Single Ascending Dose Study of Two Liquidia Bupivacaine Formulations

A Phase 1 Randomized, Controlled, Double-Blind, Single Ascending Dose Safety and Pharmacokinetic/Pharmacodynamic Study in Healthy Adult Males After LIQ865 Injection

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.

Study Overview

• Status: Completed
• Conditions: Acute Pain
• Intervention / Treatment: Drug: LIQ865A bupivacaine formulation; Drug: Diluent for LIQ865; Drug: LIQ865B bupivacaine formulation; Drug: 0.5% bupivacaine hydrochoride

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • DanTrial Aps

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LIQ865A bupivacaine formulation; Liquidia's PRINT bupivacaine free base/PLGA (poly D,L-lactic-co-glycolic acid) suspension for subcutaneous injection at doses ranging from 150mg to 600mg	Drug: LIQ865A bupivacaine formulation; single subcutaneous injection in medial calf; Other Names: Marcaine; Exparel; Sensorcaine; Marcaine Spinal; Sensorcaine-MPF; Sensorcaine-MPF Spinal; Marcaine HCl; Drug: Diluent for LIQ865; Sterile diluent composed of 12.5mg/g sodium hyaluronate, 5.8mg/g sodium chloride, 1mg/g polysorbate 80, 6.1mg/g Tris base, in sterile water for injection - single subcutaneous injection; Other Names: Hyaluronic Acid
Experimental: LIQ865B bupivacaine formulation; Liquidia's PRINT bupivacaine free base suspension for subcutaneous injection at doses ranging from 150mg to 600mg	Drug: Diluent for LIQ865; Sterile diluent composed of 12.5mg/g sodium hyaluronate, 5.8mg/g sodium chloride, 1mg/g polysorbate 80, 6.1mg/g Tris base, in sterile water for injection - single subcutaneous injection; Other Names: Hyaluronic Acid; Drug: LIQ865B bupivacaine formulation; single subcutaneous injection in medial calf; Other Names: Marcaine; Exparel; Sensorcaine; Marcaine Spinal; Sensorcaine-MPF; Sensorcaine-MPF Spinal; Marcaine HCl
Placebo Comparator: Diluent for LIQ865; Negative control for subcutaneous injection. Each subject will act as his own control, receiving a LIQ865 formulation subcutaneous injection in one calf, and a diluent subcutaneous injection in his other calf	Drug: LIQ865A bupivacaine formulation; single subcutaneous injection in medial calf; Other Names: Marcaine; Exparel; Sensorcaine; Marcaine Spinal; Sensorcaine-MPF; Sensorcaine-MPF Spinal; Marcaine HCl; Drug: Diluent for LIQ865; Sterile diluent composed of 12.5mg/g sodium hyaluronate, 5.8mg/g sodium chloride, 1mg/g polysorbate 80, 6.1mg/g Tris base, in sterile water for injection - single subcutaneous injection; Other Names: Hyaluronic Acid; Drug: LIQ865B bupivacaine formulation; single subcutaneous injection in medial calf; Other Names: Marcaine; Exparel; Sensorcaine; Marcaine Spinal; Sensorcaine-MPF; Sensorcaine-MPF Spinal; Marcaine HCl
Active Comparator: 0.5% bupivacaine hydrochoride; Positive control arm to be used with one of the LIQ865 cohorts, with each subject acting as his own positive control (i.e., one leg will receive subcutaneous injection of LIQ865A or LIQ865B, and the other leg will receive subcutaneous injection of 0.5% bupivacaine hydrochloride).	Drug: LIQ865A bupivacaine formulation; single subcutaneous injection in medial calf; Other Names: Marcaine; Exparel; Sensorcaine; Marcaine Spinal; Sensorcaine-MPF; Sensorcaine-MPF Spinal; Marcaine HCl; Drug: LIQ865B bupivacaine formulation; single subcutaneous injection in medial calf; Other Names: Marcaine; Exparel; Sensorcaine; Marcaine Spinal; Sensorcaine-MPF; Sensorcaine-MPF Spinal; Marcaine HCl; Drug: 0.5% bupivacaine hydrochoride; single subcutaneous injection; Other Names: Marcaine; Exparel; Sensorcaine; Marcaine Spinal; Sensorcaine-MPF; Sensorcaine-MPF Spinal; Marcaine HCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment Emergent Adverse Events (AEs)	Safety assessments will include the incidence and severity of AEs during treatment and the follow-up period of the study	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic - Area under the plasma concentration curve from time zero to Day 5		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
Pharmacokinetic - Cmax (ng/mL)	Maximum plasma concentration over the entire sampling period, directly obtained from the experimental data of plasma concentration versus time curves, without interpolation.	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
Pharmacokinetic - Tmax (h)	Time to reach maximum plasma concentration	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
Pharmacokinetic - t1/2 (h)	Apparent terminal elimination half-life	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
Pharmacokinetic - CST1/2 (h)	Context-sensitive half-time measured from Tmax to time for plasma concentration to reach half of Cmax following study medication injection.	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
Pharmacodynamic Response - Pain intensity (Numeric Rating Scale) with Short Tonic Heat Stimulus (STHS) testing at various time points	Testing done to calculate time-weighted Sum of Pain Intensity Differences (SPID) at the time points noted, compared to Baseline, and time specific SPID results	1, 2, 12, 24, 48, 72, 96, and 120 hours
Pharmacodynamic Response - Change in Mechanical Pain Threshold (MPT) compared to Baseline using various time points	Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120	12, 24, 48, 72, 96, and 120 hours
Pharmacodynamic Response - Change in Heat Pain Threshold (HPT) compared to Baseline using various time points	Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120	12, 24, 48, 72, 96, and 120 hours
Pharmacodynamic Response - Change Mechanical Detection Threshold (MDT) compared to Baseline using various time points	Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120	12, 24, 48, 72, 96, and 120 hours
Pharmacodynamic Response - Change in Warmth Detection Threshold (WDT) compared to Baseline using various time points	Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120	12, 24, 48, 72, 96, and 120 hours
Pharmacodynamic Response - Change in Cold Detection Threshold (CDT) compared to Baseline using various time points	Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120	12, 24, 48, 72, 96, and 120 hours

Collaborators and Investigators

• Sponsor: Liquidia Technologies, Inc.
• Collaborators: Premier Research Group plc
• Investigators: Principal Investigator: Mads U Werner, MD, Multidisciplinary Pain Center, Rigshospitalet

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2016
• Primary Completion (Actual): March 23, 2017
• Study Completion (Actual): April 26, 2017

Study Registration Dates

• First Submitted: November 22, 2016
• First Submitted That Met QC Criteria: December 1, 2016
• First Posted (Estimate): December 6, 2016

Study Record Updates

• Last Update Posted (Actual): August 24, 2017
• Last Update Submitted That Met QC Criteria: August 23, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Anesthesia and Analgesia; Analytical, Diagnostic,Therapeutic Technique and Equipment
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Immunologic Factors; Protective Agents; Adjuvants, Immunologic; Anesthetics, Local; Viscosupplements; Bupivacaine; Hyaluronic Acid
• Other Study ID Numbers: LTI-111; 2016-002420-88 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO