Supplementary Online ContentInvestigator List for the Diabetic Retinopathy Clinical Research Network . Diabetic Retinopathy Clinical Research Network clinical sites that participated

Supplementary Online Content

Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. doi:10.1001/jama.2015.15217

eAppendix 1. Investigator List for the Diabetic Retinopathy Clinical Research Network

eAppendix 2. Additional Methods

eFigure 1. PDR Treatment With Anti-VEGF Assessed at Each Follow-up Visit After Initial Injection

eFigure 2. Mean Change in Visual Acuity (Letter Score) Through 2-Years for Eyes That Completed the 2-Year Visit

eFigure 3. Change in Visual Acuity Over Time: ≥10 Letter Score Improvement (Includes Only Eyes With Baseline Visual Acuity 20/32 or Worse) (A) or Worsening (B)

eFigure 4. Percentage of Eyes With Visual Acuity ≥15 Letter-Score Worsening Over Time

eFigure 5. Kaplan Meier Plot for Time to Center-Involved DME Development With Vision Impairment at Follow-up Among Eyes Without DME and Vison Impairment at Baseline

eTable 1. Participant Characteristics by 2-Year Visit Completion Status eTable 2. Treatment for Proliferative Diabetic Retinopathy and Diabetic Macular Edema: Ranibizumab Group

eTable 3. Panretinal Photocoagulation Characteristics: PRP Group

eTable 4. Treatment for Diabetic Macular Edema: PRP Group

eTable 5. Visual Acuity at 2 Years per-Protocol/Sensitivity Analyses

eTable 6. Visual Acuity at 2 Years for Participants With Two Study Eyes (2-Year Visit Completers Only)

eTable 7. Visual Acuity at 2 Years Sensitivity Analysis

eTable 8. Visual Acuity Outcomes at 2 Years

eTable 9. Change in Visual Acuity Letter Score From Baseline to 2-Years: Pre-Planned Subgroup Analysis (2-Year Visit Completers Only)

eTable 10. Visual Acuity Outcomes at 2 Years Stratified by Baseline DME Status

eTable 11. Functional Outcomes: Humphrey Visual Field Test

eTable 12. Functional Outcome: Humphrey Visual Field Test-Mean Deviation (No. of Eyes)

eTable 13. National Eye Institute Visual Functioning Questionnaire-25 (No. Participants)

eTable 14. University of Alabama-Birmingham Low Luminescence Questionnaire (No. Eyes)

eTable 15. Optical Coherence Tomography Central Subfield Thickness Outcomes at 2 Years

eTable 16. Change in Retinal Volume at 2 Years

eTable 17. Changes in Diabetic Retinopathy Outcomes Through the 2-Year Visit

eTable 18. Adverse Events by MedDRA System Organ Class (One Event per Participant)

eTable 19. Listing of All Systemic Adverse Events Through 2 Years

This supplementary material has been provided by the authors to give readers additional information about their work.

© 2015 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Non-Human Traffic (NHT) User on 03/01/2020

Page 2 of 61 DRCR.net PRP vs Ranibizumab for PDR

eAppendix 1. Investigator List for the Diabetic Retinopathy Clinical Research Network

Diabetic Retinopathy Clinical Research Network clinical sites that participated on this protocol:

Sites are listed in order by number of subjects enrolled into the study. The number of subjects enrolled is noted in

parenthesis preceded by the site location and the site name. Personnel are listed as (I) for Study Investigator, (C) for

Coordinator, (V) Visual Acuity Technician, and (P) for Photographer.

Charlotte, NC Charlotte Eye, Ear, Nose and Throat Assoc., PA (21): Justin C. Brown(I); Andrew N. Antoszyk(I);

David Browning(I); Angela K. Price (C,V); Sherry L. Fredenberg (C,V); Jenna T. Herby (C,V); Merri F Walker (C,V);

Christina J. Fleming (C,V); Ashley A. McClain (C,V); Angella S. Karow(V); Autumn C. Grupp(V); Kelly R

Gallagher(V); Sarah A. Ennis(V); Donna McClain(P); Joan P. Mondello(P); Autumn K. Finch(P); Kathryn Kimrey(P);

Loraine M. Clark(P); Lisa A. Jackson(P); Lynn Watson(P); Jeff A. Kuopus(P); Robin Kerr(P); Swann J Bojaj(P);

Susannah J Held(P); Uma M. Balasubramaniam(P); Michael D. McOwen(P); Matt Dunlap(P) Baltimore, MD Elman

Retina Group, P.A. (16): Michael J. Elman(I); Henry A. Leder(I); JoAnn Starr(C); Jennifer L. Belz(C); Charlene K.

Putzulo(C); Dena Y. Salfer-Firestone(V); Perel M. Simpson(V); Pamela V. Singletary(V); Jennifer L. Simmons(V);

Teresa Coffey(V); Dallas R. Sandler(V); Ashley Davis(V); Ashley M. Metzger(P); Peter Sotirakos(P); Terri Cain(P);

Daniel J. Ketner(P) Lakeland, FL Florida Retina Consultants (14): Scott M. Friedman(I); Nader Moinfar(I);

Kimberly A. Williamson (C,V); Karen Sjoblom (C,V); Katrina L. Dawson(C); Damanda F. Fagan (C,V); Paige N.

Walters(V); Steve Carlton(P); Allen McKinney(P) Paducah, KY Paducah Retinal Center (14): Carl W. Baker(I);

Ron H. Tilford(I); Tracey M. Caldwell(C); Lynnette F. Lambert (C,V); Margaret J. Orr(V); Mary J. Palmer(V); Tracey

R. Martin(V); Alecia B. Camp(P); Samantha Kettler(P); Tana R. Williams(P) Augusta, GA Southeast Retina Center,

P.C. (13): Dennis M. Marcus(I); Harinderjit Singh(I); Siobhan O. Ortiz(C); Teresa J. Acklie(C); Michele

Woodward(C); Courtney N. Roberts(C); Geri L Floyd(C); Judith Hendrickson(V); Lindsay Allison Foster(V); Christy

Coursey(V); Virginia Mims(V); Jared C. Gardner(P); Kimbi Y. Overton(P); Ken Ivey(P)

Austin, TX Retina Research Center (12): Brian B. Berger(I); Chirag D. Jhaveri(I); Tori Moore(C); Ivana Gunderson

(C,V); Rachel A. Walsh(C); Ginger J. Manhart(C); Jenny J. Tracy(C); Dietrich Riepen(V); Boris Corak(V); Chelsey A.

Bravenec(V); Brandon Nguyen(V); Ryan M. Reid(V); Yong Ren(P); Christopher C. Stovall(P); Ben Ostrander(P)

Santa Barbara, CA California Retina Consultants (12): Dante J. Pieramici(I); Alessandro A. Castellarin(I); Sarah

Fishbein (C,V); Michelle S. Hanna (C,V); Erica D. Morasse (C,V); Gina Hong (C,V); Jack Giust(C); Lisha Wan (C,V);

Melvin D. Rabena(C); Sara Esau (C,V); Jerry Smith(V); Kelly Avery(V); Layne J. Bone(V); Aimee Walker(P);

Matthew Giust(P); Nitce L. Ruvalcaba(P); Aimee H. Shook(P) Columbia, SC Carolina Retina Center (10): Jeffrey G.

Gross(I); Michael A. Magee(I); Barron C. Fishburne(I); Amy M. Flowers (C,V); Christen Ochieng (C,V); Riley

Stroman (C,V); Angelique SA McDowell(V); Randall L. Price(P); Hunter Matthews(P) Lubbock, TX Texas Retina




Associates (10): Michel Shami(I); Sushma K. Vance(I); Yolanda Saldivar(C); Keri S. Neuling(C); Brenda K. Arrington

(C,P,V); Ashaki Meeks(V); Natalie R. Garcia(V); Kayla Blair(P); Janet Medrano(P); Ginger K. Rhymes(P) Plantation,

FL Fort Lauderdale Eye Institute (10): Stuart K. Burgess(I); Tirso M. Lara(I); Noel H. Pereda (C,V); Cindy V.

Fernandez (C,V); Evelyn Quinchia(V); Deborah Davis(V); Karen Workman(P) Trumbull, CT New England Retina

Associates, PC (10): Nauman A. Chaudhry(I); Sumit P. Shah(I); Gregory M. Haffner(I); Emiliya German(C); Laura A.

Fox (C,V); JoAnna L. Pelletier(C); Jennifer M. Matteson(C); Shannan Moreau(C); Kristin E. Brown(V); Michelle

Esler(V); Alison Fontecchio(V); Emily Morse(P); Marie Grace Laglivia(P); Justin A. Cocilo(P); Greg McNamara(P);

Stefanie R DeSantis(P); Marissa L. Scherf(P); Angela LaPre(P)

McAllen, TX Valley Retina Institute (9): Victor Hugo Gonzalez(I); Nehal R. Patel(I); Rohit Adyanthaya(I); Roberto

Diaz-Rohena(I); Deyla Anaya(C); Crystal A. Alvarez(C); Ruth Iracheta(C); Edna E. Cruz(C); Jessica Rodriguez(C);

Gabriela Zavala(C); Kethsaly J. Salinas(C); Tabitha Trevino(V); Krystle R. Lozano(V); Karina Miranda(V); Monica

R. Cantu(V); Maricela Garza(V); Hector Jasso(V); Rebecca R. Flores(V); Rachel Rodriguez(V); Samuel Alonso(P);

Amanda L. Sandoval(P); Santos Garza(P); John Trevino(P); Lazaro Aguero(P); Monique Montemayor(P) Portland,

OR Retina Northwest, PC (9): Mark A. Peters(I); Paul S. Tlucek(I); Michael S. Lee(I); Colin Ma(I); Stephen Hobbs

(C,V); Stephanie L. Ho (C,V); Amanda C. Milliron(V); Marcia Kopfer(V); Joe Logan(P); Christine Hoerner(P) San

Antonio, TX Retinal Consultants of San Antonio (9): Calvin E. Mein(I); R. Gary Lane(I); Moises A. Chica(I); Sarah

Elizabeth Holy(I); Lita Kirschbaum (C,V); Vanessa D Martinez(C); Jaynee Baker(C); Adriana A. Lopez(C); Christa G.

Kincaid(V); Sara L Schlichting(P); Brenda Nakoski(P); Christopher Sean Wienecke(P); Elaine Castillo(P); Clarissa M.

Marquez(P) Worcester, MA Vitreo-Retinal Associates, PC (8): Frank J. McCabe(I); Brad J. Baker(I); Melvyn H.

Defrin(I); Marie V. Lampson(C); Heather Pratte(V); Selena A. Baron(V); Aundrea S. Borelli(V) Fort Myers, FL

National Ophthalmic Research Institute (7): A. Thomas Ghuman(I); Paul A. Raskauskas(I); Glenn Wing(I); Ashish

G. Sharma(I); Joseph P. Walker(I); Eileen Knips (C,P); Natalie N. Torres(C); Crystal Y. Peters(C); Cheryl Ryan(C);

Laura Greenhoe(C); Cheryl Kiesel(C); Rebecca J Youngblood(C); Anita H. Leslie(V); Danielle Turnbo(V); Etienne C.

Schoeman(P); Raymond K. Kiesel(P) Houston, TX Retina Consultants of Houston, PA (7): Charles C. Wykoff(I);

Eric Chen(I); David M. Brown(I); Matthew S. Benz(I); Tien P. Wong(I); Amy C. Schefler(I); Richard H. Fish(I); James

C. Major(I); Rosa Y. Kim(I); Meredith Lipman(C); Ashley E. Chancey(C); Amy Hutson(C); Cassie Cone(C); Stacy

M. Supapo(C); Nubia Landaverde(C); Belinda A. Almanza(V); Brenda Dives(V); Veronica A. Sneed(V); Eric N.

Kegley(P); Cary A. Stoever(P); Beau A Richter(P) Loma Linda, CA Loma Linda University Health Care,

Department of Ophthalmology (7): Joseph T. Fan(I); Mukesh Bhogilal Suthar(I); Michael E. Rauser(I); Gisela

Santiago (C,V); Brandi J Perez (C,V); Liel Marvyn Cerdenio (C,V); Kara E. Halsey (C,V); William H. Kiernan(V);

Raquel Hernandez(V); Diana Povero(P); Jesse




Knabb(P) Portland, OR Casey Eye Institute (6): Andreas K. Lauer(I); Christina J Flaxel(I); Ann D. Lundquist (C,V);

Mitchell Schain (C,V); Shelley A. Hanel(C); Susan K. Nolte(V); Shirley D. Ira(V); Scott R. Pickell(P); Peter N.

Steinkamp(P); Jocelyn T. Hui(P); Jordan Barth(P); Dawn M. Ryan(P); Chris S Howell(P); Michelle Brix(P)

Beachwood, OH Retina Associates of Cleveland, Inc. (5): Michael A. Novak(I); David G. Miller(I); Llewelyn J.

Rao(I); Jerome P. Schartman(I); Joseph M. Coney(I); Lawrence J. Singerman(I); Susan C. Rath (C,V); Veronica A.

