ANZCTR - Registration

Registration number

ACTRN12621000549820

Ethics application status

Approved

Date submitted

24/02/2021

Date registered

11/05/2021

Date last updated

28/04/2024

Date data sharing statement initially provided

11/05/2021

Date results information initially provided

9/12/2021

Type of registration

Retrospectively registered

Titles & IDs

Public title

This is a dose-finding study followed by 2-year extension study to evaluate safety and tolerability of Tinlarebant in adolescent subjects with Stargardt disease

Scientific title

Phase 1/2, open label, dose-finding followed by 2-year extension study to evaluate safety and tolerability of Tinlarebant in adolescent subjects with Stargardt disease

Secondary ID [1]

Protocol No. LBS-008-CT02

Universal Trial Number (UTN)

U1111-1244-6659

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Stargardt disease

Condition category

Condition code

Eye

Diseases / disorders of the eye

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Tinlarebant, in the Phase 1b study, 5mg orally in cycle 1 once a day for 14 days, 2mg, 5mg or 10mg orally in cycle 2 once a day for 14 days.

Tinlarebant, in the Phase 2 study
Subjects continuing from Phase 1b into Phase 2 will receive their individualised optimal dose of tinlarebant, as determined in Phase 1b, orally once daily for 24 months (corresponding to 96 weeks).
New subjects enrolling in Phase 2 will undergo dose optimisation as per the Optimal Dose Selection Criteria and receive their individualised optimal dose orally once daily for 24 months (corresponding to 96 weeks).

The optimal dose of tinlarebant is defined as the dose that reduces a subject’s plasma RBP4 levels to a concentration of less than or equal to 1 µM without producing an adverse event (AE), which in the opinion of the Investigator would result in discontinuation of the subject from the study.

Optimal dose selection criteria:
Tinlarebant will be self-administered orally once daily for 2 cycles, 14 days per cycle. Each subject enrolled in the study will receive 5 mg tinlarebant (starting dose) in Cycle 1. Pharmacodynamic and safety data (based on general safety assessments and vision questionnaire) will be collected on Day 1 and Day 8 of each cycle. Subjects will receive 10 mg tinlarebant in Cycle 2 if the plasma RBP4 concentration is above 1 µM and there are no safety concerns; 5 mg tinlarebant if the plasma RBP4 concentration is equal to or below 1µM and there are no safety concerns; 2 mg tinlarebant if there are safety concerns. General safety assessments include vital signs, physical examination, 12-lead ECG, Clinical Laboratory Testing, visual acuity, dark adaptation and adverse events.

The SRC will oversee dose escalation, de-escalation, and discontinuation per subject, throughout the Phase 1b portion and for any new subjects joining the study in Phase 2 (i.e., those who have not previously completed Phase 1b). A Data Safety Monitoring Board (DSMB) will meet periodically throughout both Phase 1b and Phase 2 to provide full study oversight (e.g., after 3-5 subjects have completed Phase 1b) and to determine progression from Phase 1b to Phase 2.

The optimal dose selection criteria were specifically designed for this study.

Phase 2 (new subjects only)
The starting dose for any subjects enrolled in Phase 2 who have not been through Phase 1b will be as per the Phase 1b dosing plan or may be guided by the DSMB based on available data. The individualised optimal dose for new subjects joining the study in Phase 2 will be determined based on their RBP4 and safety data [based on the optimal dose definition and selection criteria described for Phase 1b]. For dose optimisation, only new subjects who are enrolled in Phase 2 of the study will be required to undergo blood sampling for PK (plasma tinlarebant), and PD (plasma RBP4, and serum retinol [Vitamin A]) analyses at Visits 1-6. The SRC will provide oversight of dose escalation during the Phase 2 portion for new subjects.

