Anxiety disorders, obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are common in children and adolescents and can lead to significant impairment. Cognitive behavioural therapy (CBT) with exposure is the first-line treatment, yet approximately half of treated youth do not achieve full remission. Dysfunctional cognitions—negative automatic thoughts, maladaptive beliefs and distorted interpretations—are considered key targets of CBT, but evidence in youth is mixed and underpowered. This study will examine whether change in dysfunctional cognitions mediates treatment outcome in anxiety, OCD and PTSD symptoms and whether this association varies across individual characteristics.

An individual participant data meta-analysis (IPDMA) of randomised controlled trials of CBT for youth aged 5–18 years with anxiety disorders, OCD or PTSD will be conducted. The search strategy includes the databases APA PsycINFO, MEDLINE and Web of Science Core Collection from inception to 8 September 2025. It is supplemented by screening reference lists, trial registries, grey literature and outreach to relevant research groups. Eligible trials must include at least one validated measure of dysfunctional cognitions administered at minimum pre- and post-treatment, and clinical outcomes assessed at post-treatment and follow-up. The two primary outcomes are (1) child-reported symptom severity and (2) clinician-rated clinical severity. Data will be harmonised for dysfunctional cognition scores, moderators (age, gender, socioeconomic status, comorbidity), and primary outcomes. One-stage Bayesian mixed-effects models will examine whether changes in dysfunctional cognitions predict improvements in primary outcomes and whether these effects are moderated by individual characteristics. Missing data will be addressed using multiple imputation within the Bayesian framework, and study-level heterogeneity will be modelled using random intercepts and slopes.

All datasets will be de-identified and managed under General Data Protection Regulation standards. Each included trial will have ethical approval permitting data sharing and reuse, and the secondary analysis of the shared datasets has been approved by the University of Amsterdam. Findings will be disseminated via a peer-reviewed publication, scientific conferences and open sharing of analysis scripts and harmonisation procedures.

CRD420251139130.

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