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Trial registered on ANZCTR


Registration number
ACTRN12618001769279
Ethics application status
Approved
Date submitted
22/10/2018
Date registered
29/10/2018
Date last updated
16/07/2019
Date data sharing statement initially provided
29/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and tolerability Phase I study of a new immunomodulatory drug in healthy participants after single and repeat doses.
Scientific title
A Phase I, randomised, double blind, placebo-controlled, dose-escalating study of the safety, tolerability and pharmacokinetics of single and repeat doses and food effect of AK-119 administered orally to healthy volunteers.
Secondary ID [1] 296382 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 310134 0
Condition category
Condition code
Inflammatory and Immune System 308880 308880 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part A, Single Ascending Dose (SAD), involves the oral capsule administration of 0.5 mg up to 24 mg (proposed dose levels are 0.5mg, 2mg, 6mg, 12mg, 24mg) of AK-119, each participant consuming one dose only. The one selected dose cohort will return for a food effect evaluation after at least a 7-day wash-out. The selected dose cohort will participate in a two-way crossover design and return to the clinical unit to receive AK-119/placebo administration of the same for evaluation of the food effect after a washout of at least 7 days. Subjects will undergo the same study assessments in Period 2 as in Period 1, byby the Safety Review Committee (SRC), and will have their follow-up assessment visit 7 days after dose administration in their second period. Subjects will be randomised to receive either no breakfast or a high fat breakfast on the first period and the alternate breakfast in the second period. The cohort and dose selected for the food effect evaluation may be changed after review of the safety data from the first two cohorts of Part A. This part of the study can be conducted in parallel to the higher determined dosing for the subsequent groups. Part B, Multiple Ascending Dose (MAD): up to 16 (2 cohorts) of healthy volunteers will be dosed daily for seven days. Part C, Multiple Ascending Dose (MAD): One cohort of up to 8 healthy volunteers will be dosed daily for up to 28 days. The dose levels for Parts B and C will be selected following review of safety and pharmacodynamics data from the preceding part(s) of the study. Drug will be administrated at the site under supervision of trained staff monitoring adherence.
Intervention code [1] 312720 0
Treatment: Drugs
Comparator / control treatment
Placebo (microcrystalline cellulose tables) controlled treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 307852 0
To determine the safety and tolerability of ascending dose levels of AK-119 when administered as a single dose (Part A) and multiple oral doses (Part B & C) to healthy volunteers. The study assessments will include: vital signs, triplicate 12-lead ECGs, 24-hour holter monitoring, telemetry, blood and urine samples for laboratory, pharmacokinetic (PK) and pharmacodynamic (PD) assessments, review of concomitant medications and adverse events (AE).
Timepoint [1] 307852 0
The primary timepoints are for Part A: Days 1, 2-3, 4 and 7 after a single dose: for Part B; Days 1, 2-7, 8-9, 10 and 14 after multiple oral dosing for 7 days: for Part C: Days 1, 2-28 and 35 after multiple dosing for 28 days.
Primary outcome [2] 307867 0
To determine the food effect on AK-119 absorption when administered as a single dose (Part A) in one cohort of healthy volunteers in Part A. The study will include AK-119 pharmacokinetics (AUC, T1/2, Tmax, Cmax) as assessed by plasma assay or Absolute lymphocyte count as assessed by serum assay.
Timepoint [2] 307867 0
The blood samples for pharmacokinetics at pre-dose and 30 minutes and 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose; the pharmacodynamic blood samples to determine the absolute lymphocyte count (ALC) at pre-dose, 2, 4, 6, 8, 12, 16, and 24 hours post-dose;
the pre-dose urine sample for pharmacokinetics (within 30 minutes prior to Investigational Product administration) and bulk urine samples over the collection periods of 0-4, 4-12, 12-24 and 24-48 hours post dose.
Secondary outcome [1] 353156 0
Single-dose AK-119 plasma pharmacokinetics (AUC, Tmax, T1/2). The plasma concentration will be determined by validated liquid chromatography-tandem mass spectrometry method.

