| Outcome Measures: |
To evaluate the safety of GDD3898 topical gel in over-weight or obese subjects with presumed NAFLD[Safety as assessed by reported treatment-emergent adverse events (AEs), changes in vital signs, physical examination, ocular assessments, ECGs, and laboratory tests.<br>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. <br>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).<br>Physical examination will be assessed at screening and day 1, 7, 28, 56, 84 & 98 post-intervention commencement.<br>Safety Laboratory Tests will be assessed at screening and day 1, 7, 14, 28, 56, 84 & 98 post-intervention commencement.<br>Ocular assessments will be performed at screening and day 14, 56 & 84 post-intervention commencement.<br>ECG will be performed at screening and day 84 post-intervention commencement.<br><br>];To evaluate the tolerability of GDD3898 topical gel in over-weight or obese subjects with presumed NAFLD[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.<br>]To evaluate the pharmacokinetic (PK) profile of GDD3898 topical gel and its major metabolite GDD3990 in this population.
<br>The PK analysis will use blood samples.
<br>The following parameters will be calculated following the first application on Day 1: AUC, Cmax, Kel, Tmax, t1/2 and CL/F.
<br>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).[Serial pharmacokinetic (PK) samples will be collected at:
<br>Day 1 ?€? Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 1
<br>Day 2 - 12 hours after Day 1 second application
<br>Day 7 ?€? Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 7
<br>Day 8 - 12 hours after Day 7 second application
<br>Day 14 ?€? Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 14
<br>Day 28 ?€? Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 28
<br>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
<br>Day 84 ?€? Pre-application, 1, 2, 4, 6, 8, and 12 hours after first application on Day 84
<br>Day 85 ?€? 24 hours after Day 84 morning application
<br>Day 86 ?€? 48 hours after Day 84 morning application
<br>];To evaluate surrogate markers of efficacy and mechanism of action in overweight or obese subjects with features of presumed NAFLD.[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.]
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