1. What data in particular will be shared?
   Response - All of the individual participant data collected during the trial, after de-identification.
   


2. What additional supporting information will be shared?
   Response -  Study Protocol
   Response -  Statistical Analysis Plan
   Response - Informed Consent Form
   Response - Clinical Study Report
   
   
3. Who will be able to view these files?
   Response - Researchers whose proposed use of the data has been approved by an independent review committee identified for this purpose.
   


4. For what types of analyses will this data be available?
   Response - Any purpose.
   


5. By what mechanism will data be made available?
   Response - Proposals should be directed to [anil@mgmeye.org].
   


6. For how long will this data be available start date provided 01-04-2027 and end date provided 31-03-2032?
   Response - Beginning 3 months and ending 5 years following article publication.
   


7. Any URL or additional information regarding plan/policy for sharing IPD? 
   Additional Information - NIL

Efficacy and Reactivation rates between Biosimilar and Innovator Ranibizumab in Aggressive retinopathy of prematurity—A prospective multicentre cohort study

Aggressive retinopathy of prematurity (A-ROP) is severe form ROP, with rapid progression to retinal detachment in absence of treatment.^{1, 2} In an Indian scenario, A-ROP constitutes a significant proportion of infants requiring treatment.³ Due to higher rate of unfavourable outcomes with laser mono therapy, particularly in zone 1 and posterior zone 1, use of intravitreal  anti vascular endothelial growth factor (anti VEGF) with or without laser, has been viewed as an effective therapy for managing A-ROP.^4-6 In India, A-ROP remains the main indication for use of anti VEGF in ROP. ⁷

Following the guidelines from Drug Controller General of India (DCGI), All India Ophthalmological Society (AIOS) and Vitreoretina Society of India (VRSI) on use of Bevacizumab in ophthalmology, about one fourth of the surveyed ophthalmologists switched to innovator Ranibizumab, yet it was not seen as the most commonly used anti VEGF agent, possibly due to a higher cost of the drug.⁷ Contrarily, due to lower cost and approvals from DCGI for some  of the ophthalmic indications, including ROP, bio similar Ranibizumab ( Razumab, Intas pharmaceuticals, India) has been seen as an alternative to the innovator drug. Moreover, a recent retrospective case series demonstrated that bio similar Ranibizumab is safe and effective in infants with ROP.⁸ However, to best of our knowledge, there is no study comparing the innovator and bio similar Ranibizumab in ROP. The current study aims to compare the efficacy, safety and reactivation between the innovator and bio similar Ranibizumab, in a cohort of preterm Indian infants with A-ROP.

Methodology

This will be a multicentre prospective, interventional study. Infants diagnosed with A- ROP as per ICROP 3 will be included in study. Infants with hybrid disease will be excluded from the study.  Infants diagnosed with A-ROP at any of the collaborating centres will undergo fundus imaging using pediatric wide field fundus camera (RetCam Shuttle^®, Clarity Medical Systems, Inc.; Pleasanton, CA, USA or 3netraNeo^®Forus Health Pvt Ltd, Bengaluru, India). The parents of the infants will be explained about the efficacy, adverse effects and cost of treatment with both the drugs. The enrolled infants will be treated with either innovator Ranibizumab (Accentrix, Novartis India) (IR) or bio similar Ranibizumab (Razumab, Intas pharmaceuticals, India) (BR) group. A written informed consent will be obtained from either of the parents of the infant, after explaining possible benefits and risks associated with the participation. Helsinki guidelines will be adhered to for all participants. The treatment will be provided free of cost at one of the centre (PGIMER), while at other two centre (MGMEI, HVDEH) the parents will need to pay for the treatment as per institute’s norms. For the parents not able to afford the cost of treatment, it will provided free of cost from institute’s funds. The type of treatment (IR or BR) in such cases will be decided by the treating ophthalmologist. One of the centres (PGIMER) will be enrolling patients in BR group only while the remaining centres will enrol the infants in either of groups as per the parental consent. For both the drugs, half of adult dose (0.25 mg/ 0.05ml) will be injected intravitreally at 1.5 mm from limbus under topical anesthesia. The procedure will be performed by the experienced vitreoretinal surgeons (SK/ DK/ ABG/ SMP/ SRS) in NICU or ophthalmic operation theatre simultaneously but sequentially. Topical antibiotic (Tobramycin) will be administered in both eyes four times a day for a week after the procedure. The treated infants will be followed up on post operative day one, one weekly for two weeks and fortnightly after that until reactivation or complete vascularisation of retina. Fundus imaging will be performed using pediatric wide field camera before initial treatment, a week after initial treatment and the reactivation or rescue treatment after reactivation the scheduled last follow up as per the protocol. The primary success or failure of initial treatment will be judged by the treating ophthalmologist. If the images for complete vascularisation of retina or PAR are not captured with sufficiently good clarity for analysis, then the clinical observations reported by the PI or CI will be regarded as the final outcome. The reactivation will be treated with laser in all the infants with or without reappearance of plus or preplus disease or progression to stage 3. Laser photo coagulation, whenever indicated, will be performed under either topical anesthesia (infants weighing < 2000 grams at the time of laser) or general anaesthesia (infants weighing > 2000 grams at the time of laser) using Diode (810 nm) or double frequency NdYAG (532nm) laser. Infants not showing features of reactivation by 24 weeks of initial treatment will undergo examination under anesthesia and if PAR is noted during the EUA, it will be prophylactically treated with laser in the same setting.

