A Phase 2, Multi-Center Study To Compare The Efficacy And Safety Of A Chemokine CCR2/5 Receptor Antagonist With Ranibizumab In Adults With Diabetic Macular Edema

A Phase 2, Randomized, Double-Masked, Placebo-Controlled, Parallel Group, Multi-Center Study To Compare The Efficacy And Safety Of A Chemokine CCR2/5 Receptor Antagonist (PF-04634817) With That Of Ranibizumab In Adult Subjects With Diabetic Macular Edema

The study hypothesis under test is that administration of the CCR2/5 antagonist has the potential to be as effective as the current treatment options for subjects with diabetic macular edema. The current treatment option for these subjects is an injection directly into the eye, while this CCR2/5 antagonist would be an oral drug which has the potential to be just as effective. This CCR2/5 antagonist also has a broader anti-inflammatory potential and might be able to provide an alternative mechanism to treat Diabetic Macular Edema.

Study Overview

• Status: Terminated
• Conditions: Macular Edema, Diabetic
• Intervention / Treatment: Drug: Ranibizumab; Drug: Placebo; Drug: PF-04634817; Drug: Masked Sham Therapy

Detailed Description

Study recruitment was stopped on April 9, 2015. This decision was taken for business reasons due to changes in the prioritization of the drug development portfolio. This decision was not as a result of any evolving safety, efficacy issue or changes in the risk:benefit assessment of this product or regulatory interactions.

• Study Type: Interventional
• Enrollment (Actual): 199
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria, 1612
    • MC Comac Medical
• Czech Republic
  • Hradec Kralove, Czech Republic, 500 05
    • Fakultní nemocnice Hradec Králové, Ocni klinika
  • Hradec Kralove, Czech Republic, 50005
    • Fakultní nemocnice Hradec Králové, Nemocnicni lekarna
  • Ostrava - Poruba, Czech Republic, 70852
    • Fakultni nemocnice Ostrava, lekarna
  • Ostrava - Poruba, Czech Republic, 70852
    • Fakultni Nemocnice Ostrava, Oční Klinika
  • Praha 10, Czech Republic, 10034
    • Fakultni nemocnice Kralovske Vinohrady, Oftalmologicka klinika
  • Praha 10, Czech Republic, 10034
    • Fakultni nemocnice Kralovske Vinohrady, Ustavni lekarna
• Germany
  • Berlin, Germany, 12200
    • Charite - Universitaetsmedizin Berlin, Campus Benjamin Franklin
  • Goettingen, Germany, 37075
    • Universitaetsmedizin Goettingen
  • Mainz, Germany, 55131
    • Universitätsmedizin Mainz
  • Muenster, Germany, 48145
    • Augenärzte am St. Franziskus-Hospital
  • Muenster, Germany, 48159
    • Universitaetsklinikum Muenster
  • Sulzbach, Saar, Germany, 66280
    • Knappschaftsklinikum GmbH
  • Tubingen, Germany, 72076
    • Universitatsklinikum Tubingen
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Universitätsklinikum Regensburg
• Hungary
  • Budapest, Hungary, 1133
    • Budapest Retina Associates Kft.
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem, Szemeszeti Klinika
  • Budapest, Hungary, 1106
    • Bajcsy-Zsilinszky Korhaz, Szemeszet
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum, Szemklinika
  • Pecs, Hungary, 7621
    • Ganglion Orvosi Központ
  • Veszprem, Hungary, 8200
    • Csolnoky Ferenc Korhaz, Szemeszeti Osztaly
• Israel
  • Jerusalem, Israel, 91120
    • Hadassah Medical Organization, Hadassah Medical Center, Ein Karem
  • Kfar Saba, Israel, 44281
    • Meir Medical Center
  • Petah Tikva, Israel, 49100
    • Rabin Medical Center, Beilinson Hospital
  • Rehovot, Israel, 76100
    • Kaplan Medical Center
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, MD-2025
    • Spitalul Clinic Republican
• Poland
  • Wroclaw, Poland, 50-367
    • Uniwersytecki Szpital Kliniczny Im. Jana Mikulicza Radeckiego We Wrocławiu, Klinika Okulistyki
• Romania
  • Bucuresti, Romania, 010719
    • Med Life SA, Sectia Oftalmologie
  • Bucuresti, Romania, 020475
    • Institutul National de Diabet, Nutritie si Boli Metabolice "N.C.Paulescu"
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85014
      • Retinal Consultants of Arizona
    • Phoenix, Arizona, United States, 85014
      • Retina Research Institute, LLC
    • Phoenix, Arizona, United States, 85018
      • Sunny View Medical Center
    • Phoenix, Arizona, United States, 85027
      • Premier Research Group Limited
    • Tucson, Arizona, United States, 85704
      • Retina Centers, P.C.
  • California
    • Arcadia, California, United States, 91007
      • Retina Institute of California
    • Beverly Hills, California, United States, 90211
      • Retina Vitreous Associates Medical Group
    • Campbell, California, United States, 95008
      • Retinal Diagnostic Center
    • Laguna Hills, California, United States, 92653
      • Retina Associates of Orange County
    • Palm Desert, California, United States, 92211
      • Southern California Desert Retina Consultants
    • Whittier, California, United States, 90603
      • American Institute of Research (Administrative Only)
  • Connecticut
    • New London, Connecticut, United States, 06320
      • New England Retina Associates
  • Florida
    • Miami, Florida, United States, 33136
      • Bascom Palmer Eye Institute
    • Plantation, Florida, United States, 33324
      • Fort Lauderdale Eye Institute
    • Winter Haven, Florida, United States, 33880
      • Center for Retina and Macular Disease
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Southeast Retina Center, PC
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Midwest Eye Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Jackson, Michigan, United States, 49202
      • TLC Eyecare & Laser Center
    • Royal Oak, Michigan, United States, 48073
      • Wm Beaumont Medical Office Building
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Charlotte Eye Ear Nose and Throat Associates PA
  • Ohio
    • Cleveland, Ohio, United States, 44122
      • Retina Associates of Cleveland, Inc.
    • Youngstown, Ohio, United States, 44505
      • Retina Associates of Cleveland
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Dean McGee Eye Institute
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma -OU Physicians
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Retina Vitreous Consultants
    • West Mifflin, Pennsylvania, United States, 15122
      • Associates in Ophthalmology Ltd
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Black Hills Regional Eye Institute
  • Texas
    • Austin, Texas, United States, 78705
      • Retina Research Center
    • Austin, Texas, United States, 78705
      • Brain B.Berger,MD,PA
    • Houston, Texas, United States, 77030
      • Retina Consultants of Houston, PA
    • San Antonio, Texas, United States, 78240
      • Medical Center Ophthalmology Associates
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Rocky Mountain Retina Consultants

