Featured
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Article
| Open Access
Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial
Immunotherapy using dendritic cell (DC)-based vaccination has been exploited in the clinic for cancer treatment. Here the authors report the results of a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived DC cell-based therapy in patients with stage IIIB and IIIC melanoma.
- Kalijn F. Bol
- , Gerty Schreibelt
- & I. Jolanda M. de Vries
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Article
| Open Access
Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients
In this clinical trial, the authors show that a 5-day molnupiravir treatment reduces SARS-CoV-2 viral load in at-risk outpatients by day 5 but mostly fails to clear virus, leads to lower spike antibody response by day 14 and higher virus mutation rates.
- Joseph F. Standing
- , Laura Buggiotti
- & Francis Yongblah
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Article
| Open Access
WASH interventions and child diarrhea at the interface of climate and socioeconomic position in Bangladesh
Household water, sanitation, and handwashing (WASH) interventions can reduce diarrhoea-related morbidity in young children. Here, the authors report findings from a pre-specified secondary analysis of a cluster-randomised trial assessing how WASH impacts vary by socioeconomic position and season.
- Pearl Anne Ante-Testard
- , Francois Rerolle
- & Benjamin F. Arnold
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Article
| Open Access
Geographic pair matching in large-scale cluster randomized trials
Geographic location can be a key determinant of human health outcomes. Here, the authors show that in large-scale trials, randomization that is pair matched by geography can lead to substantial improvements in statistical efficiency and enable insights into spatially varying intervention effects.
- Benjamin F. Arnold
- , Francois Rerolle
- & Jade Benjamin-Chung
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Article
| Open Access
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.
- Peter Sandercock
- , Janet Darbyshire
- & Martin J. Landray
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Article
| Open Access
Autonomous artificial intelligence increases screening and follow-up for diabetic retinopathy in youth: the ACCESS randomized control trial
Diabetic retinopathy is a complication of diabetes that can be prevented through screening, yet adherence is low. Here, the authors show that autonomous AI increases diabetic eye exam completion in a diverse cohort of youth with diabetes.
- Risa M. Wolf
- , Roomasa Channa
- & Michael D. Abramoff
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Article
| Open Access
NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease
Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.
- Haakon Berven
- , Simon Kverneng
- & Charalampos Tzoulis
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Article
| Open Access
Evaluation of pragmatic oxygenation measurement as a proxy for Covid-19 severity
There is a need for an accurate measure of pulmonary oxygenation function that can be used as an intermediate endpoint in pragmatic clinical trials, to increase statistical power and efficiency. Here, the authors show that the S/F94, a modification of the S/F ratio, is a simple, meaningful and effective intermediate outcome measure.
- Maaike C. Swets
- , Steven Kerr
- & J. Kenneth Baillie
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Article
| Open Access
Dostarlimab or pembrolizumab plus chemotherapy in previously untreated metastatic non-squamous non-small cell lung cancer: the randomized PERLA phase II trial
Several PD-(L)1 inhibitors have been approved or are in development for the treatment of NSCLC, showing promising efficacy and tolerable safety profiles. Here, the authors present a randomized phase II clinical trial comparing two different anti-PD-1 antibodies, dostarlimab and pembrolizumab, both combined with chemotherapy as first-line treatment in patients with metastatic NSCLC.
- Sun Min Lim
- , Solange Peters
- & Filippo de Marinis
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Article
| Open Access
A standardized metric to enhance clinical trial design and outcome interpretation in type 1 diabetes
The use of a standardized outcome metric enhances clinical trial interpretation and cross-trial comparison. Here, the authors show the implementation of such a metric using type 1 diabetes trial data, reassess and compare results from these trials, and extend its use to define response to therapy.
- Alyssa Ylescupidez
- , Henry T. Bahnson
- & Carla J. Greenbaum
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Review Article
| Open AccessChallenges in developing Geroscience trials
Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This article reports a discussion of a research Task Force on the challenges posed by the clinical research in Geroscience so that future gerotherapeutic clinical trials can be conducted successfully.
- Yves Rolland
- , Felipe Sierra
- & Alex Zhavoronkov
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Article
| Open Access
Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Neuroinflammation and autophagy are two pillars of ALS pathogenesis targeted by rapamycin. Here, in a randomized, double-blind, phase 2 clinical trial, the authors find rapamycin to be safe and well tolerated in ALS patients, supporting further studies.
- Jessica Mandrioli
- , Roberto D’Amico
- & Andrea Cossarizza
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Article
| Open Access
Safety and immunogenicity of Ad5-nCoV immunization after three-dose priming with inactivated SARS-CoV-2 vaccine in Chinese adults
Here the authors provide safety and immunogenicity data for an AdV5-based SARS-CoV-2 vaccine, administered intramuscularly as heterologous booster after three-doses of inactivated SARS-CoV-2 vaccine in Chinese adults.
- Hangjie Zhang
- , Nani Xu
- & Huakun Lv
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Article
| Open Access
Safety and immunogenicity of a phase 1/2 randomized clinical trial of a quadrivalent, mRNA-based seasonal influenza vaccine (mRNA-1010) in healthy adults: interim analysis
Here the authors report initial findings of a phase 1 clinical trial, showing that an investigational, mRNA-based vaccine for seasonal influenza (mRNA-1010) has no safety concerns and produces immune responses in adults that are similar or higher than a licensed comparator vaccine.
- Ivan T. Lee
- , Raffael Nachbagauer
- & Robert Paris
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Article
| Open Access
A randomized trial of Trendelenburg position for acute moderate ischemic stroke
The effect of head positioning in acute stroke is controversial. Here, the authors report the results of a clinical trial suggesting that the procedure, initiated within 24 hours of onset, is safe and feasible, but does not improve functional outcome in acute moderate stroke patients with large artery atherosclerosis.
- Hui-Sheng Chen
- , Nan-Nan Zhang
- & Thanh N. Nguyen
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Article
| Open Access
11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial
Glucocorticoids prescribed to limit inflammation, have significant adverse effects. Here the authors show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.
- Nantia Othonos
- , Riccardo Pofi
- & Jeremy W. Tomlinson
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Article
| Open Access
Safety and immunogenicity following a homologous booster dose of CoronaVac in children and adolescents
Few countries have approved SARS-CoV-2 booster doses in children and adolescents due to insufficient evidence about the safety and interval vaccination. Here, the authors assess the safety and immunogenicity of a homologous booster dose of CoronaVac in a cohort of 3–17 year olds.
- Lei Wang
- , Zhiwei Wu
- & Qiang Gao
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Article
| Open Access
A randomized phase 3 trial of Gemcitabine or Nab-paclitaxel combined with cisPlatin as first-line treatment in patients with metastatic triple-negative breast cancer
Platinum agents, such as carboplatin and cisplatin, have been recommended in combination with gemcitabine for the treatment of metastatic triple negative breast cancer (TNBC). Here the authors report the results of a randomized phase 3 trial to compare the efficacy of first-line nab-paclitaxel/cisplatin to gemcitabine/cisplatin in patients with TNBC.
- Biyun Wang
- , Tao Sun
- & Xichun Hu
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Article
| Open Access
Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients in a randomized phase 2 trial
SARS-CoV-2 variants with immune escape capability highlight the need for the development of cross-neutralising vaccines and regimens. Here, the authors assess the immunogenicity and safety of NVSI-06-08, that integrates antigens from multiple SARS-CoV-2 strains into a single immunogen, as a heterologous booster in adults previously vaccinated with the inactivated vaccine.
- Nawal Al Kaabi
- , Yun Kai Yang
- & Qi Ming Li
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Article
| Open Access
Six-month follow-up of a booster dose of CoronaVac in two single-centre phase 2 clinical trials
Following a booster dose of CoronaVac in two single-centre phase 2 clinical trials, the authors show that neutralising antibody titres decline approximately 4-fold and 2.5-fold from day 28 to day 180 in adults aged 18-59 years and in adults aged 60 years and older, respectively.
- Qianqian Xin
- , Qianhui Wu
- & Lin Wang
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Comment
| Open Access
The potential of polygenic scores to improve cost and efficiency of clinical trials
Polygenic scores can identify individuals with high disease risk based on inborn DNA variation. We explore their potential to enrich clinical trials by identifying individuals based on higher risk of disease (‘prognostic enrichment’), or increased probability of benefit (‘predictive enrichment’).
- Akl C. Fahed
- , Anthony A. Philippakis
- & Amit V. Khera
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Article
| Open Access
Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients
Clinical studies have suggested that the therapeutic potential of polyclonal convalescent plasma is highest in the first days of symptoms. Here, the authors present results from a pooled analysis of two clinical trials in COVID-19 outpatients that did not provide conclusive evidence in favor of convalescent plasma.
- Pere Millat-Martinez
- , Arvind Gharbharan
- & Michael Marks
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Article
| Open Access
Randomized clinical trial to assess the protective efficacy of a Plasmodium vivax CS synthetic vaccine
In this phase 2 clinical trial, the authors assess protective efficacy of a Plasmodium vivax circumsporozoite vaccine in naïve and semi-immune individuals from controlled human malaria infection as well as antibody and IFN-γ response to vaccination.
- Myriam Arévalo-Herrera
- , Xiomara Gaitán
- & Sócrates Herrera
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Article
| Open Access
Cancer patient survival can be parametrized to improve trial precision and reveal time-dependent therapeutic effects
Analysis of more than 150 Phase 3 oncology clinical trials supports parametric statistical analysis, significantly increasing the precision of small early-phase trials and relating deviations from the Cox proportional hazards model to trial duration.