Management of complication- If any of complication related to the IVI is noted by the investigators, it will be reported to the respective infection control committee or similar body of the concern institute immediately. The complication will be managed as per the protocol of the concern institute. The cost for management of the complications will be paid by the parents (MGMEI, HVDEH) or it will be done free of charge (PGIMER)

Operational definitions

A- ROP: As per ICROP 3

Primary treatment success – Regression of plus disease or flat new vessels at or within 1 weeks of initial intravitreal injection

of either of the drug

Primary treatment failure- persistent plus disease or flat new vessels at 1 weeks following initial intravitreal injection of either

of the drug

Reactivation- Reappearance of acute retinopathy changes (peripheral stage, plus or preplus disease, or pre retinal

haemorrhages)  after initial resolution after initial treatment

Poor structural outcome- Progression to fractional retinal detachment ( Stage 4/ stage 5) or significant pre retinal haemorrhage covering the fovea requiring pars plana vitrectomy

Reactivation interval- Time between initial IVI to first clinical appearance reactivation ( measured in days and converted to

weeks)

Persistent avascular retina-Inability of the normal retinal blood vessels reach within 2 disc diameter of temporal ora serrata by the last follow up (24 weeks after initial treatment with IVI of Ranibizumab)

Sample size: 100 infants (50 in each group)

Primary objective

To compare the proportion of infants achieving primary success between IR and BR groups

Secondary objectives

Comparison of the  incidence, the reactivation interval and type of reactivation between IR and BR groups

To compare the incidence and types of post injection complications/ adverse events and structural outcomes at final follow up between IR and BR groups

Data management and statistical analysis

Following details about the infant, disease and treatment details will be collected in proforma or data management software for this study

Demographic details-gender, gestational age (GA) in weeks, birth weight (BW) in grams, postmenstrual age (PMA) in weeks at the time of diagnosis, PMA at final follow up, duration of follow up in weeks

Clinical features- Zone of A-ROP

Treatment details- Drug used (IR/ BR)

Primary success or failure at postoperative one week

Postoperative complications-Cataract, endophthalmitis, retinal tear, vitreous hemorrahge, retinal detachment

Status of retinal vascularisation after initial-Zone of vascularisation, reactivation if any with details (type, zone, plus disease, preretinal hemorrahge)

Type of good structural outcome at final follow up- Complete vascularisation of retina or Reactivation----Laser or PAR---prophylactic laser

Type of poor structural outcome at final follow up- Progression to TRD (Stage 4 or stage 5), significant premacular hemorrahge requiring PPV.

References

1. Chiang MF, Quinn GE, Fielder AR, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021;128(10):e51-e68. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991-999.
2. Gangwe AB, Parchand S, Agrawal D, Azad RV, Barwar G, Singh A. Comment on: Evaluation of clinical profile and screening guidelines of retinopathy of prematurity in an urban level III neonatal intensive care unit. Indian J Ophthalmol. 2023;71(6):2623-2624.
3. Sanghi G, Dogra MR, Katoch D, Gupta A. Aggressive posterior retinopathy of prematurity: risk factors for retinal detachment despite confluent laser photocoagulation. Am J Ophthalmol. 2013;155(1):159-164.
4. Katoch D, Dogra MR, Aggarwal K, et al. Posterior zone I retinopathy of prematurity: spectrum of disease and outcome after laser treatment. Can J Ophthalmol. 2019;54(1):87-93.
5. Shah PK, Subramanian P, Venkatapathy N, Chan RVP, Chiang MF, Campbell JP. Aggressive posterior retinopathy of prematurity in two cohorts of patients in South India: implications for primary, secondary, and tertiary prevention. J AAPOS. 2019;23(5):264.e1-264.e4.Gangwe A, Agrawal D, Vinekar A, Azad RV, Parchand SM, Agrawal D. Anti-vascular endothelial growth factor in the management of retinopathy of prematurity: A survey among the members of Indian Retinopathy of Prematurity Society. Indian J Ophthalmol. 2021;69(8):2158-2163.
6.  Prajapati V, Choudhary T, Chauhan W, et al. Efficacy of a biosimilar ranibizumab monotherapy for the treatment of retinopathy of prematurity. Indian J Ophthalmol. 2023;71(2):411-415.