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with Diabetes Mellitus (Type 1 or Type 2) Showing Diabetic Macular Edema in the Eye
• Reduced visual acuity resulting from retinal thickening
• Female subjects of non-childbearing potential ≥18 years and male subjects greater than or equal to 18 years. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.

• Female subjects who are not of childbearing potential must meet at least one of the following criteria:

  • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
  • Have medically confirmed ovarian failure; or
  • Achieved post-menopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females.

Exclusion Criteria:

• Severe Impaired Renal Function
• Any intraocular condition or previous surgery in either eye that would likely require medical or surgical intervention during the study duration or if allowed to progress untreated for the 16 weeks of study duration, would likely contribute to a reduction in visual acuity.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1; Intravitreal administration of ranibizumab (either 0.3 or 0.5 mg, given monthly, as detailed in the prescribing information and label content approved for the country governing the study site) plus an oral placebo.	Drug: Ranibizumab; Intravitreal Injection supplied as: 10 mg/mL in a 0.2 mL vial with instructions on preparation and administration of the 0.5 mg (0.05 mL) dose.; 6 mg/mL in a single use vial with instructions on preparation and administration of the 0.3 mg (0.05 mL) dose.; Adminstered once a month for 12 weeks; Drug: Placebo; Oral Placebo is provided in tablet form to match the 50mg dose of PF-04634817. Dose is 4 tablets each day for 12 weeks
Experimental: Arm 2; Oral PF-04634817 200 mg, once daily plus a masked sham therapy (given monthly).	Drug: PF-04634817; Four 50mg tablets PF-04634817 once a day for 12 weeks.; Drug: Masked Sham Therapy; Empty, needle-less syringe is used by the unmasked team once a month.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Letter Change From Baseline at Week 12 in Best Corrected Visual Acuity (BCVA)	Refraction and visual acuity were assessed through the BCVA obtained using the retro illuminated early treatment diabetic retinopathy study (ETDRS) charts. Distance visual acuity was expressed as an ETDRS score (number of letters correctly read).	Baseline (Day 0) and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Subjects Gaining 15 ETDRS Letters in BCVA From Baseline at Week 12	Refraction and visual acuity were assessed through the BCVA obtained using the retro illuminated ETDRS charts. Distance visual acuity was expressed as an ETDRS score (number of letters correctly read).	Baseline (Day 0) and Week 12
Mean Change From Baseline in Central Subfield Retinal Thickness in the Study Eye at Week 12	A central reading center was used for the evaluation. A photographer or technician pre certified ("study certified") by the Central Reading Center ought to perform all optical coherence tomography (OCT) imaging. Use of a Spectralis or Cirrus OCT was acceptable.	Baseline (Day 0) and Week 12
Mean Change From Baseline in The Area of Fluorescein Leakage in the Study Eye at Week 12	Fluorescein Angiography (FA) using certified digital systems was taken by a photographer who had been pre-certified ("study-certified") by the Central Reading Center. They were evaluated by the Central Reading Center.	Baseline (Day 0) and Week 12
Mean Change From Baseline in Steps of Diabetic Retinopathy Step (ETDRS Severity Scale) in the Study Eye at Week 12	Stereo color fundus photographs using certified digital systems were taken by a photographer who had been pre-certified ("study certified") by the Central Reading Center. They were evaluated by the Central Reading Center.	Baseline (Day 0) and Week 12
Plasma Concentration of PF-04634817 up to Week 12		Week 0, Week 4, Week 8, and Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.	Week 0 to Week 16
