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Trial registered on ANZCTR


Registration number
ACTRN12622000171718
Ethics application status
Approved
Date submitted
9/12/2021
Date registered
2/02/2022
Date last updated
3/05/2023
Date data sharing statement initially provided
2/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A Double-Blind, Randomised, Vehicle-Controlled Phase 1b Study to Evaluate the Safety and Pharmacokinetics of GDD3898 Topical Gel in Over-weight or Obese Subjects with Presumed Nonalcoholic Fatty Liver Disease (NAFLD)
Scientific title
A Double-Blind, Randomised, Vehicle-Controlled Phase 1b Study to Evaluate the Safety and Pharmacokinetics of GDD3898 Topical Gel in Over-weight or Obese Subjects with Presumed Nonalcoholic Fatty Liver Disease (NAFLD)
Secondary ID [1] 305488 0
GDD3898-104
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nonalcoholic fatty liver disease 323872 0
Obesity 323873 0
Condition category
Condition code
Metabolic and Endocrine 321387 321387 0 0
Other metabolic disorders
Diet and Nutrition 322258 322258 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-center, double-blind, randomised, vehicle-controlled study designed to assess the safety, tolerability, and pharmacokinetics of GDD3898 topical gel following twice daily application for 12 weeks in over-weight or obese subjects with presumed Nonalcoholic Fatty Liver Disease.

The study will be comprised of two cohorts:

Cohort 1:
12 subjects will be randomised to receive either 1.75% GDD3898 topical gel or vehicle which will be applied to the subject's face, over an area of approximately 540cm2, approximately every 12 hours for 84 consecutive days.

Cohort 2:
12 subjects will be randomised to receive 1.75% GDD3898 topical gel or vehicle which will be applied to the subject’s anterior aspect of one thigh, over an area of approximately 1260 cm2, approximately every 12 hours for 84 days.

In both cohorts, subjects will be confined in the unit beginning on Day -1 and will be discharged on Day 8. Follow up visits will occur on Day 14, 28, 42, 56, 70, and 84. During the out-patient period, study medication tubes will be weighed at each clinic visit to monitor compliance. Additionally, subjects will complete a daily diary recording the date and time of each dose applied, any missed doses, and a comment section should the subjects have a comment, e.g., recorded potential Adverse Events (AE's). The study team will review the diaries and use the information to question the subject regarding compliance and AEs and then record appropriate information in the participants study notes.

After completion of treatment, all subjects will have a follow up visit on Day 85, 86, and 98.
Intervention code [1] 321888 0
Treatment: Drugs
Comparator / control treatment
Active: GDD3898 Topical Gel 1.75%
Control: Vehicle Topical Gel containing only excipients of the active gel and 0% GDD3898
Control group
Placebo

Outcomes
Primary outcome [1] 329158 0
To evaluate the safety of GDD3898 topical gel in over-weight or obese subjects with presumed NAFLD
Timepoint [1] 329158 0
Safety as assessed by reported treatment-emergent adverse events (AEs), changes in vital signs, physical examination, ocular assessments, ECGs, and laboratory tests.
Adverse Events, such as eye irritation, dry skin and headache, will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE V5) at screening and day 1, 7, 8, 14, 28,42, 56, 70, 84, 85, 86 & 98 post-intervention commencement.
Vital signs will be assessed at screening and day 1, 7, 8, 14, 28,42, 56, 70, 84, 85, 86 & 98 post-intervention commencement. This will include body temperature (measured using a tympanic or oral thermometer) blood pressure and pulse (measured using a digital monitor), respiratory rate (measured by a visual count), height (measured using a wall mounted height measure), weight (measured using digital scales) and waist and thigh circumference (measured using a tape measure).
Physical examination will be assessed at screening and day 1, 7, 28, 56, 84 & 98 post-intervention commencement.
Safety Laboratory Tests will be assessed at screening and day 1, 7, 14, 28, 56, 84 & 98 post-intervention commencement.
Ocular assessments will be performed at screening and day 14, 56 & 84 post-intervention commencement.
ECG will be performed at screening and day 84 post-intervention commencement.
Primary outcome [2] 330017 0
To evaluate the tolerability of GDD3898 topical gel in over-weight or obese subjects with presumed NAFLD
Timepoint [2] 330017 0
Local tolerability as assessed by physician-assessed and subject-reported application site reactions. The assessment will be performed pre-application and 1 hour 20 minutes after first application on Day 1 and 1 hour 20 minutes post-morning application on Days 7, 14, 28, 56, and 84.
Secondary outcome [1] 401683 0
To evaluate the pharmacokinetic (PK) profile of GDD3898 topical gel and its major metabolite GDD3990 in this population.
The PK analysis will use blood samples.
The following parameters will be calculated following the first application on Day 1: AUC, Cmax, Kel, Tmax, t1/2 and CL/F.
The following parameters will be calculated following the first application on Days 7, 14, 28 & 84: AUC, Cavg, CLss/F, Cmax-ss, Cmin, %Fluc, Kel, Tmax, t1/2 and Rac(AUC), Rac(Cmax).
Timepoint [1] 401683 0
Serial pharmacokinetic (PK) samples will be collected at:
Day 1 – Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 1
Day 2 - 12 hours after Day 1 second application
Day 7 – Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 7
Day 8 - 12 hours after Day 7 second application
Day 14 – Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 14
Day 28 – Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 28
Days 42, 56, 70 - A single PK sample at each clinic visit. Time and day of last application will be recorded to assess time of PK sample from last application
Day 84 – Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 84
Day 85 – 24 hours after Day 84 morning application
Day 86 – 48 hours after Day 84 morning application
Secondary outcome [2] 404627 0
To evaluate surrogate markers of efficacy and mechanism of action in overweight or obese subjects with features of presumed NAFLD.
Timepoint [2] 404627 0
Analysis will use tissue from skin biopsies on the thigh(s). For subjects assigned to Cohort 2 (thigh application): a biopsy will taken from the treated thigh at end of treatment and from the contralateral (untreated) thigh pre- and end of treatment. For subjects assigned to Cohort 1 (facial application) a biopsy will be taken from the thigh (same or different) pre- and end of treatment.

