clinical trial research articles

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Trials encompasses all aspects of the performance and findings of randomized controlled trials in health. We publish articles on general trial methodology and research into trial processes, as well as study protocols and statistical analysis plans for randomized controlled trials, commentaries and traditional results papers - regardless of outcome or significance of findings.

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Refining physical exercise training studies in patients with inflammatory bowel disease: patient selection and assessment of physical fitness changes

Authors: Karlijn Demers, Bart C. Bongers, Daisy M. A. E. Jonkers, Marieke J. Pierik and Laurents P. S. Stassen

Pressure injury treatment by intermittent electrical stimulation (PROTECT-2): protocol for a multicenter randomized clinical trial

Authors: Chase Donaldson, Marcelo Gama de Abreu, Edward J. Mascha, James Rowbottom, Eric Harvester, Ashish Khanna, Tanmay Sura, Daniel I. Sessler, Fabio Rodriguez Patarroyo, Alper Gulluoglu, Paul Zajic, Utkarsh Chauhan, Hani Essber and Andrea Kurz

Upstrapping to determine futility: predicting future outcomes nonparametrically from past data

Authors: Jessica L. Wild, Adit A. Ginde, Christopher J. Lindsell and Alexander M. Kaizer

Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial

Authors: Phiona E. Namale, Linda Boloko, Marcia Vermeulen, Kate A. Haigh, Fortuna Bagula, Alexis Maseko, Bianca Sossen, Scott Lee-Jones, Yoliswa Msomi, Helen McIlleron, Ayanda Trevor Mnguni, Thomas Crede, Patryk Szymanski, Jonathan Naude, Sakeena Ebrahim, Yakoob Vallie…

Approaches and experiences implementing remote, electronic consent at the Leeds Clinical Trials Research Unit

Authors: William J Cragg, Chris Taylor, Lauren Moreau, Howard Collier, Rachael Gilberts, Niamh McKigney, Joanna Dennett, Sandra Graca, Ian Wheeler, Liam Bishop, Adam Barrett, Suzanne Hartley, John P Greenwood, Peter P Swoboda and Amanda J Farrin

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Palliative long-term abdominal drains versus repeated drainage in individuals with untreatable ascites due to advanced cirrhosis: study protocol for a feasibility randomised controlled trial

Authors: Lucia Macken, Louise Mason, Catherine Evans, Heather Gage, Jake Jordan, Mark Austin, Nick Parnell, Max Cooper, Shani Steer, Justine Boles, Stephen Bremner, Debbie Lambert, David Crook, Gemma Earl, Jean Timeyin and Sumita Verma

The Correction to this article has been published in Trials 2018 19 :488

Through the looking glass: understanding non-inferiority

Authors: Jennifer Schumi and Janet T Wittes

Oral corticosteroids for post-infectious cough in adults: study protocol for a double-blind randomized placebo-controlled trial in Swiss family practices (OSPIC trial)

Authors: Christoph Merlo, Stefan Essig, D. Oana Brancati-Badarau, Jörg Daniel Leuppi, Benjamin Speich, Tobias E. Erlanger, Lars G. Hemkens and Andreas Zeller

Sample size requirements to estimate key design parameters from external pilot randomised controlled trials: a simulation study

Authors: M Dawn Teare, Munyaradzi Dimairo, Neil Shephard, Alex Hayman, Amy Whitehead and Stephen J Walters

Managing clinical trials

Authors: Barbara Farrell, Sara Kenyon and Haleema Shakur

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Article collection The use of electronic consent (e-Consent) in randomised trials

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Article collection Impact of COVID-19 on clinical trials

Thematic series The future of pragmatic trials Edited by Prof Marion Campbell and Prof Sandra Eldridge

Thematic series Big data for randomized trials Edited by Dr Lars Hemkens

Article collection Sample size calculations and specifying the target difference for randomized trials

Thematic series Building capacity for evidence informed trial management Edited by Dr Roberta Littleford and Prof Shaun Treweek

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As a journal dedicated to improve the reporting and publication of clinical trials, we aim to embrace all content that is relevant, including general methodology papers, and research into the trial processes, protocols and statistical analysis plan for randomized controlled trials, as well as traditional research and commentary papers. However, it requires an in-depth subject knowledge to properly evaluate papers on the topic of complementary and alternative medicine to assess the intervention, the design of the trials, as well as the primary and secondary outcomes. Hence we feel it’s better to refer authors of these papers to the journals that are more equipped with the expertise required.

As of  1 st  September 2021 , Trials will no longer be considering papers on the topic of complementary and alternative medicine. We recommend the below journals from the BMC family that can accommodate studies in this area, do please check each journal scope carefully before submitting:

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Peter is a clinical epidemiologist and general internist, and the Director of the Applied Health Research Centre (AHRC) at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital. He holds a Tier 1 Canada Research Chair in Clinical Epidemiology of Chronic Diseases and is a Professor at the Department of Medicine and the Institute of Health Policy, Management and Evaluation at the University of Toronto. Peter is known for his methodological work and for his clinical research on the management of cardiovascular and musculoskeletal disorders. He has had leading roles in major cardiovascular trials, served as a member of several task forces of the European Society of Cardiology, and contributed to the Cochrane Risk of Bias tools for randomized and non-randomized studies.

