Background Most treatments reported to favourably impact on experimental lupus nephritis failed to reproduce these results in multicenter randomized controlled trials (RCT) in patients. Preclinical multicenter RCT (pRCT) may help to close the gap between preclinical and clinical trials. We therefore performed the first pRCT in lupus nephritis. We selected the Jak1/2 inhibitor baricitinib as a therapeutic intervention given that similar Jak/Stat inhibitors have shown protective effects in single center animal studies and baricitinib is currently tested in several clinical trials recruiting patients with systemic lupus (NCT 03843125, 03616964, 03616912).
Methods The effect of baricitinib was tested in a randomized, controlled, blinded pre-set study design at two Spanish (Madrid, Barcelona) and two German (Munich, Freiburg) academic sites. Each site included MRL/lpr mice of their own breeding colonies or from diverse commercial providers and kept at housing conditions as per their local standard operating procedures. Group size calculation was based on the assumption that baricitinib would reduce the primary endpoint, i.e. protein/creatinine ratio, by 20%, with a type I error of 0.05, type II error of 0.2, and a power of 0.8. Eligibility criteria were: female, 13–14 weeks old, had developed signs of systemic lupus erythematosus, had stress scores of less than 2, and had no visible tumor or signs of infection. Block randomization was used to randomly assign mice at a 1:1 ratio to receive either 20 mg/kg baricitinib in 0.5% methylcellulose or vehicle daily by oral gavage for 4 weeks. Medication was provided in a blinded fashion by the coordinating study center. Periodically, each site collected urine and blood samples, and scored urine proteinuria, skin lesions and lymphadenopathy. At the end of the treatment interval, kidney, lung, spleen, skin, plasma and urine samples were collected and shipped to the coordinating study center for blinded analysis. All histopathological assessments were performed by an independent kidney pathology institute (RWTH Aachen, Germany) in a blinded fashion. The pre-set primary endpoint was urinary protein/creatinine ratio. Secondary endpoint analyses included plasma auto-antibodies levels, kidney histologic scores (activity and chronicity indices). Glomerular filtration rate and flow cytometry of splenocytes was performed on subgroups of mice at single centers.
Results A total of 56 mice were used, of which 13 in Madrid, 15 in Barcelona, 14 in Freiburg, and 14 in Munich. Mice were randomly assigned to baricitinib treatment (n=28) or vehicle (n=28). At treatment initiation, the average score of proteinuria (tested by sticks 0–4), skin lesion (0–4), and lymphadenopathy (0–6) for baricitinib group were 1.38 ± 0.99, 0.95 ± 1.28, and 2.10 ± 1.80, respectively; above scores for vehicle group were 1.45 ± 1.10, 0.77 ± 1.02, and 1.81 ± 2.02, respectively. Data analysis is ongoing and will be presented at the conference.
Conclusions Preclinical double-blind, randomized, controlled, multicenter trials are a novel tool in preclinical drug testing that might help to predict the outcome of randomized clinical trials.
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