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NCT02953938: ZIPANGU

Study to Show a Superior Benefit in Terms of Reduction of Ranibizumab Injections in Patients Receiving Ranibizumab Plus Laser Photocoagulation Combination Therapy Without Loss of Efficacy and Safety

Completed Phase 4 Results posted Last updated 25 February 2020
What this trial tests

Phase 4 trial testing Ranibizumab in Macular Edema Secondary to Branch Retinal Vein Occlusion (BRVO) in 59 participants. Completed in 28 December 2018.

Timeline
15 December 2016
Primary endpoint
28 December 2018
28 December 2018

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 4
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment59
Start date15 December 2016
Primary completion28 December 2018
Estimated completion28 December 2018
Sites7 locations across Japan

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

20 and older, any sex, with Macular Edema Secondary to Branch Retinal Vein Occlusion (BRVO). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Difference in Mean Number of Ranibizumab Injections Primary · Month 1 through Month 12

Number of ranibizumab treatments from Day 1 to Month 11 using full analysis set (observed) based on a stratified Cochran-Mantel-Haenszel (CMH) test. Stratification was done based on categories of baseline decimal VA (\<0.3, or =\>0.3). Difference of mean number of injections, 95% confidence interval (CI) of difference and one-sided p-value of the CMH test was reported. Analysis was conducted within the FAS with observed data. Stratification was based on baseline visual acuity on logMAR scale (\<0.52, \>=0.52). Test was one-sided.

GroupValue95% CI
Ranibizumab 0.5 mg4.3± 2.51
Ranibizumab 0.5 mg Laser4.1± 2.41
The Mean Change in Best Corrected Visual Acuity (BCVA) Using Decimal Chart and Early Treatment Diabetic Retinopathy Study (ETDRS) Compared to Baseline Secondary · Month 1 through Month 12 (for ETDRS: Month 6 and Month 12)

Summary of BCVA (letters) absolute value and change from Baseline at Month 12 in the study eye - full analysis set (LOCF) was based on an analysis of variance (ANOVA) model with treatment group, and stratification factors. Stratification was done based on categories of baseline decimal VA (\<0.3, or =\>0.3). The analyses was conducted within the FAS using the LOCF approach Stratification was based on baseline visual acuity on logMAR scale (\<0.52, \>=0.52). Test was one-sided.

baseline
GroupValue95% CI
Ranibizumab 0.5 mg52.86± 13.384
Ranibizumab 0.5 mg Laser54.03± 9.828
month 12
GroupValue95% CI
Ranibizumab 0.5 mg74.83± 9.740
Ranibizumab 0.5 mg Laser69.59± 8.842
change from baseline to month 12
GroupValue95% CI
Ranibizumab 0.5 mg21.97± 14.749
Ranibizumab 0.5 mg Laser15.00± 10.296
The Mean Change in BCVA From Month 1 Through Month 12 Compared to Baseline (Day 1) by the Treatment Arms Secondary · Month 1 through Month 12

Summary of BCVA (logMAR) absolute value and change from Baseline at Month 12 in the study eye - full analysis set (LOCF) was based on an analysis of variance (ANOVA) model with treatment group, and stratification factors. Stratification was based on baseline visual acuity (\< 0.52, \>= 0.52). The analyses was conducted within the FAS using the LOCF approach

baseline
GroupValue95% CI
Ranibizumab 0.5 mg0.553± 0.2276
Ranibizumab 0.5 mg Laser0.558± 0.1719
month12
GroupValue95% CI
Ranibizumab 0.5 mg0.075± 0.1909
Ranibizumab 0.5 mg Laser0.143± 0.1682
change from baseline to month 12
GroupValue95% CI
Ranibizumab 0.5 mg-0.478± 0.2586
Ranibizumab 0.5 mg Laser-0.413± 0.1969
BCVA (Letters) Number and Proportion of Patients With a BCVA Improvement vs. Baseline, Loss Less Than 15 Letters, or Attainment of Greater Than or Equal to 85 Letters at Month 6 and at Month 12 in the Study Eye Secondary · Month 6 and Month 12

Endpoints related to the number and proportion of patients with BCVA letter gain or loss from Baseline (Day1) was analyzed via stratified CMH test with stratification factors as described in primary model. The mean (SD) average (per patient) BCVA (logMAR) change from Baseline through Month 12 Summary of BCVA (logMAR) mean average change from Baseline from Month 1 through Month 12 in the study eye

Month 6 - BCVA improvement of >=1
GroupValue95% CI
Ranibizumab 0.5 mg27
Ranibizumab 0.5 mg Laser24
month 6 - BCVA improvement of >=5
GroupValue95% CI
Ranibizumab 0.5 mg26
Ranibizumab 0.5 mg Laser21
month 6 - BCVA improvement of >=10
GroupValue95% CI
Ranibizumab 0.5 mg22
Ranibizumab 0.5 mg Laser16
Month 6 - BCVA improvement of >=15
GroupValue95% CI
Ranibizumab 0.5 mg17
Ranibizumab 0.5 mg Laser12
Month 6 - BCVA improvement of >=30
GroupValue95% CI
Ranibizumab 0.5 mg4
Ranibizumab 0.5 mg Laser1
month 6 Score >=73
GroupValue95% CI
Ranibizumab 0.5 mg12
Ranibizumab 0.5 mg Laser10
month 6 Score >=80
GroupValue95% CI
Ranibizumab 0.5 mg8
Ranibizumab 0.5 mg Laser2
month 6 Score >=85
GroupValue95% CI
Ranibizumab 0.5 mg3
Ranibizumab 0.5 mg Laser1
The Mean Change in Change in Central Subfield Foveal Thickness (CSFT) From Month 1 Through Month 12 Compared to Baseline (Day1) by the Treatment Arms Secondary · Month 1 through Month 12

The mean change in investigator-assessed CSFT from Month 1 through Month 12 was compared to Baseline (Day1) by the treatment arms. The analyses at each visit was based on an analysis of variance (ANOVA) model as analogous to BCVA. The analyses was conducted within the FAS using the Last-Observation-Carried-Forward (LOCF) approach

baseline
GroupValue95% CI
Ranibizumab 0.5 mg563.3± 146.92
Ranibizumab 0.5 mg Laser553.3± 182.39
month 12
GroupValue95% CI
Ranibizumab 0.5 mg257.0± 43.44
Ranibizumab 0.5 mg Laser285.1± 82.80
change in baseline from month 12
GroupValue95% CI
Ranibizumab 0.5 mg-306.3± 164.35
Ranibizumab 0.5 mg Laser-261.3± 180.23

Adverse events — posted to ClinicalTrials.gov

Time frame: AEs and SAEs were collected for the maximum duration of treatment and follow up for a participant per protocol for approximately 12 months.. Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Ranibizumab 0.5 mg
Serious: 1/29 (3%)
Deaths: 0/29
Ranibizumab 0.5 mg+ Laser
Serious: 2/30 (7%)
Deaths: 0/30
Total
Serious: 3/59 (5%)
Deaths: 0/59

Serious adverse events (3 terms)

ReactionSystemRanibizumab 0.5 mgRanibizumab 0.5 mg+ LaserTotal
Bowen's diseaseNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Putamen haemorrhageNervous system disorders
HaematuriaRenal and urinary disorders
Other adverse events (30 terms — click to expand)

ReactionSystemRanibizumab 0.5 mgRanibizumab 0.5 mg+ LaserTotal
NasopharyngitisInfections and infestations
NauseaGastrointestinal disorders
Intraocular pressure increasedInvestigations
HeadacheNervous system disorders
HypertensionVascular disorders
Dry eyeEye disorders
Seasonal allergyImmune system disorders
InfluenzaInfections and infestations
DizzinessNervous system disorders
TinnitusEar and labyrinth disorders
Conjunctival haemorrhageEye disorders
Corneal erosionEye disorders
KeratitisEye disorders
Macular fibrosisEye disorders
PhotopsiaEye disorders
Feeling abnormalGeneral disorders
Hepatic function abnormalHepatobiliary disorders
PeriodontitisInfections and infestations
Urinary tract infectionInfections and infestations
Foot fractureInjury, poisoning and procedural complications
Tooth fractureInjury, poisoning and procedural complications
ArthritisMusculoskeletal and connective tissue disorders
Back painMusculoskeletal and connective tissue disorders
Muscular weaknessMusculoskeletal and connective tissue disorders
DysarthriaNervous system disorders
HemiplegiaNervous system disorders
MigraineNervous system disorders
Atrophic vulvovaginitisReproductive system and breast disorders
Dry skinSkin and subcutaneous tissue disorders
ErythemaSkin and subcutaneous tissue disorders

Most-reported serious reactions: Bowen's disease, Putamen haemorrhage, Haematuria.

Data from ClinicalTrials.gov NCT02953938 adverse events section.

Sponsor's own description

This is a Phase IV, randomized, open-label, active-controlled, 2-arm, multicenter study. The primary objective was assessed by the difference in the mean number of ranibizumab injections applied up to Month 11 between the 2 treatment arms. Patients were randomized in a 1:1 ratio to 1 of the 2 treatment arms; i.e. Arm 1 ranibizumab monotherapy, Arm 2 ranibizumab with Grid\&Direct short pulse laser photocoagulation combination therapy. There were 3 periods in this study: Screening Period (visit 1), Treatment Period (visit 2 to Visit 13) and Follow-up Period (visit 14). In addition to screening and Baseline (visit 2), there were monthly visits from Month 1 to Month 12. This study included male and female patients (≥20 years old) diagnosed with visual impairment due to ME secondary to BRVO.

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Nanomaterials for Antiangiogenic Therapies for Cancer: A Promising Tool for Personalized Medicine.
    Alsaab HO, Al-Hibs AS, Alzhrani R, Alrabighi KK, et al · · 2021 · cited 32× · PMID 33562829 · DOI 10.3390/ijms22041631
  2. The randomized ZIPANGU trial of ranibizumab and adjunct laser for macular edema following branch retinal vein occlusion in treatment-naïve patients.
    Murata T, Kondo M, Inoue M, Nakao S, et al · · 2021 · cited 12× · PMID 33436683 · DOI 10.1038/s41598-020-79051-1
  3. Estimating ranibizumab injection numbers and visual acuity at 12 months based on 2-month data on branch retinal vein occlusion treatment.
    Murata T, Kondo M, Inoue M, Nakao S, et al · · 2022 · PMID 35538139 · DOI 10.1038/s41598-022-11113-y

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing