Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (the STOP-ROP Multicenter Trial)

Purpose | Background | Description | Patient Eligibility | Recruitment Status | Current Status | Results | Publications | Clinical Centers | Resource Centers | NEI Representative

Purpose

To test the efficacy, safety, and costs of providing supplemental oxygen in moderately severe retinopathy of prematurity (prethreshold ROP).

Background

ROP remains one of the important morbidities among extremely premature infant survivors who are otherwise experiencing great gains in survival and in pulmonary and neurologic sequelae. While the use of cryo- or laser ablation of peripheral retina during the severe stages of ROP reduces the proportion of infants who progress to retinal detachments, less destructive treatment would be desirable.

More than 80 percent of infants who develop ROP heal the retinal neovascularization spontaneously, while only the minority progress to severe stages. Apparently, the normal physiologic control of retinal vascular growth is usually enough to control ROP. This observation led to basic studies on the control of normal and abnormal retinal vascularization that have identified tissue oxygen levels as important in the control of vessel growth. Combined with the observation of marginally low oxygen levels in the sickest of premature infants during their long convalescence from lung disease, an idea emerged. The hypothesis was that marginally low blood oxygen levels could interfere with control of retinal neovascularization -- the low levels further stimulating the vessel overgrowth. When that proved true in animal studies, the reverse experiment was tested and showed that raising the oxygen slightly over normal was enough to improve the retinopathy in its convalescent stages. Therefore, the STOP-ROP clinical trial was designed to test the hypothesis that supplemental oxygen in moderately severe (prethreshold) ROP would reduce the proportion of eyes that would progress to severe (threshold) levels of ROP.

Description

Infants who develop moderately severe ROP are recruited to participate in STOP-ROP. Following informed consent, eligible infants are randomized to oxygen administration with continuous saturation monitoring at conventional levels (target pulse oximetry, 89-94 percent saturation) versus supplemental levels (target pulse oximetry, 96-99 percent saturation). Pulse oximetry is monitored continuously, and feedback to the bedside nurses is provided in a variety of formats on a laptop computer screen. Compliance with study targets is recorded systematically. Exact severity of ROP is confirmed by two independent, masked ophthalmologists at study entry and again if severe ROP (threshold) occurs. Infants remain on study-assigned oxygen saturation ranges for at least 2 weeks and until both eyes have reached study end points.

An adverse end point is progression to threshold ROP (with referral for possible ablative therapy). A favorable end point is regression of the ROP into zone 3 for at least two examinations, or complete retinal vascularization. Weekly examinations of the infants by study-certified, masked ophthalmologists ensure timely identification of study end points and limit use of study-assigned treatment and equipment to what is absolutely necessary. The pediatric end points of rate of growth, cardiopulmonary stability, and achievement of early motor milestones are also measured as secondary end points. All infants receive a final followup examination to confirm retinal status and pediatric end points at 3 months following their expected full-term due date (usually 5-6 months following birth).

To make it possible to detect a reduction in progression to threshold ROP from 30 percent to 20 percent, 880 infants will be enrolled. The Data and Safety Monitoring Committee monitors primary and secondary outcome measures and all adverse events over the course of the study.

Study Organization
The STOP-ROP study is uniquely funded and organized to promote research on behalf of vision in children. The NEI fully funds the Study Headquarters, the Data and Safety Monitoring Committee, and seven participating centers. The NEI and the National Institute of Child Health and Human Development (NICHD) support another 10 centers through the NICHD Neonatal Network for Clinical Trials. The National Institute of Nursing Research also contributes to the support of the study. The remaining centers are participating with alternative funds or through volunteer efforts and with a capitation from the NEI provided per patient enrolled.

Patient Eligibility

Newborns with prethreshold ROP in one or both eyes are eligible.

Patient Recruitment Status

Completed. Recruitment was completed on March 31, 1999 with 649 infants enrolled.

Current Status of Study

Ongoing. No longer recruiting.

Results

A total of 649 infants were enrolled from 30 centers over 5
years. Of that number, 325 received conventional oxygen supplementation (89 percent to 94 percent pulse oximetry saturation) and 324 received supplemental oxygen (96 percent to 99 percent pulse oximetry saturation). Five hundred
ninety-seven (92.0 percent) infants attained known ophthalmic endpoints, and 600 (92 percent) completed the ophthalmic 3-month assessment.

