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Trial registered on ANZCTR


Registration number
ACTRN12619001131145
Ethics application status
Approved
Date submitted
30/07/2019
Date registered
13/08/2019
Date last updated
19/02/2020
Date data sharing statement initially provided
13/08/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
An interventional study to evaluate the effects of dosages on the Pharmacokinetics (PK, the measure of how the human body processes a substance), Tolerability (how well a substance is tolerated by participants), and Safety of different dosages of XG005 when given to healthy participants as either a single oral dose, or as multiple oral doses.
Scientific title
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Ascending, Single and Multiple Oral Dose Study of the Pharmacokinetics, Safety, and Tolerability of XG005 in Healthy Volunteers
Secondary ID [1] 298884 0
XG005-02
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Analgesia 313852 0
Condition category
Condition code
Anaesthesiology 312251 312251 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
XG005 Tablet 250 mg (equivalent to 125 mg of naproxen and 87 mg of pregabalin) taken orally.

The planned treatments in the Single Ascending Dose (SAD) portion (Part 1) are as follows:
Cohort 1: XG005 250 mg or matching placebo
Cohort 2: XG005 500 mg or matching placebo
Cohort 3: XG005 1000 mg or matching placebo
Cohort 4: XG005 1250 mg or matching placebo
It is planned for cohorts in the SAD portion to be dosed approximately 1 week apart, following escalation approval by the Safety Review Committee (SRC).

The Multiple Ascending Dose (MAD) portion (Part 2) will include a titration period; the plan for which is as follows:
Cohort 1: Day 1- XG005 250 mg or matching placebo, once.
Cohort 2: Day 1- XG005 250 mg or matching placebo, once. Days 2 and 3- XG005 250 mg or matching placebo, two times per day (12 hours apart).
Cohort 3: Day 1- XG005 250 mg or matching placebo, once. Days 2 and 3- XG005 250 mg or matching placebo, two times per day (12 hours apart). Days 4 and 5- XG005 500 mg or matching placebo, two times per day (12 hours apart).
Cohort 4: Day 1- XG005 250 mg or matching placebo, once. Days 2 and 3- XG005 250 mg or matching placebo, two times per day (12 hours apart). Days 4 and 5- XG005 500 mg or matching placebo, two times per day (12 hours apart). Days 6 and 7- XG005 1000 mg or matching placebo, two times per day (12 hours apart).
The titration period will be followed by the target dosing period.
During the target dosing period, participants will receive study drug twice daily for 7 days, 12 hours apart (only morning dose on Day 7). The planned treatments in the MAD target dosing period are as follows:
Cohort 1: XG005 250 mg two times per day or matching placebo
Cohort 2: XG005 500 mg two times per day or matching placebo
Cohort 3: XG005 1000 mg two times per day or matching placebo
Cohort 4: XG005 1250 mg two times per day or matching placebo
It is planned for cohorts in the MAD portion to commence the target dosing approximately 1 month apart, following escalation approval by the Safety Review Committee (SRC).

Subjects who participate in Part 1 of the study will be given the option to also participate in Part 2 of the study (if eligible).
Adherence to the study treatments will be monitored by inpatient stay and observation; participants in both SAD and MAD portions will be confined to the study unit from check-in on Day -1 through to discharge at 72-hour post last dose.
Intervention code [1] 315148 0
Treatment: Drugs
Comparator / control treatment
Matching Placebo Tablet containing lactose.
Control group
Placebo

Outcomes
Primary outcome [1] 320899 0
The composite primary outcome is to determine the plasma and urinary PK profile of single and multiple oral doses of XG005 in healthy subjects.
Blood samples will be collected and the following PK parameters will be assessed in plasma-
Part 1:
Peak concentration (Cmax)
Time to peak concentration (Tmax)
terminal elimination rate constant (Kel)
half-life (t1/2)
Apparent oral clearance (CL/F)
Apparent oral volume of distribution (Vd/F)
Area under the concentration-time curve from time 0 to the last measurable concentration timepoint (AUC0-t)
Area under the concentration-time curve from time 0 and extrapolated to infinity (AUC0-infinity)
Part 2:
maximal concentration at steady-state (Cmax,ss)
minimum concentration (Cmin)
Tmax
Kel
t1/2
steady-state oral clearance (CLss/F)
steady-state volume of distribution (Vss/F)
area under the concentration-time curve for the dosing interval (AUC0-T)

