Treatment of Central Retinal Vein Occlusion Using Stem Cells Study

Study Overview
=================
Brief Summary
-----------------
This study evaluates whether intravitreal autologous CD34+ stem cell therapy is safe, feasible and potentially beneficial in eyes with vision loss from central retinal vein occlusion (CRVO). Half of the participants will receive immediate cellular therapy followed by sham therapy 6 months later, while the other half will receive immediate sham therapy followed by cellular therapy 6 months later. Participants will be followed for a total of 1 year.

Detailed Description
-----------------
The goal of this phase I/II prospective, randomized, sham-controlled, double-masked clinical trial is to determine whether intravitreal autologous CD34+ stem cell therapy is safe, feasible and potentially beneficial in eyes with vision loss from central retinal vein occlusion (CRVO). Retinal Vein Occlusion (RVO) is a leading retinal vascular cause of vision loss in the elderly. CD34+ stem cells in human bone marrow are mobilized into the circulation in response to tissue ischemia for tissue revascularization and repair. Since local delivery of CD34+ stem cells benefits ischemic tissue, intravitreal delivery of CD34+ stem cells may benefit vision and retinal ischemia in eyes with RVO. A pilot clinical trial has shown no major safety or feasibility concerns using intravitreal autologous CD34+ bone marrow stem cells. In this proposed expanded phase I/II study, 20 participants (20 eyes) with persistent vision loss from CRVO will be enrolled and followed for 1 year. Participants will be randomized 1:1 to immediate cell therapy/deferred sham therapy or immediate sham therapy/deferred cell therapy. At month 6, the cell treated eye will receive sham treatment and the sham treated eye will get cell therapy. The cellular therapy involves bone marrow aspiration, isolation of CD34+ cells from the aspirate under Good Manufacturing Practice (GMP) conditions, and intravitreal injection of isolated CD34+ cells. The sham therapy involves a sham bone marrow aspiration with penetration of the skin but no penetration of the bone and a sham intravitreal injection without penetrating the eye. The participant, examining ophthalmologist, visual acuity examiner, photographers and OCT, perimetry, and electroretinography (ERG) technicians will remain masked to study treatment assignment for study duration. A comprehensive eye examination with ETDRS best-corrected visual acuity, optical coherence tomography (OCT) and OCT angiography (OCTA), autofluorescence, fundus photography, fluorescein angiography, microperimetry, and electroretinography will be performed at baseline and serially. A subset of participants with good fixation on microperimetry and clear media on exam and commercial-grade OCTA and who give consent will have ultra-high resolution cellular retinal imaging using research-grade OCT and OCTA and adaptive optics-OCT at baseline. Participants with high quality images will have repeat imaging at 1 month after stem cell treatment, with at least 2 of the participants randomized to the deferred cellular therapy arm also having imaging 1 month after sham therapy. For all participants in whom at least 1.5 million CD34+ cells are harvested, about 200,000 cells will be set aside for post-release flow cytometry characterization to determine the composition of the CD34+ enriched final product in terms of hematopoietic versus angiogenic stem cells based on cell surface markers (i.e., CD133(+)/CD45(+)/CD34(+) vs CD31(+)/VEGFR-2(+)/CD45(-)/CD34(+)). The long-term objective is to determine whether intravitreal autologous CD34+ cell therapy can minimize, or reverse vision loss associated with retinal ischemia without compromising safety.

Official Title
-----------------
Phase I/II Randomized, Prospective, Double-masked, Sham-controlled Study of Intravitreal Autologous Bone Marrow CD34+ Stem Cell Therapy for Central Retinal Vein Occlusion