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• Published: 23 December 2022

11 clinical trials that will shape medicine in 2023

• Carrie Arnold 1 &
• Paul Webster 2  

Nature Medicine volume  28 ,  pages 2444–2448 ( 2022 ) Cite this article

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An Author Correction to this article was published on 27 February 2023

This article has been updated

Nature Medicine asks leading researchers to name their top clinical trial for 2023, from cervical and prostate cancer screening to new drugs for Parkinson’s disease and Alzheimer’s disease.

2022 has been a rollercoaster year for biopharma, as it has faced an industry-wide slowdown and late-stage clinical trial failures, as well as breakthroughs and regulatory approvals.

COVID-19 has continued to disrupt nearly all aspects of clinical trial infrastructure, from patient recruitment to supply chains, but despite this, 2023 promises to bring many new readouts from different branches of medicine (Table 1 ).

We asked 11 leading experts for their top clinical trials to watch in the coming year.

A diabetes drug for Parkinson’s disease

Roger Albin: For both purely scientific issues and clinical practice issues, the phase 3 trial for exenatide in Parkinson’s disease is a very attractive trial. It has the big advantage of being a repurposed drug that is already widely used in older patients. If there were a positive result, it is something that could be really adopted into clinical practice in a very practical way. The drug had reasonable preclinical data and some promising phase 2 data, and in the Parkinson’s disease world, in which there is not an animal model for really great predictive validity, this is probably about as good as it gets. The community is looking for unequivocal results, whether positive or negative. A clear positive response would be great, but a clear negative response is actually just as important.

Roger Albin is a professor of neurology and co-director of the Movement Disorders Clinic in the Department of Neurology at the University of Michigan Medical School .

ADC for ovarian cancer

Robert L. Coleman: The most imminent and important upcoming trial result expected in my field in 2023 is mirvetuximab soravtansine, from ImmunoGen. This received accelerated approval from the US Food and Drug Administration (FDA) on 14 November, based on results of a single-arm trial that enrolled 106 patients with platinum-resistant ovarian cancer whose tumors had high expression of folate receptor-α and who had been treated with up to three prior regimens, at least one of which included bevacizumab (Avastin).

Under accelerated approval, the sponsor can market their drug under the indication agreed to by the FDA — in this case, patients with recurrent, platinum-resistant ovarian cancer. For the drug to move from accelerated approval to regular approval, a confirmatory trial needs to be conducted to confirm the overall safety and efficacy of the agent of interest. In this case, initial results for the confirmatory phase 3 MIRASOL trial are expected in early 2023.

This drug is an antibody–drug conjugate (ADC); these agents are already being used for the treatment of several solid and liquid tumors, but this is the first for ovarian cancer. It will be aligned with a companion diagnostic test that mirrors the expression in tumors needed for clinical trial eligibility. We expect about one-third of patients with recurrent, platinum-resistant ovarian cancer to have high expression of folate receptor-α. The ADC field is expanding rapidly, with trastuzumab deruxtecan approved in April 2022 for use against breast cancer, but it has been a long time since a new cytotoxic agent has been approved for ovarian cancer. Among treatments for gynecological cancers, this is only the second ADC approved so far, after Tisotumab vedotin (in September 2021) for patients with recurrent previously treated cervical cancer. Now we have one in ovarian cancer. Several other ADCs are in development, and successful approval will provide a solid framework for clinical trials evaluating novel combinations in several disease settings.

Robert L. Coleman is chief scientific officer at US Oncology Research .

CRISPR–Cas9 for muscular dystrophy

Simone Spuler: Muscle stem cells are the only cells that can regenerate muscle. In patients who have a genetic muscular dystrophy in which muscle wastes for genetic reasons, these stem cells carry mutations, but these mutations can now be corrected with CRISPR–Cas9 and other tools. Correcting muscle stem cells means muscle can be rebuilt, which was not been previously possible whatsoever in these muscular dystrophies.

Muscular dystrophies are a group of about 50 different diseases that lead young people and children to lose their ability to walk, or to breathe, and make them wheelchair-bound within a couple of years. We are working with corrected muscle stem cells able to rebuild muscles and we will test this in a trial called bASKet. In the bASKet trial , there are two major questions. The first is about safety. We would like to see that nothing happens to the patients that makes the disease worse, such as a gene encoding a tumor suppressor being switched on. We do all kinds of preclinical safety tests to preclude that possibility. New proteins will be made by these stem cells, which probably have not been seen by the patient’s immune system, so it could attack this foreign protein. We will inject the cells that are repaired into the patient in an autologous manner, and check a few months later to see if new muscle is built. The second question we are addressing is about clinical improvement. This is something the regulatory agencies asked us to do. We hope to have the first data a few months after we begin treating patients in June and July 2023.

Simone Spuler leads the myology research group and the Outpatient Clinic for Muscle Disorders at the Experimental and Clinical Research Center, a joint institution established by the Max Delbrück Center and the Charité–Universitätsmedizin, in Berlin, Germany .

