Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001823268
Ethics application status
Approved
Date submitted
3/11/2018
Date registered
9/11/2018
Date last updated
29/01/2019
Date data sharing statement initially provided
9/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and tolerability Phase I study of LBS-008 in healthy adult subjects after single and multiple doses
Scientific title
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LBS-008 in Healthy Adult Subjects
Secondary ID [1] 296467 0
LBS-008-CT01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dry age-related macular degeneration 310253 0
Condition category
Condition code
Eye 308977 308977 0 0
Normal eye development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single Ascending Dose (SAD) group:

The SAD portion will have up to 6 cohorts and up to a total of 48 subjects (8 subjects per cohort). The starting dose of LBS-008 will be 50 mg and the planned doses for subsequent cohorts are 100, 200, 400, 800, and 1200 mg, once daily.

The Multiple Ascending Dose ( MAD)portion will have up to 3 cohorts and up to a total of 24 subjects (8 subjects per cohort). The starting dose of LBS-008 will be 200 mg and the planned doses for subsequent cohorts are 400 and 600 mg, once daily. The final doses will be determined based on the outcome of SAD portion.

Route of administration: Oral
Duration: SAD on Day 1 and MAD from day 1 to day 14

The strategies used to monitor adherence to the study drug will be: administration under direct medical supervision, mouth inspection for checking the ingestion, appropriate record of the dosing information, counts of the number of capsules.
Intervention code [1] 312791 0
Treatment: Drugs
Comparator / control treatment
Placebo (microcrystalline cellulose capsule) controlled treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 307957 0
Evaluate the safety and tolerability to LBS-008, access by adverse events, clinical laboratory test result, vital sign measurement, physical examination and 12-lead ECG result.
Timepoint [1] 307957 0
Monitored daily through day 4 and day 8 of SAD; Monitored on Day 1, 2, 3,4,7,11,14,15,16,17 and 23 of MAD.
Primary outcome [2] 307994 0
To evaluate the ocular safety by access the slit lamp biomicroscopy, dilated ophthalmoscopy, and intraocular pressure, visual acuity and color vision result.
Timepoint [2] 307994 0
Monitored daily through day 4 and day 8 of SAD;
Monitored on Day 1, 2, 3,4,7,11,14,15,16,17 and 23 of MAD.
Primary outcome [3] 308027 0
Pharmacokinetics (PK) parameters (AUC0-t, AUC0-inf, Cmax, Tmax, lambda z, t1/2, CL/F, and Vz/F) of administration of LBS-008 subjects.
Timepoint [3] 308027 0
Blood PK will be collected at Day 1, 2, 3, and 4 after IP administration of SAD.
Blood PK will be collected at Day 1, 2, 3, 4, 7, 11, 14, 15, 16 and 17 after IP administration of MAD.
Secondary outcome [1] 353471 0
1. To determine the effects of LBS-008 on plasma levels of RBP4, a PD marker.
Timepoint [1] 353471 0
Blood collection of RBP4 for SAD will be on Day 1, 2, 3, 4 after IP administration and on day 1, 2, 3, 4, 7, 11, 14, 15, 16 and 17 for MAD after IP administration.
Secondary outcome [2] 353594 0
2. To determine the effects of LBS-008 on serum levels of vitamin A.
Timepoint [2] 353594 0
Blood collection of vitamin A for SAD will be on Day 1, 2, 3, 4 after IP administration and on day 1, 2, 3, 4, 7, 11, 14, 15, 16 and 17 for MAD after IP administration.

