31P-MRS experiments and examples of potential applications are also provided. As signal localization is essential for liver 31P-MRS and is important for dynamic muscle examinations as well, typical localization strategies for 31P-MR are also described

Rapid 3D absolute B1+ mapping using a sandwiched train presaturated TurboFLASH sequence at 7 T for the brain and heart

Purpose:&nbsp;To shorten the acquisition time of magnetization-prepared absolute transmit field (B1+) mapping known as presaturation TurboFLASH, or satTFL, to enable single breath-hold whole-heart 3D B1+&nbsp;mapping. Methods:&nbsp;SatTFL is modified to remove the delay between the reference and prepared images (typically 5 T1), with matching transmit configurations for excitation and preparation RF pulses. The new method, called Sandwich,&nbsp;is evaluated as a 3D sequence, measuring whole-brain and gated whole-heart B1+&nbsp;maps in a single breath-hold. We evaluate the sensitivity to B1+&nbsp;and T1&nbsp;using numerical Bloch, extended phase graph, and Monte Carlo simulations. Phantom and in vivo images were acquired in both the brain and heart using an 8-channel transmit 7 Tesla MRI system to support the simulations. A segmented satTFL with a short readout train was used as a reference. Results:&nbsp;The method significantly reduces acquisition times of 3D measurements from 360&thinsp;s to 20&thinsp;s, in the brain, while simultaneously reducing bias in the measured B1+&nbsp;due to T1&nbsp;and magnetization history. The mean coefficient of variation was reduced by 81% for T1s of 0.5&ndash;3&nbsp;s compared to conventional satTFL. In vivo, the reproducibility coefficient for flip angles in the range 0&ndash;130&deg; was 4.5&deg; for satTFL and 4.7&deg; for our scheme, significantly smaller than for a short TR satTFL sequence, which was 12&deg;. The 3D sequence measured B1+&nbsp;maps of the whole thorax in 26 heartbeats. Conclusion:&nbsp;Our adaptations enable faster B1+&nbsp;mapping, with minimal T1&nbsp;sensitivity and lower sensitivity to magnetization history, enabling single breath-hold whole-heart absolute B1+&nbsp;mapping.</p

OXSA: An open-source magnetic resonance spectroscopy analysis toolbox in MATLAB

In vivo magnetic resonance spectroscopy provides insight into metabolism in the human body. New acquisition protocols are often proposed to improve the quality or efficiency of data collection. Processing pipelines must also be developed to use these data optimally. Current fitting software is either targeted at general spectroscopy fitting, or for specific protocols. We therefore introduce the MATLAB-based OXford Spectroscopy Analysis (OXSA) toolbox to allow researchers to rapidly develop their own customised processing pipelines. The toolbox aims to simplify development by: being easy to install and use; seamlessly importing Siemens Digital Imaging and Communications in Medicine (DICOM) standard data; allowing visualisation of spectroscopy data; offering a robust fitting routine; flexibly specifying prior knowledge when fitting; and allowing batch processing of spectra. This article demonstrates how each of these criteria have been fulfilled, and gives technical details about the implementation in MATLAB. The code is freely available to download from https://github.com/oxsatoolbox/oxsa