Smith(C); Larraine Stone(C); Elizabeth McNamara (C,V); Kimberly A. DuBois(V); Vivian Tanner(V); Mary A Ilc(V);

Kim Drury(V); Cecelia Rykena(V); Trina M. Nitzsche(P); Gregg A. Greanoff(P); John C. DuBois(P) Lancaster, PA

Family Eye Group (5): Michael R. Pavlica(I); Noelle S Matta (C,V); Alyson B. Keene(P); Cristina M. Brubaker(P);

Christine M. Keefer(P) Ocala, FL Ocala Eye Retina Consultants (5): Chander N. Samy(I); Robert J. Kraut(I); Kathy

Shirley(C); Linsey Corso(C); Karen Ely(V); Elizabeth Scala(P); Vanessa Alava(P); Stewart Gross(P) Ann Arbor, MI

Kellogg Eye Center, University of Michigan (5): Thomas W. Gardner(I); Grant M. Comer(I); Pamela S. Campbell

(C,V); Lindsay M. Godsey (C,V); Linda Fournier(V); Moe Hesselgrave(V); Timothy Steffens(P); Robert Prusak(P);

Hillary Bernard(P); Linda Goings(P); Alexis L. Smith(P) Grand Blanc, MI Retina Vitreous Center (4): Rvobin D.

Ross(I); Susan M. Sanford(C); Nicole Martini Markiewicz(C); Tracy M. Utley (C,V); Shannon

Henderson(V); Mary D. Walker(V); Joanie H. Lippincott(P); Patricia Streasick(P) Boston, MA Joslin Diabetes

Center/Harvard Vanquard Medical Associates (4): Jennifer K. Sun(I); Paolo S. Silva(I); Lloyd Paul Aiello(I); Paul

Arrigg (I) Margaret E. Stockman (C,V); Hanna Kwak(C); Ann Kopple (C); Jerry D. Cavallerano(V); Rita K. Kirby(P);

Leila Bestourous(P); Elizabeth S. Weimann(P); Robert W. Cavicchi(P) Denver, CO Denver Health Medical Center

(4): Hugo Quiroz-Mercado(I); Leif S. Ryman(C); Teresa E. Rudesyle(C); Daniela Santos Canto(C); Guillermo

Salcedo-Villanueva(C); Chelsea Lynn Mastin(V); Rosemary C. Rhodes(V); Carolyn J. Jackson(P); Regina Victoria(P)

Indianapolis, IN Raj K. Maturi, M.D., P.C. (4): Raj K. Maturi(I); Ashley M. Harless (C,V); Carolee K. Novak (C,V);

Laura A. Bleau (C,V); Nicole Ellingwood(P); Thomas Steele(P); Missy Livengood(P); Alisha

Bildner(P); Abby Maple(P); Charlotte Harris(P) Jacksonville, FL University of Florida College of Med.,

Department of Ophthalmology, Jacksonville Health Science Cent (4): Kakarla V. Chalam(I); Ghulam Shabbir

Hamdani(C); Shamim A. Haji(C); Wenhua Li (C,V); Kumar Sambhav (C,V); Ashley Cowart (C,V); Nicholas

Freeman(P); Jose J. Carrion(P) Knoxville, TN Southeastern Retina Associates, P.C. (4): Joseph M. Googe(I); Stephen

L. Perkins(I); Nicholas G. Anderson(I); Kristina Oliver(C); Lisa Lovelady(C); Christy Berry(V); Cecile Hunt(V);

Jennifer Beerbower(V); Ann Arnold(V); Nicole Grindall(V); Patricia Coppola(V); Kathy L. Schulz(V); Jerry K.

Whetstone(P); Sarah M. Oelrich(P); Raul E. Lince(P); Justin Walsh(P) Milwaukee, WI Medical College of Wisconsin

(4): Judy E. Kim(I); Dennis P. Han(I); David V. Weinberg(I); William J. Wirostko(I); Thomas B. Connor(I); Vesper V.

Williams(C); Krissa L. Packard(C); Tracy L. Kaczanowski(C); Judy Flanders(V); Vicki Barwick(V); Pat A. Winter(V);

Dennis B. Backes(P); Mara Goldberg(P); Joseph R. Beringer(P); Kathy J. Selchert(P) San Antonio, TX Medical

Center Ophthalmology Associates (4): Michael A. Singer(I); Darren J. Bell(I); Catherine Ellis(C); Tamara M.

Urias(C); Beatrice A. Guajardo(C); Roxanne Gomez(V); Ann-Marie Mora(V); Celia Maria Pena(P); Vincent

Segovia(P); Rosa Escobar(P) Syracuse, NY Retina-Vitreous Surgeons of Central New York, PC (4): G. Robert

Hampton(I); Jamin S. Brown(I); Laurie J. Sienkiewycz(C); Cindy J. Grinnell(C); Lynn M. Kwasniewski(V); Michelle L.

Manley(V); Nicole E. Robarge(P); Peter B. Hay(P); Teresa M. DeForge(P) West Des Moines, IA Wolfe Eye Clinic (4):

Jared S. Nielsen(I); Kyle J. Alliman(I); Marianne Parker(C); Bethany George(C); Jennifer L. Coleman(V); Jamie

Spillman(V); Marilyn A. Johnson(V); Holly Keenan(V); Bailey R. Bennett(P); Jay Rostvold(P); Jodi Weier(P) Austin,



Page 5 of 61

DRCR.net PRP vs Ranibizumab for PDR

TX Austin Retina Associates (3): Robert W. Wong(I); Shelley Day(I); Peter A. Nixon(I); Chris A. Montesclaros(C);

Carrie E. Leung(C); Phill Le(V); Margaret A. Rodriguez(P); Mary Laremont(P); Cory Mangham(P); Codey L.

Harborth(P) Northfield, NJ Retinal and Ophthalmic Consultants, PC (3): Brett T. Foxman(I); Scott G. Foxman(I);

Natalie S. Mahan(C); Chastity Mendez(V) Rochester, NY University of Rochester (3): David Allen DiLoreto(I);

George W. O'Gara(C); Andrea M. Czubinski (C,V); Kari M. Steinmetz(C); Melissa S Keim(V); Yvonne F Yu(V); Salina

M. Tongue(V); Dan A Castillo(V); Laura Guzman(P); Lynn Singer(P); Rachel Hollar(P); Taylor A. Pannell(P);

Brittany S. Richardson(P); Brandi N Deats(P); Steven DeRidder(P); TKe Long(P) Seattle, WA University of

Washington Medical Center (3): James L. Kinyoun(I); Gurunadh Atmaram Vemulakonda(I); Susan A. Rath (C,V);

Patricia K. Ernst (C,V); Juli A. Pettingill(V); Brad C. Clifton(P); James D. Leslie(P); Ronald C. Jones(P) Spokane, WA

Spokane Eye Clinic (3): Robert S. Wirthlin(I); Eric S. Guglielmo(I); Eileen A. Dittman (C,V); Dylan C. Waidelich

(C,V); Christina Owens(V); Vicki M. Stanton(P); Adeline M. Stone(P); Ashley Nicole Oakes(P); Cristofer J. Garza(P)

Walnut Creek, CA Bay Area Retina Associates (3): Stewart A. Daniels(I); Tushar M. Ranchod(I); Stacey Touson

(C,V); Shannon R. Earl(C); Jessica Garcia(V); Melissa C Bartlett(V); Christine Fernando(V); Jose Carlos Suazo(P);

Grace M. Marudo(P); Matthew D. Hughes(P); Fred Hanamoto(P); Cathy Walker(P); Betty Hom(P); Leah M.

McNeil(P); Yesenia Cerna(P) Grand Rapids, MI Retina Specialists of Michigan (2): Thomas M. Aaberg(I); Scott J.

Westhouse(I); Holly L. Vincent (C,V); Rebecca Malone(V); Kristine L. VanDerKooi(P); Casey Le Roy(P); Kathy L.

Karsten(P) Houston, TX Retina and Vitreous of Texas (2): Joseph A. Khawly(I); H. Michael Lambert(I); Pam S.

Miller (C,V); Valerie N. Lazarte(V); Debbie Fredrickson(V); Colin Blank(P); Donald K. Lowd(P); Desiree Lopez(P);

Jason E. Muniz(P); Lorena R. Martinez(P) Houston, TX Baylor Eye Physicians and Surgeons (2): Petros Euthymiou

Carvounis(I); Robert E. Coffee(I); Pejman Hemati (C,V); Cindy J. Dorenbach (C,V); Annika S. Joshi (C,V); April

Leger(V); Dana B. Barnett(P); Joseph F. Morales(P) Monroeville, PA Retina Vitreous Consultants (2): Karl R.

Olsen(I); P. William Conrad(I); Pamela P. Rath(I); Judy C Liu(I); Bernard H. Doft(I); Robert L. Bergren(I); Lori A.

Merlotti(C); Mary E. Kelly(C); Holly M. Mechling(C); Jennifer L. Chamberlin(C); Missy A. Forish(V); Veronica L.

Bennett(V); Christina M. Schultz(V); Grace A. Rigoni(V); Lois Stepansky(V); Kimberly A. Yeckel(V); Kellianne

Marfisi(V); Christina R. Fulwylie(V); Julie Walter(V); Courtney L. Foreman(P); David Steinberg(P); Brandi L.

Sherbine(P); Amanda Fec(P); Keith D McBroom(P) Philadelphia, PA University of Pennsylvania Scheie Eye

Institute (2): Alexander J. Brucker(I); Benjamin J. Kim(I); Sheri Drossner (C,V); Joan C. DuPont (C,V); Armin

Farazdaghi(V); Laurel Weeney(P); Michael Bodine(P); Beth Serpentine(P); Cheryl Devine(P); Jim M. Berger(P);

William Nyberg(P) Tampa, FL Retina Associates of Florida, P.A. (2): Ivan J. Suner(I); Marc C. Peden(I); Mark E.

Hammer(I); Janet R. Traynom(C); Rochelle DenBoer(C); Susan Ramsey(V); Heidi Vargo(V); Debra Jeffres(P); Anita

Kim Malzahn(P) Baltimore, MD Wilmer Eye Institute at Johns Hopkins (1): Sharon D. Solomon(I); Susan

Bressler(I); Lisa K. Levin(C); Mary Frey (C,V); Deborah Donohue (C,V); Rita L. Denbow(V); Keisha Murray(V);

David Emmert(P); Joe Belz(P); Janis Graul(P); Jacquelyn McDonald(P); Nick Rhoton(P) Bronx, NY Montefiore

Medical Center (1): Umar Khalil Mian(I); Rebecca L. Riemer(C); Louise V. Wolf(C); Evelyn Koestenblatt(C); Erica



Page 6 of 61


Otoo(V); Irina Katkovskaya(V); Christine Kim(V); Kevin A. Ellerbe(P); Caroline Costa(P); Kenneth Boyd(P)

Campbell, CA Retinal Diagnostic Center (1): Amr Dessouki(I); Joel M. Barra(C); Jessenia Perez(C); Rose

Monahan(C); Kelly To(V); Hienmy Dang(V); Tim Kelley(P) Chicago, IL Rush University Medical Center (1):

Mathew W. MacCumber(I); Eileen E. Tonner (C,V); Danielle R. Carns(C); Denise L. Voskuil-Marre (C,V); Evan R.

Rosenberg(V); Kisung Woo(P) Dallas, TX Texas Retina Associates (1): Gary E. Fish(I); Sally Arceneaux (C,V);

Karen Duignan(V); Nicholas Hesse(P); Michael Mackens(P) Glenview, IL North Shore University Health System

(1): Manvi P. Maker(I); Mira Shiloach (C,V); Courtney Kastler(P); Lynn Wasilewski(P) Lexington, KY Retina

Associates of Kentucky (1): Thomas W. Stone(I); John W. Kitchens(I); Diana M. Holcomb (C,V); Jeanne Van

Arsdall(V); Edward A Slade(P); Michelle Buck(P) Palm Desert, CA Southern California Desert Retina Consultants,

MC (1): Clement K. Chan(I); Maziar Lalezary(I); Kimberly S. Walther(C); Tiana Gonzales(C); Lenise E. Myers(V);

Kenneth M. Huff(P) Phoenix, AZ Retinal Consultants of Arizona (1): Karim N. Jamal(I); David T. Goldenber(I);

Sachin Mehta(I); Scheleen R. Dickens(C); Jessica L. Miner(C); Heather Dunlap(V); Lydia Saiz(V); Dayna Bartoli(P);

John J. Bucci(P); Rohana Yager(P) Sarasota, FL Sarasota Retina Institute (1): Melvin Chen(I); Peggy A.

Jelemensky(C); Tara L. Raphael(V); Mark Sneath(P); Evelyn Inlow(P) St. Louis, MO The Retina Institute (1): Kevin

J. Blinder(I); Ginny S. Nobel(C); Rhonda F. Weeks (C,V); Maria A. Stuart(V); Brook G. Pulliam(V); Kelly E.

Pepple(V); Lynda K. Boyd(V); Timothy L Wright(P); Dana L Gabel(P); Jarrod Wehmeier(P)

Protocol Development Committee: Jeffrey G. Gross (Protocol Chair), Lloyd Paul Aiello, Roy W. Beck, Neil M.

