Clinical trial NCT02982889: Single Ascending Dose Study of Two Liquidia Bupivacaine Formulations
Official title: A Phase 1 Randomized, Controlled, Double-Blind, Single Ascending Dose Safety and Pharmacokinetic/Pharmacodynamic Study in Healthy Adult Males After LIQ865 Injection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Pain
Keywords: Analytical, Diagnostic,Therapeutic Technique and Equipment
Anesthesia and Analgesia
Lead sponsor: Liquidia Technologies, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Premier Research Group plc
First posted: 2016-12-06
Enrollment: 29
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: BASIC_SCIENCE

Brief summary: This study is designed to assess and characterize the safety and tolerability profile of LIQ865A and LIQ865B formulations compared to diluent or aqueous bupivacaine hydrochloride when infiltrated into a defined area of the medial calf, and to characterize bupivacaine plasma pharmacokinetic (PK) and pharmacodynamic (PD) profiles after a single dose of LIQ865A or LIQ865B, and to determine the individual plasma concentration/time curves and mean PK parameters of each product.

Detailed description: Infiltration of an aqueous local anesthetic, for example, bupivacaine, into surgical sites at closure provides temporary analgesia, typically lasting up to 6 hours, and is one aspect of the multimodal approach to postsurgical analgesia or fast-track surgery. However, the limited duration of action of local anesthetics, even longer acting agents such as bupivacaine, result in patients who are likely to experience end of duration breakthrough pain before they are able to take or tolerate oral analgesics, thus necessitating the use of strong parenteral analgesics in the immediate postsurgical period. LIQ865A and LIQ865B are two distinct formulations of bupivacaine manufactured via Liquidia Technologies PRINT (Particle Replication In Non-wetting Templates), which Liquidia intends to pursue for product approval. Both formulations being tested have the potential for producing long-lasting control of post-surgical incisional pain.

Eligibility criteria: Inclusion Criteria:

* provide written informed consent prior to enrollment
* be a non-smoking male, American Society of Anesthesiologist (ASA) physical class 1 or 2
* have a BMI between 18.5 and 25 kg. inclusive, and a weight of at least 60 kg
* be willing and able to participate for the duration of the study
* be healthy on the basis of pre-study physical examination (PE), medical history review, vital signs, lab test results as specified in the protocol
* negative urine drug test results
* negative alcohol screening test
* negative antibody test results for hepatitis B, hepatitis C, and HIV

Exclusion Criteria:

* allergic to bupivacaine, or other amide local anesthetics, or the excipients in the LIQ865 formulations or the diluent
* has taken any concomitant medications or supplements for the 3 days prior to Day 0
* has been on blood thinner or medication affecting platelet formation for the 7 days prior to Day 0
* in the opinion of the investigator, is either a hyper or hypo-responder to screening sensitivity testing
* has a history of moderate or severe renal or hepatic impairment, moderate or severe active hepatic disease, or any other clinically significant medical condition that may preclude safe study participation
* has a clinically significant test result for any screening lab parameter
* has a history or ECG screening documentation of a clinically meaningful conduction abnormality
* has scarring, tattoos, infections, or other skin changes in the area of planned study medication injection
* has known neurological disease or dysfunction (central or peripheral) that may interfere with assessments
* is unable to adequately communicate with study staff, properly give informed consent, or otherwise comply with study procedures, particularly the ability to return for outpatient follow up visits
* has participated in another interventional clinical study (investigational or marketed product) within the 30 days prior to Day 0.

Primary outcomes:
measure: Incidence of Treatment Emergent Adverse Events (AEs)
timeFrame: 30 days
Secondary outcomes:
measure: Pharmacokinetic - Area under the plasma concentration curve from time zero to Day 5
timeFrame: Timepoints (draws) at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 hours and 2, 3, 4, 5 days after treatment
measure: Pharmacokinetic - Cmax (ng/mL)
timeFrame: Timepoints (draws) at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 hours and 2, 3, 4, 5 days after treatment
measure: Pharmacokinetic - Tmax (h)
timeFrame: Timepoints (draws) at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 hours and 2, 3, 4, 5 days after treatment
measure: Pharmacokinetic - t1/2 (h)
timeFrame: Timepoints (draws) at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 hours and 2, 3, 4, 5 days after treatment
measure: Pharmacokinetic - CST1/2 (h)
timeFrame: Timepoints (draws) at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24 hours and 2, 3, 4, 5 days after treatment
measure: Pharmacodynamic Response - Pain intensity (Numeric Rating Scale) with Short Tonic Heat Stimulus (STHS) testing at various time points
timeFrame: 1, 2, 12, 24, 48, 72, 96, and 120 hours
measure: Pharmacodynamic Response - Change in Mechanical Pain Threshold (MPT) compared to Baseline using various time points
timeFrame: 12, 24, 48, 72, 96, and 120 hours
measure: Pharmacodynamic Response - Change in Heat Pain Threshold (HPT) compared to Baseline using various time points
timeFrame: 12, 24, 48, 72, 96, and 120 hours
measure: Pharmacodynamic Response - Change Mechanical Detection Threshold (MDT) compared to Baseline using various time points
timeFrame: 12, 24, 48, 72, 96, and 120 hours
measure: Pharmacodynamic Response - Change in Warmth Detection Threshold (WDT) compared to Baseline using various time points
timeFrame: 12, 24, 48, 72, 96, and 120 hours
measure: Pharmacodynamic Response - Change in Cold Detection Threshold (CDT) compared to Baseline using various time points
timeFrame: 12, 24, 48, 72, 96, and 120 hours
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: DanTrial Aps
Study officials:
affiliation: Multidisciplinary Pain Center, Rigshospitalet
name: Mads U Werner, MD
role: PRINCIPAL_INVESTIGATOR
References: