ANZCTR - Registration

Registration number

ACTRN12619000816156

Ethics application status

Approved

Date submitted

8/05/2019

Date registered

4/06/2019

Date last updated

14/02/2020

Date data sharing statement initially provided

4/06/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

A Randomized, Double-Masked (Sponsor-Open), Placebo-Controlled, Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Escalating Single Doses and Multiple Ascending Doses of STG-001 in Healthy Subjects

Scientific title

A Randomized, Double-Masked (Sponsor-Open), Placebo-Controlled, Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Escalating Single Doses and Multiple Ascending Doses of STG-001 in Healthy Subjects

Secondary ID [1]

Nil

Universal Trial Number (UTN)

Trial acronym

STG-001-1

Linked study record

Health condition

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

Stargardt’s Disease

Condition category

Condition code

Eye

Diseases / disorders of the eye

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Intervention: STG-001
Administration: Oral capsule
Part 1: Single Ascending Dose (SAD) study
Cohort 1 Fasted: STG-001 6 active (1 at 0.2 and 5 at 1 mg) and 2 placebo
Cohort 2 Fasted: STG-001 5mg (6 active, 2 placebo)
Cohort 3 Fasted and Fed : STG-001 10mg (6 active, 2 placebo)
Cohort Fasted 4: STG-001 20mg (6 active, 2 placebo)
Cohort Fasted 5: STG-001 40mg (6 active, 2 placebo)
Optional Cohort Fasted 9: STG-001 80mg (6active, 2 placebo)
The Fed period will be conducted in Cohort 3 after a washout period of >=28 days and, based on prior SAD data, dose of STG-001 will be determined to be studied under fed conditions.

Part 2: (Multiple Ascending Dose) MAD Study (STG-001 starting dose to be confirmed based on SAD results and subsequent ascending dose to be determined by study investigator based on safety and PK data,). IP will be administered once daily for 7 days.
Cohort 6 Fasted: STG-001 'X' mg (7 active and 2 placebo)
Cohort 7 Fasted: STG-001 'Y' mg (7 active and 2 placebo)
cohort 8 Fasted: STG-001 'Z' mg (7 active and 2 placebo)
Optional cohort 10 Fasted: STG-001 'A' mg (7 active and 2 placebo)

New participants will be enrolled in each cohort. In cohort 3, participants will return after >=28 days for Fed dosing during which subjects will all receive a dose of STG-001 within 30 minutes after completing a high-fat meal (- 2 normal fried eggs, 2 slices white toast, 250 mL whole milk, 2 full rashes middle bacon, 2 serves butter for cooking, 2 serves butter for toast, 2 hash browns)
The cohorts will run sequentially such that the study periods for Cohort 2 occur after Cohort 1. MAD cohort will commence after completion and safety review of SAD cohort 4.

Participants in SAD and MAD cohorts will not be the same.

At the discretion of Sponsor, and with approval of the Review Committee, Sponsor may enroll an additional cohort in the SAD portion of study (Cohort 9) and an additional cohort in the MAD portion of study (Cohort 10). The dose of the MAD cohort will be determined by the Review committee.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Matching Placebo comprising of di-calcium phosphate anhydrous (fine granular) (A Comprez),Sodium starch glycolate (Explotab), Silicon dioxide (Aerosil 200) and Magnesium stearate (Ligamed MF-2-V)

Control group

Placebo

Outcomes

Primary outcome [1]

Part 1: The primary endpoint of the study is safety assessed by incidence and/or clinically significant changes of a combination of ocular and non-ocular adverse events of single ascending PO doses of STG-001.
Systemic adverse reactions will be assessed by physical exam, vital signs, EKG and blood testing (CBC, chemistry, and urinalysis). Ocular adverse reactions, including delayed dark adaptation, will be assessed by ocular exam, visual acuity and color vision testing, intraocular pressure testing, retina exam and a night vision questionnaire. Additional diagnostic testing to monitor ocular adverse events will include ocular coherence tomography, fundus autofluorescence, dark adaptometry and electroretinogram.

Timepoint [1]

Physical Examination: Screening and Day 3
Vitals: Screening, Day1,2,3,4 and Day 8
ECG: Screening, Day, 2, 3, Day 8
Telemetry: Day 1, 2 and 3
Lab assessments: Screening, Day 2, Day 4 and Day 8
Visual Acuity , color vision and intra ocular pressure: Screening, Day 3 and Day 8
FAF will be performed at Screening, Day 3 and Day 8
DA will be performed at Screening, Day -1, Day 3 and Day 8
ERG will be performed at Screening, Day 3 and Day 8
OCT will be performed at Screening, Day 3 and Day 8
AE: Screening, Day 1, 2, 3, 4 and Day 8
Night Vision Questionnaire: Screening, Day 2, Day 3 and Day 8

Primary outcome [2]

Part 1: – To characterize the safety and tolerability of single PO doses of STG-001 in healthy subjects in a food effect study.

Timepoint [2]

Physical Examination: Screening and Day 3
Vitals: Screening, Day1,2,3,4 and Day 8
ECG: Screening, Day, 2, 3, Day 8
Telemetry: Day 1, 2 and 3
Lab assessments: Screening, Day 2, Day 4 and Day 8
Visual Acuity , color vision and intra ocular pressure: Screening, Day 3 and Day 8
FAF will be performed at Screening, Day 3 and Day 8
DA will be performed at Screening, Day -1, Day 3 and Day 8
ERG will be performed at Screening, Day 3 and Day 8
OCT will be performed at Screening, Day 3 and Day 8
AE: Screening, Day 1, 2, 3, 4 and Day 8
Night Vision Questionnaire: Screening, Day 2, Day 3 and Day 8

Primary outcome [3]

Part 2: The primary endpoint of the study is safety assessed by incidence and/or clinically significant changes of a combination of ocular and non-ocular adverse events of multiple ascending PO doses of STG-001.
Systemic adverse reactions will be assessed by physical exam, vital signs, EKG and blood testing (CBC, chemistry, and urinalysis). Ocular adverse reactions, including delayed dark adaptation, will be assessed by ocular exam, visual acuity and color vision testing, intraocular pressure testing, retina exam and a night vision questionnaire. Additional diagnostic testing to monitor ocular adverse events will include ocular coherence tomography, fundus autofluorescence, dark adaptometry and electroretinogram.

Timepoint [3]

Physical Examination: Screening and Day 8
Vitals: Screening, Day1,2,3,4,5,6,7,8,9 and Day 15
ECG: Screening, Day1, 2, 7,8 and Day 15
Telemetry: Day 1 to Day 9 daily
Lab assessments: Screening, Day 2, Day 4 , Day 6, Day 9 and Day 15
Visual Acuity , color vision and intra ocular pressure: Screening, Day 3, Day 9 and Day 15
FAF will be performed at Screening, Day 9 and Day 15
DA will be performed at Screening, Day 3, Day 9 and Day 15
ERG will be performed at Screening, Day 9 and Day 15
OCT will be performed at Screening, Day 9 and Day 15
AE: Screening, Day 1 to Day 10 all days and Day 15
Night Vision Questionnaire: Screening, Day 2, Day 9 and Day 15

Secondary outcome [1]

Parts 1 and 2:
-Percentage of subjects who experience at least 1 TEAE (Treatment emergent adverse events).
Systemic adverse reactions will be assessed by physical exam, vital signs, EKG and blood testing (CBC, chemistry, and urinalysis). Ocular adverse reactions, including delayed dark adaptation, will be assessed by ocular exam, visual acuity and color vision testing, intraocular pressure testing, retina exam and a night vision questionnaire. Additional diagnostic testing to monitor ocular adverse events will include ocular coherence tomography, fundus autofluorescence, dark adaptometry and electroretinogram

Timepoint [1]

Treatment-emergent adverse events will be summarized by placebo, each STG-001 dose level, cohort and STG-001 overall for each part of the study.
Part 1
Physical Examination: Screening and Day 3
Vitals: Screening, Day1,2,3,4 and Day 8
ECG: Screening, Day, 2, 3, Day 8
Telemetry: Day 1, 2 and 3
Lab assessments: Screening, Day 2, Day 4 and Day 8
Visual Acuity , color vision and intra ocular pressure: Screening, Day 3 and Day 8
FAF will be performed at Screening, Day 3 and Day 8
DA will be performed at Screening, Day -1, Day 3 and Day 8
ERG will be performed at Screening, Day 3 and Day 8
OCT will be performed at Screening, Day 3 and Day 8
AE: Screening, Day 1, 2, 3, 4 and Day 8
Night Vision Questionnaire: Screening, Day 2, Day 3 and Day 8

