Vascular Endothelial Growth Factor in Stage V ROP

Retinopathy of Prematurity Clinical Trial

Official title:

Vascular Endothelial Growth Factor Levels in Aqueous, Vitreous and Subretinal Fluid in Patients With Retinopathy of Prematurity Stage V.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00500396
• Other study ID #: VEGFROP
• Status: Terminated
• Phase: Phase 4
• Start date: March 2007
• Est. completion date: June 2007

Study information

• Verified date: May 2024
• Source: Asociación para Evitar la Ceguera en México
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Vascular Endothelial Growth Factor (VEGF) is a dimeric glycoprotein, naturally expressed in epithelial and tumor cells (1). Normal Retinal vascularization has two phases: In the first fase, cells of mesenquimatous origin form the first superficial plexus (14-21 weeks of gestation). In the second phase, denominated "angiogenesis phase", the superficial and deep capillary plexus are formed (15,20). The Retinopathy of Prematurity (ROP) was described for the first time in 1942 (4), at the present moment it is a public health problem in the developing countries. The International Classification of ROP classifies it in 5 stages, dividing it in 3 anatomical zones. It is a public health problem that continuous without having an effective prophylaxis. The early diagnosis and treatment in thresholds stages have changed the prognosis of this disease (11,12).

Description:

Vascular Endothelial Growth Factor (VEGF) is a dimeric glycoprotein, naturally expressed in epithelial and tumor cells (1). In conditions of hypoxia it is secreted by the pericytes, the Retina Pigmented epithelium (RPE)and glial cells, including a the Müller cells (1,2,4,5) favoring the formation of new abnormal vessels (1). Its activity is mediated by two high affinity receptors: the receptor VEGF 1 (FLT-1) and VEGF 2 (FLT-2) (1,9). The FLT-1 promotes cellular proliferation whereas FLT-2 the migration and cell- extracellular matrix interaction (9). The VEGF is essential as much for the normal retinal vascularization as for pathological (5,14).

Normal Retinal vascularization has two phases: In the first fase, cells of mesenquimatous origin form the first superficial plexus (14-21 weeks of gestation). In the second phase, denominated "angiogenesis phase", the superficial and deep capillary plexus are formed (15,20). The second phase is highly dependent of VEGF induced by hypoxia (15,20). In the normal retina the growth occurs from the optical nerve to the periphery (17).

The scientific progress in the neonatal intensive care units in the last years has allowed the survival of a larger number of premature newborns(15).

The Retinopathy of Prematurity (ROP)(ROP) was described for the first time in 1942 (4), at the present moment it is a public health problem in the developing countries. Of each 100.000 blind child in Latin America, 24.000 are due to ROP (240/1000 blind child) (17). It is the main cause of blindness in premature new born (1,4,5). It is of multifactorial etiology (17) but it has been related to a short gestational age (smaller to 32 weeks of gestation) (4), to low birth weight (less of 1500gr) or very low birth weight (less 1250gr)(1,4,5,17,18,20), to the administration of high oxygen concentration immediately after birth (1,3,18), low levels of the Insulin-like growth factor(IGF-I) and excessive production of VEGF (3,17).

All this, combined with large periods of hyperoxia-hypoxia, Produces that the normal vascularization of the retina stops. This also produces vascular-occlusive changes, arteriovenous anastomoses in the edge of the vascularized with the none-vascularized retina (18), begins the formation of abnormal vessels towards the vitreous, finally lead to retina detachment in the most severe cases (2,3,4,5).

The International Classification of ROP classifies it in 5 stages, dividing it in 3 anatomical zones. A threshold stage is considered when we have the presence of stage 3, in zone 1 or 2 in 5 continuous hour uses or 8 discontinuous with plus disease (15,16,17). The pre-threshold stage is divided in two types: type 1 is any stage of the disease in zone 1 with plus disease, stage 3, without plus disease in zone 1 or stage 2 or 3 with plus in zone

2. Type 2 is stage 1 or 2 without plus disease in zone 1 or stage 3 without plus disease in zone 2 (17,19). The threshold stage happens approximately in 5% of the patients with very low weight to the birth, of which the 10-15% develop blindness (6,8)

It is a public health problem that continuous without having an effective prophylaxis (5), nevertheless the use of constant oxygen concentrations, avoiding the periods of hyperoxia-hypoxia, has demonstrated to produce a decrease of the presentation of advanced stages of the disease and the necessity of ophthalmological surgery (5). The early diagnosis and treatment in thresholds stages have changed the prognosis of this disease (11,12). The use of the laser as treatment in the threshold and prethreshold stages is successful in the 91-95% of the cases(10), the ablative effect on the neurons, probably diminishes the VEGF production (15). The use of the vitrectomy in the early cases of retinal detachment also has good results (13).

