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.