Pharmacogenetics to Avoid Loss of Hearing (PALOH) trial UK [PALOH-UK]

Gentamicin is an aminoglycoside antibiotic used to treat a range of infections. Thirty years ago, researchers determined that profound irreversible sensorineural hearing loss following gentamicin was associated with a variant (m.1555A>G) in the RNR1 mitochondrial gene. Guidance from the MHRA and clinical pharmacogenetics implementation consortium recommend avoiding gentamicin in individuals with this variant. Individuals affected by cystic fibrosis, who are likely to be prescribed aminoglycosides for infection, are preemptively tested for m.1555A>G and aminoglycosides can be avoided accordingly. Guidance from NICE (NG195) recommends that neonates at risk of, or affected by, sepsis should be prescribed gentamicin and benzylpencillin within one hour of the decision to treat. With laboratory genetic testing only generating results in days, testing in not feasible in this clinical setting. With approximately 100,000 babies admitted to neonatal care in the UK each year, 200 babies are at risk of profound, irreversible hearing loss. We developed a point of care genetic test (POCT) with our technology partner, Genedrive, to generate a result in 26 minutes from a cheek swab at the bedside for the m.1555A>G variant. In a NIHR i4i funded study (PALOH), we implemented this POCT at two large NICUs. Testing 751 babies identified three with the variant who were prescribed an alternative antibiotic and avoided hearing loss. Use of the POCT did not impact the time to administration of antibiotics. The study was published in JAMA Pediatrics and underwent a positive NICE Early Value Assessment. To generate the data requested to fill the evidence gaps, we propose a 24 month study (PALOH-UK). We will collect data from nine neonatal units where the RNR1 POCT will already be routinely used. In addition, to provide geographical spread, we have enlisted five neonatal units of different sizes, including small non-specialist centres, in England, Wales Scotland and Northern Ireland. The study is powered to identify the true failure rate of the system, assuming it is below that found in PALOH. We propose recruiting 5,550 babies. We will collect time to administration of the antibiotic, details on the clinical decisions taken and data on the ethnicities of the babies tested. Each tested sample will be retained and tested by an orthogonal laboratory method to determine the analytical validity of the test. All aspects of the study are co-designed with our parent/public team and we have an extensive Patient and Public Involvement, Engagement and Participation program mirroring the successful programme in PALOH. We will also generate a portfolio of implementation best practice packages, including a standardised training plan for use of the POCT and a quality assured plan for validation of the POCT at each neonatal unit. We will undertake an economic assessment to assess the healthcare costs, health consequences, and impact of introducing the RNR1 assay. Using qualitative mixed-methods approaches the feasibility and acceptability of system integration will be assessed from healthcare professional and parent perspectives. In summary, PALOH-UK will generate the evidence for RNR1 POCT implementation at scale.