Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001228279
Ethics application status
Approved
Date submitted
17/07/2018
Date registered
23/07/2018
Date last updated
9/04/2019
Date data sharing statement initially provided
9/04/2019
Date results information initially provided
9/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety, tolerability and pharmacokinetics of ATN-249 in healthy volunteers when dosed over several days
Scientific title
A Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending-Dose Study to Determine the Safety, Tolerability and Pharmacokinetics of ATN-249 in Healthy Male Participants
Secondary ID [1] 295577 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hereditary Angioedema 308861 0
Condition category
Condition code
Inflammatory and Immune System 307783 307783 0 0
Normal development and function of the immune system
Human Genetics and Inherited Disorders 307784 307784 0 0
Other human genetics and inherited disorders
Cardiovascular 307785 307785 0 0
Other cardiovascular diseases
Skin 307786 307786 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will enrol up to thirty-two (32) healthy male participants, aged 18 to 55 years, into up to four (4) cohorts. Withdrawn participants will only be replaced at the discretion of the Sponsor.

Up to 28 days before enrolment into the study, participants will be required to sign a consent form, after which screening assessments will be carried out.

Cohort 1 (8 participants) will receive once a day dosing of either ATN-249 100 mg (n=6, 2 x 50 mg capsule) or matching placebo (n=2) for 14 days, with an overnight fast for at least 10 hours prior to dosing.

Cohort 2 (8 participants) will receive once a day dosing of either ATN-249 150 mg (n=6, 3 x 50 mg capsule) or matching placebo (n=2) for 14 days, with an overnight fast for at least 10 hours prior to dosing.

An optional Cohort 3 (8 participants) will receive twice a day 12h apart dosing of either ATN-249 100 mg (n=6, 2 x 50 mg capsule BID) or matching placebo (n=2) for 14 days, with an overnight fast for at least 10 hours prior to the AM dose and at least 2 hours prior to the PM dose.

An optional Cohort 4 (8 participants) will receive once a day dosing of either ATN-249 200 mg (n=6, 1 x 200 mg capsule QD) or matching placebo (n=2) for 14 days, with an overnight fast for at least 10 hours prior to the dosing.

Participants will remain on site from the day before dosing until review of the 48-hour post-final dose assessments. Dosing in Cohort 2 will not commence until SMC review of complete PK and safety data from Cohort 1.
Optional Cohort3 and/or optional Cohort 4 will be run depending on the PK results of Cohorts 1 and 2. Dosing in these optional Cohorts (3 and/or 4) will not commence until SMC review of complete PK and safety data from Cohort 2

The duration of the study is of approximately 7 weeks (this includes a 28-day screening period, one 16-day study period with 16 overnight stays and a follow up visit 7 days after the last dose of study medication). Adherence to study treatment will be verified by hand and mouth check.
Intervention code [1] 301874 0
Treatment: Drugs
Comparator / control treatment
Size 4 hard gelatin capsules identical to those containing 50 mg of ATN-249. The composition is lactose hydrate (75mg), microcrystalline cellulose (48.75mg) and magnesium stearate (1.25mg); OR
Size 0 hard gelatin capsules identical to those containing 200 mg of ATN-249. The composition is lactose hydrate (300mg), microcrystalline cellulose (195mg) and magnesium stearate (5mg).
Control group
Placebo

Outcomes
Primary outcome [1] 306771 0
Safety and tolerability of once daily (QD) and twice daily (BID) multiple ascending oral dosing regimens of ATN-249 in healthy participants.
Assessments include vital signs, physical examinations, clinical laboratory testing (hematology, coagulation, serum chemistry and urinalysis/urine microscopy), ECGs and Adverse Events.
Timepoint [1] 306771 0
#A Cohorts 1, 2 and 4 (QD dosing regimen):
Adverse Events: Throughout the study
Vital signs: Day -1, Day 1 (pre-dose and 1h, 2h, 3h, 4h, 5h, 7h, 9h, 12h and 16h post-dose), Days 2 to 13, Day 14 (same schedule as Day 1), Day 15, Day 16 and Day 21.
ECG: Day -1, Day 1 (pre-dose and 1h, 2h, 3h, 4h, 5h, 7h, 9h and 12h post-dose), Days 2 to 13, Day 14 (same schedule as Day 1), Day 15, Day 16 and Day 21.
Physical Examination: Day -1, Day 1 (pre-dose and 7h post-dose), Day 2, Day 7, Day 14 (pre-dose and 7h post-dose), Day 15 and Day 21.
Clinical Laboratory Testing: Day -1, Day 2, Day 7, Day 14, Day 15 and Day 21.

