A Study of the Criteria Establishing the Need for Re-treatment With Ranibizumab Upon Relapse in Patients With Visual Impairment Due to Choroidal Neovascularization Secondary to Pathologic Myopia. (OLIMPIC)

• ClinicalTrials.gov Identifier: NCT02034006
• Recruitment Status: Completed
• First Posted: January 13, 2014
• Results First Posted: February 18, 2019
• Last Update Posted: February 18, 2019
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: January 9, 2014
• First Posted Date: January 13, 2014
• Results First Submitted Date: July 11, 2017
• Results First Posted Date: February 18, 2019
• Last Update Posted Date: February 18, 2019
• Actual Study Start Date: June 10, 2014
• Actual Primary Completion Date: July 15, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 8, 2018)

• Number of Patients Treated and Re-treated Based on Presence/Absence of Active Leakage [ Time Frame: Screening, Month 2, Month 6 ]
  Presence of active leakage on fluorescein angiography (FAG) was assessed at screening (14 to 3 days before baseline visit), month 2 and month 6. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of active leakage (Yes/No). For retreated patients, the presence/absence of active leakage was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable
• Number of Patients Treated and Re-treated Based on Presence/Absence of Macular Edema [ Time Frame: Screening, Month 2, Month 6, Month 12 ]
  Presence of macular edema from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of macular edema (Yes/No). For retreated patients, the presence/absence of macular edema was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable
• Number of Patients Treated and Re-treated Based on Presence/Absence of Cysts [ Time Frame: Screening, Month 2, Month 6, Month 12 ]
  Presence of cysts from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of cysts (Yes/No). For retreated patients, the presence/absence of cysts was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable
• Number of Patients Treated and Re-treated Based on Presence/Absence of Intra-retinal Fluid [ Time Frame: Screening, Month 2, Month 6, Month 12 ]
  Presence of Intra-retinal fluid from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of Intra-retinal fluid (Yes/No). For retreated patients, the presence/absence of Intra-retinal fluid was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable
• Change in Central Subfield Thickness (CSFT) [ Time Frame: Screening, Month 2, Month 6, Month 12 ]
  Central subfield thickness (CSFT) from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change in CSFT versus previous visit. For retreated patients, the change in CSFT was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
• Change in Central Subfield Volume (CSV) [ Time Frame: Screening, Month 2, Month 6, Month 12 ]
  Central subfield volume (CSV) from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change in CSV versus previous visit. For retreated patients, the change in CSV was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
• Number of Patients Treated and Re-treated Based on Presence/Absence of Sub-retinal Fluid [ Time Frame: Screening, Month 2, Month 6, Month 12 ]
  Presence of sub-retinal fluid from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. The regression model for sub-retinal fluid was not valid because "Yes" was reported in almost all subjects causing a quasi-complete separation of data points. *NE = Not evaluable
• Number of Patients Treated and Re-treated Based on Presence/Absence of Clinically Significant Abnormalities [ Time Frame: Baseline, Month 1, Month 2, Month 3, Month 6, Month 12 ]
  Presence of clinically significant abnormalities was assessed at baseline, month 1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of clinically significant abnormalities (Yes/No). For retreated patients, the presence/absence of clinically significant abnormalities was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
• Number of Patients Treated and Re-treated Based on Improvement in Best Corrective Visual Acuity (BCVA) < 5 Letters [ Time Frame: Baseline, Month 1, Month 2, Month 3, Month 6, Month 12 ]
  Improvement in BCVA < 5 letters (Yes/No) was assessed at month1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of improvement in BCVA < 5 letters (Yes/No) which was reported as Gain >= 5 letters versus Gain < 5 letters. For retreated patients, Gain >= 5 letters and Gain < 5 letters were considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
• Number of Patients Treated and Re-treated Based on Improvement in Best Corrective Visual Acuity (BCVA) < 10 Letters [ Time Frame: Baseline, Month 1, Month 2, Month 3, Month 6, Month 12 ]
  Improvement in BCVA < 10 letters (Yes/No) was assessed at month1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of improvement in BCVA < 10 letters (Yes/No) which was reported as Gain >= 10 letters versus Gain < 10 letters. For retreated patients, Gain >= 10 letters and Gain < 10 letters were considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
• Number of Patients in Different Categories of Changes From Baseline in BCVA [ Time Frame: Baseline, Month 1, Month 2, Month 3, Month 6, Month 12 ]
  Changes from baseline in BCVA are described for the ETDRS parameter considering the following categories at each assessment: "no change" if the change was equal to 0 letter, "worsening" if change < 0 letter , "improvement" if change > 0 letter. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change from baseline in BCVA (improved/worsened/stable) which was reported as Improved versus no change and worsened versus no change. For retreated patients, this variable was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.