Reproducibility of human cardiac phosphorus MRS (31P‐MRS) at 7 T

Purpose: We test the reproducibility of human cardiac phosphorus MRS (31P‐MRS) at ultra‐high field strength (7 T) for the first time. The primary motivation of this work was to assess the reproducibility of a ‘rapid’ 6½ min 31P three‐dimensional chemical shift imaging (3D‐CSI) sequence, which if sufficiently reproducible would allow the study of stress‐response processes. We compare this with an established 28 min protocol, designed to record high‐quality spectra in a clinically feasible scan time. Finally, we use this opportunity to compare the effect of per‐subject B0 shimming on data quality and reproducibility in the 6½ min protocol. Methods: 10 healthy subjects were scanned on two occasions: one to test the 28 min 3D‐CSI protocol, and one to test the 6½ min protocol. Spectra were fitted using the OXSA MATLAB toolbox. The phosphocreatine to adenosine triphosphate concentration ratio (PCr/ATP) from each scan was analysed for intra‐ and intersubject variability. The impact of different strategies for voxel selection was assessed. Results: There were no significant differences between repeated measurements in the same subject. For the 28 min protocol, PCr/ATP in the midseptal voxel across all scans was 1.91 ± 0.36 (mean ± intersubject SD). For the 6½ min protocol, PCr/ATP in the midseptal voxel was 1.76 ± 0.40. The coefficients of reproducibility (CRs) were 0.49 (28 min) and 0.67 (6½ min). Per‐subject B0 shimming improved the fitted PCr/ATP precision (for 6½ min scans), but had negligible effect on the CR (0.67 versus 0.66). Conclusions: Both 7 T protocols show improved reproducibility compared with a previous 3 T study by Tyler et al. Our results will enable informed power calculations and protocol selection for future clinical research studies.</p

OXSA: An open-source magnetic resonance spectroscopy analysis toolbox in MATLAB

In vivo magnetic resonance spectroscopy provides insight into metabolism in the human body. New acquisition protocols are often proposed to improve the quality or efficiency of data collection. Processing pipelines must also be developed to use these data optimally. Current fitting software is either targeted at general spectroscopy fitting, or for specific protocols. We therefore introduce the MATLAB-based OXford Spectroscopy Analysis (OXSA) toolbox to allow researchers to rapidly develop their own customised processing pipelines. The toolbox aims to simplify development by: being easy to install and use; seamlessly importing Siemens Digital Imaging and Communications in Medicine (DICOM) standard data; allowing visualisation of spectroscopy data; offering a robust fitting routine; flexibly specifying prior knowledge when fitting; and allowing batch processing of spectra. This article demonstrates how each of these criteria have been fulfilled, and gives technical details about the implementation in MATLAB. The code is freely available to download from https://github.com/oxsatoolbox/oxsa

Reproducibility of human cardiac phosphorus MRS (31P‐MRS) at 7 T

Purpose: We test the reproducibility of human cardiac phosphorus MRS (31P‐MRS) at ultra‐high field strength (7 T) for the first time. The primary motivation of this work was to assess the reproducibility of a ‘rapid’ 6½ min 31P three‐dimensional chemical shift imaging (3D‐CSI) sequence, which if sufficiently reproducible would allow the study of stress‐response processes. We compare this with an established 28 min protocol, designed to record high‐quality spectra in a clinically feasible scan time. Finally, we use this opportunity to compare the effect of per‐subject B0 shimming on data quality and reproducibility in the 6½ min protocol. Methods: 10 healthy subjects were scanned on two occasions: one to test the 28 min 3D‐CSI protocol, and one to test the 6½ min protocol. Spectra were fitted using the OXSA MATLAB toolbox. The phosphocreatine to adenosine triphosphate concentration ratio (PCr/ATP) from each scan was analysed for intra‐ and intersubject variability. The impact of different strategies for voxel selection was assessed. Results: There were no significant differences between repeated measurements in the same subject. For the 28 min protocol, PCr/ATP in the midseptal voxel across all scans was 1.91 ± 0.36 (mean ± intersubject SD). For the 6½ min protocol, PCr/ATP in the midseptal voxel was 1.76 ± 0.40. The coefficients of reproducibility (CRs) were 0.49 (28 min) and 0.67 (6½ min). Per‐subject B0 shimming improved the fitted PCr/ATP precision (for 6½ min scans), but had negligible effect on the CR (0.67 versus 0.66). Conclusions: Both 7 T protocols show improved reproducibility compared with a previous 3 T study by Tyler et al. Our results will enable informed power calculations and protocol selection for future clinical research studies.</p