ABSTRACT
BACKGROUND: This phase 1, randomized, one-day, five-period crossover study in adults with type 1 diabetes on continuous subcutaneous insulin infusion investigated local infusion site pain following infusion of the excipients of ultra rapid lispro (URLi; without insulin) across infusion sites and depths. METHODS: Forty participants (mean age, 40.5 years; body mass index [BMI], 27.5) were randomized to one of five infusion site sequences consisting of the arm, thigh, buttock (6 mm cannula depth), and abdomen (6 and 9 mm depth). Basal infusion of sodium citrate and treprostinil in diluent with magnesium chloride was initiated (10 µL/h) and at three, six, and nine hours after basal initiation, 15 unit-equivalent boluses (150 µL) were given. Participants rated their pain on a 0 to 100 mm validated visual analog scale (VAS) at 5 minutes pre-bolus and 1 and 15 minutes post-bolus. RESULTS: At one minute post-bolus, increased VAS scores were occasionally reported. Most one minute post-bolus scores were ≤10 mm (little to no discomfort) while 7 of 577 were >45 mm (generally considered clinically meaningful pain). Painful infusions were reported more frequently for the arm, and mean VAS scores were higher for the arm compared with the thigh and abdomen. The VAS score distributions were similar between cannula depths. By 15 minutes post-bolus, VAS scores returned to pre-bolus levels. CONCLUSIONS: Local infusion site discomfort after infusion of URLi excipients was reported by a small subset of participants; it was transient, tolerable, and dependent on infusion site but not infusion depth. Given differences within individuals, patients may consider using a different infusion site if they experience discomfort. CLINICALTRIAL.GOV IDENTIFIER: NCT05067270.
ABSTRACT
AIMS: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. METHODS: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. RESULTS: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] -0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI -0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. CONCLUSION: These data provide the first human evidence suggesting endothelial-protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.