Conditions
-----------------
Central Retinal Vein Occlusion

Intervention / Treatment
-----------------
* Biological: Autologous Bone Marrow CD34+ Stem Cells
* Biological: Sham Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Study Eye Inclusion/Exclusion Criteria: Inclusion criteria for the study eye: Clinical diagnosis of central retinal vein occlusion (CRVO) confirmed by review of medical records and screening assessment. Best Corrected Visual Acuity (BCVA) obtained during the screening period is in the range of 20/40+ to 20/400- (ETDRS letter score in the range of 18 to 73, inclusive). Duration of vision loss from CRVO >= 6 months to <=42 months. Exclusion criteria for the study eye: Previous eye treatment with intravitreal or periocular steroids, laser or intraocular surgery within 6 months prior to enrollment (i.e., date ICF signed) or treatment expected to be given during the study period. For eyes requiring treatment to prevent recurrent macular edema, on-going intravitreal anti-VEGF treatment is expected to be given at an interval < every 8 weeks during the study period or anti-VEGF therapy was started less than 24 weeks prior to informed consent. History of concurrent ocular herpes infection. Active non-herpetic eye infection diagnosed within 8 weeks from enrollment (i.e., date Informed Consent Form (ICF) signed). Glaucoma requiring treatment with more than 2 medications, laser or intraocular surgery. Active uveitis or history of recurrent uveitis or uveitis involving the posterior segment. Presence of cataract that is impairing vision. Presence of lens or lens implant subluxation. History of ocular trauma that is currently impairing vision. Any concurrent optic nerve or retinal disease that is visually significant or likely to progress to visual significance during the 1-year study follow-up. The excluded eyes include eyes with AREDS category 2 to 3 age-related macular degeneration (AMD) with foveal involvement of drusen or RPE changes, and any AREDS category 4 AMD eyes. For eyes with ERM, the excluded eyes include eyes with OCT evidence of foveal deformation. For optic nerve disease, eyes with any associated visual field deficit or history of associated CNVM are excluded. For glaucoma eyes, eyes requiring glaucoma laser trabeculectomy or glaucoma surgery to maintain IOP are excluded. Active retinal or iris neovascularization. Macular edema requiring on-going therapy or where treatment is expected during the study period, with the exception of anti-VEGF treatment given at an interval of 8 weeks or greater. Significant media opacity precluding view of the fundus for examination, photography or optical coherence tomography (OCT) including cataract and vitreous haze. High myopia (>= 9 diopters) Amblyopia Other cause contributing to vision loss at screening. History of any of the following procedures: corneal transplant, glaucoma surgery, or intraocular silicone oil. Participant-level Inclusion/Exclusion Criteria: Participant-level inclusion criteria: Age >=18 years Female participants of child-bearing potential must not be pregnant or breastfeeding and have a negative urine pregnancy test within 14 days prior to sham injection and/or CD34+ cell injection. Females of childbearing potential must have had a hysterectomy, be completely abstinent from intercourse or must agree to practice effective contraception for the duration of the study. Acceptable methods of contraception include hormonal contraception, intrauterine device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization (tubal ligation). Able and willing to sign informed consent. Able to keep follow-up appointments for at least 12 months as determined by the investigator. Participant-level exclusion criteria: Concurrent treatment with an investigational drug or device. Concurrent use of systemic immunosuppressive therapy or history of use within 3 months prior to enrollment (i.e., date ICF signed). Concurrent use of anticoagulation therapy except for aspirin without an acceptable safe stopping plan for study treatments. Known history of coagulopathy or other hematologic abnormality that may put participant at risk for bleeding or infection or raise concerns about quality or quantity of CD34+ cells isolated. History of allergy to fluorescein dye. Participant who has had a prior or concomitant malignancy with the exception of the following: 1) adequately treated basal or squamous cell carcinoma of the skin, or 2) any other malignancy from which the patient has remained disease free for more than five years. Current active systemic infection as evidenced by fever greater than 100.4 or any evidence of systemic infection as determined by the study physician. Any diagnosis of active infection or vaccination within 8 weeks of study treatment. Diabetes mellitus with known systemic complications by self-report or physician-determined by medical history or examination. History of prior radiotherapy to head/neck area. Poorly controlled hypertension with systolic > 180 or diastolic > 95. Serious medical or psychiatric condition that, in the opinion of the Investigator, would make study participation hazardous to the participant or compromise study findings or would prevent the participant from completing the study. Any physical characteristic that precludes ability to perform study diagnostic testing.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Immediate Cellular Therapy / Deferred Sham Therapy<br>At baseline: Bone marrow aspiration followed by intravitreal injection of CD34+ cells. At 6 months: Sham bone marrow aspiration and sham intravitreal injection. | Biological: Autologous Bone Marrow CD34+ Stem Cells<br>* Single intravitreal injection of autologous bone marrow CD34+ stem cells. The number of cells to be injected per eye will range from 800,000 to 10 million, depending on the yield of the bone marrow aspiration and the isolation procedure.<br>Biological: Sham Therapy<br>* Sham bone marrow aspiration procedure that penetrates the skin, but does penetrate the bone followed by sham intravitreal injection without penetration of the eye<br>|