Use of supplemental oxygen did not cause additional progression of prethreshold ROP but also did not significantly reduce the number of infants requiring peripheral retinal ablative surgery. A subgroup analysis suggested a benefit of supplemental oxygen among infants who have prethreshold ROP without plus disease, but this finding requires additional study. Supplemental oxygen increased the risk of adverse pulmonary events including pneumonia and/or exacerbations of chronic lung disease and the need for oxygen, diuretics, and hospitalization at 3 months of corrected age. Although the relative risk/benefit of supplemental oxygen for each infant must be individually considered, clinicians need no longer be concerned that supplemental oxygen, as used in this study, will worsen active prethreshold ROP.

Publications

The STOP-ROP Multicenter Study Group: Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP). A randomized, controlled trial. I: Primary outcomes Pediatrics 105: 295-310, 2000.

Phelps DL, Palmer EA, Wood NE: Supplemental oxygen for prethreshold retinopathy of prematurity (a description of the study background and design), in Shapiro MJ, Biglan AW, Miller MT (eds). Proceedings of the International Conference on Retinopathy of Prematurity, Amsterdam, Kugler Publications 139-141, 1995.

Clinical Centers

Arkansas
J. David Bradford, M.D.
University of Arkansas
Department of Ophthalmology
4301 West Markham, Mail Slot 523
Little Rock, AR 72205
Telephone: (501) 686-5150
Fax: (501) 686-7037

California
David K. Stevenson, M.D.
Stanford University Medical Center
Division of Neonatology
750 Welch Road, Suite 315
Palo Alto, CA 94304
Telephone: (415) 723-5711
Fax: (415) 725-8351

Florida
Mitchell E. Stern, M.D.
Sheridan Children's Healthcare Services, Inc.
Plantation General Hospital
401 Northwest 42nd Avenue
Plantation, FL 33317
Telephone: (305) 797-6460
Fax: (305) 797-6488

Michael W. Stewart, M.D.
Retina Associates, P.A.
Suite 715
1801 Barrs Street
Jacksonville, FL 32204
Telephone: (904) 388-8446
Fax: (904) 384-6261

Hawaii
David Easa, M.D.
Kapiolani Medical Center
1319 Punahou Street, #724
Honolulu, HI 96826
Telephone: (808) 973-5233
Fax: (808) 973-5240

Illinois
Michael J. Shapiro, M.D.
University of Illinois at Chicago
Department of Ophthalmology
1905 West Taylor Street L109
Chicago, IL 60612
Telephone: (312) 996-6660
Fax: (330) 413-0158

Indiana
James A. Lemons, M.D.
James Whitcomb Riley Hospital
Indiana University Medical Center
702 Barnhill Drive, RR 208
Indianapolis, IN 46202-5210
Telephone: (317) 274-4715
Fax: (317) 274-2065

Kentucky
Charles C. Barr, M.D.
University of Louisville
School of Medicine
Ophthalmology and Visual Sciences
301 East Muhammad Ali Boulevard
Louisville, KY 40292
Telephone: (502) 852-5470
Fax: (502) 852-7298

Maryland
Mark W. Preslan, M.D.
University of Maryland Hospital
Department of Ophthalmology N6W46
22 South Greene Street
Baltimore, MD 21201
Telephone: (410) 328-5746
Fax: (410) 328-6346

Massachusetts
Cynthia Cole, M.D.
New England Medical Center
Newborn Medicine, NEMC #84
750 Washington Street
Boston, MA 02111
Telephone: (617) 636-5322
Fax: (617) 636-1456

Michigan
Patrick J. Droste, M.D.
Cook Institute for Research
1000 East Paris Avenue, SE
Grand Rapids, MI 49546
Telephone: (616) 957-0866
Fax: (616) 957-4102

Minnesota
Terri Young, M.D.
University of Minnesota
Department of Ophthalmology
420 Delaware Street SE, Box 493
Minneapolis, MN 55455-0591
Telephone: (612) 625-4400
Fax: (612) 626-3119

New York
Dale L. Phelps, M.D.
University of Rochester School of Medicine
Pediatrics/Neonatology, Room 4-4167
601 Elmwood Avenue, Box 651
Rochester, NY 14642
Telephone: (716) 275-5884
Fax: (716) 273-1010

Pamela A. Weber, M.D.
University Hospital at Stony Brook
Department of Ophthalmology
HSC L-2, Room 152
Stony Brook, NY 11794-1110
Telephone: (516) 444-1110
Fax: (516) 444-1543

Ohio
Edward Donovan, M.D.
University of Cincinnati, College of Medicine
Department of Pediatrics
PO Box 670541
Cincinnati, OH 45267-0541
Telephone: (513) 558-0586
Fax: (513) 558-7770

Frank W. Kokomoor, M.D.
Children's Hospital Medical Center of Akron
One Perkins Square
Akron, OH 44308
Telephone: (216) 379-8350
Fax: (216) 379-8356

