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    Summary
    EudraCT Number:2019-002738-36
    Sponsor's Protocol Code Number:AKST4290-205
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-10-04
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2019-002738-36
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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)
    A.4.1Sponsor's protocol code numberAKST4290-205
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAlkahest, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAlkahest, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlkahest, Inc.
    B.5.2Functional name of contact pointEsther Rawner
    B.5.3 Address:
    B.5.3.1Street Address125 Shoreway Road, Suite D
    B.5.3.2Town/ citySan Carlos
    B.5.3.3Post codeCA 94070
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16508010469
    B.5.5Fax number+16508010480
    B.5.6E-mailerawner@alkahest.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAKST4290
    D.3.2Product code AKST4290
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAKST4290
    D.3.9.1CAS number 1251528-23-0
    D.3.9.2Current sponsor codeAKST4290
    D.3.9.3Other descriptive name2-[[[(2R)-1-[1-[(4-CHLORO-3-METHYLPHENYL)METHYL]-4- PIPERIDINYL]-5-OXO-2-PYRROLIDINYL]CARBONYL]AMINO]- N,N,6-TRIMETHYL-4-PYRIDINECARBOXAMIDE,DIHYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB191358
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Newly Diagnosed Neovascular Age-Related Macular Degeneration
    E.1.1.1Medical condition in easily understood language
    Newly Diagnosed Neovascular Age-Related Macular Degeneration
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10075568
    E.1.2Term Wet age-related macular degeneration
    E.1.2System Organ Class 100000004853
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 which could require the use of systemic corticosteroids within the study period.
    24. Use of intravitreal or implanted corticosteroids:
    a. Dexamethasone or triamcinolone within 6 months prior to Visit 1.
    b. Fluocinolone within 48 months prior to Visit 1.
    25. Subjects with clinically relevant, abnormal screening hematology, blood chemistry, or urinalysis, if the abnormality defines a significant disease as defined in other exclusion criteria (e.g., AST or ALT > 3.0-fold the ULN; total bilirubin (TBR) or prothrombin time (PT) > 1.5 times the ULN). Laboratory testing may be repeated once during the screening phase.
    26. Alcohol/drug abuse within the past 2 years.
    27. Based on ECG reading, subjects with a risk of QT prolongation incl.:
    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. Use of concomitant medications known to prolong the QT/QTc interval.
    28. Significant disease or other medical conditions that may result in the any of the following:
    a. Puts subject at risk because of study participation.
    b. Influences the study results.
    c. Cause concern regarding the patient’s ability to participate in the study.
    29. Patients with malignancy for which the patient has undergone resection, radiation or chemotherapy within past 5 years. Patients with treated basal cell carcinoma or fully cured squamous cell carcinoma are allowed.
    E.5 End points
    E.5.1Primary end point(s)
    Mean change from baseline in BCVA per the ETDRS testing method.
    E.5.1.1Timepoint(s) of evaluation of this end point
    36 weeks
    E.5.2Secondary end point(s)
    • Time to PRN injection (Arms 1 and 2 only).
    • Time to first visit where PRN injection criteria are met.
    • Median number of injections received beginning at Week 12.
    • Proportion of subjects with BCVA change of ≥ 15 letters.
    • Mean change in CST compared with control through Week 12.
    • Mean change in BCVA per the ETDRS testing method compared with control through Week 12.
    • Safety as assessed by incidence and intensity of AEs.
    E.5.2.1Timepoint(s) of evaluation of this end point
    36 weeks
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Dose Ranging Study with two different dosages of IMP
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months24
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state48
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-02-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-09-16
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