Osteogenesis imperfecta (OI) is the most common inherited cause of bone fragility (approximately 1 in 16 000). People with OI suffer bone fragility causing fractures, pain and deformity; sarcopenia causing fatigue and poor endurance; aortic root dilatation and hearing loss. No drug currently has market authorisation to treat OI in Europe. Current standard-of-care is multidisciplinary, with pharmacological interventions—primarily bisphosphonates—directed at increasing bone mass; however, such interventions are of equivocal efficacy. The structural damage that can accumulate as a result of repeated fractures over time may not be reversible. The lack of a treatment with clearly defined efficacy in terms of reducing fracture frequency or the sarcopenia, that is increasingly recognised in this condition, leads to the consideration of alternatives based on what is known about the molecular pathophysiology of the condition. For reasons that are currently unclear, transforming growth factor beta (TGFβ) pathway signalling is increased in OI, and both studies in mouse models and more recently also in humans suggest that reducing TGFβ pathway signalling could be of benefit in OI. This demonstrator project tests the hypothesis that losartan, an antihypertensive agent known to reduce circulating TGFβ, will reduce bone turnover and bone loss and have a positive effect on muscle function and quality of life in adults and older adolescents with OI.

This is a phase 2/pilot, open-label, dose-escalating study. This study aims to identify the effective dose for losartan in this population to inform the design of a pivotal phase III study. The study aims to recruit 30 adolescents and adults aged 16 years and above with OI across secondary care study sites in the UK and Italy. Participants will be recruited from the patient populations attending for treatment of OI at the participating hospital sites or referred by clinicians at the Participant Identification Centres (PIC sites). Participants will be randomised to one of three ‘final doses’—25, 50 or 75 mg losartan once daily. All participants will start on 25 mg once daily. Those assigned to higher ‘final doses’ will increase in 25 mg once daily increments on day 8 and day 15 following safety assessments. The primary outcome measures are to establish the effective dose of losartan in OI patients, based on maximal reduction in the bone resorption marker carboxy-terminal crosslink of type I collagen telopeptide (CTX) over the 24-week period of the study.

Secondary outcome measures are to determine the changes in proxy efficacy outcomes for bone (turnover, mass, architecture and strength) using blood tests, high-resolution peripheral quantitative CT (HRpQCT), dual-energy X-ray absorptiometry (DXA) and muscle (strength) using the ‘Timed Up and Go’ test. In addition, the changes in quality of life, including pain and fatigue, will be evaluated by using a disease-specific tool (OI-QOL) and a validated generic tool (EQ-5D-5L-VAS).

In the UK, the study protocol and amendments have been approved by the London Bridge Research Ethics Committee (REC reference: 23/LO/015) and by the Medicines and Healthcare products Regulatory Agency (MHRA). In Italy, the study protocol and amendments have been approved by the Italian and European ethics and regulatory authorities (Clinical Trials Information System European Union (CTIS EU) portal according to EU Regulation 536/2014). Final version of study protocol: Version 3.2, 05.03.2025. Final results will be disseminated in peer-reviewed journals through local OI, orthopaedic and other relevant clinical networks and at national and international meetings. Sheffield Children’s National Health Service Foundation Trust (UK) and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Ortopedico Rizzoli (Italy) are the joint study sponsors.

ISRCTN (ISRCTN13317811).

The only supportive therapy for patients with severe acute kidney injury (AKI), a common complication among the critically ill, is dialysis. Based on the literature and current guidelines, continuous renal replacement therapy (CRRT) with a total effluent dose of 20–25 mL/kg/hour and adjustments to ensure such dose is delivered despite down time (eg, due to surgical procedures) is recommended. However, experimental and clinical studies suggest that azotaemia, which can be induced by lowering the effluent dose, may accelerate renal recovery. This clinical study investigates whether a lower effluent dose (10–15 mL/kg/hour) for a maximum of 7 days or until successful (>24 hours) liberation of CRRT in critically ill patients with a dialysis-dependent AKI accelerates renal recovery and reduces time on CRRT compared with guideline-directed standard dose (25–30 mL/kg/hour).

The Ketzerei trial is an international, multicentre randomised, controlled trial, designed to investigate if a lower effluent dose (10–15 mL/kg/hour) accelerates renal recovery and reduces the time on CRRT compared with the guideline directed standard effluent dose (25–30 mL/kg/hour). The study aims to enrol 150 critically ill patients with a dialysis-dependent AKI. Eligible patients will be randomised to receive either a standard effluent dose (control group, 25–30 mL/kg/hour) or lower effluent dose (interventional group, 10–15 mL/kg/hour). The primary endpoint is the number of days free from CRRT and alive (from randomisation through day 28). Key secondary endpoints include the number of (serious) adverse events due to potential uremia, the duration of RRT and intensive care unit survival.

The Ketzerei trial has been approved by the Ethics Committee of the Chamber of Physicians Westfalen-Lippe (2023–343 f-s), the University of Muenster and subsequently by the corresponding Ethics Committee of the participating sites. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.

clinicaltrials.gov (NCT06021288).