#B Cohort 3 (BID dosing regimen)
Adverse Events: Throughout the study
Vital signs: Day -1, Day 1 (pre-dose and 1h, 2h, 3h, 4h, 6h, 8h, 12h, 13h, 14h, 16h and 18h post-dose), Days 2 to 13, Day 14 (same schedule as Day 1), Day 15, Day 16 and Day 21.
ECG: Day -1, Day 1 (pre-dose and 1h, 2h, 3h, 4h, 6h, 8h, 12h, 13h, 14h, 16h and 18h post-dose), Days 2 to 13, Day 14 (same schedule as Day 1), Day 15, Day 16 and Day 21.
Physical Examination: Day -1, Day 1 (pre-dose and 8h post-dose), Day 2, Day 7, Day 14 (pre-dose and 8h post-dose), Day 15 and Day 21.
Clinical Laboratory Testing: Day -1, Day 2, Day7, Day 14, Day 15 and Day 21.
Primary outcome [2] 306772 0
Plasma concentration of QD and BID multiple ascending oral dosing regimens of ATN-249 in healthy participants.
Pharmacokinetic parameters will be calculated using non-compartmental approach and will include Tmax, Cmax, AUC and apparent Kel.
Timepoint [2] 306772 0
#A Cohorts 1, 2 and 4 (QD dosing regimen):
Up to 48 hours following last administration (on Day 14). Sampling points are on Day 1 (pre-dose; and 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 7h, 9h, 12h and 16h post-dose); on Days 1 to 13 (once a day at the same time; on Day 14 (same schedule as Day 1); on Day 15 and Day 16 (once a day at the same time).
#B Cohort 3 (BID dosing regimen)
Up to 48 hours following last administration (on Day 14). Sampling points are on Day 1 (pre-dose; and 15min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 12.25h, 12.5h, 13h, 13.5h, 14h, 14,5h, 16h and 18h post-dose); on Days 1 to 13 (once a day at the same time; on Day 14 (same schedule as Day 1); on Day 15 and Day 16 (once a day at the same time).
Primary outcome [3] 306800 0
Pharmacokinetics parameters of QD and BID multiple ascending oral dosing regimens of ATN-249 in healthy participants.
Pharmacokinetic parameters will be calculated using non-compartmental approach and will include Tmax, Cmax, AUC and apparent Kel.
Timepoint [3] 306800 0
PK parameters calculated as PK profile on the basis of plasma concentration data from dosing to Day 16.
Secondary outcome [1] 349539 0
Pharmacodynamics of ATN-249 on contact pathway activation.
Contact pathway activation will be assessed by means of blood assay.
Timepoint [1] 349539 0
#A Cohorts 1, 2 and 4 (QD dosing regimen):
Up to 24 hours following last administration (on Day 14). Sampling points are on Day 1 (pre-dose; and 2h, 4h, 9h, and 12h post-dose); on Day 2 and Day 7 (once a day at the same time; on Day 14 (same schedule as Day 1); on Day 15 (once a day at the same time).
#B Cohort 3 (BID dosing regimen)
Up to 24 hours following last administration (on Day 14). Sampling points are on Day 1 (pre-dose; and 2h, 4h, 12h, 14h and 16h post-dose); on Day 2 and Day 7 (once a day at the same time; on Day 14 (same schedule as Day 1); on Day 15 (once a day at the same time).