Adherence monitoring
For phase 1b a 1-week supply of the study drug will be dispensed on Day 1 and 8 of each cycle. Subjects should bring the study drug medication bottle(s), including any unused capsules and drug administration diary, back to the clinic for drug accountability on Day 8 of each cycle and Cycle 2 Day 14.
For all subjects in phase 2 the study drug will be dispensed at Visit 1, for subjects continuing from Phase 1b this will be a 6-week supply, and for new subjects joining the study in Phase 2 this will be a 1-week supply and the study drug will be dispensed weekly until Visit 5. Subjects should bring the study drug medication bottle(s), including any unused capsules and drug administration diary, back to the clinic for drug accountability on each visit following the initial visit.

Throughout phase 1b and 2 accurate records will be kept regarding when and how much study drug is dispensed and used by each subject in the study. Reasons for departure from the expected dispensing regimen must also be recorded. At the completion of the study, all study drugs will be reconciled

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

To evaluate systemic safety and tolerability of tinlarebant as assessed by;
- physical examination findings
- vital sign measurements (systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature)
- clinical laboratory test results (including serum chemistry and haematology panels and urinalysis,)
- retinol chemistries (retinol, plasma RBP4)
- 12-lead electrocardiogram (ECG) results (including heart rate, PR, QRS, QT, QTcB, and QTcF intervals)
- monitoring and recording of non-ocular AEs
- monitoring and recording concomitant medications

Timepoint [1]

Phase 1b: day 1 and day 8 of cycle 1; day 1, day 8 and day 14 of cycle 2; 14 days post last treatment

Phase 2:
For new subjects joining the trial in Phase 2:
First visit (day 1) in Phase 2, weekly during weeks 1-4, then week 7, week 13, week 19, week 25, week 31, week 37, week 43, week 49, week 55, week 61, week 67, week 73, week 79, week 85, week 91, week 97, and 28 days post last treatment*

For subjects continuing into Phase 2 from Phase 1b:
First visit (day 1) in Phase 2, then week 7, week 13, week 19, week 25, week 31, week 37, week 43, week 49, week 55, week 61, week 67, week 73, week 79, week 85, week 91, week 97, and 28 days post last treatment*

*the target day for each visit is the first day of that study week.

Primary outcome [2]

To determine the optimal dose of tinlarebant by identifying the dose level which reduces a subject’s plasma RBP4 levels to a concentration of less than or equal to 1 µM without any safety concerns.

Timepoint [2]

Phase 1b: day 1 and day 8 of cycle 1; day 1, day 8 and day 14 of cycle 2; 14 days post last treatment

Primary outcome [3]

To evaluate Ocular safety and tolerability as assessed by:
- ophthalmic examination (slit lamp biomicroscopy, dilated ophthalmoscopy, and intraocular pressure [IOP] measurement),
- vision questionnaire (by IVI-C)
- decrease in visual acuity using Early Treatment Diabetic Retinopathy Study (EDTRS) chart
- dark adaptometry
- monitoring and recording of ocular AEs, assessed by Severity classified as mild, moderate and severe

Timepoint [3]

Phase 1b: day 1 and day 8 of cycle 1; day 1, day 8 and day 14 of cycle 2; 14 days post last treatment

Phase 2:
For new subjects joining the trial in Phase 2:
First visit (day 1) in Phase 2, weekly during weeks 1-4, then week 7, week 13, week 19, week 25, week 31, week 37, week 43, week 49, week 55, week 61, week 67, week 73, week 79, week 85, week 91, week 97, and 28 days post last treatment*

For subjects continuing into Phase 2 from Phase 1b:
First visit (day 1) in Phase 2, then week 7, week 13, week 19, week 25, week 31, week 37, week 43, week 49, week 55, week 61, week 67, week 73, week 79, week 85, week 91, week 97, and 28 days post last treatment*

*the target day for each visit is the first day of that study week.