Eligibility
Key inclusion criteria
1. Man or woman 18 to 60 years of age at the time of consent.
2. Body mass index (BMI) >/= 27.0 and < /= 41.0 kg/m2 at screening.
3. Alanine aminotransferase (ALT) >/= 30 IU/mL.
4. MRI-PDFF value of 6% or higher.
5. Women of childbearing potential are required to use a protocol-approved highly effective contraceptive method for at least 4 weeks prior to screening until at least 4 weeks after the last application.
6. Males with female partners of childbearing potential must use reliable forms of contraception from screening to 4 weeks after the end of treatment.
7. Willingness to undergo skin biopsies of the thigh(s).
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subject is a woman who is breastfeeding, pregnant, or who is planning to become pregnant during the study.
2. Subject has a history of skin disease or presence of skin condition (e.g., atopic dermatitis, psoriasis, etc.) that, in the opinion of the Investigator, would interfere with the study assessments.
3. Subject has had corneal or eyelid surgery, such as eyelid repair, reconstruction, and/or lifts, corneal transplantation, laser-assisted in situ keratomileusis (LASIK), photorefractive keratectomy, and/or radial keratotomy surgery, and/or has a history or presence of dry eye.
4. Subject has any history or evidence of hepatic cirrhosis and/or portal hypertension or complications (e.g. ascites, GI bleeds) or clinically meaningful hepatic impairment including:
a. ALT and/or AST >3 x ULN
b. Direct Bilirubin >/=6.9 mg/dL
c. Albumin < 3.6 g/dL
d. INR >/= 1.4
e. Platelets < 140 x109/mm3
f. FIB-4 >/= 2.67
g. If available, Histology: fibrosis score >/= 4 or Ishak score 5 or 6
h. Transient elastography >16 kPa
Note: Subjects with documented Gilbert’s Syndrome (elevated unconjugated hyper-bilirubinemia but normal conjugated bilirubinemia) will be allowed to participate in the study.
5. History or presence of other concomitant liver diseases including hepatitis due to hepatitis B or C virus (HCV, HBV) infection, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), alcoholic liver disease, or definite autoimmune liver disease.
6. Subject with known history of or positive results for human immunodeficiency virus (HIV).
7. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening, other substance abuse within the prior two years of Screening, or positive urine drug, cotinine, or alcohol test at Screening. Significant alcohol consumption is defined as > 2 drinks/day or > 14 drinks/week for men and > 1 drink/day or > 7 drinks/week for women.
8. Prior or planned (during the study period) bariatric surgery (e.g., gastric bands, gastroplasty, roux-en-Y gastric bypass) or ileal resection.
9. Presence of scars, birthmarks, tattoos, or excessive hair at the application site(s) that would impede the assessment of local tolerability assessments.
10. Subject has a history of cancer or lymphoproliferative disease within 5 years prior to Day 1. Subjects with successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or localised carcinoma in situ of the cervix may be included.
11. Subject had a major surgery within 8 weeks prior to Day 1 or has a major surgery planned during the study.
12. Subject has any clinically significant medical condition or physical/laboratory/ECG/vital signs abnormality that would, in the opinion of the Investigator, put the subject at undue risk by study participation or interfere with interpretation of study results (e.g., QTcF >450 msec for men or >470 msec for women).
13. Subjects with uncontrolled diabetes mellitus defined as hemoglobin A1c > 8.5%, hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg), or history of cardiovascular disease at Screening.
14. Subject has a known or suspected allergy to GDD3898 or any component of the study drug or the vehicle.
15. Unable to refrain from or anticipates the use of:
a. Any drugs known to be moderate/strong inhibitors of CYP3A4 enzymes (such as boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) for 14 days or 5 times the half-life of the product (whichever is longer) prior to the first dose of study drug, throughout the period of dose application and until the last PK blood draw is collected.
b. Any drugs known to be significant (i.e., strong or moderate) inducers of CYP enzymes, including St. John’s Wort, for 28 days prior to the first dose of study drug, throughout the period of dose application and until the last PK blood draw is collected.
16. Recent use of any medications that may promote fatty liver disease, such as systemically administered glucocorticoids, estrogens, etc.
17. Subjects who have major and/or clinically significant psychiatric disorders which would impede conduct of the research, including but not limited to, uncontrolled depression, suicidal ideation or uncontrolled bipolar disease at Screening.
18. Blood donation within 60 days prior to dosing or plasma donation within 14 days prior to dosing and during the study participation.
19. Subject has worn contact lens within 10 days prior to screening and/or is unable to avoid wearing them throughout the period of dose application and until the end of study ophthalmological examination.
20. Subject has any other known unstable medical condition that, in the opinion of the Investigator, puts the subject at undue risk or may limit the ability of the subject to comply with the protocol at Screening.
21. Following conditions or behavior likely to affect conduct of study:
a. Weight loss or weight gain of > 10% in the past 6 months
b. Unable to walk without assisted device
c. Have plans to make a significant lifestyle change to their diet and exercise regimens during the study
22. Subject has pyrexia, cough, malaise or any other symptoms or signs consistent with SARS-CoV-2 viral infection at any time within 14 days prior to screening or baseline visits.