Cervical cancer screening in the vaccinated

Karen Canfell: Prophylactic vaccines against human papilloma virus (HPV), first rolled out 15 years ago, protect women against cervical cancer and are now routinely offered to young girls in most high-income countries. As time moves on, more women who were vaccinated as girls become eligible for cervical cancer screening, and it is important to understand the most effective screening approaches in a vaccinated population. This trial is important, as it is the first large-scale randomized controlled trial internationally that will assess primary HPV screening in a population that is heavily vaccinated against HPV. The findings from the secondary randomization will assess newer approaches for managing HPV-positive women, which will be important for cervical screening programs that are transitioning to primary HPV testing. The COMPASS trial is also assessing new next-generation HPV testing platforms and technologies for triage testing, which are expected to improve the overall performance of HPV testing at a program level.

Karen Canfell is chair of the Cancer Screening and Immunisation Committee of Cancer Council Australia .

The Mediterranean diet for weight loss

Jordi Salas Salvadó: No study has ever demonstrated that weight loss and maintenance using an energy-reduced healthy diet and physical activity lowers the risk of cardiovascular disease in people who are overweight or who have obesity. The Look AHEAD trial in the USA, conducted in people with diabetes, has been discontinued owing to lack of efficacy in reducing the risk of cardiovascular events and mortality after approximately 10 years of follow-up, despite achieving significant differences between interventions in long-term weight loss.

We hypothesize that an intensive lifestyle-intervention program aimed at weight loss and based on the traditional Mediterranean diet is a sustainable long-term approach for achieving weight loss in overweight and obese adults, and that the lifestyle changes achieved will have a beneficial effect on cardiovascular morbidity and mortality.

Jordi Salas Salvadó is a Distinguished Professor of Nutrition at Rovira i Virgili University and Principal Investigator at CIBER-Obn Instituto de Salud Carlos III, Spain .

Safe treatment for sleeping sickness

Olaf Valverde: In 2023, we will receive the complete results of our clinical trial testing of a breakthrough, all-oral, safe medicine for treating the variant of sleeping sickness caused by Trypanosoma brucei rhodesiense . Also known as human African trypanosomiasis, this neglected parasitic disease transmitted by the bite of the tse tse fly causes severe neuropsychiatric disorders. In contrast to T. brucei gambiense , for which humans are considered the primary reservoir, T. brucei rhodesiense is highly zoonotic, with animals and livestock considered the primary reservoir. It is endemic in eastern and southern Africa, evolves quickly, and can kill in weeks to months if left untreated.

For decades, doctors in endemic countries had to treat sleeping sickness by using melarsoprol, an arsenic derivative so toxic that it killed 5% of patients. Our organization started developing a series of improved drugs, and in 2018 registered fexinidazole, a safe and effective first all-oral drug for the variant of the disease caused by T. brucei gambiense . But for patients with the variant caused by T. brucei rhodesiense , doctors still have to use the dreaded melarsoprol for advanced cases. This clinical trial is assessing the efficacy of fexinidazole for sleeping sickness caused by T. brucei rhodesiense , in comparison with the efficacy of the existing drugs melarsoprol and suramin. Full results will be presented to the European Medicines Agency in 2023, and we expect to get a favorable opinion.

Olaf Valverde is the clinical project leader of the human African trypanosomiasis team of the Drugs for Neglected Diseases initiative .

Circulating tumor cells

Nicola Aceto: My lab is interested in metastasis. More than 90% of people with cancer die when metastasis happens. It is a big unsolved problem. We recently found that metastasis is driven mostly by clusters of circulating tumor cells (CTCs), which are multicellular aggregates of tumor cells that depart from the existing tumor , circulate in the bloodstream , and then metastasize. This finding challenged the prevailing dogma in the metastasis field, as until a few years ago, people thought metastasis happened one cell at a time. Thanks to new technologies, we could finally investigate blood samples from patients and in animal models, which allowed us to identify CTC clusters.

We have also found that there are drugs, such as digoxin, that have the ability to dissociate these cells and dissolve the clusters, which shuts down metastasis in preclinical models. We have now set up a small phase 1 trial as a proof of mechanism. We screen the blood of patients with advanced metastatic breast cancer, and when we find CTC clusters, we give the patients the drug for 3 weeks, during which time we measure the abundance and features of the clusters. Digoxin is a well-known drug used to treat heart conditions, but it has this beautiful side effect. Should the trial be successful, we envision the generation of improved cluster-dissociating molecules, able to achieve full cluster dissolution and specifically designed to treat cancer. This is the next ambitious goal: enabling a novel cancer-treatment modality that is aimed at blocking the spread of cancer.

Nicola Aceto is an associate professor of molecular oncology at ETH Zurich .

Lecanemab for Alzheimer’s disease

Allan Levey: In 2023, I expect to see more peer-reviewed publications and data on lecanemab, an investigational monoclonal antibody to amyloid-β protofibrils, for the treatment of mild cognitive impairment with Alzheimer’s disease. The developer, Eisai, announced positive topline results from their large global phase 3 confirmatory Clarity AD clinical trial of lecanemab in late September. We saw extensive data on lecanemab at the Clinical Trials on Alzheimer’s Congress in late November and early December 2022 and a landmark publication in the New England Journal of Medicine was published on 29 November 2022.