Bressler, Susan B. Bressler, Ronald P Danis, Joseph T. Fan, Frederick Ferris, Adam R. Glassman, Dennis M. Marcus,

Michael R. Pavlica, Ingrid U. Scott, Cynthia R. Stockdale, Jennifer K. Sun

DRCR.net Coordinating Center: Jaeb Center for Health Research, Tampa, FL (staff as of 6/01/2015): Adam R.

Glassman (Director and Principal Investigator), Roy W. Beck (Executive Director), Allison R. Ayala, Alyssa Baptista,

Eureca Battle, Wesley T. Beaulieu, Jasmine Conner, Sharon R. Constantine, Brian B. Dale, Simone S. Dupre, Meagan L.

Huggins, Seidu Inusah, Paula A. Johnson, Brenda L. Loggins, Shannon L. McClellan, Michele Melia, Carrie Preston,

Cynthia R. Stockdale, Danielle Stanley

Duke Reading Center: (Staff as of 6/01/2015) Glenn Jaffe, MD (Principal Investigator), Brannon Balsley, Michael

Barbas, Russell Burns, Dee Busian, Ryan Ebersohl, Cynthia Heydary, Sasha McEwan, Justin Myers, Amanda

Robertson, Kelly Shields, Garrett Thompson, Katrina Winter, Ellen Young

Fundus Photograph Reading Center: University of Wisconsin-Madison, Madison, WI (staff as of 6/01/15): Barbara

Blodi (Principal Investigator) Ronald P. Danis, Matthew D. Davis, Yijun Huang, Amitha Domalpally, James Reimers,

Pamela Vargo, Hugh Wabers, Dawn Myers, Daniel Lawrence, James Allan



Page 7 of 61


University of Iowa Visual Field Reading Center: (staff as of 6/01/15): Chris Johnson (Principal Investigator), Michael

Wall, Tuyet Dorau, Tana Wagschal

DRCR.net Network Chair: Lee M. Jampol (2013-present), Neil M. Bressler (2006-2012)

DRCR.net Vice Chairs: Andrew Antoszyk (2013 – present), Carl W. Baker (2011-2013), Jennifer K. Sun (2012-

present), John A. Wells, III (2013- present), Scott Friedman (2009-2012), Susan B. Bressler (2009-2011), Ingrid U. Scott

(2009-2010)

National Eye Institute: Eleanor Schron (2009-current), Donald F. Everett (2003-2006, 2007-2009), Päivi H. Miskala

(2006-2007)

Data Safety and Monitoring Committee: Gary Abrams, Deborah R. Barnbaum, Harry Flynn, Kyle D. Rudser, Ruth S.

Weinstock, Charles P. Wilkinson, Stephen Wisniewski, John Connett (Chair, 2003-2015) , Saul Genuth (2006-2013),

Robert Frank (2006-2012)

Executive Committee: Lloyd Paul Aiello (2002-present; Chair 2002 – 2005), Andrew N. Antoszyk (2009; 2013 -

present), Carl W. Baker (2009-present), Roy W. Beck (2002-present), Barbra Blodi (2014-present), Neil M. Bressler

(2006-present; Chair 2006 - 2008), Susan B. Bressler (2009-Present), Matthew D. Davis (2002-present), Michael J.

Elman (2006-present; Chair 2009 and 2012), Frederick L. Ferris III (2002-present), Adam R. Glassman (2005-present),

Jeffrey G. Gross (2012-present), Glenn J. Jaffe (2012-present), Lee M. Jampol (2012-present; Chair 2013-present), Raj

K. Maturi (2009-2011, 2013- Present), Eleanor Schron (2009-present), Jennifer K. Sun (2009-present), John A. Wells, III

(2012-present). Prior Members: Abdhish Bhavsar (2007-2008, 2010-2012), Alexander J. Brucker (2009-2011), Kakarla

V. Chalam (2009-2011), Ronald P. Danis (2004-2015), Donald F. Everett (2002-2009), Joan Fish (2008 - 2009), Scott

Friedman (2007 –2013), Joseph Googe, Jr. (2009-2011), Diana M. Holcomb (2011-2012), Andreas Lauer (2007-2008),

Dennis M. Marcus (2011-2012), Ashley McClain (2013); Brandi J. Perez (2013), Ingrid U. Scott (2009-2010), JoAnn

Starr (2009-2011).



Page 8 of 61


eAppendix 2. Additional Methods

Eligibility Criteria

Participants

Inclusion Age ≥ 18 years. Type 1 or type 2 diabetes. At least one eye meeting the study eye criteria listed below

Exclusion Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant

A condition that, in the opinion of the investigator, would preclude participation (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control)

Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval for the indication being studied

Known allergy to any component of the study drug Blood pressure >180/110 (systolic above 180 or diastolic above 110)

Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months prior to randomization

Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization

For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 3 years

Individual is expecting to move out of the area of a DRCR.net clinical center during the next 3 years

Study Eyes

Inclusion Presence of PDR which the investigator intends to manage with PRP alone but for which PRP can be deferred for at least 4 weeks in the setting of intravitreal ranibizumab, in the investigator’s judgment

Best corrected E-ETDRS visual acuity letter score ≥ 24 (i.e., 20/320 or better)

Media clarity, pupillary dilation, and individual cooperation sufficient to administer PRP and obtain adequate fundus photographs and OCT

Exclusion History of prior PRP, defined as ≥100 burns outside of the posterior pole Traction retinal detachment involving the macula

Exam evidence of neovascularization of the angle (neovascularization of the iris alone is not an exclusion if it does not preclude deferring PRP for at least 4 weeks in the investigator’s judgment)

If macular edema is present, it is considered to be primarily due to a cause other than diabetic macular edema (e.g. post-surgical macular edema or epiretinal membrane)

An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might alter visual acuity during the course of the



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study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.)

Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye were otherwise normal)

History of intravitreal anti-VEGF treatment at any time in the past 2 months

History of corticosteroid treatment (intravitreal or peribulbar) at any time in the past 4 months

History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization

History of YAG capsulotomy performed within 2 months prior to randomization Aphakia Uncontrolled glaucoma (in investigator’s judgment)

Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis

Randomization Overview Randomization was based on a permuted block design

One Study Eye Stratification

Participants with one study eye were randomly assigned using the DRCR.net website with equal probability (using a permuted blocks design stratified by site and presence of central-involved DME)

Two Study Eyes Stratification

Participants with two study eyes were randomly assigned with equal probability to receive either 1) Ranibizumab in the eye with greater OCT central subfield and PRP in the eye with lower OCT central subfield OR 2) PRP in the eye with greater OCT central subfield and Ranibizumab in the eye with lower OCT central subfield

Reading Centers

OCT OCTs were obtained by certified personnel based on a standard acquisition protocol. Baseline and 2-year OCT scans were graded by the Duke Reading Center (Durham, NC)

Fundus Photographs

7-Field or 4-Wide field images were obtained by certified personnel based on a standard acquisition protocol. If NV was not identified within the standard images additional fields where taken to confirm the NV. If additional fields were obtained at baseline, they were repeated at follow-up. All images were graded by the Wisconsin Reading Center (Madison, Wisconsin)

Visual Field Humphrey visual field testing was processed at the University of Iowa Visual Field Reading Center

Protocol Defined Thickened OCT

Zeiss Cirrus/ Optovue RTVue Women ≥ 290 µm or Men ≥ 305 µm



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Heidelberg Spectralis Women ≥ 305 µm or Men ≥ 320 µm

Zeiss Stratus Women ≥ 250 µm or Men ≥ 250 µm

Humphrey Visual Field Testing

Baseline and Annually

Visual fields measured the total point score (sum of retinal sensitivities of all points) tested on 30-2 and 60-4 which included the mid-peripheral and peripheral visual fields

Visual Function Questionnaires

Baseline and Annually NEI-Visual Functioning Questionnaire-25

Baseline and Annually University of Alabama-Birmingham Low Luminescence Questionnaire

Sample Size

Assumptions A non-inferiority margin of 5 letters, type I error of 2.5% and 85% power, letter score standard deviation of 16, correlation between baseline and follow-up visual acuity of 0.21, and 7% loss to follow up

Multiple Imputation

Multiple imputation with the Markov chain Monte Carlo method was based on treatment group, baseline visual acuity and central subfield thickness, and all available visual acuity data from the 16-week visits was used to impute missing 2-year visual acuities

Panretinal Photocoagulation

Full PRP was defined as 1200 to 1600 burns using conventional laser or 1800 to 2400 using an automated pattern delivery system and was completed over 1 to 3 visits

VEGF = vascular endothelial growth factor, DRCR.net = Diabetic Retinopathy Clinical Research Network, PDR = proliferative diabetic retinopathy, PRP = panretinal photocoagulation, E-ETDRS = Electronic- Early Treatment Diabetic Retinopathy Study, OCT = optical coherence tomography, NV = neovascularization, NEI = National Eye Institute.



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eFigure 1. PDR Treatment with Anti-VEGF Assessed at Each Follow-up Visit After Initial Injection

NV = neovascularization; VH = vitreous hemorrhage †Failure = any of the following: 1) growth of NV present at study entry or new NV of the retina, disc OR iris since the last visit such that the NV, including fibrosis, is greater in extent than at baseline and at least 4 study injections have been given over the previous 4 months; 2) new or worsened NV of the angle; or 3) definite worsening of NV or fibrous proliferation of the retina, disc OR iris at least 1 day after the last injection that the investigator believes is likely to lead to substantial vision loss if PRP is not performed within 1 week (protocol chair approval required). Futility = continued persistence or recurrence of NV at 1.5 years or later follow-up that is equal to or greater than the extent of the NV present at baseline and at least 5 study injections performed over the preceding 6 months (protocol chair approval required for PRP).



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eFigure 2. Mean Change in Visual Acuity (Letter Score) through 2-Years for Eyes that Completed the 2-Year Visit. Bars Represent 95% Confidence Interval on the Mean.

N (Eyes) =

Ranibizumab 160 157 155 156 154 148 160 PRP 168 162 159 163 154 155 168



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eFigure 3. Change in Visual Acuity over Time: ≥10 Letter Score Improvement (includes only eyes with baseline visual acuity 20/32 or worse) (A) or Worsening (B).

N (Eyes) =

Ranibizumab 104 100 91 91 84 75 81

PRP 110 99 95 93 80 81 86

A.



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eFigure 3 Continued. Change in Visual Acuity over Time: ≥10 Letter Score Improvement (includes only eyes with baseline visual acuity 20/32 or worse) (A) or Worsening (B).

N (Eyes) =

Ranibizumab 191 183 172 170 163 152 160 PRP 203 189 178 178 163 159 168

B.



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eFigure 4. Percentage of Eyes with Visual Acuity ≥15 Letter-Score Worsening Over Time

N (Eyes) =

Ranibizumab 191 183 172 170 163 152 160 PRP 203 189 178 178 163 159 168



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eFigure 5. Kaplan Meier Plot for Time to Center-Involved DME Development with Vision Impairment at Follow-up among Eyes without DME and Vison Impairment at Baseline

Number at Risk (Eyes)

Ranibizumab 147 134 130 125 119 116 114 PRP 155 135 120 108 99 95 93

Note: Vertical tics on the curve represent censored data. The cumulative probability of developing central DME with vision impairment by 2 years was 9% versus 28% (adjusted difference 19% more frequently in the PRP group, 95% CI: 10% to 28%, P<0.001) in the ranibizumab and PRP groups. Treatment group difference, confidence interval, and P-value was obtained using marginal Cox proportional hazards model, with adjustment for number of study eyes, baseline central subfield thickness, correlation between 2 study eyes of the same participant.



