A Double-Masked, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy of Oral AKST4290 with Loading Doses of Aflibercept in Patients with Newly Diagnosed Neovascular Age-Related Macular Degeneration (PHTHALO – 205)

Phase 1

Conditions: ewly Diagnosed Neovascular Age-Related Macular Degeneration
MedDRA version: 20.0Level: LLTClassification code 10075568Term: Wet age-related macular degenerationSystem Organ Class: 100000004853
Therapeutic area: Diseases [C] - Eye Diseases [C11]

Registration Number: EUCTR2019-002738-36-HU

Lead Sponsor: Alkahest, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 150

Inclusion Criteria

1. Men and women with newly diagnosed active CNV secondary to AMD, diagnosed by a retinal specialist with all the following characteristics and ophthalmic inclusion criteria applied to the study eye, as assessed by a central reader.
a. Has been examined by a retinal specialist and found to be eligible to receive IAI in the study eye.
b. No prior treatment for nAMD in the study eye.
c. Study eye has not undergone pars plana vitrectomy or glaucoma filtering surgery.
d. No previous participation in any studies of investigational drugs within 1 month preceding screening (Visit 1).
e. CST thickness = 250 microns on SD-OCT (exclusive of subretinal pigment epithelial fluid, inclusive of SRF).
f. Presence of SRF and/or IRF on SD-OCT.
g. Total lesion size not greater than 12 disc areas on FA.
h. If present, subretinal hemorrhage must comprise < 50% of the total lesion area on FA.
i. No subfoveal fibrosis or atrophy on FA.
j. Active CNV membranes with subfoveal leakage or juxtafoveal leakage too close for laser photocoagulation.
2. BCVA in the study eye between 70 and 24 letters inclusive at screening (Visit 1).
3. Subjects 50 years of age or older at screening (Visit 1).
4. Body mass index (BMI) between 18 and = 40 at screening (Visit 1).
5. Signed informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in the trial, which includes medication washout and restrictions.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

Exclusion Criteria

1. Previous participation in any studies of investigational drugs within 1 month preceding screening.
2. Any form of macular degeneration that is not age-related.
3. Additional disease in the study eye that could compromise BCVA.
4. Presence of RPE tears or rips in the study eye.
5. Anterior segment and vitreous abnormalities in the study eye that would preclude adequate visualization with fundus photography/FA or SD-OCT.
6. Intraocular surgery in the study eye within 3 months prior to screening.
7. Aphakia or total absence of the posterior capsule (yttrium aluminum garnet [YAG] laser capsulotomy permitted in an eye with a posterior chamber intraocular lens if performed a minimum of 1 month prior to enrollment) in the study eye.
8. Known allergy to fluorescein sodium.
9. Women of childbearing potential (WOCBP).
10. Current or planned use of medications known to be toxic to the retina, lens, or optic nerve.
11. Medical history or condition:
a. Uncontrolled diabetes mellitus, with hemoglobin A1c (HbA1c) > 8%.
b. Myocardial infarction or stroke within 12 months of screening.
c. Active bleeding disorder.
d. Major surgery within 1 month of screening or planned within the study period.
e. Current, active liver disease: > 3-fold elevation of liver enzymes over upper limit of normal [ULN].
f. Uncontrolled high blood pressure.
g. Positive test result for hepatitis B virus, hepatitis C virus, human immunodeficiency virus, or tuberculosis (by QuantiFERON testing) at screening.
12. Prior treatment within 4 weeks or planned use of potent cytochrome P450 3A4/5 (CYP3A4/5) or P glycoprotein (P-gp) inhibitors or inducers during the study.
13. Planned concomitant use of CYP3A4/5 and/or P-gp sensitive substrates that have a narrow therapeutic index.
14. Planned concomitant use of CYP3A4/5 sensitive substrates, such as fentanyl.
15. Planned concomitant use of drugs with a narrow therapeutic window that are metabolized predominantly by CYP2C8, or are CYP2C8 sensitive substrates .
16. Planned concomitant use of Organic Anion Transporter 1 (OAT1) and OAT3 sensitive substrates.
17. Subjects with renal impairment AND with current or planned concomitant use of organic cation transporter 2 (OCT2) substrates with a narrow therapeutic index or OCT2 inhibitors.
18. Subjects with renal impairment eGFR < 45 mL/min/1.73m2 who are NOT on metformin.
19. Use of any nonselective monoamine oxidase inhibitors (MAOIs) (MAOI-Bs are acceptable).
20. Use of systemic corticosteroids (> 10 mg prednisone or equivalent/day) within 14 days of first dose of study agent or known diseases which could require the use of systemic corticosteroids within the study period.
21. Use of intravitreal or implanted corticosteroids:
a. Dexamethasone or triamcinolone within 6 months prior to screening.
b. Fluocinolone within 48 months prior to screening.
22. Subjects with clinically relevant, abnormal screening hematology, blood chemistry, or urinalysis, if the abnormality defines a significant disease as defined in other exclusion criteria. Laboratory testing may be repeated once during the screening phase.
23. Significant alcohol or drug abuse within the past 2 years.
24. Based on electrocardiogram (ECG) reading, subjects with a risk of QT prolongation including:
a. A baseline prolongation of QTc with confirmation on a repeat ECG.
b. A history of additional risk factors for Torsades de pointes arrhythmia.
c. The use of concomitant medications known to prolong the QT/QTc interval.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of the study is to evaluate the potential therapeutic effects of a 36-week, b.i.d. oral dosing regimen of AKST4290, with loading doses of IAI, by assessing the improvement in best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) method. ;Secondary Objective: The secondary objectives include the time to PRN injection (Arms 1 and 2 only), mean number of injections, proportion of subjects with a mean change in BCVA letter score of = 15 letters, mean change in central subfield thickness (CST), and overall safety. ;Primary end point(s): Mean change from baseline in BCVA per the ETDRS testing method.;Timepoint(s) of evaluation of this end point: 36 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Time to PRN injection (Arms 1 and 2 only).<br>• Mean number of injections.<br>• Proportion of subjects with BCVA change of = 15 letters.<br>• Mean change in CST compared with control.<br>• Safety as assessed by incidence and intensity of adverse events.<br><br><br>;Timepoint(s) of evaluation of this end point: 36 weeks

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