Procedures
INM004 was formulated by Inmunova and manufactured under GMP standards and supplied in vials containing: Total proteins (equines) 125,0 mg; Sodium chloride 45,0 mg; Hydrochloric Acid/Sodium Hydroxide as much as suffices to keep pH between 6,0 and 7,0; Water for injection as much as suffices to 5 mL.
Safety monitoring and tolerability of INM004 were assessed by monitoring adverse events (AEs), laboratory test values, and vital signs (blood pressure, heart rate and complete physical examination and 12 lead electrocardiogram examinations).
The trial was divided into two stages. In Stage I, 8 study subjects were divided in two cohorts of 4 patients to receive a single dose of INM004 or placebo at an INM004:placebo rate of 3:1 with dose escalation design. Thus, after a screening period of two weeks, study participants in the first and second cohort received 2 mg.kg-1 protein of INM004 or placebo and 4 mg.kg-1 of INM004 or placebo, respectively. We selected an initial dose of 2 mg.kg-1 based on the kinetics and effectiveness determined in preclinical studies. This dose was determined after applying a correction factor of 5 to the maximum dose of 116 mg.kg-1 administered in mice following the allometric approach recommended by the US Food and Drug Agency´s guidelines. We used this correction factor since the NOAEL was not reached with the highest dose tested in mice, and similar equine Fab products already available for human use have demonstrated safety in humans at higher protein doses.
Four participants received sequentially an initial dose of 2 mg.kg-1 intravenously, with ClNa 0.9% in a total volume of 100 ml administered at 2 ml.min-1. Once we established that the drug was well tolerated, four more volunteers were enrolled and received 4 mg.kg-1. Both cohorts of stage I had a INM004:placebo rate of 3:1.
Stage II recruited and randomized sequentially 6 study subjects to receive INM004 or placebo (INM004:placebo rate of 5:1). After a screening period of two weeks, participants received three repeated doses of 4 mg.kg-1 of INM004 or placebo every 24 hours.
Four visits for PK sampling and a final safety follow-up visit at 30 days after hospital discharge were pre-scheduled. In case of occurrence of adverse events (AEs), unscheduled visits or hospitalizations were performed until resolution of the event.