New clinical trial design in precision medicine: discovery, development and direction

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Март 4, 2024

Abstract In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to underestimation significant heterogeneity across participants in traditional “one-size-fits-all” trials, patient-centered trials could provide optimal therapy customization specific biomarkers were developed including basket, umbrella, platform trial designs under master protocol framework. recent years, successive FDA approval indications based on biomarker-guided demonstrated these new clinical ushering tremendous opportunities. Despite rapid increase number current research understanding designs, as compared remains limited. The majority focuses methodologies, there is lack in-depth insight concerning underlying biological logic designs. Therefore, we this comprehensive review discovery development their perspective medicine. Meanwhile, discuss future directions potential design view “Precision Pro”, “Dynamic Precision”, “Intelligent Precision”. This would assist trial-related researchers enhance innovation feasibility by expounding logic, which be essential accelerate progression

Язык: Английский

---

Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial

BMC Infectious Diseases, Год журнала: 2024, Номер 24(1)

Опубликована: Янв. 15, 2024

Abstract Brief summary In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance. Background Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir been recommended for the treatment of some countries. Methods a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with were randomised one ten arms including (3.6g on day 0 followed by 1.6g daily complete 7 days treatment) or no study drug. The primary outcome was rate clearance (derived under linear mixed-effects model from log 10 densities standardised duplicate oropharyngeal swab eluates taken over 8 [18 swabs per patient]), assessed modified intention-to-treat population (mITT). safety included all who received at least allocated intervention. This ongoing registered ClinicalTrials.gov (NCT05041907) 13/09/2021. Results final analysis, mITT contained data 114 and 126 concurrently Under fitted density estimates first randomisation (4,318 swabs), there difference between given receiving drug; -1% (95% credible interval: -14 14%) difference. High well-tolerated. Interpretation does COVID-19. estimated quantitative measurements eluate assesses efficacy drugs vivo comparatively few studied patients.

Язык: Английский

---

Clinical course and management of COVID-19 in the era of widespread population immunity

Nature Reviews Microbiology, Год журнала: 2023, Номер 22(2), С. 75 - 88

Опубликована: Дек. 19, 2023

Язык: Английский

---

The emergence and implications of SARS-CoV-2 omicron subvariant BA.2.86 on global health

International Journal of Surgery, Год журнала: 2024, Номер 110(4), С. 2498 - 2501

Опубликована: Янв. 11, 2024

The SARS-CoV-2 subvariant BA.2.86 ‘Pirola’, first identified in Denmark August 2023, has manifested with a significantly mutated spike protein profile, suggesting heightened ability to evade vaccine-induced and infection-induced antibodies. This article outlines the epidemiological spread, immune response implications, global responses BA.2.86. Preliminary observations indicate community transmissions of subvariant, even among those previously infected or vaccinated. Notably, infection shown potential amplify antibody responses. variant’s emergence evoked memories Omicron rise late 2021, though immunity levels might modulate impact differently. Continuous genomic surveillance, coupled integrated diagnostic strategies, proves crucial early detection management. reaffirms unpredictable nature COVID-19 pandemic, emphasizing need for ongoing research, adaptability, collaboration.

Язык: Английский

---

The relationship between viral clearance rates and disease progression in early symptomatic COVID-19: a systematic review and meta-regression analysis

Journal of Antimicrobial Chemotherapy, Год журнала: 2024, Номер 79(5), С. 935 - 945

Опубликована: Фев. 5, 2024

Abstract Background Effective antiviral drugs accelerate viral clearance in acute COVID-19 infections; the relationship between accelerating and reducing severe clinical outcomes is unclear. Methods A systematic review was conducted of randomized controlled trials (RCTs) therapies early symptomatic COVID-19, where data were available. Treatment benefit defined clinically as relative risk hospitalization/death during follow-up (≥14 days), virologically SARS-CoV-2 rate ratio (VCRR). The VCRR rates intervention control arms. virological treatment effects assessed by mixed-effects meta-regression. Results From 57 potentially eligible RCTs, VCRRs derived for 44 (52 384 participants); 32 had ≥1 endpoint each arm. Overall, 9.7% (R2) variation explained with an estimated linear coefficient −0.92 (95% CI: −1.99 to 0.13; P = 0.08). However, this estimate highly sensitive inclusion recent very large PANORAMIC trial. Omitting outlier, half (R2 50.4%) [slope −1.47 CI −2.43 −0.51); 0.003], i.e. higher associated increased benefit. Conclusion determining studies vary greatly. As prohibitively sample sizes are now required show therapeutic assessments, a reasonable surrogate endpoint.