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eTable 1. Participant Characteristics by 2-Year Visit Completion Status

Did not Complete Completed

Ranibizumab

Group

(N = 31

Eyes)

PRP Group

(N = 35

Eyes)

Ranibizumab

Group

(N = 160

Eyes)

PRP

Group

(N = 168

Eyes)

Participant Characteristics

Gender: Women - N (%) 12 (39%) 15 (43%) 71 (44%) 77 (46%) Age (yrs) - Median (25th, 75th percentile) 52 (43, 59) 50 (40, 60) 52 (44, 59) 51 (44, 59) Participants with two study eyes - N (%) 15 (48%) 15 (43%) 74 (46%) 74 (44%) Race/Ethnicity - N (%)

White 12 (39%) 17 (49%) 88 (55%) 84 (50%) Hispanic 11 (35%) 9 (26%) 37 (23%) 42 (25%) Black/African-American 7 (23%) 8 (23%) 31 (19%) 35 (21%) Other 1 (3%) 1 (3%) 4 (3%) 7 (4%)

Diabetes Type - N (%)

Type 1 5 (16%) 11 (31%) 38 (24%) 30 (18%)

Type 2 23 (74%) 24 (69%) 117 (73%) 131 (78%)

Uncertain 3 (10%) 0 (0%) 5 (3%) 7 (4%) Duration of Diabetes (yrs) - Median (25th, 75th percentile)

17 (9, 21)

18 (13, 23)

19 (12, 26)

16 (10, 23)

Hemoglobin A1c* (%) - Median (25th, 75th percentile)

8.1 (6.7, 10.5)

9.3 (6.9, 10.5)

8.6 (7.5, 10.4)

8.7 (7.5, 10.4)

Ocular Characteristics

Visual Acuity Letter Score Median (75th, 25th percentile)

75 (68, 80)

75 (63, 81)

78 (72, 85)

78 (70, 85)

~ Snellen Equivalent - Median (75th, 25th percentile)

20/32 (20/50, 20/25)

20/32 (20/63, 20/25)

20/32 (20/40, 20/20)

20/32 (20/40, 20/20)

≥ 84 letter score (20/20 or better) 2 (6%) 7 (20%) 50 (31%) 51 (30%)

83 – 69 letter score (20/25 to 20/40) 21 (68%) 18 (51%) 78 (49%) 84 (50%)

68 – 49 letter score (20/50 to 20/100) 4 (13%) 8 (23%) 27 (17%) 27 (16%) 48 – 24 letter score (20/125 to 20/320) 4 (13%) 2 (6%) 5 (3%) 6 (4%)



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OCT Central Subfield Thickness†‡ (µm) -

Median (25th, 75th percentile) 223 (198, 295)

240 (203, 263)

223 (196, 266)

229 (203, 265)

Mean ± Standard Deviation 272 ± 119 243 ± 64 260 ± 107 250 ± 90 Presence of CI-DME with Visual Acuity

Loss§‡ 9 (30%) 9 (26%) 33 (21%) 37 (22%)

Presence of CI-DME Regardless of Visual

Acuityǁ‡ 11 (37%) 12 (35%) 44 (28%) 50 (30%)

Neovascularization on Clinical Exam

Neovascularization of the disc 22 (71%) 22 (63%) 74 (46%) 81 (48%)

Neovascularization elsewhere 29 (94%) 30 (86%) 137 (86%) 144 (86%)

Lens Status Phakic (clinical exam) - N (%) 25 (81%) 30 (86%) 145 (91%) 157 (93%) Diabetic Retinopathy Severity¶ (ETDRS

level)

Severe NPDR or less (level 10-20,35,43,47,53)

1 (3%) 3 (9%) 18 (11%) 23 (14%)

Prior PRP; without current PDR (level 60) 0 0 0 1 (<1%)

Mild PDR (level 61) 6 (19%) 3 (9%) 24 (15%) 28 (17%)

Moderate PDR (level 65) 11 (35%) 13 (38%) 57 (36%) 54 (33%)

High risk PDR (level 71 and 75) 12 (39%) 15 (44%) 57 (36%) 58 (35%)

Advanced PDR (level 81 and 85) 1 (3%) 0 2 (1%) 1 (<1%)

Prior Treatment for DME - N (%) 5 (16%) 5 (14%) 38 (24%) 31 (18%)

Prior Focal/Grid Laser for DME - N (%) 1 (3%) 4 (11%) 29 (18%) 25 (15%)

Prior Anti-VEGF for DME - N (%) 4 (13%) 1 (3%) 17 (11%) 12 (7%)

Final Completed Visit Distribution of last completed visit (days)

Median (75th, 25th percentile) 279

(97, 462) 252

(97, 435)

Visual Acuity at last completed visit.

Median (75th, 25th percentile) 81 (75, 85)

75 (65, 85)

83 (75, 90)

80 (71, 86)

Snellen Median 20/25 20/32 20/25 20/25

Mean ± Standard Deviation 78.6 ± 8.7 71.4 ± 17.9 78.7±16.3 76.2 ± 14.2

Snellen Mean 20/32 20/40 20/32 20/32



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PRP = panretinal photocoagulation, OCT = optical coherence tomography, CI-DME = center-involved diabetic macular edema, ETDRS = Early Treatment Diabetic Retinopathy Study, NPDR = non-proliferative diabetic retinopathy, PDR = proliferative diabetic retinopathy, DME = diabetic macular edema, anti-VEGF = anti- vascular endothelial growth factor. * Hemoglobin A1c missing for 7 in the Ranibizumab group and 5 in the PRP group. † Assessments from OCT machines other than Zeiss Stratus were converted to equivalent on Zeiss Stratus. ‡ OCT central subfield thickness measurements missing for 2 in the Ranibizumab group (one completer and one non-completer) and 2 in the PRP group (one completer and one non-completer). § For Heidelberg Spectralis defined as central subfield thickness ≥305 for women and ≥320 for men with visual acuity letter score 78 or less (approximate Snellen equivalent 20/32 or worse). For Zeiss Cirrus and Optovue RTVue, defined as central subfield thickness ≥290 for women and ≥305 for men with visual acuity letter score 78 or less (20/32 or worse). For Zeiss Stratus defined as central subfield thickness ≥250 with visual acuity letter score 78 or less (20/32 or worse). ǁ For Heidelberg Spectralis defined as central subfield thickness ≥305 for women and ≥320 for men. For Zeiss Cirrus and Optovue RTVue, defined as central subfield thickness ≥290 for women and ≥305 for men. For Zeiss Stratus defined as central subfield thickness ≥250. ¶ Missing diabetic retinopathy level for 2 in the Ranibizumab group (both completers) and 4 in the PRP group (one did not complete, 3 completed)



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eTable 2. Treatment for Proliferative Diabetic Retinopathy and Diabetic Macular Edema: Ranibizumab Group

Overall Eyes With

Baseline DME‡ Eyes Without

Baseline DME€

Intravitreous Ranibizumab

Number of Injections Prior to 52 Week Visit* (Maximum = 13) – N (%) N = 170 Eyes N = 36 Eyes N = 133 Eyes

0 0 0 0 1-3 2 (1%) 0 (0%) 2 (2%) 4-7 91 (54%) 10 (28%) 80 (60%) 8-10 64 (38%) 17 (47%) 47 (35%) 11-13 13 (8%) 9 (25%) 4 (3%)

Median injections (25th, 75th percentile) 7 (5, 9) 9 (7, 11) 7 (5,9) Mean ± standard deviation 7.3 ± 2.3 8.9 ± 2.4 6.9 ± 2.1

Number of Injections Prior to 104 Week Visit† (Maximum = 26) – N (%)

N = 160 Eyes N = 33 Eyes N = 126 Eyes

0 0 0 0 1-3 3 (2%) 0 (0%) 3 (2%) 4-7 44 (28%) 5 (15%) 38 (30%) 8-10 37 (23%) 5 (15%) 32 (25%) 11-13 29 (18%) 6 (18%) 23 (18%) 14-16 24 (15%) 7 (21%) 17 (13%) 17-20 21 (13%) 9 (27%) 12 (10%) 21-26 2 (1%) 1 (3%) 1 (<1%)

Median injections (25th, 75th percentile) 10 (7, 14) 14 (10,17) 10 (6,13) Mean ± standard deviation 10.8 ± 4.7 13.3 ± 4.7 10.1 ± 4.5

Number of Injections Between 52 Week and 104 Week Visit¥ (Maximum = 13) – N (%)


0 34 (22%) 4 (13%) 30 (24%) 1-3 47 (30%) 8 (25%) 38 (31%) 4-7 56 (36%) 14 (44%) 42 (34%) 8-10 17 (11%) 6 (19%) 11 (9%) 11-13 2 (1%) 0 2 (2%)

Median injections (25th, 75th percentile) 3 (1, 6) 5 (2, 7) 3 (1, 5) Mean ± standard deviation 3.6 ± 3.0 4.6 ± 3.0 3.3 ± 2.9

Injection Deferred when Protocol Indicated Required for PDR Treatment (#deferred when required/#required) (%)

57/1955 (3%)

10/404 (2%)

47/1541 (3%)



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Injection Received when Protocol Indicated Investigator Discretion for PDR Treatment (# injections given/# discretion visits) (%)

262/2290 (11%)

162/473 (34%)

99/1798 (6%)

Panretinal Photocoagulation


Number of Eyes Receiving PRP 12 (6%) 5 (12%) 7 (5%) Number of days from randomization to first PRP -Median (25th, 75th percentile)

407 (314, 599)

346 (64, 553)

428 (317, 662)

Other DME Treatment

N = 191 Eyes N = 42 Eyes N = 147 Eyes Number of Eyes Receiving Focal/grid Photocoagulation for DME

15 (8%) 8 (19%) 7 (5%)

Eyes receiving 1 or more alternative treatment for DME (other than ranibizumab or focal/grid laser)

1 (<1%) 0 (0%) 1 (<1%)

PDR = Proliferative diabetic retinopathy, PRP = Panretinal photocoagulation, DME = Diabetic macular edema * Only includes participants that completed the 1 year visit † Only includes participants that completed the 2 year visit ¥ Only includes participants that completed the 1 and 2 year visit ‡ Defined as central involved DME on OCT at baseline with visual acuity letter score ≤ 78 (20/32 or worse) € Defined as either no central involved DME on OCT at baseline OR visual acuity letter score ≥ 79 (20/25 or better) Note: One eye with missing OCT was excluded from stratified analysis since DME status could not be categorized.



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eTable 3. Panretinal Photocoagulation Characteristics: PRP Group (N = 203 Eyes) Participants with Complete PRP* 198 (98%) Number of PRP sittings performed† 1 106 (54%) 2 78 (39%) 3 14 (7%) Total number of burns on dial* - Median (25th, 75th percentile)

Manual Slit-lamp Delivery System Conventional or Pascal (N = 112) 1440 (1274, 1600) Indirect Laser (N = 11) 1593 (1222, 1675)

Automated Delivery System (Pascal) (N = 26) 2190 (1831, 2416) Size of Burn on the Retina‡ - Median (25th, 75th percentile)

Manual Slit-lamp Delivery System Conventional or Pascal (N = 113) 500 (431, 500) Indirect Laser (N = 12) 500 (400,500)

Automated Delivery System (Pascal) (N = 28) 400 (400, 400)

Supplemental PRP

Percentage of Eyes with additional PRP (after completing initial PRP session)

92 (45%)

Distribution of Timing to Additional PRP (days) From Baseline: Median (25th, 75th percentile) 221 (116, 386) From Completion of First Full PRP: Median (25th, 75th percentile) 210 (109, 385)

*Five eyes failed to receive ‘Complete’ PRP. Reasons given included the following: Vitreous hemorrhage precluding sufficient treatment (2), patient did not tolerate treatment (1), patient to return for remaining treatment (1), and patient did not return (1). †Only includes participants with ‘Complete PRP’ and exclude patients who switched machines. ‡Based on first sitting only



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eTable 4. Treatment for Diabetic Macular Edema: PRP Group

Overall Eyes With

Baseline DME* Eyes Without

Baseline DME†

Intravitreous Ranibizumab

Timing of First Ranibizumab Injection (All Eyes) ‡ N = 203 Eyes N = 46 Eyes N = 155 Eyes

Never 95 (47%) 0 93 (60%) Baseline 72 (35%) 45 (98%) 27 (17%) 16 Weeks 16 (8%) 0 16 (10%) 32 Weeks 11 (5%) 1 (2%) 10 (6%) 52 Weeks 5 (2%) 0 5 (3%) 68 Weeks 2 (<1%) 0 2 (1%) 84 Weeks 2 (<1%) 0 2 (1%)

Number of Injections Prior to 52 Week Visit§ ǁ (Maximum = 13) – N (%) N = 178 Eyes N = 42 Eyes N = 135 Eyes

0 87 (49%) 0 (0%) 86 (64%) 1-3 41 (23%) 13 (31%) 28 (21%) 4-7 27 (15%) 14 (33%) 13 (10%) 8-10 17 (10%) 11 (26%) 6 (4%) 11-13 6 (3%) 4 (10%) 2 (1%)

Median injections (25th, 75th percentile) 1 (0, 4) 5 (3,9) 0 (0, 2) Mean ± standard deviation 2.4 ± 3.3 5.7±3.4 1.4 ± 2.6

Number of Injections Prior to 104 Week Visit¶ ** (Maximum = 26) – N (%)


0 74 (44%) 0 (0%) 73 (56%) 1-3 35 (21%) 9 (24%) 26 (20%) 4-7 26 (15%) 8 (22%) 18 (14%) 8-10 13 (8%) 6 (16%) 7 (5%) 11-13 7 (4%) 4 (11%) 3 (2%) 14-16 7 (4%) 6 (16%) 1 (<1%) 17-20 6 (4%) 4 (11%) 2 (2%) 21-26 0 0 0

Median injections (25th, 75th percentile) 1 (0, 6) 9 (4,15) 0 (0,3) Mean ± standard deviation 3.7 ± 5.1 9.1 ± 5.8 2.2 ± 3.7

Number of Injections Between 52 Week and 104 Week Visit†† (Maximum = 13) – N (%)


0 109 (67%) 13 (35%) 95 (76%) 1-3 31 (19%) 10 (27%) 21 (17%) 4-7 19 (12%) 11 (30%) 8 (6%) 8-10 4 (2%) 3 (8%) 1 (<1%) 11-13 0 0 0