Secondary outcome [1]

To measure the change in atrophic lesion size (definitely decreased autofluorescence, DDAF) by fundus autofluorescence (FAF) photography from baseline to 24 months in phase 2

Timepoint [1]

Phase 2: week 25, week 49, week 61, week 73, week 85, week 97 post commencement of intervention*
*the target day for each visit is the first day of that study week

Secondary outcome [2]

To measure the change in retinal thickness by spectral domain optical coherence tomography (SD-OCT) from baseline to 24 months in phase 2

Timepoint [2]

Phase 2: week 25, week 49, week 61, week 73, week 85, week 97 post commencement of intervention*
*the target day for each visit is the first day of that study week

Secondary outcome [3]

To measure the change in lesion size (questionably decreased autofluorescence, QDAF) by FAF photography from baseline to 24 months in phase 2

Timepoint [3]

Phase 2: week 25, week 49, week 61, week 73, week 85, week 97 post commencement of intervention*
*the target day for each visit is the first day of that study week

Secondary outcome [4]

Plasma levels of RBP4 will be measured using a validated commercial enzyme-linked immunosorbent (ELISA) assay.

Timepoint [4]

Phase 1b: day 1 and day 8 of cycle 1; day 1, day 8 and day 14 of cycle 2; 14 days post last treatment

Phase 2: week 13, week 25, week 37, week 49, week 61, week 73, week 85, week 97, 28 days post commencement of intervention*

*the target day for each visit is the first day of that study week

Secondary outcome [5]

To evaluate pharmacokinetics (PK) of tinlarebant at selected time points by calculation of:

• Area under the plasma concentration versus time curve from time 0 to the last quantifiable concentration (AUC0-t)
• Area under the plasma concentration versus time curve from time 0 extrapolated to infinity (AUC0-inf)
• Maximum observed plasma concentration (Cmax)
• Time to maximum observed plasma concentration (Tmax)
• Terminal elimination rate (?z)
• Terminal phase half-life (t1/2)
• Apparent total body clearance (CL/F)
• Apparent volume of distribution during the terminal phase (Vz/F)
• Accumulation ratio (Racc)

Timepoint [5]

Phase 1b: day 1 (0hrs, 2hrs and 4hrs post dose) and day 8 (0hrs, 2hrs and 4hrs post dose) of cycle 1; day 1 (0hrs post dose), day 8 (0hrs post dose) and day 14 (0hrs, 2hrs and 4hrs post dose) of cycle 2; 14 days post last treatment (anytime during visit).
Note, if the dose level of Cycle 2 is escalated/de-escalated, additional timepoints at 2hr and 4hr are required on Cycle 2 Day 1 and Cycle 2 Day 8

Phase 2:
For new subjects joining the trial in Phase 2: First visit (day 1) in Phase 2, weekly during weeks 1-4, then week 7, week 13, week 25, week 37, week 49, week 61, week 73, week 85, week 97, and 28 days post last treatment (anytime during visit)*

For subjects continuing into Phase 2 from Phase 1b: First visit (day 1) in Phase 2, then week 13, week 25, week 37, week 49, week 61, week 73, week 85, week 97, and 28 days post last treatment (anytime during visit)*

*the target day for each visit is the first day of that study week
Phase 2 samples are taken at 0hrs post dose with the exception of new participants joining at phase 2 who follow the same schedule as phase 1b up to and including the week 7 visit
Participants continuing from phase 1b will attend initial visit and then week 13 onwards

Secondary outcome [6]

To measure the change in quantitative autofluorescence (qAF) level using SD-OCT from baseline to 24 months in phase 2

Timepoint [6]

Phase 2: week 25, week 49, week 61, week 73, week 85, week 97 post commencement of intervention*
*the target day for each visit is the first day of that study week

Secondary outcome [7]

To measure the change in retinal sensitivity by microperimetry from baseline to 24 months in phase 2 only

Timepoint [7]

Phase 2: week 25, week 49, week 61, week 73, week 85, week 97 post commencement of intervention*
*the target day for each visit is the first day of that study week

Secondary outcome [8]

To measure the change in retinal morphology by spectral domain optical coherence tomography (SD-OCT) from baseline to 24 months in phase 2

Timepoint [8]

