PF-04523655 Dose Escalation Study, and Evaluation of PF-04523655 With/Without Ranibizumab in Diabetic Macular Edema (DME) (MATISSE)

An Open-Label Dose Escalation Study of PF-04523655 (Stratum I) Combined With a Prospective, Randomized, Double-Masked, Multi-Center, Controlled Study (Stratum II) Evaluating the Efficacy and Safety of PF-04523655 Alone and in Combination With Ranibizumab Versus Ranibizumab Alone in Diabetic Macular Edema (MATISSE STUDY)

This is a two-part study. The first part (Stratum I) is an open-label, dose escalation, safety, tolerability and pharmacokinetic study, where active study drug (PF-04523655) will be given to all patients who participate. Stratum I will determine the maximum tolerated dose and any dose-limiting toxicities. The second part (Stratum II) is a prospectively randomized, multi-center, double-masked, dose ranging study evaluating the efficacy and safety of PF-04523655 alone and in combination with ranibizumab versus ranibizumab alone in patients with DME.

Study Overview

• Status: Completed
• Conditions: Diabetic Retinopathy; Diabetic Macular Edema; Choroidal Neovascularization
• Intervention / Treatment: Drug: PF-04523655 (Stratum II); Drug: ranibizumab; Drug: PF-04523655 (Stratum I)

Detailed Description

Patients will be enrolled concurrently according to one of two sets of criteria designated as Stratum I and Stratum II.

1. Stratum I will enroll up to 24 subjects with low vision, inclusive of possible intermediate doses, in up to 4 cohorts of 3-6 evaluable subjects.
2. Stratum II will enroll approximately 240 subjects with DME 1:1:1:1 in up to 4 cohorts of 60 evaluable subjects.

