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Font: https://www.nature.com/articles/s41591-023-02699-5
From Nature Medicine, a list of clinical trials that would set the course for 2024 was compiled, based on the main trials of different leading researchers, from database editing and an HIV vaccine to artificial intelligence tools for lung cancer and patient classification.
11 experts were asked which trials next year are likely to have a huge impact on medicine, resulting in the following:
About 1 in 300 people are born with heterozygous familial hypercholesterolemia, making it one of the most common inherited genetic diseases. The disease is caused by mutations in the gene PCSK9 , which encodes a protein that breaks down receptors for low-density lipoprotein (LDL), a type of cholesterol. Although statins may reduce the risk of cardiovascular disease in these patients, most cannot achieve optimal LDL cholesterol levels with chronic therapy.
The heart-1 trial is the world's first human study of DNA base editing in vivo and has the potential to demonstrate proof of concept for base editing treatment approaches targeting PCSK9 to permanently reduce LDL cholesterol.
VERVE-101 is an investigational, in vivo, base editing medication designed to be a single course treatment, which inactivates the PCSK9 in the liver to permanently reduce disease-causing LDL cholesterol.
The components of VERVE-101 are an mRNA encoding an adenine base editor, as well as a guide RNA, which are packaged within a lipid nanoparticle and administered via intravenous infusion. The provisional results are presented at the 2023 American Heart Association Scientific Sessions .
Early diagnosis of lung cancer saves lives. Although almost three-quarters of lung cancers are diagnosed late, at stages 3 or 4, earlier diagnosis at any stage allows for better, more effective treatment. A chest x-ray is usually the first test to suggest lung cancer and, if quickly followed by a computed tomography (CT) scan, can advance the diagnosis.
The ongoing randomized control trial with 150,000 patients in six UK hospitals tests whether artificial intelligence (AI) applied to chest x-rays as soon as they are taken shortens the time to CT scan and diagnosis.
It has previously been shown that immediate reporting of chest x-rays by radiologists can make a substantial difference, almost halving the time to diagnosis, from 63 days to 32 days. Patients referred from primary care for chest x-ray are included for analysis by the AI. Recruitment will be completed in July 2024 and results are expected to be available this year. The hypothesis, based on previous research, is that lung cancer can be identified earlier and reduce time to diagnosis by up to 50%.
AI is often being implemented in hospitals without adequate analysis of clinical impacts, which is of concern. If the trial finds a significant improvement in time to diagnosis, it will likely lead to an immediate change in the standard of care to include AI at the time of chest x-ray.
The purpose of the trial is to evaluate the safety, reactogenicity and immunogenicity of VIR-1388, a vaccine for the prevention of human immunodeficiency virus (HIV) infection. This multicenter, randomized, double-blind, placebo-controlled, phase 1 study involves adults 18 to 55 years of age in good general health and without HIV who will receive one of three dose levels of VIR-1388 or placebo.
VIR-1388 is a cytomegalovirus (CMV) vector vaccine that induces strong, unique, and sustained T cell responses that can potentially prevent HIV acquisition. This follows a proof-of-concept trial of VIR-1111 that demonstrated its safety, albeit without a strong immune response; VIR-1388 is less attenuated than VIR-1111 and we believe it should be more immunogenic.
The overall study design includes two parts. Part A will be an initial phase with enrollment of a small number of people of childbearing age who are seropositive for the CMV vector, with frequent monitoring for safety.
Part B will expand enrollment to a broader population of CMV-seropositive participants, including people of childbearing potential (who will be required to use two forms of contraception), with a safety monitoring schedule similar to Part A. an optional long-term follow-up study that would extend participation up to 3 years after the first dose.
Doses were recently administered to the first study participants. The trial is being conducted by the HIV Vaccine Trials Network at ten sites in the United States and two in South Africa, with support from the U.S. National Institute of Allergy and Infectious Diseases and the Bill & Melinda Gates Foundation. From a public health perspective, having an HIV vaccine would obviously have a tremendous impact.
Many parts of the world face challenges in providing adequate and effective mental health care, but the lack of trained professionals is especially acute in low- and middle-income countries.
Funded by the UK National Institute for Health and Care Research's Global Health Transformation Research and Innovation, a team led by the University of Liverpool has developed an app that allows a woman from the same community with no prior experience in childbirth healthcare to offer a cognitive therapy-based intervention to women in the second or third trimester of pregnancy who have major depression.
This trial will compare the app to the standard face-to-face version of Thinking Healthy Program therapy delivered by community health workers in rural Pakistan. The results of this study are expected to stimulate further innovation and research in this important area that can be a game-changer in addressing the treatment gap for a globally common mental disorder.
Most clinical trials for Parkinson's disease study patients with advanced disease. As a result, patients at a much earlier stage of the disease, who might be more susceptible to treatment, are often left out of trials.
The STEM-PD trial will transplant dopaminergic neurons derived from human embryonic stem cells into the brains of patients aged 50 to 75 years with moderate Parkinson's disease. It is important because it is one of the few trials testing a human embryonic stem cell therapy in Parkinson's disease and because it targets people with moderate disease, giving them the greatest opportunity to benefit from the therapy.
The first patients were administered doses in February 2023 and preliminary results are expected by the end of 2024.
Identifying which patients in the emergency department are at high or low risk soon after admission could assist in decision making for patient care. Various clinical risk scores and classification systems have been developed for patient stratification, but they often underperform in clinical practice.
Furthermore, most of these risk scores have only been validated diagnostically in an observational group, but never for their real clinical impact.
In a recent retrospective study conducted at Maastricht University Medical Center, a new clinical risk score, the RISKINDEX, was introduced.
An AI model was used to predict 31-day mortality for patients who sought treatment in an emergency department. The tool was developed and evaluated in four Dutch hospitals, based on data from 266,327 patients with 7.1 million laboratory results available. RISKINDEX outperformed internal medicine specialists, but the extent to which these AI models have beneficial value when implemented in clinical practice remains unknown.
MARS-ED is a prospective, multicenter, randomized, open-label, non-inferiority pilot clinical trial of risk-scored attendance to physicians in the emergency department.
The objective is to determine the diagnostic accuracy, policy changes, and clinical impact of RISKINDEX as a basis for conducting a large-scale, multicenter, randomized trial. Recruitment for the study is about halfway complete and results are expected to be seen in 2024.
If the AI model is validated, its effects could include identifying patients who will deteriorate despite clinical judgment. It's hard to predict how doctors will react when challenged by an AI model, but we've seen that while they don't change their minds often, they may become more careful.
In melanoma, the efficacy of neoadjuvant checkpoint inhibition versus the current standard of adjuvant therapy needs to be confirmed in a phase 3 trial before neoadjuvant therapy can be considered a standard option for this patient population.
The NADINA trial is an international, open-label, randomized, two-arm Phase 3 trial, including 420 patients in Australia, Europe and the USA with unknown primary or stage III cutaneous melanoma. The current standard for resectable stage III melanoma is adjuvant anti-PD-1 therapy, which improves recurrence-free survival, but a substantial proportion of patients relapse in the years following therapeutic lymph node dissection and There has been no overall survival benefit found so far.
The NADINA trial aims to compare the efficacy of neoadjuvant ipilimumab plus nivolumab with that of adjuvant nivolumab in stage III macroscopic melanoma. Patients diagnosed with recurrent or de novo stage III melanoma, including up to three in-transit metastases, will be randomly assigned to receive neoadjuvant treatment or adjuvant treatment.
Patients in the experimental group will receive two cycles of 80 mg ipilimumab plus 240 mg nivolumab and will undergo therapeutic lymph node dissection at week 6. In the case of partial pathological response or no response, surgery will be followed by Adjuvant nivolumab (11 cycles) or adjuvant dabrafenib plus trametinib (for 46 weeks).
Patients in the standard control group will undergo initial therapeutic lymph node dissection, followed by 12 cycles of 480 mg nivolumab. The primary endpoint will be event-free survival, defined as the time from randomization to progression to unresectable stage III or IV melanoma, recurrent melanoma, a new primary melanoma, or death due to melanoma or treatment.
An overall survival benefit is expected to be seen, which could become a practice change for the treatment of stage III melanoma.
A major problem with malaria vaccines, and one of the reasons it has taken more than 100 years to implement a vaccine, is that an exceptionally high antibody response is needed for the vaccine to work.
Forty vaccines with the same circumsporozoite protein antigen have reached the clinic, and only two of them have shown useful efficacy: RTS,S and R21. Vaccine efficacy against RTS,S/ASO1 drops from 55% to around 30% 4 years after vaccination, so long-term follow-up is really important.
A multicenter, randomized controlled phase 3 trial of the R21/Matrix-M vaccine against clinical malaria in African children is midway through. This includes standard age-based and also seasonal vaccination regimens used in children 5 to 36 months of age.
In each group, a booster dose (fourth) of the same vaccine was administered 12 months after the third dose. Initial follow-up will be 2 years after the third dose, with a primary analysis at 12 months. There are 2,400 participants registered to receive the standard vaccination regimen in malaria-endemic areas in Burkina Faso, Kenya and Tanzania. An additional 2,400 participants will be enrolled to receive the seasonal vaccination regimen in Burkina Faso and Mali.
It is believed that R21 will show better efficacy than RTS,S, particularly later in the trial, as R21 uses a nanoparticle that has a much higher density of the antigen on the surface. Vaccines such as the human papillomavirus vaccine work throughout life due to this characteristic.
This trial is funded by the Serum Institute of India, which has committed to producing 100 million doses of the vaccine at a cost of US$3 to US$4 per dose. Now they have the first results on a prepress server and, in the coming years, more analyzes on the safety, immunogenicity and efficacy of the vaccine will continue to be published.
Brain metastasis is a major problem in advanced breast cancer, affecting approximately half of HER2-positive patients, but with only one treatment approved by the US Food and Drug Administration for this patient population.
DESTINY-Breast12 is a international, multicenter and open study evaluating the efficacy and safety of trastuzumab deruxtecan (Enhertu), an antibody-drug conjugate (ADC) targeting HER2, in participants with or without brain metastasis. Patients had been previously treated for advanced metastatic HER2-positive breast cancer that had progressed on prior anti-HER2-based regimens and had not received more than two lines or regimens of therapy in the metastatic setting (excluding tucatinib).
The intercranial activity for this treatment is based only on prospective studies or very small prospective case series in individual countries (as well as on a mixed population of patients with active and stable brain metastases in the DESTINY-Breast01, 02 and 03 studies), but These have shown encouraging responses.
Following discontinuation of the study intervention, all participants will undergo a treatment completion visit within 7 days of discontinuation and will be followed for safety assessments for 40 days. All participants will be followed for survival status and duration of treatment on any subsequent therapy every 3 months until death, withdrawal of consent, or end of study.
The study is important not only to evaluate the drug itself but also to understand the intracranial activity of ADCs and will represent the largest number of patients with brain metastases treated with trastuzumab deruxtecan. There is increasing data showing that several ADCs could have intercranial activity, despite their large size.
Almost 100,000 children are currently in care across the UK and many of them face behavioral challenges and an uncertain future. Children who are removed from their homes due to abuse and neglect are one of the most vulnerable groups in any society. They are at much higher risk of suicide, unemployment and incarceration, as well as most mental health disorders and many physical health disorders.
Better approaches are needed to help these children reach their full potential, such as the New Orleans Intervention Model, which provides intensive assessment and treatment for children ages 0 to 5 years.
The first randomized controlled trial of its kind, the Best Services Trial (BeST?), led by Helen Minnis at the University of Glasgow, will investigate the effectiveness and cost-effectiveness of the New Orleans Intervention Model for Children's Mental Health in relation to Regular social work services for children aged 0-5 years in foster care in Glasgow and London.
The children will be assessed for 2.5 years and their mental health outcomes will be compared. If this model proves advantageous, it could radically change the way these children are supported, not only in the UK but globally.
Two large-scale, randomized, controlled trials have shown that lung cancer screening with CT can reduce lung cancer mortality. Other smaller trials have shown comparable results.
However, implementation of lung cancer screening is likely to be limited, slow and of variable quality, in part because initial CT scans show no signs of cancer in nine out of ten people.
4-IN THE LUNG RUN will compare whether screening every 2 years is as effective in preventing cancer deaths as annual screening in those who do not have abnormalities at their first screening.
The trial will examine 26,000 people in six European countries. If the implementation of lung cancer screening can be optimized, it is expected that many people will quickly benefit from this high-quality screening technology, others will face less harm than previously anticipated, and healthcare costs will be reduced.
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