Richard E. McClead, M.D.
Children's Hospital
Section of Neonatology
700 Children's Drive
Columbus, OH 43205-2696
Telephone: (614) 722-4529
Fax: (614) 722-4565

Malini Satish, M.D.
Children's Medical Center of Northwest Ohio
Toledo Hospital, Division of Neonatology
2142 North Cove Boulevard
Toledo, OH 43606
Telephone: (419) 471-4225
Fax: (419) 479-6193

Oklahoma
Mark Scott, M.D.
Dean A. McGee Eye Institute
608 S. L. Young Boulevard
Oklahoma City, OK 73104
Telephone: (405) 271-7819
Fax: (405) 271-3016

Oregon
Raul C. Banagale, M.D.
Legacy Emanuel Children's Hospital
Legacy Research
2801 North Gantenbein Avenue
Portland, OR 97227
Telephone: (503) 413-2491
Fax: (503) 413-4942

Pennsylvania
Beverly S. Brozanski, M.D.
Magee-Women's Hospital
Department of Pediatrics
300 Halket Street
Pittsburgh, PA 15213-3180
Telephone: (412) 641-4109
Fax: (412) 641-5313

Alan R. Spitzer, M.D.
Thomas Jefferson University
Neonatology Department, Suite 727
1025 Walnut Street
Philadelphia, PA 19107
Telephone: (215) 955-6966
Fax: (215) 923-9519

Tennessee
Stephen S. Feman, M.D.
Vanderbilt University Medical Center
Department of Ophthalmology
8000 Medical Center East
Nashville, TN 37232-8808
Telephone: (615) 936-1445
Fax: (615) 936-1594

Sheldon Korones, M.D.
E.H. Crump Hospital
Division of Neonatology
Room 201
Memphis, TN 38163
Telephone: (901) 448-5950
Fax: (901) 448-4701

The following participating clinical centers have reached their enrollment goals.
Connecticut
Richard A. Ehrenkranz, M.D.
Children's Hospital at Yale-New Haven
New Haven, CT

Georgia
Barbara Stoll, M.D.
Grady Memorial Hospital
Atlanta, GA

Louisiana
Robert Gordon, M.D.
Tulane University Hospital
Department of Ophthalmology SL-69
New Orleans, LA

Michigan
Mary Bedard, M.D.
Children's Hospital of Michigan
Detroit, MI

Ohio
Avroy Fanaroff, M.D.
Rainbow Babies and Childrens Hospital
Cleveland, OH

Rhode Island
William Oh, M.D.
Women and Infants' Hospital
Providence, RI

Texas
Jon E. Tyson, M.D.
University of Texas
Southwestern Medical Center
Dallas, TX

Virginia
Brian R. Wood, M.D.
Children's Hospital of The King's Daughters
Norfolk, VA

Resource Centers

Study Headquarters
Dale Phelps, M.D.
University of Rochester
School of Medicine
Pediatrics/Neonatology, Room 4-4167
601 Elmwood Avenue, Box 651
Rochester, NY 14642
Telephone: (716) 275-5884
Fax: (716) 273-1010

Coordinating Center
Anne Linblad, Ph.D.
The EMMES Corporation
11325 Seven Locks Road, Suite 214
Potomac, MD 20854
Telephone: (301) 299-8655
Fax: (301) 299-3991

NEI Representative

Donald F. Everett, M.A.
National Eye Institute
National Institutes of Health
Executive Plaza South, Suite 350
6120 Executive Boulevard, MSC 7164
Bethesda, MD 20892-7164
Telephone: (301) 496-5983
Fax: (301) 402-0528

Data and Safety Monitoring Committee

Colin B. Begg, Ph.D.
Memorial Sloan-Kettering Cancer Center
Department of Epidemiology/Biostatistics
New York, NY

Edward G. Buckley, M.D.
Duke University Medical Center
Department of Ophthalmology
Durham, NC

Burton J. Kushner, M.D.
University of Wisconsin
Department of Ophthalmology
Madison, WI

Carol R. Taylor, R.N., M.S.
Holy Family College
Philadelphia, PA

Edward F. Bell, M.D.
University of Iowa
Department of Pediatrics
Iowa City, IA

William W. Hay, M.D.
University of Colorado Health Sciences Center
Department of Pediatrics/Neonatology
Denver, CO

Barbara S. Hawkins, P.h.D.
The Johns Hopkins University
School of Medicine
Baltimore, MD

Linda Snouck-Hurgronje, R.N., M.S.
St. Agnes Hospital
Division of Neonatology
Baltimore, MD

Last Updated: 2/10/00