Number of Participants With Potentially Clinically Important Post-Baseline Vital Signs	Number of participants who met the categorical summary of post-baseline criteria at any time point, defined as: supine pulse rate <40 beats per minute (bpm) or >120 bpm; supine systolic blood pressure (SBP) ≥30 millimeters of mercury (mmHg) change from baseline in same posture; supine diastolic BP (DBP) ≥20 mmHg change from baseline in same posture; supine SBP <90 mmHg; supine DBP <50 mmHg.	Week -5 to Week 16
Number of Participants With Laboratory Abnormalities	The following laboratory parameters were analyzed for abnormalities at any time point: hematology (hemoglobin, hematocrit, red blood cell count (RBC), white blood cell count (WBC) with differential, and platelet count); blood chemistry (sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, albumin, calcium, total, direct and indirect bilirubin, gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), alkaline phosphatase, creatine phosphokinase (CPK), uric acid, amylase and lipase); follicle-stimulating hormone (FSH) (Weeks -5 to 0 only, for postmenopausal women who have been amenorrheic for at least 12 consecutive months prior to screening visit).	Week -5 to Week 16
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings	ECG parameters included PR interval, QRS interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval greater than or equal to (>=)300 milliseconds (msec) or >=25% increase when baseline is greater than (>)200 msec and >=50% increase when baseline is less than or equal to (≤)200 msec; QRS interval >=200 msec or >=25% increase when baseline is greater than (>)200 msec and >=50% increase when baseline is less than or equal to (≤)200 msec; QT interval >=500 msec; and QTcF >=450 msec or >=30 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.	Week -5 to Week 16
Number of Participants With Changes in the Anterior Segment of the Study Eye at Week 12	The anterior biomicroscopy exam was done undilated in order to assess whether there was any anterior segment inflammation caused either by ranibizumab or PF-04634817.	Week -5 to Week 16
Maximum Increase of Intraocular Pressure (IOP) From Baseline in Study Eye	IOP was measured using Goldmann applanation tonometry. To maintain consistency, it was recommended that the same examiner ought to measure IOP with the same tonometer at each visit for a given subject. Intraocular pressure ought to be measured in the study eye approximately 30 minutes after intravitreal injection or masked sham therapy (performed by unmasked study team member).	Week -5 to Week 16
Number of Participants With Change in Ophthalmoscopy Examination Results in Study Eye After Administration of Ranibizumab or Masked Sham Therapy at Week 8	Ophthalmoscopy ought to be performed after pupillary dilation to examine the vitreous body, optic nerve head, macular and peripheral retina. All findings, including the presence or absence of vitreous inflammation, ought to be documented. All post-dose ophthalmoscopy assessments ought to be made immediately following the administration of ranibizumab or masked sham therapy.	Week -5 to Week 16

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Gale JD, Berger B, Gilbert S, Popa S, Sultan MB, Schachar RA, Girgenti D, Perros-Huguet C. A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2659-2669. doi: 10.1167/iovs.17-22731.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: November 8, 2013
• First Submitted That Met QC Criteria: November 19, 2013
• First Posted (Estimate): November 25, 2013

Study Record Updates

• Last Update Posted (Estimate): October 17, 2016
• Last Update Submitted That Met QC Criteria: August 23, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Diabetes; Diabetes Mellitus; Diabetic Macular Edema; Diabetic Retinopathy; Macular Edema; Chemokine Antagonist; Anti-VEGF
• 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: B1261009; 2013-003147-27 (EudraCT Number)