Ranibizumab for Edema of the mAcula in Diabetes: Protocol 4 With Tocilizumab: The READ-4 Study

NCT02511067 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 0594-15-FB
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to investigate the safety, tolerability and efficacy of Ranibizumab and Tocilizumab alone and in combination in eyes with Diabetic Macular Edema.

Conditions

Diabetic Macular Edema

Outcome Measures

Primary Outcomes (2)

• Adverse Events

  To evaluate the safety of IV infusions of tocilizumab in treatment of subjects with diabetic macular edema (DME) as monotherapy and in combination with Ranibizumab

  6 months

• Anatomic Retinal Changes

  To evaluate the percentage change in central retinal thickness (CRT) from Baseline to Month 6 in the study eye as assessed by spectral domain-optical coherence tomography (SD-OCT).

  Month 6

Secondary Outcomes (3)

• Visual Acuity

  Month 3, 6, and 12

• Anatomic Retinal Changes

  Month 3, 6, and 12

• Rescue Therapy

  Month 6

Study Arms (3)

Ranibizumab 0.3 mg

ACTIVE COMPARATOR

Mandatory monthly treatments with Intravitreal (IVT) ranibizumab (0.3 mg) starting at Baseline (BL) until Month 6. Starting at Month 6, treatments will be administered on as-needed basis, based on retreatment criteria.

Drug: Ranibizumab

Tocilizumab (8.0 mg/kg)

EXPERIMENTAL

Mandatory monthly Intravenous (IV) infusions with tocilizumab (8.0 mg/kg) starting at Baseline (BL) until Month 6. Starting at Month 6, treatments will be administered on as-needed basis with IVT ranibizumab (0.3 mg), based on the retreatment criteria.

Drug: Tocilizumab

Tocilizumab (8.0 mg /kg) plus Ranibizumab 0.3 mg

EXPERIMENTAL

Mandatory Intravitreal (IVT) ranibizumab 0.3 mg at Baseline (BL) followed with an IV infusion of tocilizumab (8.0 mg/kg) on same day starting at Baseline (BL) until Month 6. Combination treatments (IVT ranibizumab 0.3 mg followed by IV tocilizumab 8.0 mg/kg infusion administered at same visit) will be given every month until Month 6. Starting at Month 6, treatments will continue to be administered on as-needed basis with IVT ranibizumab (0.3 mg), based on retreatment criteria.

Drug: Tocilizumab; Drug: Ranibizumab

Interventions

Tocilizumab DRUG

Intravenous Infusion of Tocilizumab ( 8.0 mg/kg)

Also known as: Actemra

Tocilizumab (8.0 mg /kg) plus Ranibizumab 0.3 mg; Tocilizumab (8.0 mg/kg)

Ranibizumab DRUG

Intravitreal injection of Ranibizumab (0.3mg)

Also known as: Lucentis, Susvimo

Ranibizumab 0.3 mg; Tocilizumab (8.0 mg /kg) plus Ranibizumab 0.3 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent and authorization of use and disclosure of protected health information
• Age ≥18 years
• Diagnosis of diabetes mellitus (type 1 or type 2)
• Serum HbA1c ≥ 5.5% and ≤10% within 12 months of randomization. (It is important to be certain that the patients in the READ-4 Study have diabetes, which will suggest that the macular edema is secondary to diabetes. The American Diabetes Association has suggested that a HbA1c ≥ 5.5% may suggest the presence of diabetes mellitus.)
• Have diabetic macular edema (DME) with central subfield thickness of ≥ 310 microns on spectral domain optical coherence tomography (SD-OCT).
• Retinal thickening secondary to diabetes mellitus involving the center of the fovea (centered-involved macular edema).
• Best corrected visual acuity score in the study eye of 20/32 to 20/400 inclusive (Snellen equivalents using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at a distance of 4 meters). If both eyes are eligible, the investigator will select the eye to be enrolled as the study eye. There is no specific visual acuity requirement for the fellow eye at time of study eye enrollment. However, if the fellow eye is to receive ranibizumab, it must have an entry visual acuity of 20/32 to 20/400 inclusive (Snellen equivalents using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at a distance of 4 meters) at the time of the initial treatment.
• In the opinion of the investigator, decreased vision in the study eye is due to foveal thickening from diabetic macular edema (DME) and not from other obvious causes of decreased vision.
• Female of childbearing potential must have a negative serum pregnancy test within 28 days of randomization
• Females of child-bearing potential may participate in this trial only if using a reliable means of contraception (e.g. physical barrier (patient and partner), contraceptive pill or patch, spermicide and barrier, or intrauterine device (IUD))
• If a non-sterile male, commitment to the use of effective contraception (birth control) for the duration of the study is necessary.