Much data have been made available for scrutiny and independent, secondary analyses with the publication. Eisai is expected to file an application with the FDA for traditional approval in the USA and marketing-authorization applications in Japan and Europe by the end of March 2023. This is a pivotal phase 3 trial that most experts consider a huge game-changer for this field. In Alzheimer’s disease, there are no disease-modifying treatments that are clearly proven (aducanumab has been approved, despite uncertain clinical efficacy). Until recently, evidence for disease modification has been lacking, despite an industry-wide focus on amyloid-based therapies for many years.

With this new lecanemab study, the results of the phase 3 study show a significant reduction in clinical progression, confirming the results of an earlier phase 2 study. All primary and secondary endpoints, including dementia severity, cognition and functional abilities, were met. The second issue is that safety has been a huge concern with previous treatments given accelerated approval. The results for lecanemab indicate that its safety is much better, although there were adverse events. These are the reasons it is a game changer. Additional important insights will be gleaned about the magnitude and duration of benefits, and a more palatable and scalable form of subcutaneous dosing when more data and analysis are published in 2023.

Allan Levey is a professor and chair of the Department of Neurology at Emory University’s School of Medicine, and director of the Emory University Goizueta Alzheimer’s Disease Research Center .

COVID-19 vaccination and HIV

Glenda Gray: In December 2021, we began a trial to enroll almost 14,500 participants in more than 50 research clinics in eight sub-Saharan African countries. The Ubuntu multicenter phase 3 clinical trial will assess the efficacy of the mRNA-1273 (Moderna) vaccine against COVID-19 in adults infected with human immunodeficiency virus (HIV) or with other comorbidities that increase the risk of severe COVID-19. This trial will include a smaller number of HIV-negative people.

There is an urgent need to characterize infection and viral clearance in people who are immunocompromised, which will be assessed in our study . The results, which we expect in 2023, should indicate how many doses of vaccine are needed for adults living with HIV, as well as in adults with other health conditions that may put them at risk for severe COVID-19. We are also expecting data on whether people who have been infected with the coronavirus SARS-CoV-2, and therefore probably have some immunity, need as many vaccine doses as those without prior infection. We also want to know if the original Moderna vaccine is inferior to the new bivalent one, which includes the spike protein from a SARS-CoV-2 variant of concern. This direct comparison of mRNA-1273 against the bivalent vaccine should give us insight into the utility of variant-specific vaccines. We hope that when these results are published next year, they will help to refine an optimal vaccine strategy and the best regimen for HIV-infected people.

Glenda Gray is president and CEO of the South Africa Medical Research Council .

Gene editing for sickle-cell disease

Luigi Naldini: We are all waiting for the first long-term data from gene-editing strategies in sickle-cell disease and thalassemia. There have been preliminary reports of efficient editing . The key question is whether these gene grafts remain stable. We have seen very safe stable long-term grafts of stem cells treated with lentiviral vectors, and prolonged safety, but will this be the same for gene-editing tools?

We may soon be seeing the interim results in 2023 of a multi-center sickle-cell disease trial of gene editing sponsored by CRISPR Therapeutics and Vertex Pharmaceuticals. This is a single-arm, open-label, multi-site, single-dose phase 1/2/3 study in people with severe sickle-cell disease. The study is evaluating the safety and efficacy of autologous CRISPR–Cas9-modified CD34 + human hematopoietic stem and progenitor cells. Participants receive a single infusion of these cells through a central venous catheter. The top outcome of interest would be participants who have not experienced any severe vaso-occlusive crisis for at least 12 consecutive months. It will be crucial to verify the long-term stability and polyclonal composition of the graft without the emergence of adverse events. Beyond this, what we are looking forward to seeing is the first clinical testing of what we call ‘writing back’ genes; that is, correcting genetic mutations by introducing editing of longer sequences, which has not been clinically achieved yet. We and others are actively working closely on that.

Luigi Naldini is a professor of cell and tissue biology and of gene and cell therapy at the San Raffaele University School of Medicine, and scientific director of the San Raffaele Telethon Institute for Gene Therapy, Milan, Italy .

Reducing harm from prostate cancer screening

Anssi Auvinen: The evidence surrounding testing for the marker PSA (prostate-specific antigen) is full of conflict, as the test may detect prostate cancer but at the expense of treating cancers with little threat to health. We aim to detect only clinically relevant, aggressive prostate cancer while minimizing the diagnosis of clinically unimportant, low-risk cancers that would constitute over-diagnosis (meaning that they would not progress even if left undetected and untreated). A previous trial showed benefits that were comparable to those of other cancer screening programs, but we wanted to put more effort into harnessing recent developments to reduce harm, including over-diagnosis and unnecessary biopsies.

Anssi Auvinen is a professor of health sciences at Tampere University, Finland .

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A Correction to this paper has been published: https://doi.org/10.1038/s41591-023-02262-2

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A novel, non-invasive treatment using electrical currents exploits physiological properties of dividing cancer cells to prolong survival and augment current therapies.

clinical trials

Randomized Controlled Trials

Affiliations.

