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-DE

Lead Sponsor: Alkahest, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 120

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. Participation in studies of investigational drugs must have been discontinued within 30 days or 5 half-lives of the drug (whichever was longer) prior to 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 (30.48 mm2)(1 disc area = 2.54 mm2) on FA.
h. If present, subretinal hemorrhage must comprise < 50% of the total lesion area on FA, SD-OCT, or FP/FAF.
i. No subfoveal fibrosis or atrophy on FA, SD-OCT, or FP/FAF.
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.
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 40
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 80

Exclusion Criteria

Exclusion Criteria abbreviated due to 5000 character limit.

1. Participation in studies of investigational drugs within 30d or 5 half-lives of the drug (whichever was longer) prior to Visit 1.
2. Known hypersensitivity to the active substance or excipients of AKST4290 or aflibercept.
3. Active or suspected ocular or periocular infection and/or active, severe intraocular inflammation.
4. Any form of macular degeneration that is not age-related.
5. Additional disease in the study eye that could compromise BCVA (i.e., uncontrolled glaucoma (IOP > 24) with visual field loss, clinically significant diabetic macular edema, history of ischemic optic neuropathy or retinal vascular occlusion, vitreomacular traction, high myopia > 6 diopters, or genetic disorders such as retinitis pigmentosa).
6. Presence of RPE tears or rips in the study eye.
7. Anterior segment and vitreous abnormalities in the study eye that would preclude adequate visualization with FP/FAF, FA, or SD-OCT.
8. Intraocular surgery in the study eye within 3 months prior to Visit 1.
9. Aphakia or total absence of the posterior capsule (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.
10. Known allergy to fluorescein sodium.
11. WOCBP.
12. Current/planned use of medications known to be toxic to retina, lens, or optic nerve.
13. Medical history or condition:
a. Uncontrolled Diabetes M.
b. MI or stroke within 12 months of Visit 1.
c. Active bleeding disorder.
d. Major surgery within 1 month of Visit 1 or planned within study period.
e. Current, active liver disease: > 3-fold ULN for ALT and AST.
f. Uncontrolled high BP (systolic >= 160 mmHg and/or diastolic >= 100 mmHg) despite treatment during the 3 months prior to dosing.
g. Positive HBV, HCV, HIV at Visit 1.
14. Prior treatment within 4 weeks or planned use of potent CYP450 3A4/5 (CYP3A4/5) or P-glycoprotein (P-gp) inhibitors or inducers during study.
15. Planned concomitant use of CYP3A4/5 and/or P-gp sensitive substrates with narrow therapeutic index (e.g., digoxin, warfarin, factor Xa inhibitors) (see Section 17.2.1).
16. Planned concomitant use of CYP3A4/5 sensitive substrates for which an increase in plasma levels could be clinically significant, such as fentanyl, simvastatin, lovastatin, atorvastin (see Section 17.2.1).
17. Planned concomitant use of drugs with a narrow therapeutic window that are metabolized predominantly by CYP2C8, or are CYP2C8 sensitive substrates for which an increase in plasma levels could be clinically significant.
18. Planned concomitant use of drugs with a narrow therapeutic window that are metabolized predominantly by CYP2C9 should be excluded, and caution for CYP2C9 sensitive substrates.
19. Planned concomitant use of OAT1 and OAT3 sensitive substrates for which an increase in plasma levels could be clinically significant.
20. Planned concomitant use of BCRP sensitive substrates for which an increase in plasma levels could be clinically significant.
21. Renal function as defined by estimated eGFR < 45 mL/min/1.73 m2 using the MDRD study equation and/or renally impaired patients (eGFR = 60) with planned concomitant use of OCT2 substrates with a narrow therapeutic index or OCT2 inhibitors.
22. Use of any nonselective MAO inhibitors (MAOI-Bs are acceptable).
23. Use of systemic corticosteroids (> 10 mg prednisone or equivalent/d) within 14 d of 1st dose of study agent or known diseases whic

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) testiing method. ;Secondary Objective: The secondary objectives include the mean change in BCVA in Arms 1 and 2 as compared with Arm 3 (control) through Week 12, the time to PRN injection (Arms 1 and 2 only), time to the first visit where PRN injection criteria are met median number of injections, proportion of subjects with a mean change in BCVA letter score of = 15 letters, mean change in central subfield thickness (CST) compared with control through Week 12, 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>• Time to first visit where PRN injection criteria are met. <br>• Median number of injections received beginning at Week 12. <br>• Proportion of subjects with BCVA change of = 15 letters. <br>• Mean change in CST compared with control through Week 12. <br>• Mean change in BCVA per the ETDRS testing method compared with control through Week 12. <br>• Safety as assessed by incidence and intensity of AEs.<br><br><br><br>;Timepoint(s) of evaluation of this end point: 36 weeks

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