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Trial registered on ANZCTR


Registration number
ACTRN12618001342202
Ethics application status
Approved
Date submitted
25/07/2018
Date registered
9/08/2018
Date last updated
7/05/2019
Date data sharing statement initially provided
7/05/2019
Date results provided
7/05/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to determine the safety and tolerability of graded doses of the drug LHF-535 (LHF-535-SDD) in healthy volunteers.
Scientific title
A double-bind, placebo-controlled, dose escalation study of the safety, tolerability, and pharmacokinetics of an oral dose of LHF-535 (LHF-535-SDD) in healthy subjects.
Secondary ID [1] 295615 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lassa Hemorrhagic Fever 308940 0
Condition category
Condition code
Infection 307841 307841 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A First-In-Human, Randomised, Double-Blind, Controlled, Dose-Ranging, Phase 1 Study in Healthy Volunteers aged 18-45 years.
A total of up to 56 healthy male and female participants will receive one oral dose of LHF-535-SDD or placebo which consists of the inert polymer HPMCAS.

Cohort 1: 6 participants will receive 0.3 milligrams per kilogram of body weight of LHF-535 and 2 participants will receive placebo
Cohort 2: 6 participants will receive 1 milligram per kilogram of body weight of LHF-535 and 2 participants will receive placebo
Cohort 3: 6 participants will receive 3 milligrams per kilogram of body weight of LHF-535 and 2 participants will receive placebo
Cohort 4: 6 participants will receive 10 milligrams per kilogram of body weight of LHF-535 and 2 participants will receive placebo
Cohort 5: 6 participants will receive 30 milligrams per kilogram of body weight of LHF-535 and 2 participants will receive placebo
Cohort 6: optional cohort, dose to be determined by the safety committee
Cohort 7: optional cohort, dose to be determined by the safety committee

The investigational study drug, LFH-535-SDD consists of LHF-535 formulated as a spray dried dispersion (SDD) with inert polymer HPMCAS (hydroxypropylmethylcellulose acetate succinate) at a 30:70 ratio of LHF-535 to HPMCAS. The LFH-535-SDD will be suspended in the commercially available suspension vehicle Ora-Blend and will be given orally after fasting for at least 8 hours.
The placebo supplied as powdered HPMCAS will be suspended in the commercially available suspension vehicle Ora-Blend and given orally after fasting for at least 8 hours.

The blinded study drug suspension (LHF-535-SDD suspension or LHF-535-placebo suspension) will be administered by the blinded study personnel using a syringe (cohorts 1-3) or dosing bottle (cohorts 3-6). This will be followed by the administration of 240 mL water orally, using a portion of the water to rinse the used syringe or dosing bottle. The date and time of study drug administration will be recorded.

As this is a first-in-human study, 2 sentinel participants (1 placebo and 1 LHF-535-SDD) in each cohort will receive the first dose and be monitored for 48 hours. If dosing of the sentinels proceeds with no clinically significant adverse events, the remaining participants in the cohort will be dosed.

Following study drug administration, all participants will be monitored at the clinic for at least 24 hours, after which they will return to the clinic on days 4, 8, 15 and 29 to be monitored.

The Investigator is responsible for product accountability during the trial and final accountability will be performed after DBL when the study is unblinded by the blinded CRA.
Intervention code [1] 301920 0
Treatment: Drugs
Comparator / control treatment
The placebo group will receive HPMCAS suspended in the commercially available suspension vehicle Ora-Blend in a dose matching the dose of the investigational product for that cohort.
Control group
Placebo