You may not qualify if:

• Panretinal photocoagulation or macular photocoagulation within 90 days prior to Day 0 in the study eye.
• Presence of active proliferative diabetic retinopathy
• Use of any intravitreal injections (including but not limited to anti vascular endothelial growth factor therapy or steroids) within 60 days prior to Day 0 in the study eye.
• Use of Tocilizumab (IV or SC) within 180 days prior to Day 0.
• Use of intravitreal dexamethasone implant within 120 days (4 months) prior to Day 0 in the study eye.
• Use of intravitreal triamcinolone within 120 days prior to Day 0 in the study eye.
• Use of intravitreal fluocinolone implant within 3 years (36 months) prior to Day 0 in the study eye.
• Intraocular surgery within 90 days prior to Day 0 in the study eye
• History of vitrectomy in study eye
• Capsulotomy within 30 days prior to Day 0 in the study eye
• Any planned ocular surgery (including cataract extraction or capsulotomy) of the study eye anticipated within the first 180 days following Day 0;
• Pupillary dilation inadequate for quality stereoscopic fundus photography in the study eye;
• Media opacity that would limit clinical visualization;
• Presence of any form of ocular malignancy in the study eye, including choroidal melanoma
• History of herpetic infection in the study eye or adnexa

Sponsors & Collaborators

• University of Nebraska: lead
• Genentech, Inc.: collaborator

Related Publications (14)

• Bourne RR, Stevens GA, White RA, Smith JL, Flaxman SR, Price H, Jonas JB, Keeffe J, Leasher J, Naidoo K, Pesudovs K, Resnikoff S, Taylor HR; Vision Loss Expert Group. Causes of vision loss worldwide, 1990-2010: a systematic analysis. Lancet Glob Health. 2013 Dec;1(6):e339-49. doi: 10.1016/S2214-109X(13)70113-X. Epub 2013 Nov 11.

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• Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006 Dec;142(6):961-9. doi: 10.1016/j.ajo.2006.06.068. Epub 2006 Aug 2.

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• Koskela UE, Kuusisto SM, Nissinen AE, Savolainen MJ, Liinamaa MJ. High vitreous concentration of IL-6 and IL-8, but not of adhesion molecules in relation to plasma concentrations in proliferative diabetic retinopathy. Ophthalmic Res. 2013;49(2):108-14. doi: 10.1159/000342977. Epub 2012 Dec 18.

  PMID: 23257933 BACKGROUND

• Sonoda S, Sakamoto T, Yamashita T, Shirasawa M, Otsuka H, Sonoda Y. Retinal morphologic changes and concentrations of cytokines in eyes with diabetic macular edema. Retina. 2014 Apr;34(4):741-8. doi: 10.1097/IAE.0b013e3182a48917.

  PMID: 23975003 BACKGROUND

• Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1987 Jul;94(7):761-74. doi: 10.1016/s0161-6420(87)33527-4.

  PMID: 3658348 BACKGROUND

• Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, Hashad Y, Whitcup SM; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014 Oct;121(10):1904-14. doi: 10.1016/j.ophtha.2014.04.024. Epub 2014 Jun 4.

  PMID: 24907062 BACKGROUND

• Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Apr;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039. Epub 2012 Feb 11.

  PMID: 22330964 BACKGROUND

• Arevalo JF. Diabetic macular edema: changing treatment paradigms. Curr Opin Ophthalmol. 2014 Nov;25(6):502-7. doi: 10.1097/ICU.0000000000000102.

  PMID: 25211039 BACKGROUND

• Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology. 2006 Oct;113(10):1706-12. doi: 10.1016/j.ophtha.2006.04.033.

  PMID: 17011952 BACKGROUND

• Do DV, Nguyen QD, Khwaja AA, Channa R, Sepah YJ, Sophie R, Hafiz G, Campochiaro PA; READ-2 Study Group. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmol. 2013 Feb;131(2):139-45. doi: 10.1001/2013.jamaophthalmol.91.

  PMID: 23544200 BACKGROUND

• Mesquida M, Molins B, Llorenc V, Sainz de la Maza M, Adan A. Long-term effects of tocilizumab therapy for refractory uveitis-related macular edema. Ophthalmology. 2014 Dec;121(12):2380-6. doi: 10.1016/j.ophtha.2014.06.050. Epub 2014 Sep 6.

  PMID: 25204610 BACKGROUND

• Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology. 2003 Sep;110(9):1690-6. doi: 10.1016/S0161-6420(03)00568-2.

  PMID: 13129863 BACKGROUND

• Shimizu E, Funatsu H, Yamashita H, Yamashita T, Hori S. Plasma level of interleukin-6 is an indicator for predicting diabetic macular edema. Jpn J Ophthalmol. 2002 Jan-Feb;46(1):78-83. doi: 10.1016/s0021-5155(01)00452-x.

  PMID: 11853719 BACKGROUND

Related Links

• Study of the Safety, Tolerability, and Bioactivity of Tocilizumab On Patients With Non-infectious UVEITIS: The STOP-UVEITIS Study. NCT01717170.

MeSH Terms

Interventions

tocilizumab; Ranibizumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Diana Do, MD

  University of Nebraska

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2015
• First Posted: July 29, 2015
• Study Start: October 1, 2016
• Primary Completion: October 5, 2016
• Study Completion: October 5, 2016
• Last Updated: August 15, 2023

Record last verified: 2023-08