| Sham Comparator: Immediate Sham Therapy / Deferred Cellular Therapy<br>At baseline: Sham bone marrow aspiration followed by sham intravitreal injection. At 6 months: Bone marrow aspiration followed by intravitreal injection of CD34+ cells. | Biological: Autologous Bone Marrow CD34+ Stem Cells<br>* Single intravitreal injection of autologous bone marrow CD34+ stem cells. The number of cells to be injected per eye will range from 800,000 to 10 million, depending on the yield of the bone marrow aspiration and the isolation procedure.<br>Biological: Sham Therapy<br>* Sham bone marrow aspiration procedure that penetrates the skin, but does penetrate the bone followed by sham intravitreal injection without penetration of the eye<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Ocular and Systemic Adverse Events | The primary safety outcome will be assessed at month 6. Adverse events (AE) that occur during the first 6 months of the trial will be broken down by whether the AE occurred following the sham or cellular treatment to assess differences in the adverse event experience between the cellular and sham therapies. | Months 0 to 6 | 
| Feasibility of the Stem Cell Therapy | Number of CD34+ cells isolated from the bone marrow aspirate and number of cells injected into the eye | Day 0 and Day 182 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Letter Score | Mean change from baseline of visual acuity letter score at Month 6. The measure is calculated by subtracting the baseline visual acuity letter score from the month 6 visual acuity letter score. The participant is refracted for best corrected vision, and then reads single letters from the ETDRS charts using a visual acuity light box at a 4 meter distance (or 1 meter for participants with sufficiently reduced vision) according to a specific algorithm. A letter score is provided that ranges from 0 (unable to ready any letters) to 100. A visual acuity letter score of 85 corresponds to a visual acuity of 20/20 as a Snellen equivalent. | Months 0 to 6 | 
| Change in % Reduced Sensitivity | Mean change from baseline of % reduced sensitivity at Month 6 as measured by microperimetry | Months 0 to 6 | 
| Change in Average Threshold | Mean change from baseline of average threshold (dB) at Month 6 as measured by microperimetry | Months 0 to 6 | 
| Change in Percent Normal Amplitude for a-wave Under Scotopic Conditions | Mean change from baseline of percent of normal amplitude for a-wave under scotopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Amplitude for b-wave Under Scotopic Conditions | Mean change from baseline of percent of normal amplitude for b-wave under scotopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Latency for a-wave Under Scotopic Conditions | Mean change from baseline of percent normal latency for a-wave under scotopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Latency for b-wave Under Scotopic Conditions | Mean change from baseline of percent normal latency for b-wave under scotopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Amplitude for a-wave Under Photopic Conditions | Mean change from baseline of percent normal amplitude for a-wave under photopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Amplitude for b-wave Under Photopic Conditions | Mean change from baseline of percent normal amplitude for b-wave under photopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Latency for a-wave Under Photopic Conditions | Mean change from baseline of percent normal latency for a-wave under photopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Latency for b-wave Under Photopic Conditions | Mean change from baseline of percent normal latency for b-wave under photopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Flicker Amplitude | Mean change from baseline in percent normal flicker amplitude at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Flicker Latency Trough | Mean change from baseline of latency trough at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Amplitude for ERG+OP (oscillatory potential) a-wave Under Scotopic Conditions | Mean change from baseline of percent normal amplitude for ERG+OP a-wave under scotopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Latency of ERG+OP a-wave Under Scotopic Conditions | Mean change from baseline of percent normal latency of ERG+OP a-wave under scotopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Amplitude for ERG+OP b-wave Under Scotopic Conditions | Mean change from baseline of percent normal amplitude for ERG+OP b-wave under scotopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Change in Percent Normal Latency of ERG+OP b-wave Under Scotopic Conditions | Mean change from baseline of percent normal latency of ERG+OP b-wave under scotopic conditions at Month 6 as measured by Full-field ERG | Months 0 to 6 | 
| Foveal Avascular Zone Integrity | Number of study eyes in each of the following categories as it relates to the integrity of the foveal avascular zone: Intact, Questionable, Disrupted (<900 microns), Disrupted (900-1800 microns), Disrupted (>1800 microns), and Cannot grade. Measured at Month 6 by fluorescein angiogram | 6 months | 
| Change in Area of Non-perfusion within ETDRS Grid | Mean change from baseline of area of non-perfusion within ETDRS grid at Month 6 as measured by fluorescein angiogram | Months 0 to 6 | 
| Change in Area of Non-perfusion within Networc Grid | Mean change from baseline of area of non-perfusion within Networc grid at Month 6 as measured by fluorescein angiogram | Months 0 to 6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Central Retinal Vein Occlusion, Retinal Vein Occlusion, Retinal Diseases, Eye Diseases, CD34+ Stem Cell Therapy, Autologous Bone Marrow Stem Cells, Stem Cells