Язык: Английский

---

A unifying model to explain frequent SARS-CoV-2 rebound after nirmatrelvir treatment and limited prophylactic efficacy

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 28, 2024

Abstract In a pivotal trial (EPIC-HR), 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days symptoms onset), decreased hospitalization and death by 89.1% nasal viral load 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis trial, frequent rebound has been observed subsequent cohorts. We develop mathematical model capturing viral-immune dynamics nirmatrelvir pharmacokinetics that recapitulates loads from this another clinical (PLATCOV). Our results suggest nirmatrelvir’s vivo potency is significantly lower than vitro assays predict. According our model, maximally potent agent would reduce the approximately 3.5 logs at 5 days. The identifies earlier initiation shorter treatment duration are key predictors post-treatment rebound. Extension 10 for Omicron variant vaccinated individuals, rather increasing dose or dosing frequency, predicted incidence significantly.

Язык: Английский

---

Symptoms, Viral Loads, and Rebound Among COVID-19 Outpatients Treated With Nirmatrelvir/Ritonavir Compared With Propensity Score–Matched Untreated Individuals

Clinical Infectious Diseases, Год журнала: 2023, Номер 78(5), С. 1175 - 1184

Опубликована: Ноя. 14, 2023

Abstract Background Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in individuals with COVID-19 who completed N/R similar untreated individuals. Methods identified symptomatic participants tested acute respiratory syndrome 2–positive were eligible a household transmission study. Index cases ambulatory settings their households contacts enrolled. collected daily symptoms, medication use, specimens for quantitative polymerase chain reaction 10 days during March 2022—May 2023. Participants (treated) propensity score matched to participants. rebound, load (VL) average VL by status measured completion or 7 onset if untreated. Results Treated (n = 130) 241) had baseline characteristics. After completion, treated greater occurrence of (32% vs 20%; P .009) (27% 7%; < .001). Average symptoms lower among without (1.0 1.6; .01) but not statistically (3.0 3.4; .5). VLs (0.9 2.6; (4.8 5.1; .7). Conclusions Individuals experienced fewer occured more often Providers should prescribe N/R, when indicated, communicate risk patients.

Язык: Английский

---

How Immunocompromised Hosts Were Left Behind in the Quest to Control the Covid-19 Pandemic

Clinical Infectious Diseases, Год журнала: 2024, Номер unknown

Опубликована: Июнь 3, 2024

The immunocompromised population was disproportionately affected by the SARS-CoV-2 pandemic. However, these individuals were largely excluded from clinical trials of vaccines, monoclonal antibodies, and small molecule antivirals. While community scientists, researchers, funding agencies have proven that therapeutics can be made tested in record time, extending this progress to vulnerable medically complex start has been a missed opportunity. Here we advocate it is paramount plan for future pandemics investing specific trial infrastructure prepared when need arises.

Язык: Английский

---

The Application of Biomaterials for the Vaccine, Treatment, and Detection of SARS-CoV-2

ACS Omega, Год журнала: 2024, Номер 9(5), С. 5175 - 5192

Опубликована: Янв. 26, 2024

The coronavirus disease-19 (COVID-19) pandemic has had a significant impact on human life worldwide since 2019. Specific vaccines and antiviral agents are the most effective means of preventing treating severe acute respiratory syndrome 2 (SARS-CoV-2) infections. Additionally, protective equipment early diagnosis also contribute to controlling spread COVID-19. utilization biomaterials in medicine pharmaceuticals is crucial ensure positive vaccines, agents, equipment. In this review, we discuss application various types biomaterials, including polymers, lipid nanoparticles, inorganic protein- or peptide-associated self-assembled other for vaccine, treatment, prevention Finally, provide perspective future opportunities challenges developing combat viral outbreaks diseases.

Язык: Английский

---

Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV)

The Lancet Infectious Diseases, Год журнала: 2024, Номер 24(9), С. 953 - 963

Опубликована: Апрель 24, 2024

Effective antiviral drugs prevent hospitalisation and death from COVID-19. Antiviral efficacy can be efficiently assessed in vivo by measuring rates of SARS-CoV-2 clearance estimated serial viral genome densities quantitated nasopharyngeal or oropharyngeal swab eluates. We conducted an individual patient data meta-analysis unblinded arms the PLATCOV platform trial to characterise changes kinetics infer optimal design interpretation pharmacometric evaluations.

Язык: Английский

---