Part 2
Physical Examination: Screening and Day 8
Vitals: Screening, Day1,2,3,4,5,6,7,8,9 and Day 15
ECG: Screening, Day1, 2, 7,8 and Day 15
Telemetry: Day 1 to Day 9 daily
Lab assessments: Screening, Day 2, Day 4 , Day 6, Day 9 and Day 15
Visual Acuity , color vision and intra ocular pressure: Screening, Day 3, Day 9 and Day 15
FAF will be performed at Screening, Day 9 and Day 15
DA will be performed at Screening, Day 3, Day 9 and Day 15
ERG will be performed at Screening, Day 9 and Day 15
OCT will be performed at Screening, Day 9 and Day 15
AE: Screening, Day 1 to Day 10 all days and Day 15
Night Vision Questionnaire: Screening, Day 2, Day 9 and Day 15

Secondary outcome [2]

Parts 1 and 2
– Assessment of diagnostic imaging changes by FAF (Fundus Autoflourescence).

Timepoint [2]

Part 1
-FAF will be performed on Day -1, Day 3 and Day 8
Part 2
FAF - will be performed on Day -1, Day 9 and Day 15

Secondary outcome [3]

Parts 1 and 2
– Additional PK parameters will be calculated if useful in the interpretation of the data
This is an exploratory outcome.

Timepoint [3]

Part 1
PK sample collection timepoints: Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose and Day 8

Part 2
PK sample collection timepoints: Day 1(Pre-dose and 1, 2, 4, 8, 12 and 24 hours post-dose), Day 7 (Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose) and Day 15

Secondary outcome [4]

Parts 1 and 2
– Additional PD parameters will be calculated if useful in the interpretation of the data.
This is an exploratory outcome.

Timepoint [4]

Part 1
PD sample collection timepoints: Pre-dose, Day 5 and Day 8

Part 2
PD sample collection timepoints: Pre-dose, Day 2, Day 7 and Day 15

Secondary outcome [5]

Parts 1 and 2
– Assessment of diagnostic imaging changes by DA (Dark Adaptometry)

Timepoint [5]

Part 1
-DA will be performed at Screening, Day -1, Day 3 and Day 8
Part 2
DA - will be performed at Screening, Day -1, Day 3, Day 9 and Day 15

Secondary outcome [6]

Parts 1 and 2
– Assessment of diagnostic imaging changes by ERG (Electroretinogram)

Timepoint [6]

Part 1
-ERG will be performed on Day -1, Day 3 and Day 8
Part 2
ERG - will be performed on Day -1, Day 9 and Day 15

Secondary outcome [7]

Parts 1 and 2
– Assessment of diagnostic imaging changes through OCT (Optical Coherence Tomography).

Timepoint [7]

Part 1
-OCT will be performed on Day -1, Day 3 and Day 8
Part 2
OCT- will be performed on Day -1, Day 9 and Day 15

Secondary outcome [8]

Parts 1 and 2:
Percentage of subjects who discontinue due to an AE.

Timepoint [8]

AE will be monitored on an ongoing basis and at every visit and post dose on Day 1 in SAD cohorts and Days 1-7 in MAD cohorts

Secondary outcome [9]

Parts 1 and 2:
Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at least once post-dose. This is assessed based on clinical observation and Investigator's assessment.

Timepoint [9]

Part 1
Lab assessments: Screening, Day 2, Day 4 and Day 8

Part 2
Lab assessments: Screening, Day 2, Day 4 , Day 6, Day 9 and Day 15

Secondary outcome [10]

Part 1 and 2
Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at least once post-dose.
This is assessed based on clinical observation and Investigator's assessment.

Timepoint [10]

Part 1
Vitals: Screening, Day1,2,3,4 and Day 8

Part 2
Vitals: Screening, Day1,2,3,4,5,6,7,8,9 and Day 15

Secondary outcome [11]

Part 1 and 2
Percentage of subjects who meet the markedly abnormal criteria (clinically significant as by the clinical investigator) for safety 12-lead ECG parameters at least once post-dose.

Timepoint [11]

Part 1
ECG: Screening, Day, 2, 3, Day 8

Part 2
ECG: Screening, Day1, 2, 7,8 and Day 15

Secondary outcome [12]

Part 1 and 2
-Maximum observed plasma concentration (Cmax).

Timepoint [12]

Part 1
PK sample collection timepoints: Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose and Day 8

Part 2
PK sample collection timepoints: Day 1(Pre-dose and 1, 2, 4, 8, 12 and 24 hours post-dose), Day 7 (Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose) and Day 15

Secondary outcome [13]

Part 1 and 2

-Time to reach Cmax (tmax).

Timepoint [13]

Part 1
PK sample collection timepoints: Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose and Day 8

Part 2
PK sample collection timepoints: Day 1(Pre-dose and 1, 2, 4, 8, 12 and 24 hours post-dose), Day 7 (Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose) and Day 15

Secondary outcome [14]

Part 1 and 2

-Area under the plasma concentration-time curve from time 0 to infinity (AUC infinity).

Timepoint [14]

Part 1
PK sample collection timepoints: Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose and Day 8

Part 2
PK sample collection timepoints: Day 1(Pre-dose and 1, 2, 4, 8, 12 and 24 hours post-dose), Day 7 (Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose) and Day 15

Secondary outcome [15]

Part 1 and 2

-Terminal elimination half-life (t1/2).

Timepoint [15]

Part 1
PK sample collection timepoints: Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose and Day 8

Part 2
PK sample collection timepoints: Day 1(Pre-dose and 1, 2, 4, 8, 12 and 24 hours post-dose), Day 7 (Pre-dose and 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours post-dose) and Day 15

Secondary outcome [16]

Part 1 and 2

PD of STG-001 (plasma RBP4 levels) parameters: % reduction from baseline, % with >60% reduction from baseline and % absolute reduction to <2 mg/dL.

Timepoint [16]

Part 1
PD samples will be collected pre dose and on Days 2 and 8.

Part 2
PD samples will be collected pre-dose and on days 2, 7 and 15

Eligibility

Key inclusion criteria

The subject must understand the study procedures and agree to participate by providing written informed consent. The subject must be willing and able to comply with all study procedures and restrictions.
To be eligible for participation in this study, the subject must:
1. Understand the study procedures and agree to participate by providing written informed consent.
2. Healthy male and female subjects.
3. Subjects aged 18 to 55 years, inclusive, with BMI of 18 to 32 kg/m2, inclusive, and body weight >=50 kg.
4. Male subjects must abstain from heterosexual activities or agree to use a double barrier method of contraception from admission to the clinical unit through 90 days after the last dose of study drug and will not donate sperm during this period. Heterosexual WOCBP who are sexually active must not be pregnant upon entering the study that is confirmed by testing (i.e., serum pregnancy test with sensitivity of >=25 mIU/mL at screening, and urine pregnancy test with sensitivity >=50 mIU/mL on Day 1 prior to dosing), be willing to use double-barrier contraception from screening through 60 days after the last dose of study drug, and will not donate eggs during this period. Highly effective double barrier contraception is defined as a condom or diaphragm AND one of the following;
o Birth control pills (The Pill)
o Birth Control Patch (e.g. Ortho Evra)
o NuvaRing®
o Depot or injectable birth control
o IUD
o Documented evidence of surgical sterilization at least 6 months prior to screening visit, i.e., tubal ligation or hysterectomy for women or vasectomy for men.
5. Sign an approved informed consent form for the study.
6. Pre-study ocular exam with no clinically significant abnormalities, including no significant macular abnormalities, DA testing within normal limits and BCVA >= 20/50 visual acuity (or equivalent)
7. Willing and able to comply with the protocol, including attending assessment visits.
8. Be judged to be in good health by the Investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, ECG, and vital sign measurements performed at the screening visit and before administration of the initial dose of study drug.