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Median injections (25th, 75th percentile) 0 (0, 2) 3 (0, 6) 0 (0,0) Mean ± standard deviation 1.2 ± 2.2 3.1 ± 3.1 0.7 ± 1.5

Other DME Treatments (All Eyes)

Number of Eyes Receiving Focal/grid Photocoagulation for DME 21 (10%) 9 (20%) 12 (8%)

Eyes receiving 1 or more alternative treatment for DME (other than ranibizumab or focal/grid laser)

4 (2%) 2 (4%) 2 (1%)

PRP = Panretinal photocoagulation, PDR = Proliferative diabetic retinopathy, DME = Diabetic macular edema *Defined as central involved DME on optical coherence tomography (OCT) at baseline with visual acuity letter score ≤ 79 (20/32 or worse) †Defined as either no central involved DME on OCT at baseline OR visual acuity letter score ≥ 78 (20/25 or better) ‡Two eyes missing OCT were excluded from stratified analysis since DME status could not be categorized

§Only includes participants that completed the 1 year visit ǁOne eye missing OCT was excluded from stratified analysis since DME status could not be categorized

¶Only includes participants that completed the 2 year visit **One eye missing OCT was excluded from stratified analysis since DME status could not be categorized

††Only includes participants that completed the 1 and 2 year visit



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eTable 5. Visual Acuity at 2 Years Per-Protocol/Sensitivity Analyses*

Ranibizumab Group

PRP Group

Adjusted Difference

95% CI

2-Year Visit: Eyes with PDR on Fundus Photographs at Baseline

N = 140 N = 141

Visual Acuity at Baseline Mean ± standard deviation 75.9 ± 12.5 75.8 ± 12.3 Snellen Equivalents 20/32 20/32

Visual Acuity Change from Baseline

Mean (95% CI) 2.6

(-0.1, +5.3) -0.6

(-3.0, +1.8) +2.7

(-0.4,+5.7) Participants that Completed the 2-Year Visit

N = 160 N = 168

Visual Acuity at Baseline Mean ± standard deviation 75.9 ± 12.1 75.8 ± 12.0 Snellen Equivalents 20/32 20/32

Visual Acuity Change from Baseline

Mean (95% CI) 2.8

(0.4, 5.2) 0.2

(-1.9, +2.3) +2.1

(-0.5,+4.6)

PDR = proliferative diabetic retinopathy, CI = Confidence interval *Plus-minus values are means ± standard deviation. Treatment group means are calculated from observed 2-year data. Treatment group differences and confidence intervals were obtained using of analysis of covariance for continuous outcomes, with adjustment for baseline visual acuity, laterality, baseline central subfield thickness, and correlation between 2 study eyes of the same participant. Only available 2-year data was used to compute confidence interval. Visual acuity change was truncated to ± 3 standard deviation from the mean (-47, +49) to minimize the effect of outliers (5 observations in the Ranibizumab group and 3 in the PRP group, all on the negative side).



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eTable 6. Visual Acuity at 2 Years for Participants with Two Study Eyes (2-Year Visit Completers

Only)*

Ranibizumab Group

N = 74 Eyes

PRP Group N = 74 Eyes

Adjusted Difference

95% CI

Visual Acuity Letter Score at Baseline Mean ± Standard Deviation 76.2 ± 10.8 76.5 ± 10.6 Snellen Equivalents 20/32 20/32

Visual Acuity Letter Score at 2-Years Mean ± Standard Deviation 77.2 ± 17.4 76.6 ± 14.1 Snellen Equivalents 20/32 20/32

Change in Visual Acuity Letter Score from Baseline

Mean (95% CI) 1.3 (-2.3, +4.9) 0 (-3.2, +3.2) +0.9 (-2.3, +4.0) * Treatment group means are calculated from observed 2-year data. Treatment group differences and confidence intervals were obtained using analysis of covariance for continuous outcomes, with adjustment for baseline visual acuity and baseline central subfield thickness. Only available 2-year data was used to compute confidence interval. Visual acuity change was truncated to ± 3 standard deviation from the mean (-47, +49) to minimize the effect of outliers (4 records in the ranibizumab group and one in the PRP group, all on the negative side).



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eTable 7. Visual Acuity at 2 Years Sensitivity Analysis

Method Used Alternative Hypothesis

One Sided Non-Inferiority

True Difference > -5

One Sided Superiority

True Difference > 0

Primary Analysis: Markov Chain Monte Carlo method of multiple imputation3 (100 imputations) used to estimate missing 2 year change in visual acuity*

P < 0.001 P = 0.053

Cube Transformation: Change in visual acuity raised to 3rd power

P < 0.001 P = 0.006

Converting Visual acuity scores to normalized ranks (van der Waerden scores) P < 0.001 P = 0.013



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eTable 8. Visual Acuity Outcomes at 2 Years*

Ranibizumab

Group PRP Group

Adjusted

Difference

95% CI

P-value

Intention-to-Treat Analysis

with Multiple Imputation

Intention-to-Treat Analysis with

Multiple Imputation

Change from Baseline in

Letter score N = 191 Eyes N = 203 Eyes

Mean letter score (95% CI)‡ 3.0 (0.6, 5.3) 0.3 (-1.8, +2.3) +2.2

(-0.5, +5.0) P = 0.11

Observed Data


Multiple Imputation

Visual Acuity at 2-Years N = 160 Eyes N = 168 Eyes

Median letter score 83 (75, 90) 80 (71, 86)

Median Snellen equivalent 20/25 20/25

Change from Baseline in letter score**

≥ 10 Improvement

(baseline letter score ≤ 78

(20/32)†

35 (43%) 31 (36%) 6% (-8%, +21%) P = 0.37

≥ 10 Worsening 15 (9%) 23 (14%) -4%

(-11%, +2%) P = 0.20

≥ 15 Worsening 12 (8%) 17 (10%) -2%

(-8%, +3%) P = 0.42

*Visual acuity is measured as a continuous integer letter score from 100 to 0 with higher numbers meaning better visual acuity. A letter score of 85 is approximately 20/20 and 70 is approximately 20/40, the legal driving limit in most states. A letter score of 35 is approximately 20/200, considered legal blindness when it is the visual acuity in the better-seeing eye. A 5-letter change for an individual is approximately equal to a 1-line change on an eye vision chart. Medians are presented with the interquartile range. Treatment group medians are calculated from observed 2-year data. ‡ Treatment group means are calculated from using multiple imputation for missing data (N= 31 and N = 35

missing 2-year visual acuity in ranibizumab and PRP group respectively). Treatment group differences, confidence intervals, and P-values were obtained using of analysis of covariance, with adjustment for baseline visual acuity, number of study eyes, baseline central subfield thickness, and correlation between 2 study eyes of the same participant, and multiple imputation for missing data. Visual acuity change was truncated to ± 3 standard deviation from the mean (-47, +49) to minimize the effect of outliers (5 and 3 eyes for ranibizumab and PRP groups respectively, all on the negative end). **Treatment group differences, confidence intervals, and P-values were obtained using of binomial regression for binary outcomes, with adjustment for baseline visual acuity, number of study eyes, baseline central subfield thickness, and correlation between 2 study eyes of the same participant, and multiple imputation for missing data. † N = 81 and 86 eyes in the ranibizumab and PRP groups with baseline visual acuity 20/32 or worse.



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eTable 9. Change in Visual Acuity Letter Score from Baseline to 2-Years : Pre-Planned Subgroup

Analysis (2-Year Visit Completers Only*)

Ranibizumab

Group

PRP Group P-Value for

Interaction†

Adjusted Difference (95% CI)

N Mean

Visual

Acuity

Change ±

SD

N Mean

Visual

Acuity

Change ±

SD

DME with Decreased Visual Acuity at Baseline 0.84

Yes 33 7.9 ± 12.9 37 1.9 ± 16.5 2.7 (-3.7, 9.1) No 126 1.8 ± 15.1 130 -0.5± 12.8 2.0 (-0.8, +4.8)

Baseline Visual Acuity 0.74¥ ≥ 79 letter score (20/25 or

better) 79 -0.7 ± 13.5 82 -3.1 ± 10.8 2.5 (-1.2, +6.2)

78-24 letter score (20/32 or worse)

81 6.2 ± 16.1 86 3.3 ± 15.4 1.6 (-2.2, +5.3)

Baseline Central DME‡ 0.21€ Central-DME 44 7.6 ± 11.6 50 0.8 ± 15.5 5.0 (-0.4, +10.3) No Central-DME 115 1.3 ± 15.6 117 -0.3 ± 12.9 1.2 (-1.6, +4.0)

Prior DME Treatment 0.02 Yes 38 2.8 ± 11.0 31 5.4 ± 9.9 -4.1 (-9.1, +0.8) No 122 2.8 ± 16.3 137 -1.0 ± 14.2 3.5 (0.6, 6.3)

Diabetic Retinopathy

Severity 0.48

Non-High Risk PDR 99 3.9 ± 12.3 106 0.9 ± 12.3 2.9 (0.2, 5.6) High Risk PDR 59 0.8 ± 19.3 59 -1.2 ± 16.3 0.7 (-4.7, +6.2)

*Two eyes in the ranibizumab and 3 eyes in the PRP are missing DR severity photos. One eye in each group is missing OCT at baseline. †Analysis of covariance based on observed data adjusted for baseline visual acuity, laterality, baseline OCT

central subfield thickness, correlation between 2 study eyes, the subgroup factor and the interaction between the subgroup factor and treatment group. ‡For Heidelberg Spectralis defined as central subfield thickness ≥305 for women and ≥320 for men. For Zeiss

Cirrus and Optovue RTVue, defined as central subfield thickness ≥290 for women and ≥305 for men. For Zeiss

Stratus defined as central subfield thickness ≥250. ¥ P-value for interaction of treatment group and baseline visual acuity as a continuous outcome: P=0.84 € P-value for interaction of treatment group and baseline OCT central subfield thickness as a continuous outcome: P = 0.23




eTable 10. Visual Acuity Outcomes at 2 Years Stratified by Baseline DME Status (2-Year Visit

Completers Only)*

Ranibizumab

Group PRP Group

Adjusted Difference 95% CI P-Value

Eyes with Baseline DME ¶

N = 33 N = 37

Visual Acuity Letter Score at Baseline

Mean ± Standard Deviation 65.8 ± 11.7 64.8 ± 12.4 Snellen Equivalent 20/50 20/50

Visual Acuity Letter Score at 2-Years


Change in Visual Acuity Letter Score from

Baseline

Median (75th, 25th percentile) 10 (0, 16) 5 (-4, 13) Mean (95% CI)¥ 7.9 (3.4, 12.5) 1.9 (-3.6, 7.4) 3.0 (-4.2, +10.3) ≥ 10 letter improvement (letter

score ≤ 78 (20/32 or worse) at

baseline)†

17 (52%) 14 (38%) +12% (-11%, +35%)

≥ 15 letter Worsening 1 (3%) 6 (16%) -7% (-22%, +8%)≥ 10 letter Worsening 3 (9%) 8 (22%) -7% (-22%, +8%)

Visual Acuity Area Under the Curve- Letter Score Mean (95% CI)** 8.0 (5.3, 10.7) 3.6 (0.2, 7.1) 3.4 (-0.5, 7.4)

P=0.08

Eyes without Baseline DME §

N = 126 N = 130

Visual Acuity Letter Score at Baseline


Visual Acuity Letter Score at

2-Years


Change in Visual Acuity Letter Score from Baseline

Median (75th, 25th percentile) 4 (-2, 8) 1 (-4, 6)

Mean (95% CI) 1.8 (-0.9, +4.4) -0.5 (-2.7, +1.7) 1.4 (-1.5, 4.4)




≥ 10 letter improvement

(letter score ≤ 78 (20/32 or

worse) at baseline)‡ 18 (38%) 16 (33%) +5% (-14%, +25%)

≥ 15 letter Worsening 10 (8%) 11 (8%) 0% (-7%, +6%) ≥ 10 letter Worsening 11 (9%) 15 (12%) -2% (-9%, +5%)

Visual Acuity Area Under the Curve- Letter Score

Mean (95% CI)€

3.5 (2.4, 4.6) -1.5 (-2.8, -0.2) 4.9 (3.5, 6.4) P<0.001

* Treatment group means are calculated from observed 2-year data. Differences, confidence intervals, andP-values were obtained using of analysis of covariance for continuous outcomes and binomial regressionfor binary outcomes, with adjustment for baseline visual acuity, laterality, baseline central subfieldthickness, and correlation between 2 study eyes of the same participant (when the model converged). Ifthe binomial model did not converge, covariates were removed from the model. Observed 2-year data wasused for analyses. Visual acuity change was truncated to ± 3 standard deviation from the mean (-47, +49)to minimize the effect of outliers.¶ Defined as central involved DME on OCT at baseline with visual acuity letter score ≤ 79 (20/32 or worse).