Eligibility
Key inclusion criteria
1. Male healthy volunteers, age 18 to 55 years, inclusive;
2. Participants must be in good general health, with no significant medical history, have no clinically significant abnormalities on physical examination at screening and/or before administration of the initial dose of study drug;
3. Participants must have a BMI between 18.0 and 30.0 kg/m2 inclusive;
4. Participants must have clinical laboratory values within normal range as specified by the testing laboratory, unless deemed not clinically significant by the Investigator or delegate;
5. Participants must be non-smokers and must not have used any tobacco products within 2 months prior to screening;
6. Participants must have no contraindications to consuming standard meals provided;
7. Participants who have not been sterilized must make a commitment to ensure that their partners (if of child bearing potential) use highly effective contraception during the period from dosing to 7-days post-final dose (acceptable forms of contraception are oral, injected or implanted hormonal methods, placement of an intrauterine device or intrauterine system, or abstinence); in addition to these measures, male participants should use a condom for sexual intercourse during this period. This requirement does not apply to participants in same sex relationships;
8. Participants must have the ability and willingness to attend the necessary visits to the study center;
9. Written informed consent signed prior to entry into the study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Prior or ongoing medical condition, medical history, physical findings or laboratory abnormality that, in the Investigator’s (or delegate’s) opinion, could adversely affect the safety of the participant;
2. Previous exposure to ATN-249;
3. Mentally or legally incapacitated, has significant emotional problems at the time of screening visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder within the last 5 years. Note: Participants who have had situational depression may be enrolled in the study at the discretion of the Investigator or delegate;
4. Fever (body temperature greater than 38°C) or symptomatic viral or bacterial infection within 2 weeks prior to screening;
5. History of severe allergic or anaphylactic reactions;
6. Resting blood pressure greater than 140/90 mm Hg, resting heart rate greater than 90 beats per minute or resting heart rateless than 50 beats per minute at screening or at Day -1. (Repeat measurements are allowed at the discretion of the Investigator. The resting heart rate measurement may be repeated only once if below 50 beats per minute);
7. Alkaline phosphatase (ALP), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than 1.5 x upper limit of normal at screening. Repeat testing at screening is acceptable for out of range values following approval by the Investigator or delegate;
8. Serum potassium less than 3.7 mmol/L or greater than 5.5 mmol/L at Screening or Day -1. Repeat testing at Screening is acceptable for out of range values following approval by the Investigator or delegate;
9. Positive test for hepatitis C antibody, hepatitis B surface antigen or HIV antibody at screening;
10. Participants with a positive toxicology screening panel (urine test including qualitative identification of barbiturates, THC, amphetamines, benzodiazepines, opiates and cocaine), cotinine test or alcohol breath test;
11. Participants with a history of substance abuse or dependency or history of recreational IV drug use over the last 5 years (by self-declaration);
12. Regular alcohol consumption defined as greater than 21 alcohol units per week (where 1 unit equal to 284 mL of beer, 25 mL of 40% spirit or a 125 mL glass of wine). Participant is unwilling to abstain from alcohol beginning 48 hours prior to admission to the CRU until completion of the final follow-up visit;
13. Participant has left ventricular hypertrophy defined as the combination of the following ECG criteria (both #a and #b must be met):
13.a. Voltage criteria (both criteria must be met):
13.a.1 S in V1 + R in V5 or V6 (whichever is larger) equal to 35 mm; and
13.a.2 R in aVL equal to 11 mm
13.b. Repolarization abnormalities (at least one criteria needs to be met):
13.b.1 At least 1mm ST depression (horizontal or down-sloping); or
13.b.2 Abnormal T wave inversions;
14. Participant has other significant ECG abnormalities that might interfere with ECG analysis including evidence of a previous myocardial infarction (MI), flat T waves (particularly in the inferior leads) or more than minor non-specific ST-T wave changes or:
14.a. QRS greater than 110 milliseconds (msec),
14.b. QT interval corrected using Fridericia’s formula (QTcF) greater than 440 msec,
14.c. PR interval greater than 220 msec
14.d. Heart rate less than 50 BPM or greater than 90 BPM (the resting heart rate measurement may be repeated only once if below 50 beats per minute)
14.e. Complete right bundle branch block or left bundle branch block;
15. History of cardiac disease or cerebrovascular disease, including coronary artery disease (including MI, angina), cardiac arrhythmias, long QT syndrome (in self or family), valvular disease, heart failure, hypertension or hypotension;
16. Family history of hereditary angioedema;
17. Use of any prescription medication or over-the-counter medication, herbal products, vitamins or minerals, within 7 days or 5 half-lives (whichever is longer) prior to study drug administration, unless in the opinion of the Principal Investigator and/or Medical Monitor the medication will not compromise participant safety or interfere with study procedures or data validity;
18. Use of any potential inducer or inhibitor of CYP3A4 or Pgp (e.g. St. John’s Wort, rifampin, cyclosporine or ritonavir) within 14 days or 5 half-lives (whichever is longer) prior to study drug administration, unless in the opinion of the Principal Investigator and/or Medical Monitor the medication will not compromise participant safety or interfere with study procedures or data validity;
19. Anticipated use of prescription medication or over-the-counter medication during study participation, with the exception of 1-2 therapeutic doses per week of paracetamol/acetaminophen or non-steroidal anti-inflammatory drugs (e.g. ibuprofen, naproxen);
20. Participant is lactose intolerant;
21. Participant is unwilling to refrain from strenuous exercise from 7 days prior to admission to the CRU until completion of the final follow-up visit;
22. Participant is unwilling to abstain from ingestion of caffeine or xanthine-containing products (e.g. tea, coffee, chocolate, cola) beginning 96 hours prior to admission to the CRU until the final PK sample has been collected;
23. Participant has consumed grapefruit and/or grapefruit juice within 14 days prior to admission to the CRU and is unwilling to abstain from consuming grapefruit and/or grapefruit juice until completion of the final follow-up visit;
24. Participant has consumed citrus fruit or citrus fruit juices within 48 hours prior to admission to the CRU and is unwilling to abstain from these items until the final PK sample has been collected;
25. Participants who are unlikely to comply with the study protocol or, in the opinion of the investigator, would not be a suitable candidate for participation in 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)
Allocation to treatment in accordance with randomization list issued prior to start of recruitment and provided to the site pharmacy. The site pharmacy is unblinded and will dispense investigational drug in accordance with the allocation sequence disclosed in the randomization list.
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
Placebo-Controlled, Multiple-Ascending-Dose Study
Phase
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/08/2018
Actual
23/08/2018
Date of last participant enrolment
Anticipated
14/09/2018
Actual
6/12/2018
Date of last data collection
Anticipated
4/10/2018
Actual
27/12/2018
Sample size
Target
32
Accrual to date
Final
32
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 11446 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 23461 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 300151 0
Commercial sector/Industry
Name [1] 300151 0
LifeSci Pharmaceuticals, inc.
Country [1] 300151 0
Barbados
Funding source category [2] 300153 0
Commercial sector/Industry
Name [2] 300153 0
Attune Pharmaceuticals
Country [2] 300153 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
LifeSci Pharmaceuticals, inc.
Address
Whitepark House, White Park Road,
Bridgetown, St. Michael
BB11135, Barbados
Country
Barbados
Secondary sponsor category [1] 299554 0
Commercial sector/Industry
Name [1] 299554 0
Attune Pharmaceuticals
Address [1] 299554 0
250 West 55th Street Suite 16B
New York, NY 10019, US
Country [1] 299554 0
United States of America
Secondary sponsor category [2] 299555 0
Commercial sector/Industry
Name [2] 299555 0
Clinical Network Services (CNS) Pty Ltd
Address [2] 299555 0
Level 4, 88 Jephson Street
Toowong, QLD 4066
Australia
Country [2] 299555 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300983 0
Bellberry Limited
Ethics committee address [1] 300983 0
129 Glen Osmond Road, Eastwood
SA 5065, Australia
Ethics committee country [1] 300983 0
Australia
Date submitted for ethics approval [1] 300983 0
16/07/2018
Approval date [1] 300983 0
19/07/2018
Ethics approval number [1] 300983 0