Minimum age

18 Years

Maximum age

55 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. The subject is an employee of the sponsor or study site or immediate family member (e.g., spouse, parent, child, sibling) of the sponsor or study site.
2. The subject is a citizen or resident of an EU member State.
3. The subject has a known hypersensitivity or contraindication to any component of STG 001.
4. The subjects has any history of an anaphylaxis event.
5. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to Check-in (Day -1). Herbal supplements and HRT must be discontinued 28 days prior to Check-in (Day -1). As an exception, paracetamol may be used at doses of less than or equal to 1 g/day. Limited use of nonprescription medications that are not believed to affect subject safety or the overall results of the study may be permitted on a case-by-case basis following approval by the Sponsor.
6. 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 of scarring not due to trauma or other secondary causes).
7. Has taken non-approved items (supplement containing vitamin A or beta-carotene, liver-based products, or prescription oral retinoid medications) within 30 days prior to admission at the clinical site.
8. Use of medications that may interact with Vitamin A metabolism within 60 days of screening (e.g. Accutane [isotretinoin], doxycycline).
9. Participation in an interventional study of a Vitamin A derivative less than or equal to months prior to screening
10. Presence of significant cardiovascular or cerebrovascular disease, including stroke.
11. Has a clinically significant abnormal electrocardiogram (ECG), or has a corrected QT interval (QTc) that is 450 ms or greater
12. Resting heart rate outside specified limits (less than 40/minute, greater than 100/min upon repeated measurement).
13. History of diabetes, hepatitis, pancreatitis, cirrhosis, liver failure, uncontrolled thyroid disease or hypervitaminosis A.
14. Any surgical procedure within three month of trial entry or anticipated during the trial. If such surgical procedure was within 3 months of trial entry and there was a full recovery with no expected impact on study procedures, data or safety, such a subject would be eligible at the discretion of the PI.
15. Women who are pregnant or nursing.
16. Abnormal blood pressure outside specified limits (90 mm Hg > Systolic > 140 mm Hg and/or 40 mm Hg > Diastolic > 90 mm Hg) upon repeated measurement.
17. Clinically significant abnormal lab results at screening, including liver function test (aspartate transaminase, alanine transaminase, bilirubin and alkaline phosphatase) greater than 1.5 x the ULN
18. Actively participating in an experimental therapy study or have received experimental therapy within 60 days of screening or 5 half-lives, whichever is longer.
19. Any history of significant eye disorders (including retinal disorders) or visual disturbances.
20. In the PI’s opinion, any acute or chronic medical condition, psychiatric condition, physical examination finding or laboratory abnormality that may increase the risk associated with study participation or administration of study treatment or interfere with the interpretation of study results. Minor medical conditions that are not currently being treated with medication and that are not expected to interfere with study procedures, data or participant safety may be considered for inclusion at the discretion of the PI.
21. Participants could be at increased risk of harm or put other people at increased risk of harm (e.g. if they are taxi or Uber drivers), if they were to experience visual impairment like impaired night time vision. Participants must agree to comply with advice of study investigators or study ophthalmologist around modifying activity and taking precautions if visual impairment occurs until such time as the visual impairment resolves, or the participant will be excluded from the study.

Study design

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

12/06/2019

Actual

12/06/2019

Date of last participant enrolment

Anticipated

9/12/2019

Actual

12/11/2019

Date of last data collection

Anticipated

14/12/2019

Actual

17/12/2019

Sample size

Target

84

Accrual to date

Final

75

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Nucleus Network - Melbourne

Recruitment postcode(s) [1]

3004 - Melbourne

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Stargazer Pharmaceuticals

Country [1]

United States of America

Primary sponsor type

Commercial sector/Industry

Name

Stargazer Pharmaceuticals

Country

United States of America

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Hospital Ethics Committee

Ethics committee address [1]

55 Commercial Rd, Melbourne, VIC 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

03/04/2019

Approval date [1]

13/05/2019

Ethics approval number [1]

Summary

Brief summary

Stargazer Pharmaceuticals. is developing STG-001 a potential oral therapy for patients with
Stargardt's disease.
This study will be conducted in up to 84 healthy volunteers who meet all of the inclusion
criteria and none of the exclusion criteria. The study is to assess the safety and tolerability of STG-001 in normal healthy volunteers.
This includes vital signs, safety labs, ECGs, and ocular and non-ocular examinations.
The drug will be given in single ascending then multiple ascending doses.
The study will also evaluate the PK and PD of the drug after dose administration.
Participants will be entered into standard study cohorts

Trial website

Public notes

Contacts

Principal investigator

Name

Dr Ben Snyder

Address

Nucleus Network Pty Ltd
5th Floor, Burnet Tower, AMREP Precinct
Commercial Road, Melbourne
VIC, 3004

Country

Australia

Phone

+61 390768960

Email

[email protected]

Contact person for public queries

Name

Jasmine Panthaki

Address

Nucleus Network Pty Ltd
5th Floor, Burnet Tower, AMREP Precinct
Commercial Road, Melbourne
VIC, 3004

Country

Australia

Phone

+61 3 9089 8247

Email

[email protected]

Contact person for scientific queries

Name

Gary Sternberg

Address

Stargazer Pharmaceuticals Inc
200 Clarendon Street, 45 floor, Mailbox 30
Boston, MA 02116

Country

United States of America

Phone

+1-510-913-8357

Email

[email protected]

Source	Title	Year of Publication	DOI
Embase	Recent developments in agents for the treatment of age-related macular degeneration and stargardt disease.	2020	https://dx.doi.org/10.1007/7355_2020_105
Dimensions AI	Therapy Approaches for Stargardt Disease	2021	https://doi.org/10.3390/biom11081179
Embase	Updates on Emerging Interventions for Autosomal Recessive ABCA4-Associated Stargardt Disease.	2023	https://dx.doi.org/10.3390/jcm12196229

Trial Review

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