A safety grading scale to support dose escalation and define stopping rules for healthy subject first-entry-into-man studies: some points to consider from the French Club Phase I working group.

AIM: To propose a relevant grading scale for clinical adverse events or laboratory results, electrocardiogram (ECG) and vital sign findings supporting both dose escalation and stopping decisions in first-entry-into-man (FIM) studies conducted in young healthy subjects. METHODS: A three-level scale was used for the proposed grading system. The grading is directly derived from the observed severity of discontinuous variables, as are most of clinical adverse events. A 'combined method' based on normal ranges and spontaneous variation is suggested for grading the findings which are continuous variables mainly numerical in nature. One grade, at the subject level, and one algorithm, at the cohort level, support the proposed decision rules. This work was managed by a Club Phase I working group. RESULTS: Examples of grade 1, 2 and 3 limits are given for the most frequent clinical adverse events and laboratory tests, ECG and vital sign findings. When available, the proposed NIH and FDA limits are also provided. The safety recommendation is to use the grade 2 at least as an alert for caution and the grade 3 as a maximum for stopping, applying the algorithm at the cohort level. CONCLUSIONS: This paper proposes a safety grading system based on relevant criteria which might be used by investigators and sponsors to support and rationalize dose escalation decisions in healthy young subject FIM studies. These proposals are designed not to be a guideline but some 'points to consider' helping the dose escalation process. This paper supports the recent reinforcement of the safety requirements for FIM studies by European authorities.

Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor.

This manuscript reports the assessment of pharmacodynamic (PD) markers of anti-coagulation in the first-in-man study with the novel direct Factor Xa (FXa) inhibitor, otamixaban, with a brief description of safety and pharmacokinetic (PK) findings. The study comprised ten consecutive parallel groups of healthy male subjects (6 active, 2 placebo per group). Eight groups received escalating intravenous doses of otamixaban as 6-hour infusions (1.7 to 183 microg/kg/h) and two groups received a bolus dose (30 or 120 microg/kg) with a 6-hour infusion (60 or 140 microg/ kg/h, respectively). PD markers included anti-FXa activity and clotting time measurements, i.e. activated Thromboplastin Time (aPTT), Prothrombin Time (PT), Heptest Clotting Time (HCT), and Russell's Viper Venom-induced clotting Time (RVVT). In addition, Endogenous Thrombin Potential (ETP) was assessed in the bolus-plus-infusion dose groups. Otamixaban was well tolerated. Otamixaban plasma concentrations increased with escalating dose, were maximal at the end-of-infusion (C(eoi)), and decreased rapidly as the infusion was stopped. Anti-FXa activity coincided with otamixaban plasma concentrations and clotting time measurements followed the same pattern. Maximal changes from baseline at C(eoi) were 1.9 +/- 0.2 for aPTT, 2.0 +/- 0.2 for PT, 5.1 +/- 0.6 for HCT, and 4.5 +/- 1.2 for RVVT. Otamixaban inhibited thrombin generation (24% decrease in ETP) and a delay in thrombin generation was noticed in vitro at high concentrations.