Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study.

There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in treating patients with COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted to two hospitals in Brazil. One hundred patients were planned to be randomised to either "standard of care" (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 h of randomisation. In the ITT population (n = 75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p = 0.24. However, in the mITT population, nebulised UFH reduced mortality (OR 0.2, p = 0.035). Length of hospital stay was similar between groups, but at day 29, there was a greater improvement in ordinal score following treatment with UFH in the ITT and mITT populations (p = 0.076 and p = 0.012 respectively), while mechanical ventilation rates were lower with UFH in the mITT population (OR 0.31; p = 0.08). Nebulised UFH did not cause any significant adverse events. In conclusion, nebulised UFH added to SOC in hospitalised patients with COVID-19 was well tolerated and showed clinical benefit, particularly in patients who received at least 6 doses of heparin. This trial was funded by The J.R. Moulton Charity Trust and registered under REBEC RBR-8r9hy8f (UTN code: U1111-1263-3136).

Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus.

OBJECTIVE: Both sirolimus and cyclosporine are immunosuppressants used in a combined regimen after organ transplantation. When coadministered with the innovator formulation of cyclosporine, sirolimus blood levels increase 3.3-fold due to a pharmacokinetic interaction. We assessed this drug interaction for potential differences when the innovator formulation is replaced by a generic cyclosporine. METHODS: In this randomized single-dose crossover study, 28 healthy subjects received 5 mg sirolimus oral solution with 250 mg cyclosporine soft gelatin capsules given as the innovator formulation (reference treatment) versus a generic formulation (test treatment). Sirolimus peak blood concentration (Cmax) and area under the concentration-time curve (AUC) were compared between test and reference treatments by standard bioequivalence testing. RESULTS: Sirolimus Cmax was significantly lower by 17% in the presence of generic versus innovator cyclosporine (p=0.0003) and failed bioequivalence criteria with a test/reference ratio of 0.83 (90% confidence interval, 0.77-0.90). Nearly half of the subjects (46%) had sirolimus Cmax changes which fell outside the bioequivalence window with individual Cmax decreases up to 52% and increases up to 39%. Sirolimus AUC was significantly lower by 11% in the presence of generic versus innovator cyclosporine (p=0.041) but satisfied average bioequivalence criteria with a test/reference ratio of 0.89 (0.83-0.95). Nonetheless, over a third of the subjects (43%) had sirolimus AUC changes outside the standard bioequivalence window with individual AUC decreases up to 39% and increases up to 42%. CONCLUSIONS: Switching between innovator and generic cyclosporine may have a clinically-relevant impact on coadministered sirolimus pharmacokinetics. If such a switch is initiated by the prescriber, follow-up therapeutic monitoring of both cyclosporine and sirolimus blood levels should be performed to guide dose adjustments as necessary. If the switch is made without consulting the prescriber, potentially significant changes in sirolimus exposure could go unnoticed by the clinician and patient.