Summary
Brief summary
Hereditary Angiodema (HAE) is a rare disease caused by low levels of C1 serine protease inhibitor in the body. Deficiencies in this protein leads to increased activation of inflammatory pathways which can cause swelling, severe abdominal pain and airway obstruction that can be life threatening. ATN-249 is a potential once a day oral treatment for HAE.

The purpose of this research study is to test the safety and tolerability of ATN-249 as well as the pharmacokinetics and pharmacodynamics of the study drug. The study is open to healthy male volunteers and the research goals are:
- Does the drug have any side-effects and is it well tolerated when given as a multiple dose over several days?
- How much of the drug gets into the blood stream, and how long does the body take to get rid of it?

This study will look at how the human body uses ATN-249 at different dose levels and under different dosing regimens (once a day or twice a day).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85514 0
Dr Peter Schrader
Address 85514 0
Linear Clinical Research
Level 1, B Block, QEII Medical
Centre,
Hospital Avenue
NEDLANDS WA 6009
Country 85514 0
Australia
Phone 85514 0
+61 (0) 8 6382 5100
Fax 85514 0
Email 85514 0
[email protected]
Contact person for public queries
Name 85515 0
Mr Alex Castellarnau
Address 85515 0
Clinical Network Services (CNS) Pty Ltd
Level 4, 88 Jephson St,
TOOWONG, QLD 4066
Country 85515 0
Australia
Phone 85515 0
+61(0)7 3719 6000
Fax 85515 0
Email 85515 0
[email protected]
Contact person for scientific queries
Name 85516 0
Mr Jason Bablak
Address 85516 0
Attune Pharmaceuticals
250 West 55th Street Suite 16B
New York, NY 10019
Country 85516 0
United States of America
Phone 85516 0
+1 412 445-1705
Fax 85516 0
Email 85516 0
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.