To explore patient and clinician experiences of participation in the MACRO randomised controlled trial (RCT)—which found endoscopic sinus surgery (ESS) to be clinically effective whereas clarithromycin was no better than placebo for chronic rhinosinusitis (CRS)—and to identify barriers and facilitators to the implementation of the trial results.

Qualitative study embedded within the multicentre MACRO RCT. Semistructured interviews with patients and clinicians were analysed using thematic analysis.

21 secondary and tertiary ear, nose and throat centres in England and Scotland participating in the MACRO RCT.

20 CRS patients (16 with nasal polyps, 4 without) were interviewed approximately 6 months after trial completion, and 17 clinical staff including principal investigators (PIs), associate PIs and research nurses.

This study explored patients’ and clinicians’ experiences of the trial to identify barriers and facilitators to implementing the findings. Adopting the outcomes of the trial would involve recommending surgery to more patients with CRS. Yet patient and clinician interviews highlighted polarised views on ESS among patients, between those with positive experiences and expectations of ESS and those expressing fear of complications and hesitancy to receive surgery. During the trial, many participants randomised to surgery reported rapid improvement in symptoms, but with postoperative challenges for some patients including pain, unexpected symptoms and variations in recovery period. Priorities for implementation include providing patients with information about risks and support to make informed choices. Clinicians also reflected on the resource implications for offering ESS to more patients.

ESS is effective for CRS, but patient hesitancy and recovery concerns persist. Implementation requires clear communication, recognition and respect for individual preferences, tailored support for decision-making and post-surgical care to optimise acceptance and outcomes.

ISRCTN36962030.

Neonatal death and later disability remain common sequelae of hypoxic-ischaemic encephalopathy (HIE) despite the now standard use of therapeutic hypothermia (HT). New therapeutic approaches to brain protection are required. Melatonin is an indolamine hormone with free-radical scavenging, antiapoptotic, anti-inflammatory and gene regulatory neuroprotective properties, which has extensive preclinical evidence of safety and efficacy. Pharmacokinetic (PK) data suggest it is necessary to reach melatonin levels of 15–30 mg/L within 6–8 hours of hypoxia-ischaemia for brain protection. We developed a novel Good Manufacturing Practice (GMP) grade melatonin in ethanol 50 mg/mL solution for intravenous use. In preclinical studies, ethanol is an adjuvant excipient with additional neuroprotective benefit; optimised dosing protocols can achieve therapeutic melatonin levels while limiting blood alcohol concentrations (BACs).

The Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN) Study is a first-in-human, international, multicentre, phase 1 safety study of intravenous melatonin in babies with moderate/severe HIE receiving HT. Sixty babies will be studied over two phases: a dose escalation study including four dose levels to establish the recommended phase 2 dose (RP2D), followed by a 6-month cohort expansion study of RP2D to further characterise PKs and affirm safety. Participants will receive a 2-hour intravenous infusion of melatonin within 6 hours of birth, followed by five maintenance doses every 12 hours to cover the period of HT. Plasma melatonin and BACs will be monitored. The RP2D will be based on the attainment of therapeutic melatonin levels while limiting BACs and the frequency of dose-limiting events (DLEs). A Bayesian Escalation with Overdose Control approach will be used to estimate the risk of DLE per dose level, with a target level of

Approval has been given by the London Central National Health Service Health Research Authority Ethics Committee (25/LO/0170) and UK Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency. Separate approvals have been sought in Ireland and Australia. Dissemination will be via peer-reviewed journals, conference presentations, public registries and plain language summaries for parent/legal guardian(s), in accordance with national requirements.

ISRCTN61218504. EU CT: 2025-520538-49-00.

Publication based on the UK protocol V.3.0, 08 May 2025