Placebo/Active Controlled, Safety, Pharmaco-Kinetic/Dynamic Study of INP105 (POD? olanzapine) in Healthy Adults

摘要

Introduction: A 2008 survey of emergency department staff (ED) found that 65% had witnessed physical attacks, 32% reported at least one verbal threat per day, and 18% had been assaulted at least once with a weapon. While many of the attacks were due to acute agitation, only 6% of the surveyed EDs had a protocol for medication selection and 40% provided training for staff. During acute agitation episodes – up to seven million/year in U.S. hospitals and EDs – olanzapine (OLZ) intramuscular (IM) is favoured due to a shorter Tmax over oral tablets or oral disintegrating tablets (ODT); however, IM administration requires cooperation, is invasive and can be painful. Uncooperative patients require restraint for the administration of OLZ IM that may be viewed as an assault, thereby reducing trust in medical personnel and increasing the likelihood of staff injuries. When possible, non-injectable forms are preferred during agitation; however, currently approved oral products have slower onset of effect, often requiring labour-intensive observation of the medicated patient until resolved.INP105 is a drug-device combination product consisting of a powder form of OLZ delivered by a precision olfactory delivery (POD?) device to the vascular-rich, upper nasal space for rapid control of agitation in a cooperative or uncooperative patient (with a potentially caregiver?administered dose). For this study a near-final formulation of OLZ was administered by the research embodiment of the POD (I231) device. For subsequent studies, INP105 will use the final commercial formulation adjustments and the commercial POD device. INP105 should provide faster onset of relief compared to oral therapy and be a more accessible dosage form compared to IM therapy without a needle. INP105 may also be suitable for early use by the patient who has insight into his or her condition and can recognize early symptoms of agitation before escalating, uncontrolled agitation leads to violence and injury to the patient, the caregiver and/or healthcare workers. The objectives of this SNAP 101 study were the following: 1) Establish safety and tolerability of three single, ascending doses of INP105; 2) compare pharmacokinetic (PK) data for OLZ)from three INP105 doses with OLZ IM (5 and 10 milligrams [mg]) and orally disintegrating tablets (OLZ-ODT) 10 mg; 3) establish and compare pharmacodynamic (PD) effects of INP105 to OLZ IM and OLZ-ODT; and 4) explore PK/PD and dose-response relationships for INP105.Methods: SNAP 101 was a randomized, double-blind, placebo- and active comparator-controlled, ascending-dose, 2-way, 2?period, incomplete block, crossover Phase 1 trial to compare the safety, tolerability, PK and PD of three doses of INP105 (5 mg, 10 mg and 20 mg) with two doses of OLZ IM (5 mg and 10 mg) and one dose of OLZ-ODT (10 mg).Period 1 was open label; Period 2 was double-blind with at least 14 days between dosing in the two periods. Dose escalation was staggered across cohorts to allow a monitoring committee to assess safety and tolerability of INP105 between doses.Following all dosings in both periods, PD assessments were made by frequent and regular vital signs recordings as well as visual analogue scale for subjective assessment of sedation, the Agitation/Calmness Evaluation Scale, an objective assessment by the investigator, and the timed Digit Symbol Substitution Test. Blood was drawn at frequent timepoints over the 120 hours post dosing for PK evaluation.All subjects were observed as inpatients for at least 72 hours post-dosing of reference therapy and IP. Follow-up occurred four, five and 14 days after dosing for each study period. The first two subjects receiving 10 mg OLZ IM had clinically significant hypotensive events following administration, and thus the study design was immediately changed with the remaining 36 subjects (12 per cohort) being randomized to OLZ 5 mg IM or OLZ ODT 10 mg. After each block of 12 subjects completed period 1 dosing, five days of observation and nine days of washout, they returned for period 2 dosing when they received INP105 (n=9) or placebo. After a further five days of observations and nine days of washout, a safety monitoring committee (SMC) reviewed the safety data before allowing dose to be escalated to the next level, ie, SMC 1 approved proceeding from INP105 5 mg to INP105 10 mg; but at SMC 2, the decision was made to reduce the dose for cohort 3 from INP105 20 mg (four capsules) to 15 mg (three capsules) due to the frequent but not substantial drops in blood pressure noted after cohort 2, period 2 dosing.Conclusion: This SNAP 101 study (completed in 2018 with results expected in December), which administered OLZ to the vascular-rich, upper nasal space with the novel POD? device, should guide further clinical development for a needle-free, easy self- or caregiver-administered, rapidly effective OLZ treatment to abort episodes of acute agitation in low-intensity community or ED settings. Safety signals