Matrix-directed therapy in older adolescents and adults with osteogenesis imperfecta – the MOI-A study
Osteogenesis imperfecta
This is a Phase II/pilot, open-label dose-escalating study. The final dose is randomly assigned. This study aims to identify the “effective” dose for losartan in this population to inform the design of such a pivotal study. Thirty participants will be randomized at baseline to one of three “final doses” - 25, 50 or 75 mg once daily for 24 weeks. Participants will be randomised sequentially and the responsible statistician will prepare a randomization schedule using the block randomisation with variable block sizes in a 1:1:1 ratio so that 10 participants will be randomized to each final dose arm i.e 10 randomized to the final dose of 25 mg, 10 participants to 50 mg and 10 participants to 75 mg. Randomization will be completed via the REDCap Cloud (RCC) online system provided by the HHTU. After randomisation on Day 1 all participants will start on the lowest dose and increase (if randomised to a higher dose) via a dose escalation pathway as described below. Day 1 – Day 7 All participants will receive 25 mg of losartan on Day 1. On Day 7, a safety assessment check will be conducted on all participants. If either the potassium level is greater than the upper limit of normal (ULN) and/or there are symptoms of persistent hypotension, the participant will be withdrawn from the study and will complete the early withdrawal visit. If both safety assessments are within acceptable limits and the participant was randomised to either the 50 mg or 75 mg groups, the losartan dose will be increased to 50 mg on Day 8. Day 14 – Day 21 On Day 14, a safety assessment check will be conducted on participants taking 50 mg. If both safety checks are within acceptable limits, the participant will either remain on 50 mg (if randomised to that group on Day 1), or increase to 75 mg (if randomised to that group on Day 1) on Day 15. However, if either the potassium level is greater than ULN and/or there are symptoms of persistent hypotension, the dose will be reduced to 25 mg. A safety a
1. Age 16 years and above 2. Diagnosed with osteogenesis imperfecta (any type) 3. Prior treatment with up to and including 6 weeks of oral bisphosphonate therapy is allowed provided there has been a 6-month washout period since the last dose of treatment 4. Prior treatment with a single dose of an intravenous bisphosphonate is allowed provided there has been a 6-month washout period since the treatment was given 5. Prior treatment with a single dose of denosumab is allowed provided there has been a 6-month washout period since the treatment was given 6. A woman of childbearing potential (WOCBP) who agrees to use an effective method of contraception from point of signing the informed consent throughout the study 7. Agreed not to participate in another interventional research project during their involvement in this study 8. Not taking prohibited concomitant medications, listed in exclusion criteria 9. Any other contraindication that makes the patient unsuitable to take part in the study in the opinion of the investigator
1. Current use of losartan 2. Prior use of losartan within the preceding 6 months to enrolment 3. Presence of other chronic illnesses including renal failure likely to affect bone metabolism or structure 4. Known severe hypotension resulting in dizziness, fainting or headaches 5. Hyperkalaemia 6. Current medication that increases potassium retention, or may increase potassium levels, such as potassium-retaining diuretics 7. Current medication with lithium 8. Current medication with other substances which may induce hypotension 9. Currently taking oral bisphosphonates or intravenous bisphosphonates 10. Prior treatment with more than 6 weeks oral bisphosphonates treatment 11. Prior treatment with more than a single dose of intravenous bisphosphonate 12. Prior treatment with more than one dose of denosumab 13. Recent (last 12 months) or current treatment likely to affect bone – this does not include inhaled or intermittent oral therapy with steroids for asthma (no more than 3 months of oral steroids in previous 12 months) 14. Severe hepatic impairment 15. Renal impairment (glomerular filtration rate [GFR] <60 ml/min/m²) if treated with aliskiren-containing products 16. Diabetes mellitus if treated with aliskiren-containing products 17. Cardiac failure treated with diuretics 18. Pregnancy or lactation 19. Known hypersensitivity to losartan or any of the excipients