Phase 2: week 25, week 49, week 61, week 73, week 85, week 97 post commencement of intervention*
*the target day for each visit is the first day of that study week

Secondary outcome [9]

To evaluate pharmacodynamics (PD) of tinlarebant from plasma and serum samples at selected time points by calculation of;
• Time to minimal RPB4 levels postdose (Tmin)
• maximal suppression to RBP4 expressed as minimum concentration of RBP4 (Cmin)
• maximal suppression to RBP4 expressed as percent (%) of baseline concentration of RBP4 (C%bmin)
• RBP4 level at 2 hours as concentration (C2h)
• RBP4 level at 2 hours as percent (%) of baseline concentration (C%b2h)
• RBP4 level at 4 hours as concentration (C4h)
• RBP4 level at 4 hours as percent (%) of baseline concentration (C%b4h)
• Half-life for recovery of RBP4 to baseline levels (PDt1/2)

Timepoint [9]

Phase 1b: day 1 (0hrs, 2hrs and 4hrs post dose) and day 8 (0hrs, 2hrs and 4hrs post dose) of cycle 1; day 1 (0hrs post dose), day 8 (0hrs post dose) and day 14 (0hrs, 2hrs and 4hrs post dose) of cycle 2; 14 days post last treatment (anytime during visit).
Note, if the dose level of Cycle 2 is escalated/de-escalated, additional timepoints at 2hr and 4hr are required on Cycle 2 Day 1 and Cycle 2 Day 8

Phase 2:
For new subjects joining the trial in Phase 2: First visit (day 1) in Phase 2, weekly during weeks 1-4, then week 7, week 13, week 25, week 37, week 49, week 61, week 73, week 85, week 97, and 28 days post last treatment (anytime during visit)*

For subjects continuing into Phase 2 from Phase 1b: First visit (day 1) in Phase 2, then week 13, week 25, week 37, week 49, week 61, week 73, week 85, week 97, and 28 days post last treatment (anytime during visit)*

*the target day for each visit is the first day of that study week
Phase 2 samples are taken at 0hrs post dose with the exception of new participants joining at phase 2 who follow the same schedule as phase 1b up to and including the week 7 visit
Participants continuing from phase 1b will attend initial visit and then week 13 onwards

Eligibility

Key inclusion criteria

1. Male or female subjects aged 12 to 18 years old.
2. Subject must have clinically diagnosed Stargardt disease with at least one mutation identified in the ABCA4 gene.
3. Ability to adequately examine fundus of study eye at enrolment.
4. Subject must have a defined aggregate atrophic lesion size.
5. Subjects must have a BCVA of 20/400 or better for the study eye based on ETDRS letter score.
6. Subject and their parent(s) or legal representative are willing to provide their consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) prior to participating in any study-related procedures.
7. The subject agrees to comply with all protocol requirements.

Minimum age

12 Years

Maximum age

18 Years

Sex

Both males and females

Can healthy volunteers participate?

No

Key exclusion criteria

1. Any ocular diseases other than Stargardt disease that will complicate assessments.
2. Ocular surgery in the study eye in the previous 3 months
3. Participated in any clinical study in the previous 3 months.
4. Use of retinol modulators or derivatives which may impact study drug effect
5. Recent use of drugs, supplements or eating foods that are moderate or strong inhibitors/inducers of cytochrome P450 enzymes and could be considered to impact subject safety or study results
6. Vitamin A deficiency.
7. Life-threatening or currently in treatment for malignancies
8. Abnormal ALT, AST and Creatinine test values.
9. Females must have a negative pregnancy test before dosing.
10. Both males and females, including their partners need to agree to have acceptable method of contraception.

Study design

Statistical methods / analysis

Up to 10 subjects will be recruited into phase 1b and a total of 10 subjects will be enrolled into phase 2. Within each Phase, any subject who is withdrawn or discontinued from the study after receiving the study drug will not be replaced. Subjects who withdraw consent before dosing may be replaced. Where fewer than 10 subjects are enrolled in Phase 1b prior to commencing Phase 2, or where some subjects enrolled in Phase 1b do not continue into the Phase 2 portion, additional subjects will be added to achieve a sample size of 10 subjects in Phase 2.