Eligibility
Key inclusion criteria
1. The subject is male or female (not of child bearing potential), 18 to 65 years of age, inclusive, at screening.
2. The subject voluntarily consents to participate in this study and provides written informed consent before the start of any study-specific procedures.
3. The subject is willing and able to remain in the study unit for the entire duration of the confinement period and return for outpatient visits.
4. Female subjects must be of nonchildbearing potential (defined as surgically sterile [i.e., had a bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 6 months before the dose of study drug] or postmenopausal for at least 1 year before study drug administration confirmed by FSH test at screening; FSH level > 40 mIU/mL).
5. Male subjects must be surgically sterile (i.e., vasectomy) for at least 3 months before screening; or remain abstinent or agree to use a highly effective form of contraception when sexually active with a female partner for 90 days after study drug administration. Highly effective contraception requires use of a condom and appropriate contraceptive measures for your female partner (i.e. oral, injected or implanted hormonal methods, or placement of an intrauterine device or intrauterine system). This requirement does not apply to subjects in a same sex relationship.
6. The subject has a body mass index (BMI) of 18 to 30 kg/m2, inclusive, and weighs 50 to 100 kg (110-220 pounds), inclusive, at screening and Check-in.
7. The subject is considered to be in stable health by the investigator, as determined by:
• Ophthalmic history may include auto refraction error within +6 and –6 spherical diopters but no other abnormalities
• Pre-study ocular exam with no clinically significant abnormalities
• Pre-study best corrected visual acuity using Early Treatment of Diabetic Retinopathy Study (ETDRS) (Method 2)
• Normal D-15 Dichotomous color vision testing (tested monocularly, with Total Error Score within normal limits)
• Vital signs at screening and Check-in within normal ranges or if outside of the normal ranges are not deemed clinically significant in the opinion of the investigator
• Liver function tests (aspartate transaminase, alanine transaminase, bilirubin, and alkaline phosphatase) within 1.5 x the upper limit of normal (ULN)
• All other pre-study clinical laboratory findings within normal range, or if outside of the normal range are not deemed clinically significant in the opinion of the investigator
• 12-Lead electrocardiogram (ECG) showing no clinically significant abnormalities
8. The subject agrees to comply with all protocol requirements.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. The subject has a history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results.
2. The subject has vitamin A deficiency as defined based upon serum values less than 20
mcg/dL (0.7 µmol/L) or clinical signs during slit-lamp examination (conjunctival or corneal xerosis; Bitot's spots; corneal ulcers or scarring not due to trauma or other secondary causes).
3. The subject has had a clinically significant new illness within 1 month before screening.
4. The subject has had symptoms or illness compatible with gastrointestinal or respiratory viral syndrome within 2 weeks before screening.
5. The subject has had previous or current participation in any clinical study with an investigational drug, biologic, or device with a last dose within 6 weeks before the screening visit.
6. The subject has a history of severe drug or excipient allergy or hypersensitivity.
7. The subject has donated or lost in excess of 500 mL of blood within 56 days of study treatment administration.
8. The subject has donated plasma within 7 days before study treatment administration.
9. The subject has a recent history (within 2 years before the screening visit) of alcohol or drug/solvent abuse or a positive screen for alcohol or drugs of abuse, including marijuana, at screening.
10. The subject has a history of retinal macular edema or other retinal disorders.
11. The subject has a history of treatment with retinal toxic medications, such as chloroquine, hydroxychloroquine, vigabatrin, isotretinoin, tamoxifen, thioridazine.
12. The subject has a history of or positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at screening.
13. The subject has a history of hypertension, coronary artery disease, or any other significant cardiovascular disease.
14. The subject has a history of diabetes.
15. The subject has a systolic blood pressure of <90 mmHg or >140 mmHg, or a diastolic blood pressure <50 mmHg or >90 at screening, on Day –1, or predose.
16. The average of triplicate safety ECGs for male subjects is a QT interval corrected using Fridericia’s formula (QTcF) of >450 msec, or for female subjects with a QTcF >470 msec on screening and Day –1.
17. The subject has a history of unexplained loss of consciousness, epilepsy or other seizure disorder, or cerebrovascular disease.
18. The subject has had a malignancy within 5 years of the screening visit (with the exception of basal cell and squamous cell skin carcinoma).
19. The subject has been on a significantly abnormal diet, in the opinion of the investigator, during the 4 weeks preceding study treatment administration.
20. The subject has used any over-the-counter medication (including nutritional or dietary supplements, herbal preparations, or vitamins) with the exception of occasional paracetamol use (up to 2g per day) within 7 days before study treatment administration.
21. The subject has used any prescription medication, except hormonal replacement therapy, within 7 days before study treatment administration.
22. The subject has used any prescription or non-prescription oral or topical retinoids (for “aging”) within 2 weeks before study treatment administration.
23. The subject has been treated with any known drugs or supplements that are moderate or strong inhibitors/inducers of cytochrome P450 (CYP) enzymes (e.g., rifampin, barbiturates, phenothiazines, cimetidine, carbamazepine, St. John’s wort) within 30 days before the dose of study drug, and that, in the investigator’s judgment, may impact subject safety or the validity of the study results.
24. The subject has engaged in strenuous exercise, as judged by the investigator, from 48 hours before the dose of study drug until the EOS visit.
25. The subject has consumed beverages or foods that contain alcohol, grapefruit, poppy seeds, broccoli, Brussels sprouts, pomegranate, star fruit, char-grilled meat, or caffeine/xanthine within 48 hours before the dose of study drug.
26. The subject has consumed more than more than 2 cups of coffee or 2 soda cans per day within 7 days before study treatment administration.
27. The subject has smoked or used tobacco- or nicotine-containing products within 28 days prior to study drug dosing or has a positive test result for cotinine at screening.
28. In the opinion of the investigator, the subject is not suitable for entry into 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
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/11/2018
Actual
15/11/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
72
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 12318 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 24554 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 301061 0
Commercial sector/Industry
Name [1] 301061 0
RBP4 Pty Ltd
Address [1] 301061 0
58 Gipps Street, Collingwood Victoria 3066, Australia
Country [1] 301061 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
RBP4 Pty Ltd
Address
58 Gipps Street, Collingwood Victoria 3066, Australia
Country
Australia
Secondary sponsor category [1] 300669 0
None
Name [1] 300669 0
Address [1] 300669 0
Country [1] 300669 0
Other collaborator category [1] 280413 0
Commercial sector/Industry
Name [1] 280413 0
Belite Bio, Inc
Address [1] 280413 0
Ugland House
Grand Cayman, KY1-1104
Cayman Islands
Country [1] 280413 0
United Kingdom