• 1 Department of Quantitative Health Sciences & Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. Electronic address: [email protected].
• 2 Department of Quantitative Health Sciences & Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
• 3 Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO.
• PMID: 32658656
• PMCID: PMC8176647
• DOI: 10.1016/j.chest.2020.03.013

Randomized controlled trials (RCTs) are considered the highest level of evidence to establish causal associations in clinical research. There are many RCT designs and features that can be selected to address a research hypothesis. Designs of RCTs have become increasingly diverse as new methods have been proposed to evaluate increasingly complex scientific hypotheses. This article reviews the principles and general concepts behind many common RCT designs and introduces newer designs that have been proposed, such as adaptive and cluster randomized trials. A focus on the many choices for randomization within an RCT is described, along with their potential tradeoffs. To illustrate their diversity, examples of RCTs from the literature are provided. Statistical considerations, such as power and type I error rates, are discussed with the intention of providing practical guidance about how to specify study hypotheses that address the scientific question while being statistically appropriate. Finally, the freely available Consolidated Standards of Reporting Trials guidelines and US Food and Drug Administration guidance documents are introduced, along with a set of guidelines one should consider when planning an RCT or reviewing RCTs submitted for publication in peer-reviewed academic journals.

Keywords: biostatistics; clinical trials; randomized controlled trials; study design.

Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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• 5 Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington
• 6 Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, California
• 7 Department of Epidemiology, University of Pittsburgh School of Public Health|Epidemiology, Pittsburgh, Pennsylvania
• 8 Department of Medicine, University of Alabama, Birmingham
• 9 Division of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, California
• 10 Department of Health Promotion Science, University of Arizona, Tucson
• 11 Department of Preventive Medicine, Northwestern University, Chicago, Illinois
• 12 MedStar Health Research Institute and Department of Medicine, Georgetown University School of Medicine, Washington, DC
• 13 Department of Epidemiology and Environmental Health, University at Buffalo–SUNY, Buffalo, New York
• 14 Department of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Importance   Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women’s Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.

Observations   The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.

Conclusions and Relevance   For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Read More About

Manson JE , Crandall CJ , Rossouw JE, et al. The Women’s Health Initiative Randomized Trials and Clinical Practice : A Review . JAMA. Published online May 01, 2024. doi:10.1001/jama.2024.6542

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News releases.

News Release

Wednesday, May 8, 2024

NIH to open long COVID clinical trials to study sleep disturbances, exercise intolerance, and post exertional malaise

Part of the NIH RECOVER Initiative, trials will test four treatments.

The National Institutes of Health (NIH) will launch clinical trials to investigate potential treatments for long-term symptoms after COVID-19 infection, including sleep disturbances, exercise intolerance and the worsening of symptoms following physical or mental exertion known as post-exertional malaise (PEM). The mid-stage trials, part of NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative, will join six other RECOVER studies currently enrolling participants across the United States testing treatments to address viral persistence, neurological symptoms, including cognitive dysfunction (like brain fog) and autonomic nervous system dysfunction. The new trials will enroll approximately 1,660 people across 50 study sites to investigate potential treatments for some of the most frequent and burdensome symptoms reported by people suffering from long COVID.

“The group of symptoms these trials will try to alleviate are truly disruptive and devastating for so many people struggling with long COVID,” said Walter J. Koroshetz, M.D., director of NIH’s National Institute of Neurological Disorders and Stroke, and co-lead of the RECOVER Initiative. “When people can’t get reliable sleep, can’t exert themselves and feel sick following tasks that used to be simple, the physical and mental anguish can lead to feelings of utter helplessness. We urgently need to come up with answers to help those struggling with long COVID feel whole again.”

RECOVER-SLEEP clinical trials will soon begin enrolling participants and include:

• A trial to test two drugs (modafinil and solriamfetol) approved by the Food and Drug Administration to treat people who have problems staying awake during the day, known as hypersomnia. These medications are well-known but have not been studied widely in people with long COVID. Participants will be randomly assigned to receive either the active study drug or a placebo control for eight to 10 weeks, depending on the assigned study drug.
• A trial to test potential treatments for complex sleep disturbances due to long COVID, including melatonin, an over-the-counter supplement commonly used to treat people with sleep disorders and general insomnia; and light therapy, which is used to help people reset their sleep cycles. Participants will be randomly assigned to receive either melatonin or a placebo control, and either high-intensity (active) light therapy or low-intensity (placebo) light therapy for eight weeks. 

RECOVER-ENERGIZE clinical trials will soon begin enrolling participants and include:

• A trial to test a program that combines exercise training, strength and flexibility training,  education, and social support, collectively known as personalized cardiopulmonary rehabilitation. The program is designed to help people who experience exercise intolerance with symptoms such as shortness of breath and fatigue during exercise after having COVID-19.  All participants in RECOVER-ENERGIZE trials will be screened for PEM. Participants who are identified as having PEM, via a validated PEM questionnaire, will not be included in this trial. Participants will be randomly assigned to receive either personalized cardiopulmonary rehabilitation or basic exercise education for three months.
• A trial to test a program known as structured pacing, which is designed to help participants with PEM identify, control, and minimize symptoms that developed after having COVID-19 by regulating or pacing their daily activities. Currently, structured pacing is the only intervention used to treat PEM. The trial will not include any exercise training or physical movement to protect participants from developing worsened symptoms of PEM. Participants will be randomly assigned to receive either structured pacing with a trained coach or basic PEM education for three months.