The sample size (N = 10) is based on clinical and practical considerations and not on a formal statistical power calculation. The sample size is considered sufficient to evaluate the objectives of the study. Statistical analyses will be largely descriptive. All data collected will be presented in data listings. For categorical variables, frequencies and percentages will be presented. Continuous variables will be summarised using descriptive statistics (number of subjects, mean, median, standard deviation [SD], minimum, and maximum). An interim analysis will be conducted at the completion of Phase 1b of this study.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

12/03/2021

Date of last participant enrolment

Anticipated

21/11/2021

Actual

7/09/2021

Date of last data collection

Anticipated

30/06/2023

Actual

15/08/2023

Sample size

Target

10

Accrual to date

Final

12

Recruitment in Australia

Recruitment state(s)

NSW,WA

Recruitment hospital [1]

Lions Eye Institute Day Surgery Centre - Nedlands

Recruitment hospital [2]

The Children's Hospital at Westmead - Westmead

Recruitment postcode(s) [1]

6009 - Nedlands

Recruitment postcode(s) [2]

2145 - Westmead

Recruitment outside Australia

Country [1]

Taiwan, Province Of China

State/province [1]

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

RBP4 PTY LTD

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

RBP4 PTY LTD

Country

Australia

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Lin BioScience, Inc

Country [1]

Taiwan, Province Of China

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited Human Research Ethics Committee A

Ethics committee address [1]

123 Glen Osmond Road Eastwood Adelaide
South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/11/2019

Approval date [1]

14/05/2020

Ethics approval number [1]

2019-10-928

Ethics committee name [2]

National Taiwan University Hospital Research Ethics Committee C

Ethics committee address [2]

7, Chung Shan South Road, Taipei,
Taiwan 100, R.O.C

Ethics committee country [2]

Taiwan, Province Of China

Date submitted for ethics approval [2]

09/11/2020

Approval date [2]

28/12/2020

Ethics approval number [2]

202011035MSC

Ethics committee name [3]

The Sydney Children’s Hospital Ethics Committee

Ethics committee address [3]

Corner Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Sydney Australia

Postal Address:
Locked Bag 4001 Westmead NSW 2145 Sydney Australia

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

06/11/2020

Approval date [3]

20/01/2021

Ethics approval number [3]

2020/ETH02176

Summary

Brief summary

Stargardt disease 1 (STGD1) is the most prevalent form of juvenile macular degeneration. It is caused by a rare, inherited autosomal recessive trait, leading to severe and irreversible blindness by the first or second decade of life. Earlier onset of the disease is related to a rapid vision loss, while patients with a later onset tend to have a better prognosis.

This study will enrol up to 10 subjects aged 12-18 years old with a confirmed clinical diagnosis of Stargardt disease type 1 (STGD1). This study will include 2 phases, the phase 1b portion is to determine the optimal dose for phase 2 based on the extent of retinol binding protein 4 (RBP4) reduction after 2 cycles of tinlarebant treatment. The phase 2 portion will evaluate the safety and efficacy of a single daily dose of tinlarebant over a 24-month treatment period.

Trial website

Public notes

Contacts

Principal investigator

Name

Dr Fred Chen

Address

Lions Eye Institute
2 Verdun St, NEDLANDS WA 6009

Country

Australia

Phone

+61 8 9381 0777

Email

[email protected]

Contact person for public queries

Name

Dr Fred Chen

Address

Lions Eye Institute
2 Verdun St, NEDLANDS WA 6009

Country

Australia

Phone

+61 8 9381 0777

Email

[email protected]

Contact person for scientific queries

Name

Dr Nathan Mata

Address

12750 High Bluff Drive Suite 475, San Diego, CA 92130

Country

United States of America

Phone

+886972080097

Email

[email protected]

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Trial Review

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