• Study Type: Interventional
• Enrollment (Actual): 258
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • University Hospital Ghent
  • Laken, Belgium, 1020
    • Brugmann Ziekenhuis
• Czech Republic
  • Brno, Czech Republic, 62500
    • Fakultni nemocnice Brno
  • Kralove, Czech Republic, 50005
    • Fakultni nemocnice Hradec Kralove
  • Ostrava, Czech Republic, 70852
    • Fakultni nemocnice Ostrava
  • Zlín, Czech Republic, 76001
    • GEMINI oční centrum, a.s
• Germany
  • Ahaus, Germany, 48683
    • Augenärzte Gemeinschaftspraxis Ahaus-Gronau-Lingen-Münster-Bad Bentheim
  • Darmstadt, Germany, 64297
    • Augenklinik Klinikum Darmstadt
  • Ludwigshafen, Germany, 67063
    • Klinikum der Stadt Ludwigshafen
  • Muenster, Germany, 48145
    • Augenklinik am St. Franziskus-Hospital Muenster
  • München, Germany, 81675
    • Klinik und Poliklinik für Augenheilkunde Klinikum rechts der Isar
• Israel
  • Beer Sheva, Israel, 84101
    • Soroka University Medical Center
  • Haifa, Israel, 31048
    • Bnai Zion Medical Center
  • Jerusalem, Israel
    • Hadassah Ein Kerem Medical Center
  • Kfar Saba, Israel, 44281
    • Meir Medical Center
  • Petah Tiqva, Israel
    • Rabin Medical Center
  • Rehovot, Israel
    • Kaplan Medical Center
  • Tel Aviv, Israel
    • Tel Aviv Sourasky Medical Center
  • Tel-Hashomer, Israel, 52621
    • The Chaim Sheba Medical Center
  • Zerifin, Israel
    • Assaf Harofe Medical Center
• Poland
  • Bydgoszcz, Poland, 85631
    • Oftalmika
  • Bytom, Poland, 41902
    • Szpital Specjalistyczny Nr 1 w Bytomiu
  • Gdańsk, Poland, 80809
    • Profesorskie Centrum Okulistyki, Hipermarket Tesco
  • Wroclaw, Poland, 51-646
    • Spectrum OOK
• United Kingdom
  • Belfast, United Kingdom, BT12 6BA
    • Eye and Ear Clinicl, The Royal Victoria Hospital
  • Bristol, United Kingdom, BS1 2LX
    • Bristol Eye Hospital
  • Leeds, United Kingdom, LS9 7TF
    • St. James University Hospital
  • London, United Kingdom, EC1V 2PD
    • Moorfields Eye Hospital
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital, Eye Department
  • Southampton
    • Shirley, Southampton, United Kingdom, SO16 6YD
      • Southamptom Eye Unit, Southampton Hospital
  • Surrey
    • Frimley, Surrey, United Kingdom, GU16 7UJ
      • Frimley Park Hospital NHS Foundation Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85014
      • Retina Consultants of Arizona
  • California
    • Arcadia, California, United States, 91007
      • Retina Institute of California
    • Beverly Hills, California, United States, 90211
      • Retina-Vitreous Associates
    • Campbell, California, United States, 95008
      • Retina Diagnostic Center
    • Sacramento, California, United States, 95819
      • Retinal Consultants Medical Group, Inc.
    • Santa Ana, California, United States, 92705
      • Orange County Reina Medical Group
  • Florida
    • Miami, Florida, United States, 33143
      • MedEye Associates
    • Winter Haven, Florida, United States, 33880
      • Center for Retina and Macular Disease
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Southeast Retina Center
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Thomas A. Cuilla, MD, PC at Midwest Eye Institute
  • New Hampshire
    • Portsmouth, New Hampshire, United States, 03801
      • Eyesight Ophthalmic Services, PA
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Retina Vitreous Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Southeast Clinical Research Associates, LLC
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Black Hills Regioinal Eye Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Retina, PC
  • Texas
    • Austin, Texas, United States, 78705
      • Retina Research Center
    • Houston, Texas, United States, 77030
      • Retinal Consultants of Houston
    • McAllen, Texas, United States, 78503
      • Valley Retina Institute
    • San Antonio, Texas, United States, 78204
      • Retinal Consultants of San Antonio
  • Virginia
    • Richmond, Virginia, United States, 23235
      • Retinal Institute of Virginia

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

Key Stratum I Inclusion Criteria:

1. Visual acuity in the study eye ≤ 20/200.
2. Low visual acuity is the result of an irreversible condition affecting the posterior segment of the study eye.

Key Stratum I Exclusion Criteria:

1. History of vitrectomy.
2. History of IVT injection in study eye within last 6 months.
3. History of vitreous hemorrhage, retinal detachment, or invasive trauma in study eye.
4. History of uveitis or endophthalmitis in either eye.
5. Any active inflammatory condition in study eye.
6. Received any drugs known to cause optic nerve or retinal toxicity within 14 days prior to dosing.
7. Any medical condition, concomitant therapy or previous incisional or laser surgery that, in the opinion of the Investigator, would preclude IVT injection in the study eye.
8. Intraocular pressure in either eye ≥25 mmHg on maximal medication.
9. Cataract surgery and laser corneal surgery within 3 months prior to dosing in the study eye and all other intraocular surgeries at any time.
10. Participation in a concurrent interventional study within 30 days prior to dosing.

Key Stratum II Inclusion Criteria:

1. History of diabetes mellitus (Type 1 or Type 2).
2. Retinal thickening secondary to the edema caused by diabetes mellitus.
3. Best corrected visual acuity (BCVA) of 20/40 or worse and up to 20/320 or better in the study eye at Screening.
4. Standard of care treatment for DME can be withheld for at least 90 days after the subject has enrolled in the study (study eye only).