For the determination and the quantification of VEGF several laboratory techniques have been used, as they are the Westernblot (1), the flow cytometry (7), CBA (7). Nevertheless, the Enzyme-linked immunoabsorbent assay (ELISA) remains the gold standard for the measurement of interleukins, growth factors and other cytokines in corporal fluids, including the vitreous, aqueous and subretinal fluid (1,5,7).

It has been demonstrated in humans that there are high vitreous concentrations of VEGF in eyes with active neovascularization (6,14). In the same way, the animal models of ROP report high levels of VEGF (2,21). The levels of this growth factor are altered in both stages, with a more marked increase during the first stage (2). Some clinical studies in patients with ROP in stage 4 and 5 have reported an increase of up to 90 times greater of the concentration of VEGF in the subretinal liquid in comparison with the found in patients with retinal detachment of any other cause (1). Finally, when it has been possible to examine retinas immediately after the treatment (due to death of the patient) have been found a low expression of mRNA of VEGF in the treated cells (6).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 15
• Est. completion date: June 2007
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months to 10 Years

Eligibility

Inclusion Criteria:

• Premature newborns with less than 32 weeks of gestation.

• Low birth weight (less than 1500gr) Stage V ROP.

• The parents has signed the informed consent.

Exclusion Criteria:

• Previous treatment of ROP.

• Surgery or another ocular pathology of any type.

• Systemic diseases, including diabetes mellitus, congestive heart failure acute renal insufficiency, Chronic renal insufficiency, high blood pressure.

• Lack of Informed consent.

Related Conditions & MeSH terms

• Premature Birth
• Retinal Diseases
• Retinopathy of Prematurity

Intervention

Procedure:
• Open-Sky Vitrectomy
Open-Sky vitrectomy with removal of the Tunica vasculosa lentis and retinal reattachment

Locations

Country	Name	City	State
Mexico	Asociación para Evitar la Ceguera en Mexico	Mexico	DF

Sponsors (1)

Lead Sponsor	Collaborator
Asociación para Evitar la Ceguera en México

Country where clinical trial is conducted

Mexico, 

References & Publications (21)

Blumenfeld LC, Siatkowski RM, Johnson RA, Feuer WJ, Flynn JT. Retinopathy of prematurity in multiple-gestation pregnancies. Am J Ophthalmol. 1998 Feb;125(2):197-203. doi: 10.1016/s0002-9394(99)80092-0. — View Citation

Chowers I, Banin E, Hemo Y, Porat R, Falk H, Keshet E, Pe'er J, Panet A. Gene transfer by viral vectors into blood vessels in a rat model of retinopathy of prematurity. Br J Ophthalmol. 2001 Aug;85(8):991-5. doi: 10.1136/bjo.85.8.991. — View Citation

Cooke RW, Drury JA, Mountford R, Clark D. Genetic polymorphisms and retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1712-5. doi: 10.1167/iovs.03-1303. — View Citation

Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: ophthalmological outcomes at 10 years. Arch Ophthalmol. 2001 Aug;119(8):1110-8. doi: 10.1001/archopht.119.8.1110. — View Citation

Early Treatment For Retinopathy Of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003 Dec;121(12):1684-94. doi: 10.1001/archopht.121.12.1684. — View Citation

Flynn JT, Chan-Ling T. Retinopathy of prematurity: two distinct mechanisms that underlie zone 1 and zone 2 disease. Am J Ophthalmol. 2006 Jul;142(1):46-59. doi: 10.1016/j.ajo.2006.02.018. — View Citation

Gaynon MW. Rethinking STOP-ROP: is it worthwhile trying to modulate excessive VEGF levels in prethreshold ROP eyes by systemic intervention? A review of the role of oxygen, light adaptation state, and anemia in prethreshold ROP. Retina. 2006 Sep;26(7 Suppl):S18-23. doi: 10.1097/01.iae.0000244292.86627.1e. — View Citation

