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

August 11, 2023 updated by: University of Nebraska

Evaluation Of the Safety, Tolerability and Efficacy of Ranibizumab and Tocilizumab in Eyes With Diabetic Macular Edema.

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

This study will evaluate the safety of intravenous (IV) infusions of Tocilizumab in the treatment of subjects with diabetic macular edema (DME) as monotherapy and in combination with intravitreal (IVT) Ranibizumab. It will also evaluate the percentage change in central retinal thickness (CRT) from baseline (BL) to Month 6 in the study eye as assessed by spectral-domain optical coherence tomography (SD-OCT). Other study objectives are to determine: the change in visual acuity (VA) from baseline to Months 3, 6 and 12, the change in CRT from baseline to Months 3, 6 and 12 in all the three treatment arms and determine the number of eyes requiring rescue therapy.

Study Type

Interventional

Phase

  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • • 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.

Exclusion Criteria:

  • • 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
    • Presence of known active or inactive toxoplasmosis in either eye
    • Ocular or periocular infection in either eye
    • Participation in other investigational drug or device clinical trials within 30 days prior to Day 0, or planning to participate in other investigational drug or device clinical trials within 180 days following Day 0. This includes both ocular and non-ocular clinical trials.
    • Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
    • Prior treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20.
    • Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
    • Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.
    • Any previous treatment with tocilizumab.
    • Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.

Concurrent Ocular Conditions

  • Proliferative diabetic retinopathy in the study eye, with the exceptions of

    . Inactive, fibrotic proliferative diabetic retinopathy that has regressed following panretinal laser photocoagulation

  • Vitreomacular traction or epiretinal membrane in the study eye evident biomicroscopically or by optical coherence tomography (OCT).
  • 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, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), macular ischemia, or organized hard exudate plaque
  • Ocular disorders in the study eye that may confound interpretation of study results, including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., Age-related macular degeneration (AMD), ocular histoplasmosis, or pathologic myopia).
  • Concurrent disease in the study eye that could compromise visual acuity or require medical or surgical intervention during the first 6-month study period
  • Cataract surgery in the study eye within 3 months of study entry; Yttrium-Aluminum-Garnet (YAG) laser capsulotomy within 1 month of study entry; or any other intraocular surgery within 3 months preceding Day 0.
  • History of vitreoretinal surgery in the study eye within 3 months of study entry
  • Uncontrolled glaucoma (defined as intraocular pressure ≥ 30 mm) Hg despite treatment with anti-glaucoma medications)

Systemic Conditions or Exclusions for General Safety:

  • Uncontrolled diabetes mellitus, as evidenced by glycosylated hemoglobin (HbA1c) value >10%
  • Blood pressure exceeding 180/100 (sitting) during the screening period
  • History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
  • Have a history of hypersensitivity to ranibizumab or any of their components
  • Presence of any ulcerative wounds
  • Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal (including dialysis), hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease
  • History of diverticulitis, diverticulosis requiring antibiotic treatment or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforations.
  • Current active liver disease as determined by principal investigator
  • Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).
  • Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening.
  • Active Tuberculosis (TB) requiring treatment within the previous 3 years. Patients should be screened for latent Tuberculosis (TB) and, if positive, treated following local practice guidelines prior to initiating tocilizumab. Patients treated for tuberculosis with no recurrence in 3 years are permitted.
  • Primary or secondary immunodeficiency (history of or currently active)
  • Evidence of active malignant disease, malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured)
  • Pregnant women or nursing (breast feeding) mothers.
  • Patients with reproductive potential not willing to use an effective method of contraception.
  • History of alcohol, drug or chemical abuse within 1 year prior to screening.
  • Patients with lack of peripheral venous access.

Laboratory Exclusion Criteria:

Subjects who meet any of the following laboratory criteria at screening should not be enrolled in the study unless the values have normalized. In addition, if any study subject meets any of the following criteria during the course of the study, the investigator can consider withholding treatment (tocilizumab and/or ranibizumab) at particular visits and initiating appropriate management, and can resume treatment with study drugs at subsequent visits once the laboratory values have normalized or once the investigator have considered that it is safe to resume therapy.

  • INR ≥ 3.0 (e.g. due to current treatment with warfarin). The use of aspirin or other anticoagulants is not an exclusion
  • Serum creatinine > 1.4 mg/dL (124 μmol/L) in female patients and > 1.6 mg/dL (141 μmol/L) in male patients. Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are >30.
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN)
  • Total Bilirubin > ULN
  • Platelet count < 100 x 109/L (100,000/mm3)
  • Hemoglobin < 8.5 g/L (8.5 g/dl; 5.3 mmol/L)
  • White Blood Cells < 3.0 x 109/L (3000/mm3)
  • Absolute Neutrophil Count < 2.0 x 109/L (2000/mm3)
  • Absolute Lymphocyte Count < 0.5 x 109/L (500/mm3)
  • Positive Hepatitis HBsAg, or Hepatitis C antibody

Other:

  • Inability to comply with study or follow-up procedures
  • Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Ranibizumab 0.3 mg
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
Intravitreal injection of Ranibizumab (0.3mg)
Other Names:
  • Lucentis, Susvimo
Experimental: Tocilizumab (8.0 mg/kg)
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
Intravenous Infusion of Tocilizumab ( 8.0 mg/kg)
Other Names:
  • Actemra
Experimental: Tocilizumab (8.0 mg /kg) plus Ranibizumab 0.3 mg
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: Ranibizumab
Intravitreal injection of Ranibizumab (0.3mg)
Other Names:
  • Lucentis, Susvimo
Drug: Tocilizumab
Intravenous Infusion of Tocilizumab ( 8.0 mg/kg)
Other Names:
  • Actemra

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse Events
Time Frame: 6 months
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
Time Frame: Month 6
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Visual Acuity
Time Frame: Month 3, 6, and 12
Change in visual acuity (VA) from baseline to months 3, 6 and 12
Month 3, 6, and 12
Anatomic Retinal Changes
Time Frame: Month 3, 6, and 12
Percentage change in change in central retinal thickness (CRT) from baseline to months 3, 6 and 12 in all the three treatment arms
Month 3, 6, and 12
Rescue Therapy
Time Frame: Month 6
Number of eyes requiring rescue therapy
Month 6

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Nebraska

Collaborators

Genentech, Inc.

Investigators

  • Principal Investigator: Diana Do, MD, University of Nebraska

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2016

Primary Completion (Actual)

October 5, 2016

Study Completion (Actual)

October 5, 2016

Study Registration Dates

First Submitted

July 27, 2015

First Submitted That Met QC Criteria

July 27, 2015

First Posted (Estimated)

July 29, 2015

Study Record Updates

Last Update Posted (Actual)

August 15, 2023

Last Update Submitted That Met QC Criteria

August 11, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0594-15-FB

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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