Urine samples will also be collected and the following PK parameters assessed:
the amount of the analyte excreted in urine during each collection interval (Aet1-t2)
Cumulative percentage of dose excreted in urine (% dose excreted, %Ae)
renal clearance (CLr)
Timepoint [1] 320899 0
Blood samples for PK will be collected at the following timepoints:
Pre-morning dose on Days 2–6 of target dose (Part 2 only)
Pre-morning dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72-hours post-morning dose on Day 1 (Part 1) and Day 7 of target dose (Part 2).

Urine samples for PK will be collected at the following intervals on Day 1 (Part 1) and Day 7 of target dose (Part 2):
Pre-morning dose, 0–4 hours, 4–8 hours, 8–12 hours, 12–24 hours, 24–36 hours, 36—48 hours, and 48–72 hours post-morning dose.
Secondary outcome [1] 373294 0
To determine the safety and tolerability of XG005 when administered orally as a single ascending
dose (SAD) and as a multiple ascending dose (MAD) to healthy subjects.
This will be assessed by looking at the incidence, severity, causality, and seriousness of adverse events;
changes in clinical laboratory evaluations; changes in vital signs parameters, and ECGs; and Columbia-Suicide Severity Rating Scale (C-SSRS)
Timepoint [1] 373294 0
Adverse event information will be recorded from the time of admission to the study unit until 7 days after
the last dose of study drug.
Clinical laboratory evaluations of serum chemistry, hematology, and urinalysis will be performed at Screening, Check-in (Day -1), on Day 3 of target dosing (Part 2 only), at Discharge from clinic (72 hours post last dose), and Follow-up/Early Withdrawal.
Vital signs, including blood pressure, pulse rate, and body temperature will be measured at Screening (including respiration rate); Check-in (Day -1); Pre-dose, and 2, 4, 8, 12 and 72 hours post-dose (Day 1, Part 1, and Day 7 of target dose in Part 2); Daily prior to the morning dose during dose titration and on Day 1 of target dosing (Part 2); Follow-up/Early Withdrawal (including respiration rate).
12-lead ECGs will be obtained at: Screening; Check-in (Day -1); Pre-dose and 1, 2, 4, 8, and 72 hours post-dose (Day 1, Part 1, and Day 7 of target dose in Part 2); Daily prior to the morning dose during dose titration and on Day 1 of target dosing (Part 2); Follow-up/Early Withdrawal
C-SSRS will be obtained in Part 2 at Screening, discharge and the Follow Up/Early Withdrawal visit.

Eligibility
Key inclusion criteria
1. Healthy males or females between 18 and 55 years of age (at the time of informed consent), inclusive;
2. Body Mass Index (BMI) 18.0 to 30.0 kg/m2, inclusive;
3. Medically healthy, with no clinically significant screening results, in the opinion of the Investigator;
4. Provide signed informed consent on Institutional Review Board (IRB)-approved consent form prior to any study procedures and can understand and comply with the requirements of the study;
5. Non-pregnant, non-breastfeeding female subjects may be enrolled if they are:
a. Documented to be surgically sterile (verbal confirmation acceptable) or postmenopausal (amenorrhea > 1 year and follicle-stimulating hormone greater than or equal to 30 mU/mL); or
b. Practicing true abstinence from at least 28 days prior to Day 1 and willing to continue until 3 months following the last dose of study drug, and must have a negative serum pregnancy test (women of child-bearing potential [WOCBP] only) at screening and a negative urine pregnancy test (WOCBP only) on Day -1 ; or
c. Practicing an effective method of contraception during treatment and for 3 months following the last dose of study drug and having a negative serum pregnancy test (WOCBP only) at Screening and a negative urine pregnancy test (WOCBP only) on Day -1;
6. Male subjects may be enrolled if they are:
a. Practicing true abstinence for at least 28 days prior to Day 1 and willing to continue until 3 months following the last XG005 dose; or
b. Surgically sterilized (vasectomy– verbal confirmation acceptable), or
c. Willing to use a condom during sexual activity throughout the study and for 3 months after last dose of XG005, plus appropriate contraceptive measures for your female partner . This requirement does not apply to subjects in a same sex relationship and female partners of non-childbearing potential; and
d. Willing to not donate sperm for 3 months after last dose of XG005 (non-vasectomized subjects).
7. Agree to frequent blood and urine sampling during the course of the study;
8. Agree to be confined in the study unit and follow study procedures;
9. Agree to comply with study-specified diet while confined in the Phase 1 unit.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Subjects with unstable or severe illness, including clinically significant malignancy, of hepatic, pulmonary, metabolic, neurologic, cardiovascular, gastrointestinal (e.g., inflammatory bowel disease), hematological, or psychiatric system as indicated on medical history, physical examination, or clinical laboratory, vital signs, and ECGs evaluations, or in the opinion of the Investigator;
2. Subjects with reported history of, or current treatment for, gastrointestinal (GI) disease such as diverticulitis, diverticulosis, irritable bowel syndrome, ulcer, inflammatory bowel disease, upper GI disorders (such as UGID, dyspepsia, heartburn), reflux esophagitis (GERD), or history of conditions such as abdominal gunshot wounds;
3. Subjects with a clinically significant history of medical condition (in the opinion of the Investigator) associated with GI events such as nausea, vomiting, constipation, and diarrhea;
4. Subjects with a history of seizures other than febrile seizures as a child;
5. Subjects with any report of acute illness or febrile event that has not resolved within 72 hours of dosing;
6. Subjects with history of, or current glucose intolerance; or with history of gestational diabetes;
7. Subjects with lifetime history of suicidal behavior or with lifetime history of suicidal ideation as indicated by the C-SSRS (non-suicidal depression will not be exclusionary) (Part 2);
8. Subjects with any use of or intent to use any medications, including prescription, over-the-counter, herbal preparations, or vitamin/mineral supplementation, other than study medications, from 7 days prior to first dose through follow-up visit (except for contraceptives as described in inclusion 5c and occasional paracetamol use, up to 1 g/day, prior to Day -1);
9. Subjects who have received any medications known to chronically alter drug absorption or elimination processes within 30 days of the first dose administration, or subjects who are taking drugs known to affect liver, renal, or hematological function in the opinion of the Sponsor or Investigator;
10. Subjects who have participated (taken investigative drug and/or device) in another clinical trial within 30 days or 5 half-lives, whichever is longer, prior to first dose;
11. Subjects with creatinine clearance < 90 mL/min (estimated using the Cockcroft and Gault equation);
12. Subjects with any elevation of liver function tests (ALT, AST, GGT, bilirubin, or alkaline phosphatase greater than 1.5 times the upper limit of normal range) at screening; isolated elevation of bilirubin without elevation of direct bilirubin is acceptable;
13. Subjects with a creatine kinase (CK) value of greater than 1.5 times the upper limit of normal (not clinically significant [NCS] abnormality is acceptable) at screening that is not explainable by exercise and that does not come back to reference range upon retest;
14. Subjects with leucocytes or lymphocytes less than 1.5 times the lower limit of normal, eosinophils above the upper limit of normal or hemoglobin < 12.0 g/dL at screening;
15. Subjects with proteinuria (more than trace) at Screening;
16. Female subjects with a positive pregnancy test at screening or Day -1, or who are breastfeeding;
17. Subjects with positive Hepatitis B surface antigen, (except due to recent Hepatitis B vaccination), HCV, or HIV;
18. Male subjects with a resting QTcB or QTcF value < 320 msec or > 450 msec, and female subjects with a resting QTcB or QTcF value < 320 msec or > 470 msec, as measured at the Screening visit;
19. Subjects who have a heart rate < 40 or > 100 bpm lying supine for 5 minutes;
20. Subjects who have a blood pressure higher than 140/90 mmHg;
21. Subjects with a history of donation of blood or blood products (with the exception of plasma as noted below), or significant blood loss (Investigator’s discretion) within 30 days prior to the first study dose;
22. Subjects with a plasma donation within 7 days prior to first study dose;
23. Subjects who have used more than 2 cigarettes, cigars, and nicotine-containing products per month within 6 months prior to first study dose, or plan to use them through completion of the follow-up visit;
24. History of drug or alcohol abuse or dependence based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria (within the 2 years prior to Screening) as reported by the subject or known to the Investigator;
25. Subjects with a positive qualitative drug screen for illegal drugs at screening visit or Day -1;
26. Subjects who have not abstained from alcoholic beverages/alcohol-containing products at least 72 hours prior to first dose, or plan to consume them through completion of the follow-up visit;
27. Subjects who have not abstained from grapefruit/Seville oranges at least 7 days prior to first dose, or plan to consume them through completion of the follow-up visit;
28. Subjects who have not abstained from caffeinated beverages/caffeine-containing products at least 48 hours prior to first study dose;
29. Subjects with an abnormal diet including lactose/gluten intolerance or other dietary restrictions (except vegetarian/vegan, religious dietary requirements – e.g. halal), as determined by the Investigator during the 60 days prior to the first study dose;
30. Subjects who cannot refrain from strenuous exercise from 72 hours prior to first study dose through completion of the follow-up visit;
31. Subjects who are employees of the study unit or their family members, students who are working in the study unit, or family members of the Investigator or Sponsor;
32. Hypersensitivity or idiosyncratic reaction to the study drug, Lyrica, Naproxen, related compounds, or aspartame.

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)
Allocation involves contacting the holder of the allocation schedule who is the off-site pharmacist with no contact with participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Other
Other design features
Participants will be assigned to different dosages and treatments depending on which study part and cohort they are enrolled into.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Total enrollment of healthy adult subjects in the planned four dose cohorts in Part 1 and Part 2 is approximately 64 (8 subjects/cohort; 6:2 XG005:placebo). The sample size for this study is based on clinical and practical considerations and not on a formal statistical power calculation.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
22/07/2019
Date of last participant enrolment
Anticipated
4/12/2019
Actual
22/10/2019
Date of last data collection
Anticipated
27/12/2019
Actual
14/11/2019
Sample size
Target
64
Accrual to date
Final
62
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 14355 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 27358 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 303425 0
Commercial sector/Industry
Name [1] 303425 0
Xgene Pharmaceutical Pty Ltd
Country [1] 303425 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Xgene Pharmaceutical Pty Ltd
Address
58 Gipps Street, Collingwood VIC 3066
Country
Australia
Secondary sponsor category [1] 303478 0
None
Name [1] 303478 0
Address [1] 303478 0
Country [1] 303478 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303956 0
Bellberry Limited
Ethics committee address [1] 303956 0
123 Glen Osmond Road Eastwood SA 5063
Ethics committee country [1] 303956 0
Australia
Date submitted for ethics approval [1] 303956 0
08/05/2019
Approval date [1] 303956 0
20/06/2019
Ethics approval number [1] 303956 0
2019-05-401

Summary
Brief summary
This research project is being conducted to look at the safety, tolerability and pharmacokinetics (PK, how the human body processes a substance) of XG005 when given to healthy volunteers orally as a single dose, and when given as multiple oral doses for up to 7 consecutive days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95370 0
Dr Jasmine Williams
Address 95370 0
Linear Clinical Research, Level 1, B Block, QEII Medical Centre, Hospital Avenue
Nedlands Western Australia 6009
Country 95370 0
Australia
Phone 95370 0
+61 8 63825100
Fax 95370 0
Email 95370 0
[email protected]
Contact person for public queries
Name 95371 0
Erin King
Address 95371 0
Syneos Health, 159 Port Road Hindmarsh SA 5007
Country 95371 0
Australia
Phone 95371 0
+61 8 72021544
Fax 95371 0
Email 95371 0
[email protected]
Contact person for scientific queries
Name 95372 0
Jasmine Williams
Address 95372 0
Linear Clinical Research, Level 1, B Block, QEII Medical Centre, Hospital Avenue
Nedlands Western Australia 6009
Country 95372 0
Australia
Phone 95372 0
+61 8 63825100
Fax 95372 0
Email 95372 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
individual participant data underlying published results only
When will data be available (start and end dates)?
Immediately following publication, no end date
Available to whom?
case-by-case basis at the discretion of Primary Sponsor
Available for what types of analyses?
only to achieve the aims in the approved proposal
How or where can data be obtained?
access subject to approvals by sponsor, Xgene Pharmaceuticals Pty Ltd.
Contact Xgene Project Manager Joey Chang [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
3619Clinical study report  [email protected]



Results publications and other study-related documents

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