Timepoint [1] 353156 0
Secondary time points: 0 (pre-dose) 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose.
Secondary outcome [2] 353287 0
Single-dose AK-119 urine pharmacokinetics. The urine concentration will be determined by validated liquid chromatography-tandem mass spectrometry method
Timepoint [2] 353287 0
At pre-dose, 0-4, 4-12, 12-24 and 24-48 hours post-dose.
Secondary outcome [3] 353288 0
Single-dose AK-119 plasma pharmacodynamics, by Absolute lymphocyte count assessed by serum assay.
Timepoint [3] 353288 0
-24, -22, -20, -18, -16, -12, -8 hrs and immediately before pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 168 hours.
Secondary outcome [4] 353289 0
Multiple-dose, once daily for seven days, AK-119 plasma pharmacokinetics (AUC, Tmax, T1/2). The plasma concentration will be determined by validated liquid chromatography-tandem mass spectrometry method.
Timepoint [4] 353289 0
Blood samples collected at 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 16 hours post dose on Day 1, immediately prior to dosing on days 2- 7; post dose on day 7 at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours .
Secondary outcome [5] 353290 0
Multiple-dose, once daily for seven days, AK-119 urine pharmacokinetics The urine concentration will be determined by validated liquid chromatography-tandem mass spectrometry method.
Timepoint [5] 353290 0
At predose, 0-4, 4-12, 12-24 and 24-48 hours after dosing on Days 1 and 7 .
Secondary outcome [6] 353292 0
Multiple-dose, once daily for 7 days, AK-119 plasma pharmacodynamics, by Absolute lymphocyte count assessed by serum assay.
Timepoint [6] 353292 0
-24, -22, -20, -18, -16, -12, -8 hrs and immediately before pre-dose, 2, 4, 6, 8, 12, 16 hours post dose on Day 1, pre-dose on Days 2-6 and on Day 7 pre-dose, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 168 hours post dose (timings may be adjusted on review of ALC response from Part A)

Secondary outcome [7] 353293 0
Multiple-dose, once daily for 28 days, AK-119 plasma pharmacokinetics (AUC, Tmax, T1/2). The plasma concentration will be determined by validated liquid chromatography-tandem mass spectrometry method.
Timepoint [7] 353293 0
At 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours post Day 1 dose, pre-dose on Days 3, 5, 8, 15, 22 and 28 and post dose 2, 4, 6, 8, 12, 16, 24 hrs post Day 28 dose
Secondary outcome [8] 353294 0
Multiple-dose, once daily for 28 days, AK-119 urine pharmacokinetics The urine concentration will be determined by validated liquid chromatography-tandem mass spectrometry method.
Timepoint [8] 353294 0
At 0-4, 4-12, 12-24 hours post-dose on Day 1 and Day 8, 15, 22, 28.
Secondary outcome [9] 353295 0
Multiple-dose, once daily for 728 days, AK-119 plasma pharmacodynamics, Absolute lymphocyte count assessed by serum assay.
Timepoint [9] 353295 0
-24, -22, -20, -18, -16, -12, -8 hrs and immediately before pre-dose, 2, 4, 6, 8, 12, 16 hours post dose on Day 1; pre dose on Days 2, 3, 4, 5, 8, 15, 22; pre-dose on 28 Day dose, 2, 4, 6, 8, 12, 16, 24, 36, 48 hours post dose of Day 28 (timings may be adjusted on review of ALC response from Parts A and B)

Eligibility
Key inclusion criteria

Healthy volunteer subjects eligible for inclusion in this study have to fulfil all of the following inclusion criteria:
1. Male and female subjects 18-55 years of age, inclusive, at the time of screening
2. Able to provide written informed consent prior to the performance of any study specific procedures
3. Subjects with a BMI between 18.0 and 30.0 kg/m2, inclusive
4. A 12-lead ECG at screening or pre-dose assessment that, in the opinion of the investigator, has no abnormalities that compromise subject’s safety in this study.
5. Female subjects of non-childbearing potential, defined as (1) having a documented tubal ligation at least 6 weeks prior to dosing; (2) having had a surgical bilateral oophorectomy (with or without hysterectomy); (3) at least 12 months of spontaneous amenorrhoea with follicle stimulating hormone (FSH) > 40 MIU/ml.
6. Female subjects of child-bearing potential with negative serum pregnancy test at screening and negative urine pregnancy test at check-in (Day -1), AND;
• Agrees to abstinence for the duration of the study and until 4 weeks after dosing with study drug;
• OR agrees to use condoms plus a highly-effective form of contraception (associated with a less than 1% failure rate when applied consistently and correctly); i.e. intra-uterine device or hormonal contraception associated with suppression of ovulation, from screening until 4 weeks after dosing with study drug;
• OR has only same-sex partners when this is her preferred and usual lifestyle.
7. Male subjects with female partners of child-bearing potential must agree abstinence or to use condoms plus partner use of a highly-effective form of contraception (intrauterine device, hormonal contraception) for the duration of the study and until 12 weeks after dosing with study drug. They must also agree to not donate semen during the same time frame.

8. Negative Human Immunodeficiency Virus (HIV), Hepatitis B and Hepatitis C Screening test results
9. Subjects who are willing and able to comply with all study assessments and adhere to the protocol schedule.
10. The participant will be normotensive at screening with systolic blood pressure (BP) between 95 and 140mmHg, diastolic BP between 50 and 95mmHg, and heart rate (HR) between 55 and 90 beats per minutes (bpm).

Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy volunteer subjects fulfilling any of the following criteria are not eligible for inclusion in this study:
11. Have received any investigational research agent within 30 days or 5 half-lives (whichever is longer) prior to the first dose of Investigational Product.
12. Have received an investigational vaccine within 6 months, a live attenuated vaccine within 60 days or a registered vaccine within 30 days prior to the first dose of the Investigational Product.
13. Clinically significant history or presence of any gastrointestinal pathology (e.g., chronic diarrhoea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g., diarrhoea, vomiting), liver or kidney disease, Gilbert’s syndrome, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
14. Any clinically significant history or presence of neurological, endocrinal, cardiovascular, pulmonary, haematological, malignant, immunologic, psychiatric, metabolic or other uncontrolled systemic disease
15. Have a bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws.
16. Have a psychiatric condition that precludes compliance with the protocol; past or present psychoses; past or present bipolar disorder; disorder requiring lithium; or within five years prior to enrolment, a history of suicide plan
17. Any clinically significant abnormality at Screening determined by medical history, physical examination, blood chemistry, haematology, urinalysis and a 12-lead ECG, positive urine screen for drugs of abuse.
18. Any other condition which in the view of the Investigator is likely to interfere with the study or put the subject at risk.
19. Have clinical signs of active infection and/or a temperature of equal or greater than 38.0°C at the time of screening. Study entry may be deferred at the discretion of the Principal Investigator
20. Have evidence of drug abuse or positive urine drug screen at screening
21. Subjects who have smoked more than 10 cigarettes a day in the last 12 months
22. Have evidence of alcohol abuse within 6 months prior to screening visit (i.e., more than fourteen units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol])
23. Be unable to provide a pre-dose blood sample without undue trauma or distress
24. Anticipate surgery within the trial period or history of major surgery within 3 months of screening
25. History of hypersensitivity to any other S1P receptor modulator
26. Use of prescription medication (including anticoagulants) within 14 days prior to administration of study treatment or over-the-counter products (including natural food supplements, vitamins, garlic as a supplement) within 7 days prior to administration of study treatment, except for topical products without systemic absorption unless otherwise agreed by sponsor.
27. A depot injection or an implant of any drug within 3 months prior to administration of study treatment, with the exception of a contraceptive implant
28. Subjects with a history or presence (at screening or first baseline) of any clinically significant ECG abnormalities including, but not limited to any type of AV blocks or any of the following ECG abnormalities at screening or baseline:
o PR > 220 ms
o QRS complex > 120 msec
o QTcF >470 msec (females) or > 450 msec (males)
o Prominent U waves or any significant morphological changes other than non-specific T-wave changes
29. Subjects with a history or presence (at screening or first baseline) of any of the following cardiovascular findings:
o Clinically significant ventricular or supraventricular arrhythmia (as judged by the investigator)
o History or presence of coronary heart disease (stable or unstable), myocardial infarction, myocarditis, cardiomyopathy or heart failure
o History or presence of long QT syndrome or any other cause of prolonged QT interval
o History or cardiac catheter ablation
o History or presence of symptomatic postural hypotension or syncopes
30. Subjects with a family history of congenital long QT syndrome or unexplained sudden cardiac death
31. Medications known to prolong the QTc interval
32. Subjects with symptomatic heart failure, unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction < 20%, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to study entry.
34. Subjects who are unable to return for all scheduled study visits
35. Any other condition, that in the opinion of the investigator would render the subject unsuitable for enrolment, or could interfere with the subject participating in and completing the study