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 computerised randomisation list will be created by an unblinded statistician or designee. Subjects will be randomised to receive GDD3898 Topical Gel or vehicle in a ratio of 1 to 3 respectively.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects who meet the required criteria will be centrally randomised using a randomisation list generated by SAS version 9.4 (or higher) statistical software package. Each subject will be assigned a subject randomisation number according to the cohort to which they are randomised. A unique, consecutive series of randomisation numbers will be provided to the study site and used to identify subjects enrolled in the study.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Analysis of Safety:
The analysis of safety data will be conducted on the Safety set which will include all randomised subjects regardless of whether or not the subject has recieved an application of study drug. Subjects will be analysed based on the treatment actually received, not based on the treatment they were randomised to; for any subjects who received at least 1 dose of GDD3898 Topical Gel 1.75%, they will be analysed in the GDD3898 1.75% group, even if they were allocated to vehicle at randomisation. The Safety set will be used to summarise all safety and tolerability results.
Analysis of the Pharmacokinetic Data:
The PK population will consist of all subjects who have received at least one application of study drug and have at least one analysable sample for plasma concentration of GDD3898 and/or GDD3990. Vehicle treated subjects will not be included in the PK set. The PK set will be used to summarise all plasma concentrations and PK results.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
4/02/2022
Actual
4/02/2022
Date of last participant enrolment
Anticipated
31/05/2022
Actual
12/05/2022
Date of last data collection
Anticipated
5/09/2022
Actual
17/08/2022
Sample size
Target
24
Accrual to date
Final
21
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 35468 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 309846 0
Commercial sector/Industry
Name [1] 309846 0
Lipidio Pharmaceuticals Australia Pty Ltd.
Country [1] 309846 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Lipidio Pharmaceuticals Australia Pty Ltd.
Address
58 Gipps Street
Collingwood, VIC 3066
Country
Australia
Secondary sponsor category [1] 310882 0
Commercial sector/Industry
Name [1] 310882 0
Inclin Pty Ltd
Address [1] 310882 0
Suite 210/ 25 Berry Street
North Sydney, NSW 2060
Country [1] 310882 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309585 0
Bellberry HREC
Ethics committee address [1] 309585 0
Ethics committee country [1] 309585 0
Australia
Date submitted for ethics approval [1] 309585 0
13/10/2021
Approval date [1] 309585 0
22/12/2021
Ethics approval number [1] 309585 0
2021-10-1254

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

Contacts
Principal investigator
Name 114678 0
Dr Kristi McLendon
Address 114678 0
Nucleus Network Pty Ltd
Level 5, 300 Herston Road
Herston, QLD 4006
Country 114678 0
Australia
Phone 114678 0
+61 7 38453620
Fax 114678 0
Email 114678 0
K.McLendon@nucleusnetwork.com.au
Contact person for public queries
Name 114679 0
Taylor Kilfoil
Address 114679 0
InClin Pty. Ltd.
Suite 210/ 25 Berry Street
North Sydney, NSW 2060
Country 114679 0
Australia
Phone 114679 0
+61408880403
Fax 114679 0
Email 114679 0
tkilfoil@inclin.com
Contact person for scientific queries
Name 114680 0
Taylor Kilfoil
Address 114680 0
InClin Pty. Ltd.
Suite 210/ 25 Berry Street
North Sydney, NSW 2060
Country 114680 0
Australia
Phone 114680 0
+61408880403
Fax 114680 0
Email 114680 0
tkilfoil@inclin.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data to remain confidential


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.