Featured
-
-
Article
| Open Access
Outcome differences by sex in oncology clinical trials
The role of sex differences in response to cancer therapy remains unclear but this could be improved by reporting sex comparisons of outcomes in clinical trials. Here, the authors characterise the sex outcome comparisons in 89,221 interventional trials, finding that while comparisons were rare, important insights could be obtained.
- Ashwin V. Kammula
- , Alejandro A. Schäffer
- & Eytan Ruppin
-
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
-
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
-
Article
| Open Access
Concordance of randomised controlled trials for artificial intelligence interventions with the CONSORT-AI reporting guidelines
The CONSORT-AI extension was developed to provide specific guidance for randomised controlled trials involving Artificial Intelligence (AI) interventions. Here, the authors show that since publication of CONSORT-AI, several AI-specific considerations remain systematically underreported.
- Alexander P. L. Martindale
- , Benjamin Ng
- & Xiaoxuan Liu
-
Article
| Open Access
Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort
CAMILLA is a basket trial evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Here, the authors present the result of the phase II in the colorectal cohort.
- Anwaar Saeed
- , Robin Park
- & Azhar Saeed
-
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
-
Article
| Open Access
A phase 1/2 clinical trial of invariant natural killer T cell therapy in moderate-severe acute respiratory distress syndrome
Invariant natural killer T (iNKT) cells recognize abnormal cells, but their T cell receptor is not variable and kill cancerous or infected target cells without MHC I restriction. Here, the authors show that in a clinical trial, donor-unrestricted allogeneic iNKT cells could be safely administered to human COVID-19 patients suffering from acute respiratory distress syndrome and trigger an anti-inflammatory response.
- Terese C. Hammond
- , Marco A. Purbhoo
- & Mark A. Exley
-
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
-
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
-
Article
| Open Access
Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients
Using longitudinal profiling of 6385 plasma proteins in hospitalised patients, the authors demonstrate that alveolar capillary barrier disruption in critical COVID-19 is reflected in the plasma proteome, and is attenuated with imatinib treatment.
- Erik Duijvelaar
- , Jack Gisby
- & Jurjan Aman
-
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
-
Article
| Open Access
Redirecting antibody responses from egg-adapted epitopes following repeat vaccination with recombinant or cell culture-based versus egg-based influenza vaccines
Here the authors report an exploratory analysis of a clinical trial that tested different influenza virus vaccination platforms. The results show that multiple seasons of recombinant or cell-based influenza vaccinations may be needed to redirect antibody responses away from immune memory to egg-adapted epitopes and refocus on epitopes on the circulating viruses.
- Feng Liu
- , F. Liaini Gross
- & Min Z. Levine
-
Article
| Open Access
A pilot study of alternative substrates in the critically Ill subject using a ketogenic feed
Critical illness leads to altered metabolic states and bioenergetic failure caused by impaired utilisation of glucose, fatty acids and amino acids. Here the authors show ketogenic diets may provide a safe and acceptable alternative metabolic fuel enabling energy production and maintaining tissue homeostasis.
- Angela McNelly
- , Anne Langan
- & Zudin A. Puthucheary
-
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
-
Article
| Open Access
Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis
Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.
- Zijian Fang
- , Giuditta Corbizi Fattori
- & Simón Méndez-Ferrer
-
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
-
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
-
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
-
Article
| Open Access
Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial
Standard of care for unfavorable-risk cancer of unknown primary (CUP) comprises platinum-based chemotherapy as first-line treatment, however therapeutic options remain limited. Here the authors report the results of a phase II trial of combined nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) in patients with unfavorable CUP.
- Maria Pouyiourou
- , Bianca N. Kraft
- & Alwin Krämer
-
Article
| Open Access
ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial
Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein the authors report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in NAFLD patients.
- Yue Hu
- , Haijun Li
- & Yanhua Ding
-
Article
| Open Access
The Personalized Nutrition Study (POINTS): evaluation of a genetically informed weight loss approach, a Randomized Clinical Trial
Genotype patterns may modify diet effects on weight loss, with greater weight loss on genotype-concordant diets. Here, the authors show that with the current ability to genotype participants as fat- or carbohydrate-responders, evidence does not support greater weight loss on genotype-concordant diets.