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
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12230 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 24409 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 300991 0
Commercial sector/Industry
Name [1] 300991 0
Akaal Pharma Pty Ltd
Address [1] 300991 0
Akaal Pharma Pty Ltd
Chemistry Department
# 301E, Thomas Cherry Bld
La Trobe University
Bundoora, VIC - 3086
Country [1] 300991 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Akaal Pharma Pty Ltd
Address
Akaal Pharma Pty Ltd
Chemistry Department
# 301E, Thomas Cherry Bld
La Trobe University
Bundoora, VIC - 3086
Country
Australia
Secondary sponsor category [1] 300578 0
None
Name [1] 300578 0
Address [1] 300578 0
Country [1] 300578 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301750 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 301750 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 301750 0
Australia
Date submitted for ethics approval [1] 301750 0
05/09/2018
Approval date [1] 301750 0
16/10/2018
Ethics approval number [1] 301750 0
429/18

Summary
Brief summary
This is a single centre, randomized, double-blind, placebo-controlled, sequential, single dose-escalation study of AK-119 administered to healthy adults and multiple dose-escalation study of AK-119 administered to healthy adults. The study comprises three parts A,B & C.
Part A of the study is a single dose escalation arm. The safety data will be reviewed after each Cohort prior to dose escalation. The selected dose cohort will participate in a two-way crossover design and return to the clinical unit to receive AK-119/placebo administration of the same for evaluation of the food effect after a washout of at least 7 days.
In Part B All subjects will be admitted to the Phase 1 unit on Day -1 for pre-treatment assessments then given a single dose of AK-119 or placebo once or twice daily from Day 1 to Day 7. They will remain inpatients until Day 10, returning as outpatients for follow-up assessments on Day 14. Part C will start after completing the multiple dose, dose escalation components in healthy volunteers in Part B, one cohort with healthy volunteers will be enrolled to receive 1 dose level of AK-119/placebo, as determined from the Part B in healthy volunteers. The dosing period will be upto 28 days as once or twice daily, commencing on Day 1 (dosing regimen to be determined from Part B).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87974 0
Dr Jason Lickliter
Address 87974 0
Nucleus Network PTY Ltd
Level 5, 89 Commercial Road
Melbourne, Victoria 3004

Country 87974 0
Australia
Phone 87974 0
+61390768917
Fax 87974 0
Email 87974 0
J.Lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 87975 0
Dr Gurmit Gill
Address 87975 0
Akaal Pharma Pty Ltd
Chemistry Department
# 301E, Thomas Cherry Bld
La Trobe University
Bundoora, VIC - 3086
Country 87975 0
Australia
Phone 87975 0
+61394792584
Fax 87975 0
Email 87975 0
gurmit.gill@latrobe.edu.au
Contact person for scientific queries
Name 87976 0
Dr Gurmit Gill
Address 87976 0
Akaal Pharma Pty Ltd
Chemistry Department
# 301E, Thomas Cherry Bld
La Trobe University
Bundoora, VIC - 3086
Country 87976 0
Australia
Phone 87976 0
+61394792584
Fax 87976 0
Email 87976 0
gurmit.gill@latrobe.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results