Original Primary Outcome Measures (submitted: January 9, 2014)

Describe current criteria driving re-treatment in patients experiencing a relapse after first ranibizumab injection [ Time Frame: Baseline to month 12 ]

The primary objective of the study is to investigate current criteria driving re-treatment in patients affected by CNV secondary to PM and experiencing a relapse of the disease after the first administration of ranibizumab. The criteria for re-treatment may consist in patient subjectivity or a clinical decision (described through clinical examination, BCVA, fundus), and/or optical coherence tomography (OCT), and/or fluorescein angiography (FAG). Descriptive statistic on the FAS population will be provided. The proportion of patients who need re-treatment will be displayed together with a 95% confidence interval. The criteria for re-treatment will be summarized, presenting, for each, frequencies, percentages and 95% CI.

Current Secondary Outcome Measures (submitted: October 8, 2018)

• Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 6 and Month 12 on Study Eye [ Time Frame: Baseline, Month 6, Month 12 ]
  Change from baseline in BCVA (Best Corrected Visual Acuity) was Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score. Patients with a BCVA ETDRS letter score of 78 to 24 in the study eye were included; A higher score represents better functioning of the study eye. A positive change from baseline shows improvement.
• Mean Number of Ranibizumab Injection [ Time Frame: Baseline to Month 12 ]
  Mean number of ranibizumab injection is reported as number of injections per patient.
• Time to Re-treatment [ Time Frame: Baseline to Month 12 ]
  Time to re-treatment, defined as time in months from the data of first dose of ranibizumab to the date of re-treatment, was evaluated.
• Number of Patients Having Ocular and/or Systemic Adverse Event (AE) [ Time Frame: Baseline to Month 12 ]
  Number of patients with any systemic AE, with serious systemic AE, with an ocular AE, with an ocular serious AE are reported
• Change in Patient Quality of Life From Baseline to Month 2 and Month 12 [ Time Frame: Baseline, Month 2, Month 12 ]
  Patient quality of life was assessed by Impact of Vision Impairment (IVI) questionnaire. IVI is a 32-item instrument, either self- or interviewer-administered, developed to measure the impact of vision impairment on daily activities in five domains. The 32 items were divided into 5 domains as follows: Leisure and work (items 1 to 5), Social and consumer interaction (items 6 to 10 and items 23-24), Household and personal care (items 11 to 14 and items 20-21), Mobility (items 15 to 19 and item 22), Emotional reaction to vision loss (items 25 to 32). Responses to the IVI items were rated on a five-category Likert scale: not at all, 0; hardly at all, 1; a little, 2; a fair amount, 3; a lot, 4; and can't do because of eyesight, 5. Total score was an arithmetic average of the items rated between 0 (the best score) and 5 (the worst score). A negative change indicates improvement. Data was computed on items with non missing response

Original Secondary Outcome Measures (submitted: January 9, 2014)

• Visual acuity changes [ Time Frame: baseline, month 6, month 12 ]
  To evaluate the mean changes in BCVA at 6M and 12M versus baseline. Summary statistics for BCVA will be provided for values at baseline and at each assessment and for changes versus baseline at each assessment. Results will be reported overall and separately for the sub-group of patients who need vs. not the re-treatment. A paired test of BCVA at 6 and 12 months vs. baseline will be also provided on all patients. An exploratory analysis of BCVA changes by class of disease duration, gender, age at entry, diopters and relevant medical conditions will be also provided.
• Mean Number of Ranibizumab Injection [ Time Frame: Baseline to Month 12 ]
  To evaluate the mean number of ranibizumab injections by patient/year. The number and percentage of patients who need re-treatment will be provided.
• time to relapse / retratment [ Time Frame: Baseline to Month 12 ]
  Time to re-treatment, defined as time in days from the data of first dose of ranibizumab to the date of re-treatment, will be evaluated. Descriptive statistics will be provided. A Kaplan-Meier curve will also be shown. The relationship between patient baseline characteristics and the need for re-treatment will be explored by means of logistic regression analysis
• Number and percentage of patients having ocular or systemic adverse events [ Time Frame: Baseline to Month 12 ]
  AEs will be summarized as following: n° and % of patients having any AE, an ocular AE, a non-ocular AE, an AE in each primary system organ class, or with at least one serious ocular or non-ocular AE. Summary tables will be presented: overall and by gender, for the subset of AEs suspected to be treatment related. Deaths, SAEs, and AEs leading to discontinuation of investigational treatment will be listed separately and, if appropriate, summarized by primary system organ class and preferred term. IOP, vital signs measurements and laboratory data, where available, will be summarized with descriptive statistics of actual values and changes from baseline values. Summary tables will be presented overall and by gender. The incidence rates of notable vital sign abnormalities will be also provided.
• Evaluation of patient quality of life [ Time Frame: baseline, month 2, month 12 ]
  To evaluate changes in the quality of life after ranibizumab injection, by means of IVI Questionnaire, a 32-item questionnaire developed to measure the impact of vision impairment on daily activities in five domains. Domain scores and total score will be summarized descriptively in actual values and changes versus baseline at each assessment. The Burden of Illness and Health Resources Utilization questionnaire will also be used ro gain information on resource consumption and burden for the patient and relatives to the disease. Summary statistic will be provided for each item.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of the Criteria Establishing the Need for Re-treatment With Ranibizumab Upon Relapse in Patients With Visual Impairment Due to Choroidal Neovascularization Secondary to Pathologic Myopia.
• Official Title: A 12-month, Open-label, Interventional, Multicentre Study to Investigate the Current Criteria Driving Re-treatment With Ranibizumab Upon Relapse in Patients With Visual Impairment Due to Choroidal Neovascularization Secondary to Pathologic Myopia
• Brief Summary: The primary objective of the study was to investigate current criteria driving re-treatment in patients affected by Choroidal Neovascularization (CNV) secondary to Pathologic Myopia (PM) and experiencing a relapse of the disease after the first administration of ranibizumab.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Choroidal Neovascularization Secondary to Pathologic Myopia

Intervention

Drug: Ranibizumab

All patients received a single initial intravitreal injection of ranibizumab 0.5 mg/0.05 ml as per Committee for Human Medicinal Products (CHMP)approval. Further injections might have been required when monitoring reveals disease activity. Disease activity, defined as reduced visual acuity and/or signs of lesion activity, was evaluated based on clinical examination (BCVA, fundus), and/or optical coherence tomography (OCT), and/or fluorescein angiography (FAG). Bilateral treatment was allowed provided at least 14 days of intercurrence.

Other Name: RFB002

Study Arms

Experimental: Ranibizumab

Patients treated with a single ranibizumab 0.5 mg/0.05ml intravitreal injection

Intervention: Drug: Ranibizumab

• Publications *: Ricci F, Staurenghi G, Varano M, Eandi C, Sinibaldi TL, Colombo L, Bartezaghi M, Bassanini S. OLIMPIC: a 12-month study on the criteria driving retreatment with ranibizumab in patients with visual impairment due to myopic choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2019 Apr;257(4):759-768. doi: 10.1007/s00417-019-04248-8. Epub 2019 Jan 24.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 9, 2014): 200
• Original Estimated Enrollment (submitted: January 9, 2014): 150
• Actual Study Completion Date: July 15, 2016
• Actual Primary Completion Date: July 15, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

INCLUSION CRITERIA:

• Written informed consent given before any study related procedure is performed
• Diagnosis of active CNV secondary to PM confirmed by complete ocular examination in the affected eye(s) using the following criteria:
• Presence of high myopia greater than -6D of spherical equivalence
• Presence of posterior changes compatible with pathologic myopia (any signs of attenuation of retinal pigment epithelium (RPE) and choroids, mottling of the RPE, tilted disc, geographic atrophy of RPE, Fuchs spots, posterior staphyloma, submacular hemorrhage, lacquer cracks) detected by fundus ophthalmoscopy and fundus photography
• Presence of active leakage from CNV observed through fluorescein angiography (FAG)
• Presence of intra or subretinal fluid demonstrated by Optical Coherence Tomography (OCT)
• BCVA > 24 letters and < 78 letters tested at 4 meters staring distance using ETDRS-like visual acuity chart
• Visual loss must be only due to the presence of any eligible types of CNV related to PM based on clinical ocular findings, FAG and OCT. (Also patients that have for example 20/60 as their best visual acuity due to PM in their history and have additional vision loss due to CNV lesion can be included)

EXCLUSION CRITERIA:

• Patients with inability to comply with study related procedures
• Pregnant or nursing (lactating) women and women of childbearing potential UNLESS using effective contraception during treatment
• Presence of confirmed systolic blood pressure > 150 mmHg or diastolic > 90 mmHg at the time of enrollment
• History of stroke
• Any type of advanced, severe or unstable medical condition or its treatment that could significantly bias the assessment of clinical status and interfere with primary and/or secondary outcome evaluations or put the patient at risk
• Presence of active infectious disease or intra-ocular inflammation in either eye at the time of enrollment
• Ocular disorders in the study eye that may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the 12-month study period (including retinal detachment, cataract and pre-retinal membrane of the macula)
• History of pan-retinal or focal/grid laser photocoagulation with involvement of the macular area in the study eye at any time
• History of intraocular treatment with any anti-vascular endothelial growth factor (VEGF), verteporfin photodynamic therapy (vPDT) and any intra-ocular surgery or corticosteroid administration within one month before study entrance
• Known hypersensitivity to ranibizumab or any component of the ranibizumab formulation
• Simultaneous participation in a study that includes administration of any investigational drug

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT02034006
• Other Study ID Numbers: CRFB002FIT01; 2013-003334-33 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: October 2018