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Trial registered on ANZCTR


Registration number
ACTRN12617001330336
Ethics application status
Approved
Date submitted
5/09/2017
Date registered
18/09/2017
Date last updated
2/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Single-Center, Randomized, Placebo-Controlled, Ascending Single-Dose Study of the Pharmacokinetics, Safety, and Tolerability of Oral XG005 in Healthy Volunteers
Scientific title
A Phase 1, Single-Center, Randomized, Placebo-Controlled, Ascending Single-Dose Study of the Pharmacokinetics, Safety, and Tolerability of Oral XG005 in Healthy Volunteers
Secondary ID [1] 292817 0
Sponsor Study Number: XG005-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Pain 304637 0
Condition category
Condition code
Inflammatory and Immune System 303958 303958 0 0
Other inflammatory or immune system disorders
Anaesthesiology 303987 303987 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will investigate five ascending doses of XG005 with 10 subjects per dose group. Period 1 will be double-blind and randomized with 8 subjects (1:1 allocation ratio by gender) assigned to XG005 and 2 subjects (1:1 allocation ratio by gender) assigned to placebo. Subjects will enroll sequentially into a total of five ascending dose levels pending safety review, and if possible, pharmacokinetic review, of Period 1 of the prior dose level. In Period 2. All subjects in the last three XG005 dose groups in Period 1 will receive approximate molar equivalents of Naproxen and Pregabalin for their corresponding XG005 doses after a washout period. Period 2 will be open-label with 10 subjects per group. Sentinel dose participants (1 for XG005 and 1 for placebo) will be included as the first dose administered at each dose level in Period 1.

Study treatments will be administered orally as below:
• XG005 (Capsules) - a drug conjugate of naproxen and pregabalin
• Naproxen (e.g. Inza® or Apo-Naproxen- Tablets)
• Pregabalin (e.g. Lyrica® - Capsules)

Dose Group 1: A single-dose of 50 mg XG005 or matching placebo.
Dose Group 2: A single-dose of 100 mg XG005 or matching placebo.
Dose Group 3: A single-dose of 250 mg XG005 or matching placebo, followed in 7 days by a single dose of combination of Naproxen and Pregabalin at doses of 125 mg and 75 mg, respectively.
Dose Group 4: A single-dose of 500 mg XG005 or matching placebo, followed in 7 days by a single dose of combination of Naproxen and Pregabalin at doses of 250 mg and 150 mg, respectively.
Dose Group 5: A single-dose of 1000 mg XG005 or matching placebo, followed in 7 days by a single dose of combination of Naproxen and Pregabalin at doses of 500 mg and 300 mg, respectively.

The expected duration of participation for each subject following enrollment will be approximately 15 days (from the day prior to dosing of Period 1, through 7 days following dosing of Period 2). The washout will be at least 7 days between the Periods.
Intervention code [1] 299066 0
Treatment: Drugs
Comparator / control treatment
Period 1 will be single-dose, randomized, placebo-controlled, double-blind portion of the study involving the following drugs:
Active:
XG005, the drug substance used for this trial, is a drug conjugate of naproxen and pregabalin with a free carboxylic acid.

Placebo: A placebo, containing only inert excipients, It is identical in appearance and similar in weight to the capsule of XG005 drug product for both dosage levels.

Period 2 will be the single-dose, open-label portion of the study, which involves the following two drugs:
• Naproxen (e.g. Inza® or Apo-Naproxen)
• Pregabalin (e.g. Lyrica®)
Control group
Placebo