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301815 0
Bellberry Human Research Ethics Committee H [EC00459]
Ethics committee address [1] 301815 0
129 Glen Osmond Rd Eastwood SA 5063
Ethics committee country [1] 301815 0
Australia
Date submitted for ethics approval [1] 301815 0
Approval date [1] 301815 0
24/09/2018
Ethics approval number [1] 301815 0

Summary
Brief summary
A double-blind, placebo-controlled, single ascending dose (SAD) study is planned to assess safety, pharmacokinetics (PK), and pharmacodynamics of LBS-008 in healthy adult volunteers. Healthy male or female adults with no significant ocular abnormalities will be enrolled. The plan is to enroll 48 subjects, in six cohorts of eight subjects each; additional cohorts (eight subjects per cohort) may be enrolled if it is deemed appropriate by the sponsor to repeat a dose level or to study another dose level. Within each cohort, six subjects will be randomized to receive active drug and two subjects will receive placebo. Each subject will participate in only one dose level. Subjects will receive single ascending doses of 50, 100, 200, 400, 800, and 1200 mg LBS-008 administered as 25 or 200 mg capsules, or an equivalent number of placebo capsules. Each dose cohort will be separated into two groups; a sentinel group of two subjects (one active and one placebo) will be dosed at least 24 hours before the remaining six subjects (five active and one placebo).
A double-blind, placebo-controlled, multiple ascending dose (MAD) study of the safety, PK, and pharmacodynamics of LBS-008 in three of healthy adult volunteers is also planned. The MAD cohorts of eight subjects will start enrollment after completion of the fourth cohort in the SAD study, at doses and frequency (e.g., daily, twice daily) to be determined based on results from the SAD study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88206 0
Dr Lara Hatchuel
Address 88206 0
QEII Medical Centre, First Floor, B Block Hospital Avenue, Nedlands, Western Australia, 6009, Australia
Country 88206 0
Australia
Phone 88206 0
+61 0424686547
Fax 88206 0
Email 88206 0
lhatchuel@linear.org.au
Contact person for public queries
Name 88207 0
Dr Lara Hatchuel
Address 88207 0
QEII Medical Centre, First Floor, B Block Hospital Avenue, Nedlands, Western Australia, 6009, Australia
Country 88207 0
Australia
Phone 88207 0
+61 0424686547
Fax 88207 0
Email 88207 0
lhatchuel@linear.org.au
Contact person for scientific queries
Name 88208 0
Miss Yvonne Chen
Address 88208 0
RBP4 Pty Ltd
58 Gipps Street, Collingwood Victoria 3066, Australia
Country 88208 0
Australia
Phone 88208 0
+61 3 94197607
Fax 88208 0
Email 88208 0
yvonnechen@linbioscience.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be available.
What supporting documents are/will be available?
Clinical study report
Summary results
Not applicable