All four trials were developed using comprehensive feedback from the community and in close partnership with patient representatives, whose insights were especially important for the PEM trial. The PEM trial was developed to address concerns expressed by patient advocacy groups about patient safety, and to better understand how this study program may help improve PEM symptoms.

“Structured pacing is currently the only intervention used to prevent post-exertional malaise, so we hope to test its effectiveness and determine how to best guide patients regarding activity management,” said Lucinda Bateman, M.D., an expert in PEM and founder of the Bateman Horne Center, Salt Lake City, a facility specializing in treating people with ME/CFS, long COVID and fibromyalgia.

Diversity among trial participants is a high priority for the RECOVER Initiative. To support diverse and inclusive representation, study sites are chosen based on geographic location, their connection to communities, and track record for enrolling diverse research participants. Teams at the selected study sites will recruit participants from their health systems and surrounding communities.

Sites currently activated for each trial can be found on ClinicalTrials.gov (RECOVER-SLEEP  NCT06404086 ,  NCT06404099 ,  NCT06404112 and RECOVER-ENERGIZE NCT06404047 ,  NCT06404060 ,  NCT06404073 ). New sites will be added to clinicaltrials.gov as they begin enrolling participants.

With the launch of these four studies, RECOVER is currently testing 13 treatments across eight clinical trials and continues to enroll participants. Those interested in learning more about RECOVER clinical trials should visit trials.recovercovid.org .

About RECOVER : The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) Initiative brings together clinicians, scientists, caregivers, patients, and community members to understand, diagnose, and treat long COVID. RECOVER has created one of the largest and most diverse groups of long COVID study participants in the world. In addition, RECOVER clinical trials are testing potential interventions across five symptom focus areas. For more information, please visit recovercovid.org . 

HHS Long COVID Coordination: This work is a part of the National Research Action Plan , a broader government-wide effort in response to the Presidential Memorandum directing the Secretary for the Department of Health and Human Services to mount a full and effective response to long COVID. Led by Assistant Secretary for Health Admiral Rachel Levine, the Plan and its companion Services and Supports for Longer-term Impacts of COVID-19 report lay the groundwork to advance progress in the prevention, diagnosis, treatment, and provision of services for individuals experiencing long COVID.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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The Trump Trials: Hope against Hope

The latest news in Donald Trump’s four criminal cases, including Hope Hicks’s emotional testimony in New York, and what to watch for this week

Welcome back to the regular Sunday evening edition of The Trump Trials newsletter, where we are still waiting on key rulings that will determine when and if three of Donald Trump’s criminal cases will go to trial. In the meantime, we’re busy in Manhattan, where the trial of Trump’s fourth criminal case is ongoing — and in the midst of some pretty gripping testimony.

Trump hush money trial

Have questions on the trials? Email us at [email protected] and [email protected] and check for answers in future newsletters.

Okay, let’s get started.

What’s ahead

The state of New York’s criminal case against Trump continues on Monday — the 12th day of trial. Prosecutors are not revealing who they will call next to the stand, and so far the witnesses have alternated between obscure figures — like the young paralegal whose job at the Manhattan district attorney’s office includes cataloguing Trump’s social media posts — and high-profile players talking about their conversations with Trump in the White House.

• The remaining expected witnesses include Stormy Daniels, the adult-film actress who was paid to keep quiet about an alleged tryst with Trump; and Michael Cohen, Trump’s former attorney , who says he coordinated the payment to Daniels and whose reimbursement is at the center of the criminal charges.

New York Supreme Court Justice Juan Merchan , who is overseeing the Manhattan trial, could rule any day now on whether Trump has continued to violate his court-imposed gag order . Merchan held a hearing Thursday on four recent alleged breaches. (More on that below.)

Podcast episode

A thousand miles away in South Florida, we’re keeping an eye on the docket of Trump’s classified documents case . Both sides have until Thursday to submit key filings — a deadline that Trump’s lawyers said will be hard for them to meet while they are busy with the New York trial. U.S. District Judge Aileen M. Cannon has not yet said whether she will push it back or keep it as is.

Now, a recap of last week’s action.

(Like what you’re reading? Get the Trump Trials newsletter in your email inbox .)

New York: State hush money case

The details: 34 charges connected to a 2016 hush money payment .

Trial date: Week 4 of the trial starts Monday.

Last week: Testimony ranged from the shady world of tabloid gossip to the inner workings of the White House. Daniels’s lawyer, Keith Davidson, took the stand and explained how the National Enquirer outbid ABC for the rights to her story of a claimed affair with Trump. A key moment for prosecutors came when Davidson said he realized that Daniels’s story was most valuable after Trump’s lewd “Access Hollywood” tape became public in October 2016, weeks before the presidential election.

• That’s key because prosecutors want to show Trump falsified his records when categorizing the reimbursement of the hush money payment to Daniels in an attempt to conceal election-related crimes . This testimony helps establish a motive, highlighting that those involved reportedly knew Trump thought any reports about the alleged tryst could hurt him with female voters.
• Defense attorneys emphasized Daniels was paid by Trump’s then-attorney, Cohen — a figure no one seems to like . When the defense questioned Davidson, they attempted to portray Trump as a victim of a shakedown , targeted because he was a rich celebrity who could be blackmailed.

The week ended with testimony from Hope Hicks , a former top Trump aide who handled the campaign’s response to the “Access Hollywood” tape and alleged affairs. Hicks seemed torn about providing testimony against her former boss, and broke down briefly on the witness stand. Her account highlighted to the jury just how worried the 2016 Trump campaign was about negative stories about him and women, and how those issues dogged Trump even after he entered the Oval Office.

Check out The Washington Post’s new podcast on video or audio , recapping and analyzing the latest in Trump’s New York trial. Our latest episode is below.

Nerd word of the week

Stipulation: An agreement made at trial between opposing sides, often about a basic fact such as the address of a business. Stipulations are a standard part of the court process, to save the time and hassle of calling witnesses to testify about incontrovertible facts. In the first weeks of the New York trial, however, Trump’s lawyers took a no-holds-barred approach and refused to agree to any stipulations. But on Friday they relented and stipulated that an October 2016 Washington Post story revealed the existence of an “Access Hollywood” tape in which Trump made offensive remarks about grabbing women’s genitalia.

Gag-tracker

Merchan ruled Tuesday that Trump violated the gag order nine times around the first week of trial. The order bars him from commenting on witnesses, jurors, prosecutors, or family members of the judge or Manhattan District Attorney Alvin Bragg .

The judge found that instances of Trump reposting someone else’s social media statements count as violations of his order — though he noted this is a largely untested area of law.

Merchan held another hearing Thursday on four more alleged gag violations. One of Trump’s attorneys later asked if simply posting a link to an article could violate the order. “I think the best advice to give your client is when in doubt, steer clear ,” Merchan replied. The judge also emphasized to Trump that nothing about the gag order prevented him from testifying in his defense, should he choose to do so.

D.C.: Federal case on 2020 election

The details: Four counts related to conspiring to obstruct the 2020 election results .

Planned trial date: Unclear

Last week: We’re waiting on the Supreme Court to rule on Trump’s claim that presidential immunity from criminal prosecutions extends to his alleged actions around Jan. 6 , 2021. The case is frozen until that decision is delivered — which is expected by the end of the court term, late June or early July.

Florida: Federal classified documents case

The details: Trump faces 40 federal charges over accusations that he kept top-secret government documents at Mar-a-Lago — his home and private club — and thwarted government demands to return them.

Planned trial date: Undecided

Last week: Prosecutors and defense attorneys met a May 2 deadline for filing motions and exhibits of evidence that may be relevant for trial. Much of this was under seal — meaning the public gets notice they were filed, but don’t yet know the contents — so we didn’t learn a whole lot of new information.

• An unsealed version of Trump’s motion to dismiss the case claiming vindictive or selective prosecution by prosecutors is now available on the court docket. The 178-page filing says Trump is being treated differently than other politicians like President Biden and former vice president Mike Pence, who were not prosecuted after classified documents were found in their homes. Trump filed this motion in February , but it was just made public Friday. Cannon has not yet ruled on the request.

Georgia: State case on 2020 election

The details: Trump faces 10 state charges for allegedly trying to undo the election results in that state. Four of his 18 co-defendants have pleaded guilty.

Planned trial date: None yet

Last week: Another quiet week in the Peach State.

Question Time

Q. Why is Judge Merchan, who is presiding over the New York trial, referred to as a Supreme Court justice? Isn’t this just a regular trial?

A. You may notice that whenever we first mention Merchan in an article we refer to him as “New York Supreme Court Justice Juan Merchan.” That may seem a bit strange, since we typically think of Supreme Court justices as sitting in either the nation’s highest court or states’ highest courts.

But in New York, the State Supreme Court is actually the trial court. That’s the court with the biggest jurisdiction in criminal and civil matters that hears most major cases. If a New York Supreme Court decision is appealed, the appeal goes to one of the state’s four appellate divisions. And the highest court in the state — the court of last resort — is known simply as the Court of Appeals. Confusing, we know.

Thanks for catching up with us. You can find past issues here .

Suggested Reading

Former Trump aide gets tearful as she testifies in his trial

Hope Hicks witnessed nearly every Trump scandal. Then she had to testify.

How Trump and his team dealt with reporters is key part of Hicks testimony

The ‘Access Hollywood’ video cemented Trump’s air of invincibility

• International edition
• Australia edition
• Europe edition

Trump appears frustrated in court while possible Cohen testimony looms

Trump’s demeanor suggests sour mood after Stormy Daniels’s testimony, and news his former lawyer may testify next week promises more angst

• Trump hush-money trial – live updates

Donald Trump arrived at the courtroom for his hush-money criminal trial on Friday, with apparent frustration, after sitting through two days of testimony from the adult film actor Stormy Daniels , who provided a detailed account of an alleged sexual liaison with him some 20 years ago.