Outcomes
Primary outcome [1] 303302 0
The primary objective of this study is to assess the pharmacokinetics of five single ascending doses of XG005 (Period 1). The pharmacokinetic profile will be analyzed by measurement of area under the concentration-time curve [AUC(0-t), AUC(0-inf)], ratio of AUC(0-t) to AUC(0-inf) (AUC % Extrapolated), peak concentration (Cmax), time to peak concentration (Tmax), half-life (T1/2), and terminal elimination rate constant (Kel).
Timepoint [1] 303302 0
PK timepoints are at 0 (pre-dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs after drug administration on Day 1, 24, 48±2, and 72±2 hrs after drug administration on Days 2-4.
Primary outcome [2] 303303 0
The primary objective of this study is to assess the safety and tolerability of five single ascending doses of XG005 (Period 1) Safety and Tolerability Assessments includes the following: Medical history, physical examination, 12-lead ECG, vital signs, adverse events, hematology, blood chemistry, and urinalysis.
Timepoint [2] 303303 0
Medical history: at screening;

Physical examination: at screening, Day -1, and Day 8 (follow-up visit) or upon early withdrawal;

ECG monitoring:
A 12-lead ECG will be performed for each subject at screening, check-in of each Period, pre-dose, at 1±0.25, 2±0.25, 4±0.25, and 8±0.25 hours post-dose each Period, and upon study completion (168 hours post-dose) or upon early withdrawal of subject(s) when possible. Additional ECGs may be performed at other times if deemed necessary.

Vital Signs:
Sitting blood pressure, heart rate, respiratory rate and temperature will be monitored at check-in, pre-dose, and at 2, 4, 8, 12, and 24 hours post-dose of Periods 1 and 2, and at the follow-up visit on Day 8 (168 hours post-dose) or upon early withdrawal of subject(s) when possible.

Adverse Events:
The subjects will be directed by the study physician or staff to report any adverse events and intercurrent illnesses experienced during the trial. Additionally, a specific inquiry regarding adverse events will be conducted 2, 4, 8, 12, 24, and 48 hours post-dose.

Safety Labs:
The full hematology panel will be performed at screening of Period 1, Day -1 and 24 hours post-dose of each Period. and at the follow-up visit 168 hours post final dose of study medication (or upon early withdrawal of subject(s) where possible).

The serum chemistry panel will be performed at screening of Period 1, Day -1 and 24 hours post-dose of each Period, and at the follow-up visit 168 hours post final dose of study medication (or upon early withdrawal of subject(s) where possible).
*Fasting glucose required at Screening visit. Non-fasting at all other timepoints.

Females only - a serum pregnancy test will be performed at screening of Period 1, Day -1 of each period, and at the follow-up visit168 hours post final dose of study medication (or upon early withdrawal of subject(s) where possible).

Urinalysis will be performed at screening of Period 1, Day -1 and 24 hours post-dose of each Period, and at the follow-up visit 168 hours post final dose of study medication (or upon early withdrawal of subject(s) where possible).
Secondary outcome [1] 338561 0
The secondary objective of this study is to collect information on the pharmacokinetics of approximate molar equivalent doses of Naproxen and Pregabalin for three clinical relevant doses of XG005 (Period 2).

The pharmacokinetic profile will be analyzed by measurement of area under the concentration-time curve [AUC(0-t), AUC(0-inf)], ratio of AUC(0-t) to AUC(0-inf) (AUC % Extrapolated), peak concentration (Cmax), time to peak concentration (Tmax), half-life (T1/2), and terminal elimination rate constant (Kel).
Timepoint [1] 338561 0
PK timepoints are at 0 (pre-dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs after drug administration on Day 1, 24, 48±2, and 72±2 hrs after drug administration on Days 2-4.
Secondary outcome [2] 338563 0
The secondary objective of this study is to collect information on the safety of the approximate molar equivalent doses of Naproxen and Pregabalin for three clinical relevant doses of XG005 (Period 2).

Safety and Tolerability Assessments includes the following:
Medical history, physical examination, 12-lead ECG, vital signs, adverse events, hematology, blood chemistry, and urinalysis.
Timepoint [2] 338563 0
Physical examination: at screening, Day -1, and Day 8 (follow-up visit) or upon early withdrawal;

ECG monitoring:
A 12-lead ECG will be performed for each subject at screening, check-in of each Period, pre-dose, at 1±0.25, 2±0.25, 4±0.25, and 8±0.25 hours post-dose each Period, and upon study completion (168 hours post-dose) or upon early withdrawal of subject(s) when possible. Additional ECGs may be performed at other times if deemed necessary.

Vital Signs:
Sitting blood pressure, heart rate, respiratory rate and temperature will be monitored at check-in, pre-dose, and at 2, 4, 8, 12, and 24 hours post-dose of Periods 1 and 2, and at the follow-up visit on Day 8 (168 hours post-dose) or upon early withdrawal of subject(s) when possible.

Adverse Events:
The subjects will be directed by the study physician or staff to report any adverse events and intercurrent illnesses experienced during the trial. Additionally, a specific inquiry regarding adverse events will be conducted 2, 4, 8, 12, 24, and 48 hours post-dose.

Safety Labs:
The full hematology panel will be performed at screening of Period 1, Day -1 and 24 hours post-dose of each Period. and at the follow-up visit 168 hours post final dose of study medication (or upon early withdrawal of subject(s) where possible).

The serum chemistry panel will be performed at screening of Period 1, Day -1 and 24 hours post-dose of each Period, and at the follow-up visit 168 hours post final dose of study medication (or upon early withdrawal of subject(s) where possible).
*Fasting glucose required at Screening visit. Non-fasting at all other timepoints.

Females only - a serum pregnancy test will be performed at screening of Period 1, Day -1 of each period, and at the follow-up visit168 hours post final dose of study medication (or upon early withdrawal of subject(s) where possible).

Urinalysis will be performed at screening of Period 1, Day -1 and 24 hours post-dose of each Period, and at the follow-up visit 168 hours post final dose of study medication (or upon early withdrawal of subject(s) where possible).

Eligibility
Key inclusion criteria
Healthy adult male or female volunteers, 18-55 years of age;
Weighing at least 60 kg for males and 48 kg for females and a BMI range of 18-30 kg/m2 for healthy adults;
Medically healthy subjects with clinically insignificant screening results (laboratory profiles, medical histories, ECGs, physical exam);
Creatinine clearance granter than or equal to 80 mL/min (estimated using the equation of Cockcroft and Gault);
Voluntarily consent to participate in the study;
Females of childbearing potential and males should either be sexually inactive (abstinent) for 14 days prior to screening and throughout the study
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, Hepatitis B, Hepatitis C, HIV, diabetic, or psychiatric disease;
History or presence of alcoholism or drug abuse within the past 2 years;
Consumption of alcohol 48 hours prior each dose throughout the sample collection period for each dose;
Hypersensitivity or idiosyncratic reaction to the study drug, Neurontin, related compounds, or aspartame;
Abnormal diet (for whatever reason) during the 30 days prior to the first dosing;
Donation (standard donation amount or more) of blood or blood products (with the exception of plasma as noted below) within 56 days prior to the study;
Plasma donation within 7 days prior to the study;
Participation in another clinical trial within 30 days prior to the first dose;
Female subjects who are pregnant or lactating;
Hemoglobin < 120 g/L.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/09/2017
Actual
3/10/2017
Date of last participant enrolment
Anticipated
Actual
29/11/2017
Date of last data collection
Anticipated
Actual
18/01/2018
Sample size
Target
50
Accrual to date
Final
50
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 297446 0
Commercial sector/Industry
Name [1] 297446 0
Xgene Pharmaceutical Inc.
Country [1] 297446 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Xgene Pharmaceutical Inc.
Address
58 Gipps Street
Collingwood,
Victoria,
Australia 3066
Country
Australia
Secondary sponsor category [1] 296443 0
Commercial sector/Industry
Name [1] 296443 0
CPR Pharma Services Pty Ltd
Address [1] 296443 0
28 Dalgleish Street,
Thebarton, Adelaide,
South Australia, 5031
Country [1] 296443 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298555 0
Bellberry Limited
Ethics committee address [1] 298555 0
Ethics committee country [1] 298555 0
Australia
Date submitted for ethics approval [1] 298555 0
02/08/2017
Approval date [1] 298555 0
28/09/2017
Ethics approval number [1] 298555 0

Summary
Brief summary
This is a single-center study. The study will investigate five ascending doses of XG005 and the approximate molar equivalent doses of Naproxen and Pregabalin for clinical relevant doses of XG005. Five XG005 treatment groups of with 10 subjects/group will be enrolled sequentially.

Period 1 will be single-dose, randomized, placebo-controlled, double-blind portion of the study and designed to meet the primary study objective. Period 2 will be the single-dose, open-label portion of the study designed to meet the secondary objective of the study. The four planned dose levels of XG005 are 50, 100, 250, 500, and 1000 mg.

Period 1 will be double-blind and randomized with 8 subjects (1:1 allocation ratio by gender) assigned to XG005 and 2 subjects (1:1 allocation ratio by gender) assigned to placebo. Safety Monitoring Committee (SMC; consisting of three members: Investigator, Sponsor Representative, and Independent Medical Monitor) will review available safety and tolerability data from Period 1 of the current dose level before proceeding to the subsequent dose. All subjects in the dose levels of 250, 500 and 1000 mg of XG005 in Period 1 will receive Naproxen and Pregabalin in Period 2 after a washout period. In Period 2, subjects will receive the combination of approximate molar equivalents of Naproxen and Pregabalin for their corresponding XG005 doses in Period 1. Sentinel dose participants (1 for XG005 and 1 for placebo) will be included as the first dose administered at each dose level in Period 1.
Safety data and available PK data will be reviewed prior to the SMC meeting. The SMC must communicate and provide approval to dose escalate prior to dosing the next dose group. The following safety data should be reviewed at each safety meeting: vital signs, ECGs, AEs, physical examination observations, safety lab data (chemistry, hematology & urinalysis) and available PK data. Based upon the data presented, a decision will be made whether to continue with dose escalation as scheduled, to alter the next dose level, or repeat the current dose level if indicated or recommend to terminate the study for safety reasons. Meeting minutes will be documented, particularly the decision to dose escalate. This document will be signed off by the Investigator and filed in the Investigator Site File. Due to the study timelines, all safety data will be reviewed in an un-monitored state, although some of the data may have been monitored by the time of the SMC meeting.
Pharmacokinetic assessments will include blood (26 collection time points with 13 timepoints/Period) samples over the course of the study.
A total of approximately 200 mL of blood (130 mL for PK and 70 mL for clinical labs) will be drawn from each subject during the study.
The expected duration of participation for each subject following enrollment will be approximately 15 days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77450 0
Prof Stephan A Schug
Address 77450 0
UWA Anaesthesiology
Level 2 MRF Building, Royal Perth Hospital,
GPO Box X2213, Perth WA 6847, AUSTRALIA
Country 77450 0
Australia
Phone 77450 0
+61 8 9224 0201
Fax 77450 0
Email 77450 0
[email protected]
Contact person for public queries
Name 77451 0
Stephan A Schug
Address 77451 0
UWA Anaesthesiology
Level 2 MRF Building, Royal Perth Hospital,
GPO Box X2213, Perth WA 6847, AUSTRALIA
Country 77451 0
Australia
Phone 77451 0
+61 8 9224 0201
Fax 77451 0
Email 77451 0
[email protected]
Contact person for scientific queries
Name 77452 0
Stephan A Schug
Address 77452 0
UWA Anaesthesiology
Level 2 MRF Building, Royal Perth Hospital,
GPO Box X2213, Perth WA 6847, AUSTRALIA
Country 77452 0
Australia
Phone 77452 0
+61 8 9224 0201
Fax 77452 0
Email 77452 0
[email protected]

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