Hellstrom A, Perruzzi C, Ju M, Engstrom E, Hard AL, Liu JL, Albertsson-Wikland K, Carlsson B, Niklasson A, Sjodell L, LeRoith D, Senger DR, Smith LE. Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5804-8. doi: 10.1073/pnas.101113998. Epub 2001 May 1. — View Citation

Hurley BR, McNamara JA, Fineman MS, Ho AC, Tasman W, Kaiser RS, Vander JF, Regillo CD, Brown GC. Laser treatment for retinopathy of prematurity: evolution in treatment technique over 15 years. Retina. 2006 Sep;26(7 Suppl):S16-7. doi: 10.1097/01.iae.0000244293.94251.20. — View Citation

Itakura H, Kishi S, Kotajima N, Murakami M. Persistent secretion of vascular endothelial growth factor into the vitreous cavity in proliferative diabetic retinopathy after vitrectomy. Ophthalmology. 2004 Oct;111(10):1880-4. doi: 10.1016/j.ophtha.2004.03.035. — View Citation

Kieselbach GF, Ramharter A, Baldissera I, Kralinger MT. Laser photocoagulation for retinopathy of prematurity: structural and functional outcome. Acta Ophthalmol Scand. 2006 Feb;84(1):21-6. doi: 10.1111/j.1600-0420.2005.00548.x. — View Citation

Kychenthal A, Dorta P, Katz X. Zone I retinopathy of prematurity: clinical characteristics and treatment outcomes. Retina. 2006 Sep;26(7 Suppl):S11-5. doi: 10.1097/01.iae.0000244285.79004.e6. — View Citation

Lashkari K, Hirose T, Yazdany J, McMeel JW, Kazlauskas A, Rahimi N. Vascular endothelial growth factor and hepatocyte growth factor levels are differentially elevated in patients with advanced retinopathy of prematurity. Am J Pathol. 2000 Apr;156(4):1337-44. doi: 10.1016/S0002-9440(10)65004-3. — View Citation

Lermann VL, Fortes Filho JB, Procianoy RS. The prevalence of retinopathy of prematurity in very low birth weight newborn infants. J Pediatr (Rio J). 2006 Jan-Feb;82(1):27-32. doi: 10.2223/JPED.1433. — View Citation

Maier R, Weger M, Haller-Schober EM, El-Shabrawi Y, Theisl A, Barth A, Aigner R, Haas A. Application of multiplex cytometric bead array technology for the measurement of angiogenic factors in the vitreous. Mol Vis. 2006 Oct 2;12:1143-7. — View Citation

Modanlou HD, Gharraee Z, Hasan J, Waltzman J, Nageotte S, Beharry KD. Ontogeny of VEGF, IGF-I, and GH in neonatal rat serum, vitreous fluid, and retina from birth to weaning. Invest Ophthalmol Vis Sci. 2006 Feb;47(2):738-44. doi: 10.1167/iovs.05-1046. — View Citation

Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 1988 Apr;106(4):471-9. doi: 10.1001/archopht.1988.01060130517027. — View Citation

Phelps DL; ETROP Cooperative Group. The Early Treatment for Retinopathy of Prematurity study: better outcomes, changing strategy. Pediatrics. 2004 Aug;114(2):490-1. doi: 10.1542/peds.114.2.490. No abstract available. — View Citation

Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol. 1996 Oct;114(10):1219-28. doi: 10.1001/archopht.1996.01100140419009. Erratum In: Arch Ophthalmol 1997 Mar;115(3):427. — View Citation

Quinn GE, Schaffer DB, Johnson L. A revised classification of retinopathy of prematurity. Am J Ophthalmol. 1982 Dec;94(6):744-9. doi: 10.1016/0002-9394(82)90298-7. — View Citation

Yoo MH, Hyun HJ, Koh JY, Yoon YH. Riluzole inhibits VEGF-induced endothelial cell proliferation in vitro and hyperoxia-induced abnormal vessel formation in vivo. Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4780-7. doi: 10.1167/iovs.05-0376. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the degree of VEGF in aqueous, vitreous and SRF in patients with ROP in stage V. Verifying that it is greater to that found in healthy newborn patients with different ocular pathology		4 months
Secondary	To establish a relation between the low and very low birth weight with the VEGF levels.		4 months
Secondary	To prove that the VEGF level found in ROP patients is greater than in other pathologies that normally produce neovessels (like in DM).		4 months