A study to compare the Efficacy, Safety and Immunogenicity of Sun’s Ranibizumab with Reference Biologic in Patients with Neovascular Age-related Macular degeneration (wet AMD)

Phase 3

Completed

• Conditions: Other specified disorders of choroid,

• Registration Number: CTRI/2020/09/027629
• Lead Sponsor: Sun Pharmaceutical Industries Limited

Brief Summary

This was a Phase III, randomized, two-arm, multicenter, active-controlled, parallel-group, double-blind, comparative study in patients with wet AMD.

The study was conducted at total 20 geographically distributed centers in India (one site did not screen any patient), having qualified Investigators. The study was initiated only after the receipt of regulatory and EC approval. Total 187 patients were screened to randomize 161 patients from 20 geographically distributed centers in India.

Each clinical trial site was provided with randomization number schedule. After obtaining informed consent, patients were screened by undergoing various assessments and after confirming the eligibility, total 161 patients were randomized in 2:1 ratio to either Sun’s Ranibizumab arm Solution 0.05 mL (0.5 mg) intravitreal injection or Reference Biologic arm (Accentrix®) intravitreal injection in double-blind fashion, as per randomization schedule.

Only one eye per patient was selected as “study eyeâ€. Only study eye received the study drug. Ranibizumab (Test or Reference) 0.5 mg was administered as intravitreal injection on the Day 1, Day 28, Day 56 and Day 84. Reference drug Accentrix®was used in this study.

Study was amended thrice.

Version No. 1.2; dated 29/SEP/2020: CTCAE as criteria for safety was considered for this study

Version 2.0 dated 12/FEB/2021: Exclusion criteria no. 21 modified to ‘Patients with HbA1c > 7’ was considered a relevant population for Ranibizumab in wet-AMD indication. Moreover, these subjects were not excluded in innovator Pivotal clinical trials conducted for approval in this indication.

Version No. 2.1; dated 30/APR/2021: Added diabetic retinopathy as a separate exclusion criteria no. 11 as per SEC recommendations and deleted diabetic retinopathy in exclusion criteria no. 12 as per SEC recommendations

Total duration of the trial was 126 (14 days screening + 112 days treatment period) comprising of total 7 visits: The study was planned as follows:

Screening: 14 days (Day -14 to Day -1)

Visit 2: Randomization/Day 1

Visit 3: Day 7 ±2

Visit 4: Day 28 ±2

Visit 5: Day 56 ±2

Visit 6: Day 84 ±2, End of Treatment (EOT)

Visit 7: Day 112 ±2, End of Study (EOS)/Early Termination (ET)

The efficacy, safety and immunogenicity were assessed during the study period. Patients who are withdrawn/ terminating early from the study completed EOS visit assessment. Day 84 were End of treatment day.

After completion of Study, based on the OCT result and Investigator’s judgement patient were further shifted on Pro Re Nata (PRN) Regimen or Treat and Extend (T&E) Regimen. After completion of study, the patient responding to treatment were provided with drug beyond the clinical trial till such duration as recommended by the Principal Investigator or as per rules of post-trial access of investigational product.

Study results conclusion:

Based on results of primary endpoint, Sun’s ranibizumab biosimilar can be considered therapeutically equivalent to reference biologic product, Accentrix®. Sun’s ranibizumab was comparable to reference product for all secondary endpoints as well. Overall, both the products were safe. There were no additional safety or immunogenicity concerns emerged during the study.

Detailed Description

Not available

Study Timeline

• Study Start: 2020-10-23
• Study Completion: 2021-10-29
• Last Update Posted: 2022-10-03

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 160

Inclusion Criteria

• 1)Ambulatory patients of either gender with ≥ 50 years of age at the time of screening and who are capable of understanding and giving written informed consent.
• 2)Active primary or recurrent subfoveal lesions with classic or occult choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) in the study eye.
• (Please note: Only one eye will be considered for study.
• If both eyes are eligible, the one with the better visual acuity will be selected for treatment unless, based on medical reasons, the investigator deemed the other eye to be more appropriate for treatment.
• If both eyes have similar visual acuity and similar medical reasons, then right eye will be selected) 3)Best corrected visual acuity, using Early Treatment of Diabetic Retinopathy Study (ETDRS) chart, of 20/40 to 20/320 (Snellen equivalent) in the study eye before pupil dilation.
• 4)Women of childbearing potential must have a negative urine pregnancy test prior to study entry and agree to use highly effective methods of contraception to prevent pregnancy from study entry till the last dose of the study medication (such contraception may include hormonal birthcontrol e.g., combined estrogen and progestogen containing [oral, intravaginal, or transdermal] or progesterone only [oral, injectable, or implantable] hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone releasing system OR bilateral tubal occlusion, vasectomized partner, or sexual abstinence) [Note: Women with childbearing potential are defined as: those who are not (1) surgically sterile (bilateral oophorectomy, hysterectomy, or bilateral tubal ligation) or (2) post-menopausal Post-menopausal woman will be defined as: Women not using hormonal replacement therapy and have had at least 12 continuous months of natural (spontaneous) amenorrhea and be greater than 45 years of age].

Exclusion Criteria

• A.Prior/Concomitant treatment 1)Prior treatment with verteporfin, external-beam radiation therapy, or transpupillary thermotherapy (TTT), intravitreal drug delivery (steroids or device implantation), anti-VEGF drugs, sub foveal laser photocoagulation, vitrectomy surgery, submacular surgery or other surgical intervene for AMD or any other therapy for AMD in the study eye 2)Intraocular surgery (including cataract surgery) in the study eye within 2 months prior to randomization.
• 3)Past or Concurrent use of systemic anti-VEGF agents 4)Previous participation in a clinical trial (for either eye) involving anti-angiogenic drugs 5)Previous participation in any studies of investigational drugs within 1 month preceding randomization (excluding vitamins and minerals) or planning to participate any other study during the course of this study.
• 6)Treatment with verteporfin photodynamic therapy in the non-study eye less than 7 days preceding day 1.
• 7)Laser Photocoagulation (juxtafoveal and extrafoveal) in study eye within 1 month prior to randomization.
• B.Ocular conditions in study eye 8)Subfoveal fibrosis or atrophy 9)Sub retinal hemorrhage that involved the center of the fovea, if the size of the hemorrhage was > 50% of the total lesion area 10)Retinal pigment epithelial tear that involved the macula 11)Any concurrent intraocular condition in the study eye (e.g., cataract, diabetic retinopathy, the refractive error more than -8 diopters of myopia etc.) that, in the opinion of the investigator, either Required medical or surgical intervention during study period to prevent or treat visual loss that may have resulted from that condition, or If allowed to progress untreated, could likely have contributed to loss of at least 2 Snellen equivalent lines of best corrected visual acuity over the study period 12)Patients with current vitreous hemorrhage or history of (1) rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) (2) glaucoma filtering surgery (3) corneal transplant 13)Aphakia or absence of the posterior capsule 14)Active intraocular inflammation (grade trace or above) 15)Uncontrolled glaucoma in the study eye (defined as intraocular pressure [IOP] ≥ 30 mmHg despite treatment with anti-glaucoma medication) 16)Patients with Polypoidal choroidal vasculopathy (PCV) disease at the time of Screening C.Concurrent ocular conditions in either eyes 17)Infectious conjunctivitis, keratitis, scleritis, or endophthalmitis 18)History of idiopathic or autoimmune-associated uveitis 19)CNV in either eye due to other causes, such as ocular histoplasmosis, trauma or pathologic myopia or CNV lesion not likely to respond to Ranibizumab.
• D.Concurrent Systemic Conditions 20)Current signs or symptoms of significant, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, any immunodeficiency and/ or immunosuppressive disease or active systemic infection, cerebral disease that renders the patient incapable of participating in the study.
• 21)Patients with controlled and uncontrolled Diabetes E.Other Criteria: 22)Known hypersensitivity to Ranibizumab or any of the components of study medication 23)Allergy to fluorescein dye 24)Presence of uncontrolled systolic blood pressure ≥ 160 mmHg or uncontrolled diastolic blood pressure ≥ 100 mmHg 25)Patients who are HIV, HBsAg, HCV test positive 26)Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality 27)Female subjects who are pregnant, breast- feeding, planning to be pregnant during the study; male patients with partner currently pregnant 28)Employee of the sponsor, investigator, or study center, with direct involvement in the proposed study as well as family members of the employees of sponsor or the investigator.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Proportion of patients losing fewer than 15 letters (approximately 3 lines) from baseline Best Corrected Visual acuity (BCVA) in the study eye at the end of week 16.	Proportion of patients losing fewer than 15 letters (approximately 3 lines) from baseline Best Corrected Visual acuity (BCVA) in the study eye at the end of week 16.

Secondary Outcome Measures

Name	Time	Method
1.Mean change in Best Corrected Visual Acuity (BCVA)	2. Proportion of patients who gained at least 15 letters (approximately 3 lines) from baseline Best Corrected Visual acuity (BCVA)

Trial Locations

Locations (20)

Amrita Institute of Medical Sciences and Research Centre, AlMS; 🇮🇳 Ernakulam, KERALA, India

Aravind Eye Hospital & Postgraduate Institute of Opthalmology; 🇮🇳 Coimbatore, TAMIL NADU, India

B.J.Govt .Medical College And Sassoon General Hospital; 🇮🇳 Pune, MAHARASHTRA, India

Chopda Medicare & Research Centre Pvt. Ltd; 🇮🇳 Nashik, MAHARASHTRA, India

Diva Eye Institute; 🇮🇳 Ahmadabad, GUJARAT, India

GSVM Medical college; 🇮🇳 Nagar, UTTAR PRADESH, India

JPM Rotary Club of Curtack Eye Hospital & Research Institute; 🇮🇳 Cuttack, ORISSA, India

King George’s Medical University; 🇮🇳 Lucknow, UTTAR PRADESH, India

KLEs Dr Prabhakar Kore Hospital & MRC; 🇮🇳 Belgaum, KARNATAKA, India

L V Prasad Eye Institute; 🇮🇳 Baleshwar, ORISSA, India

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Amrita Institute of Medical Sciences and Research Centre, AlMS

🇮🇳Ernakulam, KERALA, India

Dr Natasha Radhakrishnan

Principal investigator

9496389999

natashar@aims.amrita.edu