¥ Linear mixed model used to obtain p-value and confidence intervals because of convergence issuesusing generalized estimating equations.† N = 33 and 37 eyes in the ranibizumab and PRP groups with baseline visual acuity 20/32 or worse.** Eyes with at least 2 follow-up visits were included in the area under the curve analyses: N = 42 and N =43 for the ranibizumab and PRP groups respectively.§ Defined as either no central involved DME on OCT at baseline OR visual acuity letter score ≥ 78 (20/25

or better).‡ N = 53 and 53 eyes in the ranibizumab and PRP groups with baseline visual acuity 20/32 or worse

€ Eyes with at least 2 follow-up visits were included in the area under the curve analyses: N = 142 and N =152 for the ranibizumab and PRP groups respectively.



eTable 11. Functional Outcomes: Humphrey Visual Field Test* (No. of Eyes)

HFA 30-2 HFA 60-4 HFA 30-2 + HFA 60-4 Ranibizumab

Group PRP Group Ranibizumab

Group PRP Group Ranibizumab

Group PRP Group

Baseline

N = 84 N = 88 N = 82 N = 87 N = 81 N = 86 Cumulative Score at Baseline (dB) Median score dB (25th, 75th percentile)

2240 (2073, 2388)

2266 (2106, 2418)

1320 (1038, 1480)

1358 (1189,1516)

3553 (3085, 3879)

3607 (3243, 3921)

Mean ± SD 2142 ± 413 2192 ± 366 1224 ± 383 1293±333 3365 ± 759 3487 ± 659

1-Year Visit

N = 69 N = 71 N = 66 N = 70 N = 65 N = 67 Cumulative Score at Baseline (dB) Median score (25th, 75th percentile)

2254 (2108, 2390)

2265 (2043, 2408)

1341 (1089, 1493)

1358 (1153, 1485)

3600 (3235, 3855)

3576 (3169, 3920)

Mean ± SD 2151 ± 429 2165 ± 393 1243 ± 381 1271 ± 347 3392 ± 780 3430 ± 711

Cumulative Score at 1 Year (dB) Median score (25th, 75th percentile)

2230 (2073, 2385)

2144 (1938, 2307)

1268 (976, 1491)

1144 (928, 1312)

3555 (2925, 3800)

3247 (2875, 3578)

Mean ± SD 2173 ± 339 2077 ± 345 1187 ± 409 1062 ± 380 3360 ± 708 3139 ± 675 Cumulative Score Change from Baseline (dB) Median score (25th, 75th percentile)

-19(-117, 110)

-78(-241, 25)

-18(-167, 124)

-175(-307, -47)

-1(-274, 239)

-274(-500, -58)

Mean ± SD 14 ± 234 -104 ± 289 -49 ± 287 -199 ± 301 -36 ± 486 -305 ± 521

Relative Loss at 1-Year (%) Median score (25th, 75th percentile)

-1(-5, 5)

-4(-10, 2)

-1(-13, 10)

-13(-24, -5)

1 (-18, 14)

-17(-30, -4)

Mean ± SD 2 ± 15 -4 ± 16 -1 ± 30 -12 ± 35 0 ± 42 -16 ± 48

Page 32 of 61



HFA 30-2 HFA 60-4 HFA 30-2 + HFA 60-4

2-Year Visit

N = 60 N = 60 N = 60 N = 60 N = 58 N = 57 Cumulative Score at Baseline (dB) Median score (25th, 75th percentile)

2247 (2117, 2392)

2278 (2125, 2420)

1320 (1076, 1519)

1382 (1210, 1521)

3573 (3259, 3890)

3645 (3419, 3930)

Mean ± SD 2136 ± 457 2177 ± 415 1237 ± 394 1303 ± 340 3380 ± 822 3520 ± 708

Cumulative Score at 104 Weeks (dB) Median score (25th, 75th percentile)

2245 (2020, 2394)

2103 (1922, 2316)

1266 (1109, 1518)

1126 (885, 1304)

3488 (3139, 3896)

3264 (2888, 3563)

Mean ± SD 2154 ± 424 2038 ± 382 1208 ± 398 1039 ± 389 3371 ± 793 3098 ± 728

Cumulative Score Change from Baseline (dB) Median score (25th, 75th percentile)

17 (-111, 124)

-119(-330, 35)

-7(-177, 118)

-257(-333, -83)

-25(-232, 223)

-379(-723, -75)

Mean ± SD 2 ± 209 -146 ± 311 -29 ± 279 -261 ± 280 -23 ± 410 -422 ± 518

P-value P=0.001 P<0.001 P<0.0001Relative Loss at 2 Years (%) Median score (25th, 75th percentile)

1 (-5, 6)

-5(-14, 2)

0 (-13, 12)

-18(-26, -6)

-2(-15, 15)

-23(-44, -7)

Mean ± SD 1 ± 16 -5 ± 19 1 ± 32 -19 ± 30 2 ± 42 -24 ± 42

*Humphrey visual fields were obtained at a subset of sites. Fields with excessive false positive response or excessive fixation loss at baseline wereexcluded from analysis. A false positive response is defined as a response to a false positive test, i.e. a projector movement (or other externalstimulus) when no stimulus is presented. Excessive false positive response was defined as [(# false positive responses) ÷ (# false positive tests)]*100 > 33%. A fixation loss is defined as a response to a fixation loss test, i.e. a stimulus presented to the blind spot. Excessive fixation loss wasdefined as [(# fixation losses) ÷ (# fixation loss tests)]*100 > 33%. Twenty-seven eyes in the ranibizumab and 31 in the PRP group were excluded.Outlying values were truncated at ±3 standard deviation from the mean to minimize the effect of potential outliers.

eTable 11 was corrected on March 12, 2019.

Page 33 of 61© 2019 American Medical Association. All rights reserved.


eTable 12. Functional Outcome: Humphrey Visual Field Test-Mean Deviation* (No. of Eyes) HFA 30-2 HFA 60-4 HFA 30-2 + HFA 60-4

Ranibizumab Group

PRP Group Ranibizumab Group

PRP Group Ranibizumab Group

PRP Group

Baseline

N = 84 N = 88 N = 82 N = 87 N = 81 N = 86

Mean Deviation at Baseline

Median score (25th, 75th percentile)

-4.25(-6.52, -3.11)

-4.40(-6.17, -2.77)

-7.08(-10.99, -4.72)

-6.29(-9.57, -4.67)

-5.43(-8.81, -3.83)

-5.30(-7.66, -3.97)

Mean ± SD -5.68 ± 5.04 -5.33 ± 4.50 -8.65 ± 6.01 -7.71 ± 5.29 -7.05 ± 5.20 -6.40 ± 4.57

1-Year Visit

N = 69 N = 71 N = 65 N = 69 N = 64 N = 66


Median (25th, 75th percentile)

-4.05(-5.78, -3.15)

-4.67(-6.57, -2.78)

-6.97(-10.61, -4.72)

-6.46(-10.77, -5.14)

-5.37(-7.55, -3.87)

-5.35(-8.88, -4.20)

Mean ± SD -5.51 ± 5.25 -5.64 ± 4.88 -8.44 ± 5.87 -8.20 ± 5.47 -6.92 ± 5.33 -6.91 ± 4.92

Mean Deviation at 1Year


-4.65(-6.36, -2.68)

-5.22(-7.88, -3.61)

-7.54(-10.77, -4.41)

-10.41(-13.99, -7.33)

-5.85(-9.07, -3.81)

-7.67(-10.76, -5.28)

Mean ± SD -5.24 ± 4.06 -6.35 ± 4.16 -9.09 ± 6.17 -11.43 ± 5.98 -7.00 ± 4.72 -8.62 ± 4.75

Mean Deviation Change from Baseline


-0.19(-1.36, 1.47)

-0.55(-2.04, 0.70)

-0.23(-2.59, 2.04)

-2.89(-5.58, -0.82)

-0.01(-1.89, 1.74)

-1.73(-3.43, -0.17)

Mean ± SD 0.08 ± 2.51 -0.92 ± 3.25 -0.65 ± 4.07 -3.23 ± 4.67 -0.14 ± 2.86 -1.86 ± 3.35

Page 34 of 61



HFA 30-2 HFA 60-4 HFA 30-2 + HFA 60-4

2-Year Visit

N = 60 N = 60 N = 60 N = 60 N = 58 N = 57



-4.06(-5.81, -3.25)

-4.41(-6.17, -2.77)

-6.98(-10.23, -4.52)

-6.24(-9.16, -4.32)

-5.37(-7.53,-3.83)

-5.17(-6.88,-3.93)

Mean ± SD -5.81 ± 5.66 -5.59 ± 5.10 -8.43 ± 6.21 -7.69 ± 5.56 -6.99 ± 5.73 -6.27 ± 4.96

Mean Deviation at 2 Years Median (25th, 75th percentile)

-4.24(-6.14, -2.93)

-5.49(-7.66, - 3.61)

-7.94(-10.28, -4.30)

-10.08(-13.73, -7.69)

-5.65(-8.06, -3.81)

-7.47(-10.85, -5.79)

Mean ± SD -5.43 ± 4.95 -6.66 ± 4.45 -8.93 ± 6.36 -11.80 ± 6.42 -6.90 ± 5.25 -8.74 ± 4.93

Mean Deviation Change from Baseline Median (25th, 75th percentile)

0.20 (-1.35, 1.73)

-0.65(-3.08, 0.60)

-0.01(-2.79, 1.89)

-3.67(-5.32, -1.23)

-0.12(-1.81, 1.68)

-2.29(-3.78, -0.51)

Mean ± SD 0.09 ± 2.66 -1.20 ± 3.42 -0.51 ± 4.53 -4.06 ± 4.64 -0.08 ± 2.92 -2.50 ± 3.49P-value P=0.01 P<0.0001 P<0.0001

* Combined mean deviation is weighted by the total number of points tested. Humphrey visual fields were obtained at a subset of sites. Fields with excessive false positive response or excessive fixation loss at baseline were excluded from analysis. A false positive response is defined as a response to a false positive test, i.e. a projector movement (or other external stimulus) when no stimulus is presented. Excessive false positive response was defined as [(# false positive responses) ÷ (# false positive tests)] *100 > 33%. A fixation loss is defined as a response to a fixation loss test, i.e. a stimulus presented to the blind spot. Excessive fixation loss was defined as [(# fixation losses) ÷ (# fixation loss tests)]*100 > 33%. Twenty-seven eyes in the ranibizumab and 31 in the PRP group were excluded. Outlying values were truncated at ±3 standard deviation from the mean to minimize the effect of potential outliers.

eTable 12 was corrected on March 12, 2019.

Page 35 of 61© 2019 American Medical Association. All rights reserved.


Page 36 of 61


eTable 13. National Eye Institute Visual Functioning Questionnaire-25 (No. Participants)

Baseline 104 Weeks Changes from

Baseline to

104 weeks

Ranibizumab

Group

PRP

Group

Ranibizumab

Group PRP

Group

Ranibizumab

Group PRP

Group

N = 83 N = 92 N = 83 N = 92 N = 83 N = 92

General Health Mean ± standard deviation 45 ± 22 44 ± 21 47 ± 23 46 ± 23 2 ± 26 2 ± 21

p-value P = 0.92 General Vision Mean ± standard deviation 62 ± 17 63 ± 18 70 ± 18 68 ± 17 7 ± 19 5 ± 19

p-value P = 0.36 Ocular Pain Mean ± standard deviation 81 ± 25 79 ± 23 85 ± 21 85 ± 18 3 ± 26 6 ± 20

p-value P = 0.60 Near Activities Mean ± standard deviation 71 ± 24 67 ± 26 74 ± 25 69 ± 24 2 ± 22 1 ± 24

p-value P = 0.37 Distance Activities Mean ± standard deviation 77 ± 24 73 ± 25 75 ± 26 73 ± 25 -2 ± 20 0 ± 22

p-value P = 0.82 Social Functioning Mean ± standard deviation 89 ± 22 85 ± 21 87 ± 24 83 ± 22 -1 ± 16 -2 ± 22

p-value P = 0.43 Mental Health Mean ± standard deviation 64 ± 27 60 ± 30 73 ± 27 66 ± 29 9 ± 21 7 ± 26

p-value P = 0.21 Role Difficulties Mean ± standard deviation 70 ± 31 65 ± 32 77 ± 28 75 ± 27 6 ± 27 10 ±

28 p-value P = 0.67 Dependency



Page 37 of 61


Mean ± standard deviation 80 ± 30 77 ± 31 85 ± 27 79 ± 29 5 ± 22 1 ± 28

p-value P = 0.13 Driving Mean ± standard deviation 79 ± 18 78 ± 15 82 ± 15 79 ± 14 3 ± 16 0 ± 15

p-value P = 0.17 Color Vision* Mean ± standard deviation 91 ± 23 90 ± 19 89 ± 22 90 ± 20 -2 ± 18 0 ± 21

p-value P = 0.76 Peripheral Vision† Mean ± standard deviation 85 ± 22 77 ± 28 82 ± 25 76 ± 26 -2 ± 20 -1 ± 31

p-value P = 0.38 Note: Only includes participants with one study eye. * Missing for one eye in the ranibizumab group † Missing for 2 eyes in the ranibizumab group and 1 in the PRP group



