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Single Ascending Dose Study of Two Liquidia Bupivacaine Formulations

Primary Purpose

Acute Pain

Status

Completed

Phase

Phase 1

Locations

Denmark

Study Type

Interventional

Intervention

LIQ865A bupivacaine formulation

LIQ865B bupivacaine formulation

Diluent for LIQ865

0.5% bupivacaine hydrochoride

About this trial

This is an interventional basic science trial for Acute Pain focused on measuring Analytical, Diagnostic,Therapeutic Technique and Equipment, Anesthesia and Analgesia

Eligibility Criteria

18 Years - 45 Years (Adult)MaleAccepts Healthy Volunteers

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.

Sites / Locations

DanTrial Aps

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Active Comparator

Arm Label

LIQ865A bupivacaine formulation

LIQ865B bupivacaine formulation

Diluent for LIQ865

0.5% bupivacaine hydrochoride

Arm Description

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

Liquidia's PRINT bupivacaine free base suspension for subcutaneous injection at doses ranging from 150mg to 600mg

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

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).

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Pharmacokinetic - Area under the plasma concentration curve from time zero to Day 5

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.

Pharmacokinetic - Tmax (h)

Time to reach maximum plasma concentration

Pharmacokinetic - t1/2 (h)

Apparent terminal elimination half-life

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.

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

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

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

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

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

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

Full Information

NCT ID

NCT02982889

First Posted

November 22, 2016

Last Updated

August 23, 2017

Sponsor

Liquidia Technologies, Inc.

Collaborators

Premier Research Group plc

1. Study Identification

Unique Protocol Identification Number

NCT02982889

Brief Title

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

2. Study Status

Record Verification Date

August 2017

Overall Recruitment Status

Completed

Study Start Date

December 5, 2016 (Actual)

Primary Completion Date

March 23, 2017 (Actual)

Study Completion Date

April 26, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Liquidia Technologies, Inc.

Collaborators

Premier Research Group plc

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Pain

Keywords

Analytical, Diagnostic,Therapeutic Technique and Equipment, Anesthesia and Analgesia

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Factorial Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

29 (Actual)

8. Arms, Groups, and Interventions

Arm Title

LIQ865A bupivacaine formulation

Arm Type

Experimental

Arm Description

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

Arm Title

LIQ865B bupivacaine formulation

Arm Type

Experimental

Arm Description

Liquidia's PRINT bupivacaine free base suspension for subcutaneous injection at doses ranging from 150mg to 600mg

Arm Title

Diluent for LIQ865

Arm Type

Placebo Comparator

Arm Description

Arm Title

0.5% bupivacaine hydrochoride

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

LIQ865A bupivacaine formulation

Other Intervention Name(s)

Marcaine, Marcaine Spinal, Sensorcaine, Sensorcaine-MPF, Sensorcaine-MPF Spinal, Marcaine HCl, Exparel

Intervention Description

single subcutaneous injection in medial calf

Intervention Type

Drug

Intervention Name(s)

LIQ865B bupivacaine formulation

Other Intervention Name(s)

Marcaine, Marcaine Spinal, Sensorcaine, Sensorcaine-MPF, Sensorcaine-MPF Spinal, Marcaine HCl, Exparel

Intervention Description

single subcutaneous injection in medial calf

Intervention Type

Drug

Intervention Name(s)

Diluent for LIQ865

Other Intervention Name(s)

Hyaluronic Acid

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

0.5% bupivacaine hydrochoride

Other Intervention Name(s)

Marcaine, Marcaine Spinal, Sensorcaine, Sensorcaine-MPF, Sensorcaine-MPF Spinal, Marcaine HCl, Exparel

Intervention Description

single subcutaneous injection

Primary Outcome Measure Information:

Title

Incidence of Treatment Emergent Adverse Events (AEs)

Description

Safety assessments will include the incidence and severity of AEs during treatment and the follow-up period of the study

Time Frame

30 days

Secondary Outcome Measure Information:

Title

Pharmacokinetic - Area under the plasma concentration curve from time zero to Day 5

Time Frame

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

Title

Pharmacokinetic - Cmax (ng/mL)

Description

Maximum plasma concentration over the entire sampling period, directly obtained from the experimental data of plasma concentration versus time curves, without interpolation.

Time Frame

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

Title

Pharmacokinetic - Tmax (h)

Description

Time to reach maximum plasma concentration

Time Frame

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

Title

Pharmacokinetic - t1/2 (h)

Description

Apparent terminal elimination half-life

Time Frame

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

Title

Pharmacokinetic - CST1/2 (h)

Description

Context-sensitive half-time measured from Tmax to time for plasma concentration to reach half of Cmax following study medication injection.

Time Frame

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

Title

Pharmacodynamic Response - Pain intensity (Numeric Rating Scale) with Short Tonic Heat Stimulus (STHS) testing at various time points

Description

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

Time Frame

1, 2, 12, 24, 48, 72, 96, and 120 hours

Title

Pharmacodynamic Response - Change in Mechanical Pain Threshold (MPT) compared to Baseline using various time points

Description

Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120

Time Frame

12, 24, 48, 72, 96, and 120 hours

Title

Pharmacodynamic Response - Change in Heat Pain Threshold (HPT) compared to Baseline using various time points

Description

Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120

Time Frame

12, 24, 48, 72, 96, and 120 hours

Title

Pharmacodynamic Response - Change Mechanical Detection Threshold (MDT) compared to Baseline using various time points

Description

Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120

Time Frame

12, 24, 48, 72, 96, and 120 hours

Title

Pharmacodynamic Response - Change in Warmth Detection Threshold (WDT) compared to Baseline using various time points

Description

Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120

Time Frame

12, 24, 48, 72, 96, and 120 hours

Title

Pharmacodynamic Response - Change in Cold Detection Threshold (CDT) compared to Baseline using various time points

Description

Calculate the time-weighted sum of threshold differences (calculated as area-under-the-curve (AUC): AUC12, AUC24, AUC48, AUC72, AUC96, AUC120

Time Frame

12, 24, 48, 72, 96, and 120 hours

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mads U Werner, MD

Organizational Affiliation

Multidisciplinary Pain Center, Rigshospitalet

Official's Role

Principal Investigator

Facility Information:

Facility Name

DanTrial Aps

City

Copenhagen

ZIP/Postal Code

2400

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Single Ascending Dose Study of Two Liquidia Bupivacaine Formulations

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