- Christoph Höchsmann
- , Shengping Yang
- & Corby K. Martin
-
Article
| Open Access
Dalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial
Dalpiciclib is a CDK4/6 inhibitor, recently approved for treatment in advanced breast cancer patients in China. Here, the authors report the results of a phase II trial investigating oral dalpiciclib (CDK4/6 inhibitor) and pyrotinib (pan-HER inhibitor) in patients with HER2-positive metastatic breast cancer.
- Min Yan
- , Limin Niu
- & Huajun Li
-
Article
| Open Access
Addressing mechanism bias in model-based impact forecasts of new tuberculosis vaccines
The complex transmission chain of tuberculosis (TB) forces mathematical modelers to make mechanistic assumptions when modelling vaccine effects. Here, authors posit a Bayesian formalism that unlocks mechanism-agnostic impact forecasts for TB vaccines.
- M. Tovar
- , Y. Moreno
- & J. Sanz
-
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
-
Article
| Open Access
Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency
Here, Heitmann et al. report results from a Phase I/II trial evaluating CoVac-1, a peptide-based T-cell activator, in patients with B-cell deficiency, demonstrating potent induction of SARS-CoV-2-specific T-cell responses along with a favorable safety profile.
- Jonas S. Heitmann
- , Claudia Tandler
- & Juliane S. Walz
-
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
-
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
-
Article
| Open Access
Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study
Afatinib is a second-generation EGFR tyrosine kinase inhibitor recommended as the first-line treatment for patients with advanced EGFR mutant non-small cell lung cancer (NSCLC). Here the authors report the results of a phase II clinical trial of neoadjuvant afatinib for stage III EGFR mutant NSCLC.
- Dongliang Bian
- , Liangdong Sun
- & Peng Zhang
-
Article
| Open Access
Safety and immunogenicity of a SARS-CoV-2 Gamma variant RBD-based protein adjuvanted vaccine used as booster in healthy adults
Here the authors show in a phase 1 trial that a recombinant subunit vaccine based on the gamma variant of SARS-CoV-2 exhibits a satisfactory safety profile, and induces a broad booster response of neutralizing antibodies and a booster effect on T cell immunity in individuals previously immunized with different SARS-CoV-2 vaccine platforms.
- Karina A. Pasquevich
- , Lorena M. Coria
- & Juliana Cassataro
-
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
-
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
-
Article
| Open Access
In silico cancer immunotherapy trials uncover the consequences of therapy-specific response patterns for clinical trial design and outcome
Conventional clinical trial design methods are not necessarily tailored for the unique characteristics of immunotherapies. Here the authors use late-stage in silico cancer immunotherapy trials to investigate how design decisions affect the trial outcome.
- Jeroen H. A. Creemers
- , Ankur Ankan
- & Johannes Textor
-
Article
| Open Access
Safety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults
Here the authors present results from a randomized, double-blinded Phase 1 clinical trial, testing a thermostable presentation of a clinical-stage adjuvanted subunit tuberculosis vaccine candidate. The vaccine candidate is safe and well tolerated, and elicits comparable or improved immune responses compared to the non-thermostable presentation.
- Zachary K. Sagawa
- , Cristina Goman
- & Christopher B. Fox
-
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
-
Article
| Open Access
Forecasting individual progression trajectories in Alzheimer’s disease
Accurate prediction of disease progression in Alzheimer’s disease (AD) is necessary for optimal recruitment of patients to clinical trials. Here, the authors present AD Course Map, a statistical model which helps to predict disease progression in participants, thus decreasing the required sample size for a hypothetical trial.
- Etienne Maheux
- , Igor Koval
- & Stanley Durrleman
-
Perspective
| Open Access
Future therapies for cystic fibrosis
The cystic fibrosis landscape has changed dramatically over the last few decades, with improvements in patient quality of life, prognosis and predicted survival. In part, this is related to the availability of novel CFTR modulator drugs, although prior advances in symptom-directed therapies and diagnosis had already led to substantial improvements. However, the authors, part of a national CF focused group, recognize that more needs to be done and outline their considerations on research priorities in this perspective.
- Lucy Allen
- , Lorna Allen
- & Jane C. Davies
-
Article
| Open Access
Immunogenicity and efficacy of fourth BNT162b2 and mRNA1273 COVID-19 vaccine doses; three months follow-up
Here the authors provide immunogenicity and efficacy data at 3-month follow-up for vaccinees who have received a fourth dose of either mRNA1273 or BNT162b2. Both vaccines were highly effective against substantial symptomatic disease, but had little effect against SARS-CoV-2 infection.
- Michal Canetti
- , Noam Barda
- & Gili Regev-Yochay
-
Article
| Open Access
First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors
PIK3CA is a commonly mutated cancer-associated gene, making it an attractive therapeutic target. Here, the authors report the results of a first-in-human phase Ia trial to assess the safety and recommended phase II dose of CYH33, a PI3Kα inhibitor, in patients with advanced solid tumors.
- Xiao-Li Wei
- , Fu-Rong Liu
- & Rui-Hua Xu
-
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
-
Article
| Open Access
A phase II trial of weekly nab-paclitaxel for progressive and symptomatic desmoid tumors
In patients with progressive and symptomatic desmoid fibromatosis (DF) treatment with chemotherapy is typically prolonged, while surgery carries a high risk of relapse. Here, the authors report the results of a phase II clinical trial of short-course nab-paclitaxel in patients with progressive and symptomatic DF.
- Javier Martin-Broto
- , Andres Redondo
- & Nadia Hindi
-
Article
| Open Access
The metabolic effects of adding exenatide to basal insulin therapy when targeting remission in early type 2 diabetes in a randomized clinical trial
Combining a GLP-1 receptor agonist, to increase endogenous beta cell function, with exogenous insulin is a possible therapeutic option for the treatment of type 2 diabetes. Here, the authors show adding exenatide to basal insulin in early type 2 diabetes does not further enhance underlying pancreatic beta-cell function or the capacity to achieve diabetes remission, but may yield on-treatment glycemic benefits.
- Ravi Retnakaran
- , Chang Ye
- & Bernard Zinman
-
Perspective
| Open Access
Key considerations to reduce or address respondent burden in patient-reported outcome (PRO) data collection
The collection of patient-reported outcomes (PROs) may capture patients’ assessments of their health status. Here authors highlight PRO-specific issues that should be considered to minimise respondent burden in clinical trials and routine care.
- Olalekan Lee Aiyegbusi
- , Jessica Roydhouse
- & Melanie Calvert
-
Article
| Open Access
Estimating individual treatment effect on disability progression in multiple sclerosis using deep learning
There are limited predictive biomarkers for drug treatment responses in individuals with multiple sclerosis. Here using existing clinical trials data, the authors propose a deep-learning predictive enrichment strategy to identify which participants are most likely to respond to a treatment.
- Jean-Pierre R. Falet
- , Joshua Durso-Finley
- & Douglas Lorne Arnold
-
Article
| Open Access
Heterologous vector versus homologous mRNA COVID-19 booster vaccination in non-seroconverted immunosuppressed patients: a randomized controlled trial
Optimizing COVID-19 vaccination strategies for patients under immunosuppressive medication is of high importance. In this clinical trial including non-seroconverted immunosuppressed patients, a homologous mRNA booster vaccination resulted in higher seroconversion rate than a switch to a vector-based vaccine.
- Daniel Mrak
- , Daniela Sieghart
- & Michael Bonelli
-
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
-
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
-
Article
| Open Access
Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies
G-quadruplex stabilizers, including CX-5461, exhibit synthetic lethality with loss of BRCA1/2 in preclinical models. Here the authors report the results of a phase I study of CX-5461 in patients with solid tumors enriched for DNA-repair deficiencies.
- John Hilton
- , Karen Gelmon
- & David W. Cescon
-
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
-
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
Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial