Multiple Dose Safety and Efficacy of LKA651 in Patients With Diabetic Macular Edema

A Randomized, Active-controlled, Patient and Investigator-masked, Multiple Dose Proof-of-concept Study of Intravitreal LKA651 in Patients With Diabetic Macular Edema

The primary objectives of this study were to evaluate the safety and efficacy of LKA651 in patients with macular edema from diabetic macular edema (DME),

Study Overview

• Status: Completed
• Conditions: Diabetic Macular Edema
• Intervention / Treatment: Drug: LKA651; Drug: Lucentis

Detailed Description

This study was a 3-arm, parallel group, randomized, patient- and investigator-masked trial planned in 90 patients with Diabetic macular edema (DME). The study consisted of a screening period of 60 days, main study (12 weeks), and an extension period (12 weeks). The study was stratified such that sentinel safety cohorts were first enrolled to test the safety of the combination of LKA651 and Lucentis before proceeding with further patient randomization. After determination of safety from Day 15 data from each sentinel cohort, patients were enrolled into 1 of 3 arms: LKA651 monotherapy, LKA651 plus Lucentis, and Lucentis monotherapy. Every patient was dosed 3 times in 4 week intervals in the treatment phase and was then followed up for an extension phase of an additional 12 weeks during which Lucentis was allowed to be administered as rescue at the discretion of the Investigator. No predefined rescue criteria were outlined as guidance.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Gottingen, Germany, 37075
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Muenster, Germany, 48145
    • Novartis Investigative Site
  • Tuebingen, Germany, 72076
    • Novartis Investigative Site
• Puerto Rico
  • Arecibo, Puerto Rico, 00612
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08025
    • Novartis Investigative Site
  • Cordoba, Spain, 14012
    • Novartis Investigative Site
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41009
      • Novartis Investigative Site
  • Catalunya
    • Sant Cugat, Catalunya, Spain, 08190
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Ankara, Turkey, 06500
    • Novartis Investigative Site
  • Ankara, Turkey, 06490
    • Novartis Investigative Site
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Novartis Investigative Site
    • Rancho Cordova, California, United States, 95670
      • Novartis Investigative Site
  • Florida
    • Miami, Florida, United States, 33143
      • Novartis Investigative Site
  • Hawaii
    • 'Aiea, Hawaii, United States, 96701
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Novartis Investigative Site
  • Texas
    • Austin, Texas, United States, 78750
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78240
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Written informed consent must be obtained before any assessment is performed.
• Male and female patients age 18 to 85 years of age inclusive at screening
• Presence of type I or type II diabetes mellitus
• The Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye must be between 24 and 70 letters (approximate Snellen equivalent of 20/40-20/320). The non-study eye (fellow eye) should be ≥34 letters or better (approximate Snellen equivalent of 20/200) at screening
• Presence of Diabetic macular edema (DME) in the study eye, with decrease in vision due to foveal thickening of central macular thickness ≥ 320 µm in the central subfield, as assessed on Spectral domain optical coherence tomography (SD-OCT) and confirmed by the central reading center at screening
• Sufficiently clear ocular media and adequate pupil dilation in the study eye to permit fundus photographs of adequate clarity to measure diameters of retinal arteries and veins at screening