Key Stratum II Exclusion Criteria:

1. History of panretinal photocoagulation within 6 months or macular laser photocoagulation within 3 months of prior to dosing in the study eye.
2. Any IVT injection therapy performed in the study eye within 3 months prior to dosing.
3. Iris neovascularization, vitreous hemorrhage, tractional retinal detachment, vitreomacular traction, clinically significant epiretinal membrane or clinically significant preretinal fibrosis involving the macula in the study eye.
4. History of vitreoretinal surgery or incisional glaucoma surgery in the study eye.
5. Prior intraocular surgery or corneal laser surgery, performed within 3 months prior to dosing in the study eye.
6. Received any drugs known to cause optic nerve or retinal toxicity within 14 days prior to dosing.
7. High risk (in the opinion of the Investigator) proliferative diabetic retinopathy (PDR) in the study eye.
8. Current infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.
9. Monocular subjects.
10. History of idiopathic or autoimmune uveitis in either eye.
11. Aphakia or absence of the posterior capsule in the study eye.
12. Structural damage to the center of the macula in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema.
13. Uncontrolled glaucoma in either eye.
14. Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia.
15. Use of corticosteroids that, in the Investigator's opinion, may change the status of the subject's diabetic retinopathy in the study eye.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF-04523655 (Stratum II); Stratum II, 6 monthly injections of PF-04523655 only	Drug: PF-04523655 (Stratum II); 6 monthly IVT injections of PF-04523655 (a small interfering RNA); Other Names: PF-655
Experimental: PF-04523655 and ranibizumab; Stratum II, 6 monthly injections of PF-0423655 and ranibizumab administered in combination	Drug: PF-04523655 (Stratum II); 6 monthly IVT injections of PF-04523655 (a small interfering RNA); Other Names: PF-655; Drug: ranibizumab; 6 monthly IVT injections of ranibizumab (Stratum II); Other Names: Lucentis
Active Comparator: ranibizumab; Stratum II, 6 monthly IVT injections of ranibizumab only	Drug: ranibizumab; 6 monthly IVT injections of ranibizumab (Stratum II); Other Names: Lucentis
Experimental: PF-04523655 (Stratum I); Stratum I	Drug: PF-04523655 (Stratum I); PF-04523655 (a small interfering RNA) - a single IVT injection; Other Names: PF-655

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and dose-limiting toxicities (Stratum I)	- To determine the safety and dose-limiting toxicities of a single intravitreal (IVT) injection of PF-04523655 in subjects with low vision	6 months post-injection
Pharmacokinetics (Stratum I)	- To determine the pharmacokinetics (PK) of a single IVT injection of PF-04523655 in subjects with low vision	6 months post-injection
Safety and tolerability (Stratum II)	- To evaluate the safety and tolerability of PF-04523655 alone and in combination with ranibizumab in subjects with diabetic macular edema (DME)	30 days after the last injection
Efficacy (Stratum II)	- To evaluate the ability of PF-04523655 alone and in combination with ranibizumab to improve visual acuity compared to ranibizumab alone in subjects with DME	30 days after the last injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anatomical changes in retina and retinal nerve fiber layer morphology (Stratum II)	- To evaluate the anatomical changes in retina and retinal nerve fiber layer (RNFL) morphology following administration of PF-04523655 alone and in combination with ranibizumab compared to ranibizumab alone by fundus photography (FP) and spectral domain optical coherence tomography (SD-OCT)	30 days after the last injection

Collaborators and Investigators

• Sponsor: Quark Pharmaceuticals
• Investigators: Study Director: Rabia Ozden, MD, Quark Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: September 30, 2011
• First Submitted That Met QC Criteria: October 3, 2011
• First Posted (Estimate): October 4, 2011

Study Record Updates

• Last Update Posted (Estimate): February 23, 2015
• Last Update Submitted That Met QC Criteria: February 3, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Retinal Degeneration; Retinal Diseases; Uveal Diseases; Choroid Diseases; Macular Degeneration; Metaplasia; Diabetic Retinopathy; Macular Edema; Choroidal Neovascularization; Neovascularization, Pathologic; Edema; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: QRK202; 2011-004157-66 (EudraCT Number)