Outcomes
Primary outcome [1] 306815 0
To assess the safety and tolerability of LHF-535 given as a single oral dose in healthy subjects. Safety parameters will include the development of adverse events, physical examinations, ECGs, vital signs and clinical laboratory testings (e.g. haematology, chemistry, coagulation and urinalysis).
Timepoint [1] 306815 0
AEs will be recorded at 1 , 2, 4, 8 and 12hrs, days 2, 4, and 29.
Urinanalysis will be performed at days -1, 2, 4, 8, 15, 29.
ECG will be performed at day -1, pre-dose, 1hr, days 2, 4, 8, 15 and 29.
Vital signs pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 8 and 12 hours, days 2, 4, 8, 15, 29
Safety bloods will be performed at days -1, 2, 4, 8, 15 and 29.
Cardiac telemetry will be continuous from day -1 to day 2.
Secondary outcome [1] 349770 0
To evaluate the pharmacokinetics (PK) of LHF-535 given as a single oral dose in healthy subjects.
Blood samples will be analysed for LHF-535 levels.
PK parameters to be characterized include maximum observed plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the concentration-time curve from 0 to last measurable plasma concentration (AUC0-t), area under the concentration-time curve from 0 to infinity (AUC0-infinity), half-life (t1/2), and apparent plasma terminal elimination rate constant, where lambda Z is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase (lambda Z).
Timepoint [1] 349770 0
Bloods will be collected for PK analysis at pre-dose, 0.25, 0.5, 0.75, 1, 2, 4, 8 and 12 hours, days 2, 4, 8, and 15.

Eligibility
Key inclusion criteria
1. Male or female 18 to 45 years of age, inclusive, at the time of screening.
2. Able to understand the requirements of the study, to provide written informed consent (as evidenced by signature on an informed consent document that is approved by a Human Research Ethics Committee [HREC]), and agreeable to abide by the study restrictions.
3. Body mass index (BMI) of 18.0 to 30.0 kg/m2, inclusive, at the time of screening and check-in (Day -1).
4. Minimum weight of 50 kg at the time of screening and check-in (Day -1).
5. Good general health (e.g., no chronic health conditions such as hypertension, diabetes, chronic obstructive pulmonary disease, or cardiovascular disease) as determined by the Investigator. Subjects with mild allergies or benign conditions such as Gilbert’s disease may be enrolled at the discretion of the Investigator.
6. Female subjects of child-bearing potential, with a fertile male sexual partner, must use a highly effective method of contraception (oral contraceptive, intrauterine device, or hormonal patch, injectable, or implantable device) in conjunction with a male condom during the screening period and for the entire duration of study participation including the 28-day follow-up. True abstinence from sexual intercourse, in accordance with the preferred and usual lifestyle of the subject, is acceptable. Periodic abstinence or avoiding sexual intercourse on days while the subject is fertile (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), are not acceptable methods of contraception. Non-childbearing potential is defined as postmenopausal as documented by an elevated follicle stimulating hormone (FSH) level or surgical sterility (e.g., tubal ligation, hysterectomy, and/or bilateral salpingo-oophorectomy).
7. Male subjects must either be surgically sterile (vasectomy) or agree to use a male condom as a method of contraception for the entire duration of the study and for 90 days after dosing; the female sexual partner must also use a medically acceptable form of birth control (e.g., oral contraceptive).
8. Male subjects must agree to not donate sperm for the entire duration of the study and for at least 90 days after dosing.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Pregnancy or breastfeeding.
2. A positive screen for drugs of abuse, including alcohol. The screen may be repeated once at the Investigator’s discretion if a false-positive result is suspected.
3. Use of any tobacco- or nicotine-containing products (including but not limited to, cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to check-in (Day -1) or exposure to tobacco or nicotine within 30 days of check-in (Day -1).
4. A positive cotinine test indicating recent nicotine use. The test may be repeated once at the Investigator’s discretion if a false-positive result is suspected.
5. Donated blood within 90 days or plasma within 30 days of dosing on Day 1.
6. Active substance abuse or any medical or psychiatric condition that could jeopardize the subject’s safety.
7. Use of any medications apart from vitamins, acetaminophen, or hormonal contraception within 14 days of dosing on Day 1. Subjects with mild allergies may use antihistamines at the discretion of the Investigator after approval by the Sponsor Medical Monitor.
8. Receipt of an investigational product within 12 weeks prior to dosing on Day 1 (or 5 half-lives, whichever is longer).
9. Any history of cancer; non-melanoma skin cancer or cervical cancer in situ, resected surgically with no evidence of disease, may be enrolled at the discretion of the Investigator.
10. Receipt of an organ transplant (solid or hematopoietic), including corneal transplant.
11. Prolonged QTcF interval >450 ms on electrocardiograms (ECGs) collected during screening, on Day -1, or just prior to dosing on Day 1.
12. Other clinically significant ECG abnormality, as determined by the Investigator.
13. Any clinically significant abnormal hematology, chemistry, or urinalysis value, as determined by the Investigator.
14. Positive test for human immunodeficiency virus (HIV serology) or known HIV infection.
15. Positive result for hepatitis B surface antigen (HBsAg) or for hepatitis C virus (HCV) antibody.
16. Use of alcohol-containing foods or beverages within 72 hours prior to check-in on Day -1 or 72 hours prior to any study visit.
17. Use of caffeine-containing foods or beverages within 24 hours prior to check-in on Day -1 until discharge from the study unit.
18. Febrile illness or significant infection within 48 hours before administration of the first dose of study drug on Day 1.

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)
A randomisation list will be generated and kept secure from all site staff until the database is finalised and hard locked. In case of medical emergency, where knowledge of the treatment assignment would impact management, the investigator can access the allocated treatment for the participant experiencing the SAE by opening a sealed opaque envelope.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The unblinded study statistician will produce the randomisation list using SAS, a computerised sequence generation software.
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
The people analysing the results/data
Intervention assignment
Other
Other design features
Single ascending dose
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Descriptive statistics will be calculated on the safety and tolerability of LHF-535 by individual values and summary statistics. Incidence of treatment-emergent AEs will be tabulated by counts and percentages. Abnormalities in clinical laboratory, vital signs, ECG, and cardiac telemetry will be based on pre-defined normal ranges and will be tabulated by dose group showing subject counts and percentages. Placebo-treated subjects will be pooled across all dose groups..
Pharmacokinetic parameters will be summarised by mean, standard deviation (SD), coefficient of variance (CV), minimum, and maximum for each dose level. Dose proportionality for Cmax and AUC(s) will be assessed by plotting these parameters against dose.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
10/08/2018
Actual
7/08/2018
Date of last participant enrolment
Anticipated
16/11/2018
Actual
19/11/2018
Date of last data collection
Anticipated
14/12/2018
Actual
14/01/2019
Sample size
Target
56
Accrual to date
Final
48
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11477 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 23498 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 300195 0
Commercial sector/Industry
Name [1] 300195 0
Kineta Viral Hemorrhagic Lever, LLC
Country [1] 300195 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services (CNS) Pty Ltd
Address
Level 4, 88 Jephson St
Toowong, Brisbane, QLD, 4066
Country
Australia
Secondary sponsor category [1] 299623 0
None
Name [1] 299623 0
Address [1] 299623 0
Country [1] 299623 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301022 0
Alfred Hospital Ethics Committee EC00315
Ethics committee address [1] 301022 0
Ethics committee country [1] 301022 0
Australia
Date submitted for ethics approval [1] 301022 0
01/05/2018
Approval date [1] 301022 0
18/06/2018
Ethics approval number [1] 301022 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85622 0
Dr Ben Snyder
Address 85622 0
Nucleus Network
Level 5, Burnet Tower, AMREP Precinct,
89 Commercial Road
Melbourne, Victoria 3004
Country 85622 0
Australia
Phone 85622 0
+ 613 8593 9800
Fax 85622 0
+ 613 9076 8911
Email 85622 0
b.snyder@nucleusnetwork.com.au
Contact person for public queries
Name 85623 0
Jessica Faggian
Address 85623 0
Nucleus Network
Level 5, Burnet Tower, AMREP Precinct,
89 Commercial Road
Melbourne, Victoria 3004
Country 85623 0
Australia
Phone 85623 0
+ 613 8593 9800
Fax 85623 0
+ 613 9076 8911
Email 85623 0
J.Faggian@nucleusnetwork.com.au
Contact person for scientific queries
Name 85624 0
Portia Vliet-Gregg
Address 85624 0
Kineta Viral Hemorrhagic Fever LLC,
219 Terry Ave North, Suite 300
Seattle, Washington
98109-5208
Country 85624 0
United States of America
Phone 85624 0
+1 206-518-5563
Fax 85624 0
Email 85624 0
pvliet-gregg@kineta.us

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The data sharing statement was marked 'no' with the reason being that this is a healthy volunteers study and the individual participant results are not useful to the participants or to others outside of the sponsor


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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