Exclusion criteria

• Patient with history of intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) treatment in the study eye <90 days from baseline
• Patient with history of intraocular corticosteroids including dexamethasone intravitreal implants during the 6 month period prior to baseline. Any prior use of fluocinolone acetonide intravitreal implant (Iluvien) is prohibited regardless of timing
• Laser photocoagulation (macular or panretinal) in the study eye during the 3-month period prior to baseline.
• High risk proliferative diabetic retinopathy
• Patients, with type 1 or type 2 diabetes who have a hemoglobin A1C ≥ 12% at screening.
• Any progressive disease of the retina in the study eye (e.g. uveitis,rod-cone dystrophy) or optic nerve
• Area of macular retinal ischemia (as measured by the foveal avascular zone) ≥ 1000 μm.
• Active intraocular inflammation (graded as trace or above) or active intraocular infection in either eye.
• Current diagnosis of or laboratory evidence for anemia, defined as a hemoglobin <10 g/dL for women and <11 g/dL for men.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LKA651; LKA651 Intravitreal injection	Drug: LKA651; LKA651 5 mg Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase
Experimental: LKA651 + Lucentis; LKA651 + Lucentis Intravitreal injection	Drug: LKA651; LKA651 5 mg Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase; Drug: Lucentis; Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase
Active Comparator: Lucentis; Lucentis Intravitreal injection	Drug: Lucentis; Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation patient. The severity of the AEs (mild, moderate, severe) was based on the Common Terminology Criteria for Adverse Events (CTCAE). Number of participants in each category is reported in the table. A participant who falls multiple times in one category is counted only once.	Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye	An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation patient.	Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Number of Participants With Non-ocular Adverse Events (>=2%)	An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation patient.	Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days).
Intraocular Pressure (IOP) in Study Eye	Intraocular pressure was measured per the study site's regular practice.	Screening, and Day 85
Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye	BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. BCVA in study eye was analyzed with a mixed model for repeated measures. The model included treatment, visit, and the treatment by visit interaction as independent variables. An unstructured residual covariance structure was used. Baseline BCVA value and treatment naïve and treatment experienced variable were used as covariates. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.	Days 2, 8, 15, 29, 43, 57, and 85
Inner Macular Thickness (Inferior)	Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).	Week 12 (Day 85)
Inner Macular Thickness (Temporal)	Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).	Week 12 (Day 85)
Outer Macular Thickness (Inferior)	Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).	Week 12 (Day 85)
Outer Macular Thickness (Temporal)	Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT).	Week 12 (Day 85)
Number of Participants Without Changes in Foveal Avascular Zone as Measured by Fluorescein Angiography (FA) in Study Eye	Foveal avascular zone was assessed by fluorescein angiography (FA).	Days 29, 57, 85, End of Study (Up to Day 140)
Mixed Model Repeated Measures Analysis of Ratio to Baseline in Central Subfield Retinal Thickness (CSFT) in the Study Eye	Central subfield thickness was measured by spectral domain optical coherence tomography (SD-OCT). Central subfield retinal thickness was analyzed with a mixed model for repeated measures. The model included treatment, visit, and the treatment by visit interaction as independent variables. An unstructured residual covariance structure was used. Log-transformed baseline central subfield retinal thickness and treatment naïve and treatment experienced variable were used as covariates. Results were back-transformed to show results as a ratio to baseline.	Days 8, 15, 29, 43, 57, 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Needed Retreatment With Anti-VEGF in Study Eye After Week 12		Week 12 (Day 85) up to Day 140
Time to Retreatment in Study Eye With Anti-VEGF After Week 12	Time to retreatment with anti VEGF (as determined by the investigator) after Week 12 during the additional 12 week extension phase (that was up to 16 weeks after the last dose) was examined with a Kaplan Meier plot.	Week 12 (Day 85) up to Day 140
Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651	PK parameters were determined using non-compartmental methods using the most recent version of WinNonlin Phoenix (Version 8.2). Concentrations below the lower limit of quantification (LLOQ) were treated as 1/2 LLOQ in summary statistics.	Day 1 (0, 0.5 and 4 hrs post dose), Day 2, Day 8, Day 15, Day 29 (0, 0.5 and 4 hrs post dose), Day 43, Day 57 (0, 0.5 and 4 hrs post dose), Day 85
Summary Statistics of Pharmacokinetics - AUC0-28d of LKA651 (Serum)	Area under the curve over the dosing interval 0 to 28 days.	Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85
Summary Statistics of Pharmacokinetics - Serum Concentrations of Lucentis		Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85
Summary Statistics of Pharmacokinetics - AUC0-28d of Lucentis (Serum)	Area under the curve over the dosing interval 0 to 28 days.	Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2019
• Primary Completion (Actual): June 17, 2022
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: April 23, 2019
• First Submitted That Met QC Criteria: April 23, 2019
• First Posted (Actual): April 25, 2019

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: September 21, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: diabetic macular edema; macular edema; AMD; Lucentis; Macular degeneration; neovascular age-related macular degeneration; diabetic retinopathy; vision loss; retinal vein occlusion; RVO; DME; wet macular degeneration; age-related macular degeneration (ARMD); macula damage; retina damage; dry macular degeneration; nAMD; Diabetic Macular edema (DME); LKA651
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Macular Edema; Edema; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: CLKA651X2202; 2018-000031-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No