L-citrulline Injection in Patients Aged 6-21 Years Old with Sickle Cell Disease Presenting with Vaso-Occlusive Crisis (VOC)
brief summary
The purpose of this study is to determine if intravenous L-citrulline can abrogate an active vaso-occlusive crisis in sickle cell disease, resulting in decreased pain, reduction or elimination of opiate usage, and reduction or elimination of hospital admission. The applicant is developing intravenous L-citrulline (Turnobi™) for treatment of sickle cell disease (SCD). The current development program targets treatment of sickle cell-associated vaso-occlusive crisis (VOC) specifically. The aim of Part 1 is to identify the optimum dose regimens for the Part 2 of the trial which is a double-blind, placebo controlled adaptive 'pick-the-winner' design. This study will allow assignment of more subjects to the better treatment arm/s based on emerging data. The study, initially, will evaluate efficacy and tolerability of incremental doses of intravenous (IV) L-citrulline (Turnobi™) in patients with SCD while receiving standard of care therapy for VOC.
detailed description
Overall Design:
This is a study in children, adolescents, and young adults (6 to 21 years) with SCD presenting to an emergency department (ED) with VOC. Children below age 6 are likely to be recruited in a subsequent phase, once proof of concept is established on optimized dose regimen. Eligible subjects will have documented SCD. Intravenous L citrulline (Turnobi™) or placebo will be administered in addition to standard of care VOC therapy to children, adolescents, and young adults presenting with SCD VOC - defined as painful episode without other apparent causes of pain and without significant organ dysfunction or signs of systemic infection.
This is a single center study, conducted in 2 parts:
Part 1: This is an open-label, ascending dose part of the study. After obtaining the informed consent/assent, the enrolled subjects will be in the ED for up to 7 hours where L-citrulline will be administered as depicted in the dosing panel below. Each dose will be administered sequentially until 5 subjects per dose cohort are accrued.
Dosing panels in Part 1:
25 mg/kg bolus + 9 mg/kg/hr infusion; 50 mg/kg bolus + 9 mg/kg/hr infusion; 100 mg/kg bolus + 9 mg/kg/hr infusion; 100 mg/kg bolus + 11 mg/kg/hr infusion;
After each panel of 5 have been dosed, response to a dose is determined by the Principal Investigator (PI) with the internal review committee based primarily on analgesic effects assessed by review of Visual Analogue Scale (VAS) score, opioid dosing, and tolerability.
If the dose panel is assessed safe and 3 of 5 subjects in a cohort respond to the treatment, the current dose arm will continue to accrue a total of 10 subjects. If the dose panel is assessed as safe; however, fewer than 3 of the 5 subjects respond, the current dose arm will be stopped, and the subjects will be recruited to the next dosing panel.
Two additional panels of 5 to 10 subjects receiving doses outside these ranges may be accrued at the request of the internal review committee if determined necessary to achieve the study's objectives. As long as supported by emerging data, the subjects in these additional panels may receive a lower or higher bolus injection but no greater than 150 mg/kg bolus and/or a lower or higher infusion dose but no greater than 15 mg/kg/hour. Up to 60 subjects may be enrolled in Part 1 of the study with a likely sample size of approximately 40 subjects.
official title
A Phase I/IIA Open-label Dose-Finding Study with Subsequent Double-blind, Placebo-controlled, Randomized Study of L-citrulline in Sickle Cell Disease Presenting to Emergency Department (ED) in Vaso Occlusive Crisis (VOC) in Children, Adolescents and Young Adults (6 to 21 Years)