Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

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Summary. Sixteen patients with thalassaemia major were treated with subcutaneous desferrioxamine (DF) 50 mg/kg/d, 5 consecutive days a week, for 8 weeks. Every other week the total dose was administered by 12 h infusion pump or by rapid injection of the same dose (25 × 2 mg/kg) twice a day. The two methods of DF administration produced no significant differences in urinary iron excretion. No significant changes in serum ferritin levels were observed at the end of the study. Compared with continuous infusion, rapid injection is equally efficacious, does not induce serious side-effects, is better accepted by the patients, and can improve their compliance to the iron-chelating therapy.Keywords: iron overload, desferrioxamine, rapid infusion.Patients with thalassaemia major are at high risk of transfusional iron overload and require continuous chelating treatment to avoid severe complications such as cardiac failure. Administration of subcutaneous desferrioxamine (DF) by 12 h infusion pump is recommended for its efficacy and because it can be carried out at home (Britthenham et al, 1994). Compliance of thalassaemic patients, particularly adolescents, to this treatment is often poor, because the discomfort associated with using the pump greatly affects their quality of life (Cohen, 1987). In order to improve adherence to chelating therapy, we investigated the effects of rapid subcutaneous injection of DF as an alternative to conventional administration by infusion pump. MATERIAL AND METHODSThe study was carried out in 16 patients with thalassaemia major aged between 13 and 30 years (mean 21 . 2 years). All of them received regular blood transfusions every 2-3 weeks to maintain Hb levels above 9 . 5-10 g/dl, and 40-50 mg/kg/d subcutaneous DF by 12 h infusion pump, 5-6 d a week. After informed consent, all patients were given subcutaneous DF 50 mg/kg/d, 5 consecutive days a week, for 8 weeks, according to the following schedule: (1) 1 week during which the total dose of 50 mg/kg diluted in 20 ml distilled water was slowly administered by pump (12 h); (2) 1 week during which a dose of 25 mg/kg/d diluted in 10 ml water was rapidly injected twice a day, every 12 h. Urinary iron after DF was measured in all patients 2, 4, 6, 9, 11 and 13 d after each blood transfusion. At the end of the study, eight patients decided to continue the rapid injection treatment for another 8 weeks. Serum ferritin levels were measured by immunoradioassay at the start and at the end of the study in all patients. Statistical analysis was performed using t-test for paired data. RESULTSThere were no significant differences in urinary iron excretion after subcutaneous DF administered either in the traditional manner of 50 mg/kg/d by 12 h infusion or by rapid injection of the same overall dose twice daily (Table I).

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