Page 38 of 61


eTable 14. University of Alabama-Birmingham Low Luminescence Questionnaire (No. Eyes)

Baseline 104 Weeks Changes from Baseline to 104 weeks

Ranibizumab Group

PRP

Group

Ranibizumab Group

PRP

Group

Ranibizumab Group

PRP

Group N = 79 N = 87 N = 79 N = 87 N = 79 N = 87

Driving* Mean ± standard deviation

64 ± 32 59 ± 34 60 ± 35 60 ± 33 -4 ± 23 1 ± 28

p-value P = 0.38 Extreme Lighting Mean ± standard deviation

67 ± 25 62 ± 25 69 ± 24 62 ± 24 3 ± 20 -1 ± 22

p-value P = 0.10 Mobility Mean ± standard deviation

81 ± 24 75 ± 30 80 ± 24 74 ± 25 -1 ± 19 -1 ± 22

p-value P = 0.43 Emotional Distress Mean ± standard deviation

80 ± 24 71 ± 32 81 ± 26 74 ± 29 2 ± 22 3 ± 28

p-value P = 0.47 General Dim Lighting

Mean ± standard deviation

76 ± 22 71 ± 27 76 ± 23 70 ± 24 0 ± 19 -1 ± 21

p-value P = 0.35 Peripheral Vison Mean ± standard deviation

81 ± 22 71 ± 28 79 ± 24 70 ± 27 -2 ± 21 -1 ± 26

p-value P = 0.35 Note: Only includes participants with one study eye * Missing for 6 eyes in the PRP group



Page 39 of 61


eTable 15. Optical Coherence Tomography Central Subfield Thickness Outcomes at 2 Years*†

Ranibizumab

Group

PRP

Group

Adjusted

Difference 95% CI

P-value


LOCF


LOCF

Change from Baseline

in CST N = 191 Eyes N = 203 Eyes

Mean change (95% CI)‡ -51 (-64, -38) 4 (-8, 16) -45 (-57, -33) < 0.001

Observed Data Intention-to-Treat Analysis with

LOCF

N = 149 Eyes N = 161 Eyes Center-involved DME at 2 years (irrespective of visual acuity)‡ - N (%)

15 (10%) 41 (25%) -16% (-23%, -9%) P<0.001

Center-involved DME‡ at 2 years with visual acuity letter score ≤ 78

(20/32 or worse)

10 (7%) 22 (14%) -8% (-14%, -2%) P=0.001

Center-involved DME‡ at 2 years with 25µm increase from baseline

5 (3%) 23 (14%) -11% (-16%, -6%) P<0.001

Eyes with Baseline DME §

N = 32 Eyes N = 36 Eyes Mean CST at baseline - µm 419 ± 123 349 ± 108

Mean CST at 2 years 244 ± 86 294 ± 108

Mean CST change from baseline to 2 years - µm (95% CI)

-153 (-200, -107) -48 (-90, -6) -54 (-90, -19) P=0.006

Center-involved DME at 2 years (irrespective of visual acuity) ‡ - N (%)

10 (31%) 18 (50%) -25% (-43%, -6%) P=0.008


(20/32 or worse)

8 (25%) 13 (36%) -17% (-37%, +2%) P=0.07



Page 40 of 61


Center-involved DME‡ at 2 years with 25µm increase from baseline¥

3 (9%) 7 (19%) -12% (-26%, +1%) P=0.08

Eyes without Baseline DME ǁ

N = 117 Eyes N = 125 Eyes

Mean CST at baseline - µm 219 ± 47 219 ± 33

Mean CST at 2 years - µm 200 ± 37 228 ± 62

Mean CST change from baseline to 2 years (95% CI)

-18 (-25, -11) +10 (0, +20) -31 (-41, -21)

P<0.001

Center-involved DME at 2 years (irrespective of visual acuity) ‡ - N (%)

5 (4%) 23 (18%) -13% (-20%, -6%) P<0.001


(20/32 or worse)

2 (2%) 9 (7%) -5% (-10%, 0%) P=0.03

Center-involved DME‡

at 2 years with 25 µm increase from baseline

2 (2%) 16 (13%) -11% (-17%, -5%) P<0.001

CST = central subfield thickness, CI = Confidence interval, DME = diabetic macular edema, LOCF = Last-observation-carried-forward *Plus-minus values are means ± standard deviation. Treatment group means are calculated from observed data at the 2-year visit (unless otherwise specified). Treatment group differences, confidence intervals, and P-values were obtained using analysis of covariance for continuous outcomes and binomial regression for binary outcomes, with adjustment for number of study eyes, baseline central subfield thickness, correlation between 2 study eyes of the same participant, and imputation of missing data with last observation carried forward. If the model did not converge, covariates were removed from the model. Central subfield thickness changes were truncated to ± 3 standard deviations from the mean (-325, +276) to minimize the effect of outliers (4 eyes in the ranibizumab group on the large decrease end and 3 eyes in the PRP group [1 large decrease, 2 large increase] at the 2-year visit). All baseline and 2 year optical coherence tomography (OCT) scans were evaluated by Duke Reading Center. In addition, a random sample of OCT images from other visits and images for which the investigator believed central grading was needed also were graded by Duke Reading Center. †Optical coherence tomography values obtained by spectral-domain OCT were converted to time domain equivalent values for analysis and reporting as follows: -43.12 +1.01*Zeiss Cirrus; -72.76 + 1.03*Spectralis. (Diabetic Retinopathy Clinical Research Network. Reproducibility of spectral domain optical coherence



Page 41 of 61


tomography retinal thickness measurements and conversions to equivalent time domain metrics in diabetic macular edema. JAMA Ophthalmol. 2014;132(9):1113-22.) ‡For Heidelberg Spectralis defined as CST ≥305 for women and ≥320 for men. For Zeiss Cirrus and

Optovue RTVue, defined as CST ≥290 for women and ≥305 for men. For Zeiss Stratus defined as CST ≥250. Central involved DME at follow-up is based on only thickening unless otherwise specified. §Defined as central involved DME on OCT at baseline with visual acuity letter score ≤ 79 (20/32 or worse). ǁDefined as either no central involved DME on OCT at baseline OR visual acuity letter score ≥ 78 (20/25 or

better). Thirty-six (18 in each group) eyes had central-involved DME on OCT at baseline but had visual acuity ≥ 78. For binary outcomes, all covariates were excluded to attain convergence. ¥ Because of convergence issues using generalized estimating equations no adjustment was made to account for correlation within participant with two study eyes.



Page 42 of 61


eTable 16. Change in Retinal Volume at 2 Years* (No. of Eyes)

Ranibizumab

Group N = 105 Eyes


Adjusted Difference

95% CI P-value

Baseline Volume – Mean ± SD 7.8 ± 1.4 7.6 ± 0.9 Volume at 2 Years – Mean ± SD 6.9 ± 0.8 7.4 ± 1.0 Change in Volume from Baseline – Mean (95% CI) -0.8 (-1.0, -0.6) -0.2 (-0.4, 0.0)

-0.6 (-0.7, -0.4)

P < 0.001

Eyes with Baseline DME†

Ranibizumab Group

N = 24 Eyes


Baseline Volume – Mean ± SD 9.5 ± 1.6 8.4 ± 1.0 Volume at 2 Years – Mean ± SD 7.4 ± 0.9 7.6 ± 1.4

Change in Volume from Baseline – Mean (95% CI) -1.9 (-2.5, -1.2) -0.8 (-1.4, -0.3)

-0.7 (-1.9, 0.5)

P = 0.23

Eyes without Baseline DME‡

Ranibizumab Group

N = 81 Eyes


Baseline Volume – Mean ± SD 7.3 ± 0.9 7.4 ± 0.8 Volume at 2 Years – Mean ± SD 6.8 ± 0.7 7.4 ± 0.8

Change in Volume from Baseline – Mean (95% CI) -0.5 (-0.6, -0.4) 0 (-0.2, +0.1)

-0.5 (-0.6, -0.3)

P < 0.001

SD = standard deviation, CI = Confidence interval * Treatment group means are calculated from observed 2-year data. Differences, confidence intervals, and P-values were obtained using of analysis of covariance, with adjustment for baseline volume, laterality, and correlation between 2 study eyes of the same participant. Observed 2-year data was used for analyses. † Defined as central involved DME on OCT at baseline with visual acuity letter score ≤ 79 (20/32 or

worse). ‡ Defined as either no central involved DME on OCT at baseline OR visual acuity letter score ≥ 78 (20/25

or better).



Page 43 of 61


eTable 17. Changes in Diabetic Retinopathy Outcomes through the 2-Year Visit*† Ranibizumab

Group

PRP

Group

P-value‡

Any Retinal Detachment N = 12 N = 21 Timing of retinal detachment – Median number of days (IQR)

199 (57,369)

379 (121,531)

Vitreous Hemorrhage No. N = 52 N = 69

Onset of vitreous hemorrhage – Median number of days since enrollment (IQR)

379 (222, 539)

240 (98, 469)

Eyes with Vitrectomy No. N = 8 N = 30 Time to Vitrectomy - Median number of days (IQR) since enrollment

511 (205, 653)

465 (321, 597)

N = 169 N = 175 Eyes with NV resolution on Clinical Exam at 1 Year No. (%)

81 (48%) 66 (38%) 0.01

Diabetic Retinopathy on Fundus Photographs at 1 Year§

N = 136 N = 134 0.02

Percentage of eyes without PDR (level 60 or lower) 49 (36%) 36 (27%) Percentage of eyes with regressed NV (level 61A) 25 (18%) 16 (12%) Percentage of eyes with active NV (level 61B or higher) 62 (46%) 82 (61%)

Percentage of Eyes Improving 2 or More Steps in Diabetic Retinopathy Severity on Fundus Photos at 1 Year§ǁ

68 (50%) --

IQR = Interquartile range, NV = neovascularization, PDR = proliferative diabetic retinopathy *Unless otherwise specified diabetic retinopathy outcomes were collected at any time during study follow-up through 2-year visit. † If the 2-year visit was completed, then the visit date was used to define the 2-year time point; otherwise 728 days was used. ‡ P-values are based on binomial or multinomial regression adjusting for the correlation between 2 study eyes of the same participant. §Only includes eyes with diabetic retinopathy level 61B or worse (active neovascularization) as graded by the reading center. Use last observation carried forward if 1 year fundus photographs are available. ǁEyes at follow-up graded by the reading center as receiving PRP (level 60) are counted as not improving.



Page 44 of 61


eTable 18. Adverse Events by MedDRA System Organ Class (one event per participant)

Bilateral*

N = 89

Participants

Ranibizumab

Group

N = 102

Participants

PRP Group

N = 114

Participant

s

P value

Blood and lymphatic system

disorders

10 (11%) 11 (11%) 8 (7%) 0.49

Cardiac disorders 12 (13%) 18 (18%) 6 (5%) 0.01

Ear and labyrinth disorders 8 (9%) 7 (7%) 6 (5%) 0.58

Endocrine disorders 18 (20%) 25 (25%) 12 (11%) 0.02

Gastrointestinal disorders 26 (29%) 25 (25%) 27 (24%) 0.63

General disorders and

administration site conditions

17 (19%) 21 (21%) 22 (19%) 0.97

Hepatobiliary disorders 1 (1%) 2 (2%) 5 (4%) 0.40

Immune system disorders 5 (6%) 4 (4%) 6 (5%) 0.85

Infections and infestations 25 (28%) 28 (27%) 16 (14%) 0.02

Injury, poisoning and procedural

complications

8 (9%) 9 (9%) 7 (6%) 0.72

Investigations 12 (13%) 7 (7%) 10 (9%) 0.31

Metabolism and nutrition disorders 18 (20%) 12 (12%) 14 (12%) 0.20

Musculoskeletal and connective

tissue disorders

23 (26%) 38 (37%) 29 (25%) 0.12

Neoplasms benign, malignant and

unspecified (incl cysts and polyps)

3 (3%) 2 (2%) 0 0.11

Nervous system disorders 29 (33%) 23 (23%) 26 (23%) 0.20

Psychiatric disorders 3 (3%) 8 (8%) 11 (10%) 0.20

Renal and urinary disorders 19 (21%) 25 (25%) 18 (16%) 0.26

Reproductive system and breast

disorders

1 (1%) 2 (2%) 4 (4%) 0.63

Respiratory, thoracic and

mediastinal disorders

31 (35%) 47 (46%) 34 (30%) 0.04

Skin and subcutaneous tissue

disorders

18 (20%) 24 (24%) 12 (11%) 0.03

Social circumstances 0 0 1 (1%) 1.0



Page 45 of 61


Surgical and medical procedures 7 (8%) 24 (24%) 18 (16%) 0.01

Vascular disorders 21 (24%) 31 (30%) 27 (24%) 0.45 *Bilateral = participants with two study eyes



Page 46 of 61



System Organ Bilateral*

N = 89 Participants

Ranibizumab Group

N = 102 Participants

PRP Group


Blood and lymphatic system disorders

Anaemia 8 9 6

Anaemia of chronic disease 2 5 0

Leukaemia 0 1 0

Leukocytosis 1 0 0

Lymphoedema 0 0 1

Pancytopenia 0 1 0

Splenomegaly 0 0 1

Cardiac disorders

Angina pectoris 0 2 0

Atrial fibrillation 0 0 1

Atrial flutter 1 0 0



Page 47 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Cardiac arrest 0 2 0

Cardiac failure 2 1 1

Cardiac failure congestive 5 10 2

Cardiomyopathy 0 0 1

Coronary artery disease 4 6 2

Coronary artery restenosis 1 0 0

Coronary artery stenosis 2 1 0

Diastolic dysfunction 0 1 0

Left ventricular dysfunction 0 1 0

Myocardial infarction 3 3 2

Pericarditis 0 1 0

Ventricular hypokinesia 0 1 0

Ear and labyrinth disorders

Deafness 1 0 0

Ear discomfort 0 1 1

Ear infection 1 4 2

Ear pain 3 2 1

Eustachian tube dysfunction 0 1 1

Inner ear disorder 0 0 1

Middle ear effusion 1 0 0

Otitis media 0 1 0

Otitis media acute 1 0 0

Tinnitus 1 0 0

Endocrine disorders

Cushing's syndrome 0 1 0



Page 48 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Diabetes mellitus 3 5 2

Diabetes mellitus inadequate control 8 8 5

Diabetic ketoacidosis 0 8 4

Hyperglycaemia 5 6 3

Hyperthyroidism 1 0 0

Hypoglycaemia 4 9 1

Hypothyroidism 3 0 0

Thyroid neoplasm 0 1 0

Gastrointestinal disorders

Abdominal discomfort 0 7 0

Abdominal pain 4 3 3

Abdominal pain upper 3 2 1

Colitis ischaemic 1 0 0

Colon cancer 1 0 1

Constipation 1 2 1

Dental caries 1 0 1

Diabetic gastroparesis 1 0 1

Diarrhoea 3 2 3



Page 49 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Dyspepsia 2 1 0

Food poisoning 0 2 0

Gastritis 1 0 0

Gastroenteritis 1 1 2

Gastroenteritis viral 4 3 2

Gastrointestinal haemorrhage 0 0 1

Gastrooesophageal reflux disease 2 6 2

Haematochezia 0 0 1

Hiatus hernia 0 1 1

Impaired gastric emptying 0 0 2

Intestinal obstruction 0 0 2

Irritable bowel syndrome 0 0 1

Lactose intolerance 0 0 2

Nausea 8 10 7

Oesophageal varices haemorrhage 0 0 1

Pancreatitis 1 1 0

Tooth abscess 2 1 0

Tooth infection 2 1 0

Toothache 2 1 0

Vomiting 5 8 2

General disorders and administration site

conditions

Chest discomfort 1 0 1



Page 50 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Chest pain 5 9 5

Chills 0 1 1

Death 1 4 2

Device related infection 1 0 0

Facial pain 0 0 1

Fatigue 2 1 1

Flank pain 0 1 0

Hernia 3 0 1

Local swelling 2 1 0

Oedema peripheral 5 6 7

Pain 1 2 4

Pyrexia 1 3 0

Swelling 2 1 1

Hepatobiliary disorders

Cholecystitis acute 1 1 0

Cholelithiasis 0 2 2

Hepatic cirrhosis 0 0 2

Hepatomegaly 0 0 1

Immune system disorders

Hypersensitivity 0 1 1

Seasonal allergy 4 4 5



Page 51 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Infections and infestations

Abscess 2 0 1

Bacteraemia 0 1 0

Beta haemolytic streptococcal infection 0 0 1

Bronchopneumonia 1 0 0

Candidiasis 0 1 0

Diverticulitis 1 2 0

Escherichia infection 0 0 1

Fungal infection 0 2 0

Gastroenteritis norovirus 0 1 0

Gingival infection 1 0 0

Helicobacter infection 1 0 0

Infection 0 5 3

Influenza 9 14 8

Latent tuberculosis 1 0 0

Localised infection 4 8 1

Onychomycosis 2 0 1

Postoperative wound infection 1 0 0

Respiratory tract infection fungal 0 1 0

Sepsis 2 1 0

Staphylococcal infection 1 1 1

Injury, poisoning and procedural complications

Animal scratch 0 0 1



Page 52 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Arthropod bite 1 0 1

Burns second degree 1 1 1

Fall 3 2 5

Head injury 0 2 0

Laceration 0 1 0

Ligament rupture 1 0 0

Limb injury 0 1 0

Road traffic accident 0 1 0

Thermal burn 0 1 0

Wound 2 2 1

Investigations

Biopsy skin 0 1 0

Blood creatinine abnormal 1 1 0

Blood glucose decreased 3 0 1

Blood glucose increased 2 0 0

Blood testosterone decreased 1 0 0

Cardiac murmur 0 0 1

Colonoscopy 0 0 1

Electrocardiogram abnormal 0 3 0

Glycosylated haemoglobin increased 0 0 1

Intraocular pressure increased 1 1 0

Laboratory test abnormal 0 1 0

Low density lipoprotein increased 0 0 1

Red blood cell count decreased 0 0 1

Troponin increased 0 0 1

Metabolism and nutrition disorders



Page 53 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Acidosis 0 1 0

Dehydration 1 2 2

Fluid overload 5 7 0

Fluid retention 0 1 1

Hypercholesterolaemia 5 4 6

Hyperkalaemia 2 5 1

Hyperlipidaemia 1 2 3

Hypertriglyceridaemia 0 0 1

Hypokalaemia 1 1 1

Hypomagnesaemia 1 0 0

Hypophosphataemia 1 0 0

Iron deficiency 0 0 1

Obesity 0 0 1

Vitamin D deficiency 4 1 1

Musculoskeletal and connective tissue disorders

Ankle fracture 1 0 1



Page 54 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Arthralgia 2 2 2

Arthritis 1 0 0

Back pain 2 5 5

Bursitis 0 1 0

Exostosis 1 0 0

Foot deformity 0 1 0

Foot fracture 2 5 4

Fractured coccyx 0 0 1

Gout 1 2 2

Hand fracture 1 0 0

Intervertebral disc protrusion 0 0 1

Ligament sprain 0 5 3

Lower limb fracture 0 1 0

Medial tibial stress syndrome 0 1 0

Meniscus injury 0 1 0

Multiple fractures 2 5 2

Muscle spasms 1 0 1

Muscle strain 1 0 0

Muscular weakness 0 7 2

Musculoskeletal discomfort 0 1 0

Musculoskeletal pain 0 1 0

Myalgia 1 0 0

Neck pain 1 1 1

Neuropathic arthropathy 0 1 1

Osteoarthritis 4 1 4

Osteomyelitis 5 2 1



Page 55 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Osteopenia 0 1 0

Osteoporosis 0 1 0

Pain in extremity 2 6 4

Periarthritis 0 0 1

Plantar fasciitis 0 2 0

Polymyalgia rheumatica 0 0 1

Rheumatoid arthritis 0 1 0

Rotator cuff syndrome 1 0 0

Temporomandibular joint syndrome 0 2 0

Trigger finger 0 1 1

Wrist fracture 0 1 1

Neoplasms benign, malignant and unspecified

(including cysts and polyps)

Abdominal neoplasm 0 1 0

Acoustic neuroma 1 0 0

Hepatic cancer 1 0 0

Lung cancer metastatic 1 0 0

Myelodysplastic syndrome 0 1 0

Renal cancer 1 0 0

Nervous system disorders

Autonomic nervous system imbalance 0 1 0

Balance disorder 1 0 0

Brain neoplasm 0 0 1

Carpal tunnel syndrome 0 0 1

Concussion 0 1 0

Convulsion 1 1 2



Page 56 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Dementia 0 0 1

Diabetic neuropathy 3 0 1

Dizziness 6 6 4

Dysarthria 0 0 1

Encephalopathy 2 0 0

Headache 18 10 23

Hydrocephalus 0 0 1

Hypoaesthesia 2 0 2

IVth nerve paralysis 0 1 0

Migraine 1 2 1

Nerve injury 1 1 0

Neuropathy peripheral 1 2 0

Paraesthesia 0 1 0

Presyncope 1 0 0

Restless legs syndrome 0 1 0

Sciatica 0 1 0

Syncope 1 3 2

Temporal arteritis 0 1 0

Tremor 1 0 0

Vertigo 0 2 3

Psychiatric disorders

Anxiety 0 3 3

Depression 2 1 8

Drug abuse 1 0 0

Insomnia 0 2 2

Mental disorder 0 0 1



Page 57 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Stress 0 1 1

Suicidal ideation 0 1 0

Suicide attempt 0 0 1

Renal and urinary disorders

Azotaemia 0 6 0

Bladder cancer 1 0 0

Cystitis 2 1 1

Dysuria 1 0 0

Haematuria 2 1 0

Hydronephrosis 1 0 0

Kidney infection 1 0 0

Nephrolithiasis 2 2 2

Nephropathy 0 1 0

Nephrotic syndrome 0 0 1

Proteinuria 1 0 1

Pyelonephritis 3 3 0

Renal failure 6 10 5

Renal failure acute 3 2 1

Renal failure chronic 4 5 9

Renal impairment 1 4 1

Renal osteodystrophy 0 2 0

Urinary incontinence 0 1 0

Urinary retention 1 0 1

Urinary tract disorder 0 1 0

Urinary tract infection 6 7 5

Reproductive system and breast disorders



Page 58 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Erectile dysfunction 0 1 1

Ovarian cyst 0 0 1

Prostate cancer 1 0 0

Prostatitis 1 0 0

Prostatomegaly 0 1 0

Testicular swelling 0 0 1

Uterine leiomyoma 0 0 1

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure 1 0 1

Asthma 0 0 2

Bronchitis 3 5 2

Chronic obstructive pulmonary disease 0 0 1

Chronic sinusitis 0 1 0

Cough 9 7 5

Dyspnoea 7 7 2

Hypoxia 0 1 0

Lung neoplasm 0 1 0

Nasal congestion 3 1 3

Nasopharyngitis 16 20 10

Oropharyngeal pain 5 5 0

Pharyngitis streptococcal 0 0 1

Pleural effusion 1 1 0

Pneumonia 4 5 4

Pulmonary embolism 0 1 0

Pulmonary hypertension 0 0 1

Pulmonary oedema 1 4 0



Page 59 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Respiratory distress 0 1 1

Respiratory tract congestion 1 2 1

Respiratory tract infection 0 0 1

Respiratory tract oedema 0 0 1

Rhinitis allergic 0 1 0

Rhinorrhoea 0 1 0

Sinusitis 2 14 7

Sleep apnoea syndrome 0 1 1

Upper respiratory tract infection 2 4 2

Wheezing 0 1 0

Skin and subcutaneous tissue disorders

Acne 0 0 1

Alopecia 1 0 0

Basal cell carcinoma 1 0 2

Blister 2 0 0

Cellulitis 4 8 3

Contusion 1 0 0

Dermatitis allergic 0 1 0

Dermatitis contact 1 1 0

Diabetic foot 6 3 3

Diabetic ulcer 0 1 0

Excoriation 1 2 0

Furuncle 1 0 1

Gangrene 0 0 1

Herpes zoster 0 1 0

Hyperhidrosis 0 1 0



Page 60 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Hyperkeratosis 2 0 0

Ingrowing nail 1 1 0

Onychomycosis 1 0 0

Pruritus 0 2 0

Rash 1 2 3

Skin disorder 0 0 1

Skin infection 1 3 0

Skin ulcer 2 1 0

Social circumstances

Menopause 0 0 1

Surgical and medical procedures

Abdominal panniculectomy 0 1 0

Benign tumour excision 0 0 2

Cardiac operation 1 0 0

Cholecystectomy 1 0 0

Coronary angioplasty 0 1 0

Coronary artery bypass 0 1 1

Dental implantation 0 0 1

Gastric banding 0 0 2

Knee operation 0 0 3

Leg amputation 0 1 0

Skin lesion excision 0 1 0

Stent placement 1 1 1

Surgery 1 3 1

Toe amputation 0 3 0

Tonsillectomy 0 0 1



Page 61 of 61




N = 89 Participants

Ranibizumab Group


PRP Group


Tooth extraction 1 4 0

Vascular disorders

Arteriosclerosis 0 1 1

Arteriovenous fistula 1 0 0

Carotid artery disease 0 0 1

Cerebrovascular accident 2 2 3

Embolism 1 0 0

Hypertension 18 31 24

Hypotension 3 2 1

Iliac artery occlusion 0 0 1

Ischaemic stroke 0 0 2

Peripheral artery stenosis 1 0 0

Peripheral ischaemia 1 0 0

Peripheral vascular disorder 1 1 0

Thrombosis 1 0 0

Transient ischaemic attack 1 2 1

Varicose vein 1 0 0

*Bilateral = participants with two study eyes



Documents

Supplementary Online ContentInvestigator List for the Diabetic Retinopathy Clinical Research Network . Diabetic Retinopathy Clinical Research Network clinical sites that participated