The drama driven by their made-for-tabloid courtroom confrontation might soon be overshadowed, however, by another showdown. Michael Cohen, Trump’s consigliere-turned-key prosecution witness, might take the stand on Monday – promising still more angst for him.

This morning, the seemingly irked Trump carried a thin stack of papers in his hand and, after getting to the defense table, dropped them on to the table, so that they landed with a clack that reverberated into the gallery.

Indeed, the ex-president’s demeanor in the hallway suggested that his mood had soured since Daniels provided embarrassing details about their alleged sexual encounter, among them his seeming obsession with STIs juxtaposed with his decision not to use protection.

In the hallway outside Judge Juan Merchan’s courtroom, Trump ignored reporters’ queries about whether he would take up Daniels on her challenge to testify in his own defense. And, as Trump is wont to do, he played the victim, complaining about a gag order that prohibits him from commenting about witnesses.

“Certain words I’m not allowed to read,” Trump said, reading from news articles, the pool report said of Trump’s comments. “If I put one wrong word in, they’re gonna put me in jail.”

“They don’t like it when I talk during the day because they don’t want me talking at all,” Trump reportedly ranted, saying Thursday was “incredible” and calling the proceedings “so horrible”.

Trump, according to the poolers, also reportedly said: “I’ll go now and sit in that freezing courtroom for eight or nine hours and think about being on the campaign all day.”

Still more evidence that Daniels’s testimony struck a nerve with Trump was the defense attorney Susan Necheles’s cross-examination on Friday morning of Madeleine Westerhout, his former executive assistant and director of Oval Office operations in the White House.

She asked Westerhout whether she recalled being at the White House when news about Trump and Daniels’s alleged fling came to light.

“Did you have a conversation with President Trump about that?”

“Uh, yes I did,” she said.

Necheles asked: “What was your impression of his reaction to the news?”

“That he was very upset by it,” Westerhout said. Asked why Trump was upset, Westerhout said: “In my understanding he knew it would be hurtful to his family.”

Necheles asked whether this was based on what Trump had said to her. Westerhout reflected that, “I don’t believe he specifically said that, but I could just tell that the whole situation was very unpleasant.”

Not long after, Necheles tried to suggest on re-cross that Trump’s relationship to the Daniels scandal was always related to his family, not political embarrassment. “Just to reiterate, President Trump was very close to his family, right?” The question prompted an objection, and Westerhout did not answer.

When Westerhout was done testifying, she raised her eyebrows at Trump as she was leaving the courtroom, in a sort of greeting. Several custodial witnesses – who testified about phone records and Trump’s social media posts – followed.

As proceedings progressed, some of Trump’s affects suggested that whatever energy he had derived from pre-trial agitation had waned. At points during Westerhout’s testimony, for example, he could be seen slouching, eyes down, head slightly lolling side-to-side, suggesting tiredness.

The relationship between Trump and Daniels is central to the origins of the case because Trump’s then lawyer and personal fixer, Cohen, paid her $130,000 to keep quiet about their alleged sexual encounter during the 2016 election campaign.

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Daniels’s testimony described their relationship in graphic detail and over lengthy periods of court time, despite the alleged criminal behavior at the heart of the charges being due to the way the payments were accounted for as prosecutors have claimed they were an election expense.

Trump is charged with 34 felony counts of falsifying business records in connection with the payments and had pleaded not guilty.

After weeks of the trial, Trump’s position in the 2024 election race does not appear to have been affected much by his almost daily attendance at a courtroom in Manhattan or the salacious details that have emerged.

Trump’s criminal hush-money trial: what to know

A guide to Trump’s hush-money trial – so far

The key arguments prosecutors will use against Trump

How will Trump’s trial work?

From Michael Cohen to Stormy Daniels: the key players

Trump remains the all-but-certain pick for the Republican party’s presidential nominee to face Joe Biden in the race for the White House. He has continued to perform well in the polls, often having a narrow lead over Biden in head-to-head surveys and performing well in crucial swing states.

The hush-money case is the first of four criminal cases to reach a jury against Trump. The other three have hit serious delays, which could perhaps prevent them from starting before November’s presidential election.

They involve Trump’s attempts to overturn the 2020 election result in Georgia, his keeping of sensitive documents at his Florida resort and his conduct during the January 6 insurrection at the US Capitol.

In two of those cases – in Georgia and in Florida – other legal developments this week pushed back any likely start dates even further in what many experts see as wins for Trump’s legal team and its strategy of delaying trials until the fight for the Oval Office is finished.

With the Manhattan trial moving at a quick clip, and the other trials seeming unlikely to proceed anytime soon, it seems that he might return to the campaign unimpeded.

As trial wrapped for the week, the prosecution told Merchan: “We expect to call two witnesses and it’s entirely possible that we will rest by the end of next week.”

With additional reporting from Maya Yang and Hugo Lowell

• Donald Trump trials
• Donald Trump
• Stormy Daniels

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