ABSTRACT
We present our experience with the urgent set-up and execution of a phase 2/3 study to evaluate an investigational medicinal product (ORGN001) in Molybdenum cofactor deficiency type A (MoCDA).MoCDA is a rare inborn error of molybdenum cofactor production resulting in rapidly progressive fatal neurologic damage during the neonatal period. ORGN001 replaces the missing substrate restoring MoCo biosynthesis. It is administered as a daily IV infusion with the first dose given as soon as feasible.A potential subject was identified by prenatal genetic testing on week 12 of pregnancy and was born at 37 weeks via elective C-section. Obstetrics, neonatology and emergency transfer teams were arranged in advance in the local hospital. She was transferred within two hours of birth and was given the first dose of IMP at five hours of life.The set-up of the trial (including R&D approvals) was finalised four weeks before expected birth date in case of prematurity. Early conversations with the intensive care ward ensured appropriate bed space and an admission plan integrating research activities with standard of care. The need for urgent treatment meant careful planning of nursing, pharmacy and medical resources including set up of an on-call rota, training in study protocol and manipulation/administration of the investigational product, and timely EPIC build for prescription and trial specific templates.This is the first time that the Metabolic team takes the lead on a clinical trial of this magnitude providing ad hoc experimental treatment for one patient. Coordination of a multicentre multidisciplinary team in the midst of the COVID19 pandemic was in itself a considerable achievement. Everyone involved was essential to complete the study and achieve the best possible result.The successful execution of this clinical trial shows the adaptation capacity and resilience of GOSH as a research hospital during these difficult times.
ABSTRACT
Detailed information on intrahost viral evolution in SARS-CoV-2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. These likely arose from within-host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample-to-sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.