- Deborah Plana
- , Geoffrey Fell
- & Peter K. Sorger
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Article
| Open Access
A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients
Modulating the host immune response during tuberculosis is an emerging and critical advance in the therapeutic approach. Here the authors present data from a first-in-human phase I/II randomised trial on the safety and immunogenicity of adjuvant therapy of the H56:IC31 vaccine and cyclooxygenase-2 inhibitors in patients with tuberculosis.
- Synne Jenum
- , Kristian Tonby
- & Anne Ma Dyrhol-Riise
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Article
| Open Access
Three-year outcomes of the randomized phase III SEIPLUS trial of extensive intraoperative peritoneal lavage for locally advanced gastric cancer
Extensive intraoperative peritoneal lavage (EIPL) has been proposed as an approach to reduce peritoneal metastasis in patients with locally advanced gastric cancer undergoing gastrectomy. Here the authors report the results of the multicentric phase III SEIPLUS trial, showing that EIPL does not improve 3-year survival rate in patients with advanced gastric cancer.
- Jing Guo
- , Aman Xu
- & Dazhi Xu
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Article
| Open Access
Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial
Here the authors report the results of randomized, single-blind, placebocontrolled trial on the effects of a asingle subcutaneous dose of Peginterferon Lambda-1a (Lambda) in 120 outpatients with mild to moderate COVID-19, showing that while treatment is well tolerated it does not shorten the duration of SARS-CoV-2 viral shedding nor improves symptoms.
- Prasanna Jagannathan
- , Jason R. Andrews
- & Upinder Singh
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Article
| Open Access
The effects of releasing early results from ongoing clinical trials
Sharing early evidence, as a trial is ongoing, is fundamental for both physicians and patients to make enrollment decisions. Here, the authors report the results of a simulation study evaluating the potential effects of early release of interim efficacy and safety data on the duration and validity of an ongoing clinical trial and demonstrate that positive interim results may shorten trial duration through increased enrollment.
- Steffen Ventz
- , Sergio Bacallado
- & Lorenzo Trippa
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Article
| Open Access
Neoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer
Neoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial.
- Birendra Kumar Sah
- , Benyan Zhang
- & Zhenggang Zhu
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Article
| Open Access
A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics
The use of hydroxychloroquine therapy for the treatment of Covid-19 is controversial. In this study, Lyngbakken and colleagues present a randomized controlled trial and show that the drug has no antiviral effects in humans infected with SARS-CoV-2.
- Magnus Nakrem Lyngbakken
- , Jan-Erik Berdal
- & Olav Dalgard
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Article
| Open Access
Stress sensitization among severely neglected children and protection by social enrichment
Early adversity may sensitize people to the effects of later stress, amplifying psychopathology risk. Here, the authors show this stress sensitization effect for adolescents who experienced prolonged institutional deprivation in childhood, but not those assigned to foster care intervention.
- Mark Wade
- , Charles H. Zeanah
- & Charles A. Nelson
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Article
| Open Access
Bridging the gap between efficacy trials and model-based impact evaluation for new tuberculosis vaccines
One measurement of tuberculosis vaccine efficacy in clinical trials is prevention of disease, but different mechanisms can underlie disease prevention. Here, the authors develop a mathematical model that allows to identify mechanisms of action of a vaccine preventing TB disease.
- Mario Tovar
- , Sergio Arregui
- & Yamir Moreno
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Article
| Open Access
Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults
Declining NAD+ levels have been linked to aging-associated pathologies. Here the authors present results of a double-blind, randomized crossover trial on 30 healthy middle-aged individuals to show that nicotinamide riboside effectively elevates NAD+ levels in humans, appears to be well tolerated, and may have potential to improve cardiovascular parameters.
- Christopher R. Martens
- , Blair A. Denman
- & Douglas R. Seals
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Article
| Open Access
A randomized and open-label phase II trial reports the efficacy of neoadjuvant lobaplatin in breast cancer
Triple-negative breast cancer (TNBC) is one of the most aggressive and difficult to treat types of breast cancer. Here, a phase 2 clinical trial in TNBC patients reveals that the addition of lobaplatin to docetaxel and epirubicin regime improves pCR and ORR rates with tolerable side-effects.
- Xiujuan Wu
- , Peng Tang
- & Yi Zhang
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Article
| Open Access
Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study
Long-chain omega-3 polyunsaturated fatty acids are essential for neural development and lack of these fatty acids has been implicated in a number of mental health conditions. Here the authors report the longer-term efficacy of a randomized, double-blind, placebo-controlled clinical trial assessing the effects of fish oil capsules in individuals at ultrahigh risk for psychosis.
- G. Paul Amminger
- , Miriam R. Schäfer
- & Patrick D. McGorry
Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials