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Keywords:

  • age-related macular degeneration;
  • best-corrected visual acuity score;
  • efficacy;
  • individualized flexible interval regimen;
  • Japanese patients;
  • PRN;
  • ranibizumab;
  • safety;
  • subfoveal choroidal neovascularization

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methodology
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Purpose:  To evaluate the long-term efficacy and safety of ranibizumab administered pro re nata (PRN) in Japanese patients with choroidal neovascularization secondary to age-related macular degeneration during the extension phase of the EXTEND-I study.

Methods:  EXTEND-I, an open-label, multicenter, Phase I/II study comprised: a single-injection (Group A); a multiple-injection (Groups A and B; the latter consisted of patients who did not participate in the single-injection phase); and an extension phase. In the extension phase, a PRN regimen of ranibizumab (0.3 or 0.5 mg) guided by monthly best-corrected visual acuity (BCVA) score and other ophthalmic examinations was employed. The efficacy variables included the mean BCVA change from Month 12 to the last visit in Group B. Safety was assessed in all patients.

Results:  In the extension phase, efficacy was assessed only in Group B patients. The number of ranibizumab injections per year in the 0.3 and 0.5 mg Group B patients was 4.19 and 4.27, respectively. The mean BCVA change (SD) from Month 12 to the last visit was −3.6 (14.82) letters for 0.3 mg (n = 28) and −2.2 (7.92) letters for 0.5 mg groups (n = 33) in Group B. Conjunctival haemorrhage and nasopharyngitis were the most commonly reported adverse events. Of the 13 serious adverse events reported, cerebral infarction (two incidences) was suspected to be study-drug related.

Conclusions: Pro re nata regimen of ranibizumab guided by monthly BCVA and other ophthalmic examinations appears effective in sustaining the BCVA gained with 12 monthly injections while reducing the number of injections during the extension phase. Ranibizumab was well tolerated during the extension phase.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methodology
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly population. Of the two types of AMD, the wet form caused by choroidal neovascularization (CNV) is mainly responsible for AMD-related vision loss (Bressler 2004). According to the Hisayama study (prospective cohort study in Japan), the prevalence of neovascular AMD in residents aged 50 years or older was 0.67% in 1998, which was lower than that observed in the Caucasians (Oshima et al. 2001). However, another recent study (The Funagata study) in Japanese residents aged 35 years or older suggested that the prevalence of neovascular AMD in Japanese men was similar to that seen in the Caucasian men (Kawasaki et al. 2008).

Current evidence points to the role of vascular endothelial growth factor (VEGF) in CNV proliferation, and hence agents that block its activity are considered as a suitable therapeutic intervention in the management of this form of AMD (Ferrara et al. 2006; Waisbourd et al. 2007). Ranibizumab (Lucentis®; Novartis Pharma AG, Basel, Switzerland and Genentech Inc, South San Francisco, CA, USA) is a humanized monoclonal antibody fragment that inhibits active forms of VEGF-A, the main factor responsible for CNV proliferation and vascular permeability (Ferrara et al. 2006, 2007). Benefits of ranibizumab treatment in improving best-corrected visual acuity (BCVA) have been shown in the Caucasian population (Brown et al. 2006, 2009; Rosenfeld et al. 2006; Mitchell et al. 2010). Ranibizumab is currently approved in the United States, European Union, Japan and several other countries. EXTEND-I was the first study in Japanese patients that showed the safety and efficacy of monthly ranibizumab treatment (12-month results) during multiple-injection phase in terms of BCVA gain, reduction in total area of leakage from CNV plus retinal pigment epithelium staining and foveal retinal thickness, which were consistent with the pivotal studies performed in the Caucasian population (Tano & Ohji 2010). After the patients had completed the 12-month multiple-injection phase, all patients who provided written consent and were eligible based on the inclusion and exclusion criteria of the extension phase had the opportunity to continue to receive the ‘individualized flexible interval regimen’ [namely, pro re nata (PRN), as needed] until the approval of ranibizumab in Japan. This also provided a means to assess its long-term safety and efficacy. The PRN regimen was expected to maintain the improved visual acuity (VA) with less frequent injections in the extension phase. Current treatment guidelines in Europe recommend three initial monthly dosing followed by a maintenance phase, wherein the ranibizumab administration is decided based on monthly BCVA observation (Holz et al. 2010; Mitchell et al. 2010). This recommendation is based mainly on the results of the ranibizumab pivotal randomized phase III studies, namely MARINA (Rosenfeld et al. 2006) and ANCHOR (Brown et al. 2006) with monthly ranibizumab treatment. In these studies, the improvement of the BCVA score had stabilized (almost reached a plateau) by Month 3, and further increase in BCVA was minimal during the subsequent monthly treatments. On the other hand, in another pivotal randomized Phase IIIb study, PIER, quarterly treatment regimen could not maintain the improvement in BCVA score that was obtained by the three initial monthly injections (Regillo et al. 2008). However, there were also patients who maintained their gain in BCVA score during the quarterly regimen.

The extension phase of this study was initiated, therefore, to investigate whether ranibizumab administered PRN based on monthly BCVA scores and other ophthalmic examinations at two consecutive visits could maintain the improvement in BCVA scores. The reduction in dosing frequency was expected to reduce the risk of adverse events (AEs) associated with the intravitreal injection procedure in the elderly population as well as to address the difficulties in treating AMD through monthly injection of ranibizumab in a clinical setting.

Based on the 6-month interim results of the extension phase with PRN regimen as well as the 6- and 12-month interim analyses of monthly multiple-injection phase of this study, and the results of pivotal studies in the Caucasian population, ranibizumab was approved in Japan in January 2009. This paper presents the final data on long-term efficacy (in terms of BCVA) and safety of ranibizumab with PRN regimen from whole period of the extension phase of EXTEND-I.

Methodology

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methodology
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Study design

EXTEND-I was an open-label, multicentre, Phase I/II study comprising three phases: a single-injection phase, a multiple-injection phase and an extension phase (Fig. 1). The single-injection phase (Group A) was designed to sequentially evaluate the safety of intravitreal injections of 0.3 and 0.5 mg ranibizumab (six patients treated with each dose). The patients who successfully completed the single-dose phase (i.e., did not experience a Grade-3 targeted AE) could enter a multiple-injection phase wherein they received the same dose for an additional 11 months. The 12-month multiple-injection phase (Groups A and B; the latter consisted of patients who did not participate in the single-injection phase) evaluated the safety and efficacy of both doses administered as monthly intravitreal injections in two parallel groups of 0.3 mg dose and 0.5 mg dose (Tano & Ohji 2010). The multiple-injection phase was followed by an extension phase in which the ranibizumab (0.3 or 0.5 mg) administration was on a PRN basis, but assessments were carried out on a monthly basis. If the BCVA score decreased at two consecutive visits (except unscheduled visits) by >5 letters, considering other ophthalmic examinations, such as slit-lamp examination and ophthalmoscopy for safety, fundus photography, fluorescein angiography and optical coherence tomography for efficacy, the investigator decided whether ranibizumab treatment would be administered although no specific retreatment criteria were provided for fundus photography, fluorescein angiography and optical coherence tomography and were at the discretion of the investigators. Similarly, if the BCVA score decreased at two consecutive visits (except unscheduled visits) by ≤5 letters, in conjunction with other ophthalmic examinations, a decision was taken whether the treatment could be withheld.

image

Figure 1.  EXTEND-I treatment schedule. *Upon completion of the single-dose phase, patients in Group A were eligible to enter the multiple-injection phase, which began ≥4 weeks after the final visit of the single-injection phase. Multiple injections did not begin until both doses were shown to be well tolerated in all cohorts. **Upon completion of the multiple dose phase, based on prespecified inclusion/exclusion criteria, patients could enter the extension phase. For the extension phase, treatment as per pro re nata regimen; dose same as core phase; retreatment at the monthly visit if loss of >5 letters in best-corrected visual acuity (BCVA) on two consecutive visits (except unscheduled visits), considering other ophthalmic examinations, such as slit-lamp examination, ophthalmoscopy, fundus photography, fluorescein angiography and optical coherence tomography, the investigator decided whether ranibizumab treatment would be performed. Similarly, if the BCVA score decreased on two consecutive visits (except unscheduled visits) by ≤5 letters using ETDRS-like visual acuity chart, a decision was taken whether treatment could be withheld. In any case, other ophthalmic examinations were taken into consideration. For the extension phase, the number of patients for Group A was 3 in the 0.3 mg group and 6 in the 0.5 mg group; the number of patients for Group B was 28 in the 0.3 mg group and 33 in the 0.5 mg group.

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This study was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice (GCP) guidelines and Japanese GCP. The study was approved by Institutional Review Boards at each study centre. All patients provided written informed consent before participating in the study and the extension. The trial is registered with clinicaltrials.gov (NCT00275821).

Inclusion and exclusion criteria

All patients with subfoveal CNV secondary to AMD who completed the multiple-injection phase in either of the ranibizumab groups (Groups A or B), provided written consent and met all of the inclusion criteria set at the beginning of the study (Tano & Ohji 2010) were eligible to enrol in the extension phase. Patients were allowed to participate in the extension phase regardless of the time elapsed between the exit visit of the multiple-injection phase and the participation in the extension phase.

Patients were excluded from the extension phase if they had received any anti-angiogenic drugs (bevacizumab, pegaptanib, ranibizumab, anecortave acetate, corticosteroids or protein kinase C inhibitors) or participated in any other clinical study of an investigational drug during the period from the exit visit of the multiple-injection phase to participation in the extension phase. However, as the extension phase was not started on the day of the exit visit from the multiple-injection phase, photodynamic therapy with verteporfin was allowed for the study eye during the transition period.

Efficacy assessments

The efficacy variables of the extension phase included mean change from Month 12 in BCVA score of the study eye using ETRDS chart (at a starting distance of 2 m) at the last visit of the extension phase for Group B patients only. Group A patients were not included as they were not assessed for efficacy, but only for safety throughout the study. The other efficacy variables included the proportion of patients at the last visit with a BCVA score loss <15 letters, and ≥30 letters, or a BCVA score gain of ≥15 letters in the study eye. Proportion of patients with BCVA <34 letters, approximate Snellen equivalent of 20/200 or worse, were also evaluated (ETDRS charts at a starting distance of 2 m). In the extension phase, colour fundus photography, fluorescein angiography and optical coherence tomography were performed in accordance with the routine procedures specified at each study site.

Safety assessments

All safety evaluations were based on the enrolled population (Groups A and B) of the extension phase. Safety assessments consisted of recording the frequency of the treatment collecting all AEs, serious adverse events (SAEs), with their severity, and relationship to study drug. It also included monitoring of haematology, serum chemistry, urinalysis and regular assessments of vital signs. Grade 3 targeted AEs (Tano & Ohji 2010), intraocular inflammation, myocardial infarction and stroke and AEs potentially related to systemic VEGF inhibition were analysed separately. Serum samples for the evaluation of immunoreactivity to ranibizumab (antiranibizumab antibodies) were obtained from patients prior to study administration at Month 23 and the last visit for Group A patients, and Month 24 and the last visit for Group B patients. At the last visit as well as at early termination, the assessments were performed if at least 6 months had passed since the previous measurement, on or after Month 11 for Group A patients and Month 12 for Group B patients. The last measurement in the multiple-injection phase of the study was performed at Month 11 for Group A and Month 12 for Group B.

Statistical analysis

The patient population included all enrolled patients in the extension phase. This population was used for all analyses in Groups A and B. All efficacy data presented were for observed cases without the last observation carried forward method.

Descriptive statistics of the number of injections, duration of exposure and reason of injection were presented for the enrolled population. The duration of treatment varied for each patient in the extension phase. To reduce a possible bias because of the patients who discontinued early without injection, the number of injections per year was calculated as 365.25 × sum of total number of injections in the group/duration of the PRN regimen for the respective group. The number of injections per year was calculated for the respective group and not per patient. Duration of the PRN regimen was the date of the last potential treatment visit minus the date of Month 11 visit (the last treatment visit of multiple-injection phase) plus 1.

All efficacy analyses were based on the study eye. Descriptive statistics (mean, median, standard deviation, standard error, minimum and maximum) of the change from baseline (the single-injection phase of Group A and the multiple-injection phase of Group B), Month 11 and Month 12 in Group B were performed by treatment and visit. The 95% confidence intervals based on t-distributions and p-values based on paired t-tests were determined for the change from baseline. Exact 95% confidence intervals were calculated for the proportion of patients with the specified response rates.

Results

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methodology
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Patients

Overall, 70 patients at 11 sites participated in the extension phase from 20 March 2007 to 20 January 2009: 9 in Group A (3 and 6 in the 0.3 and 0.5 mg dose groups, respectively) and 61 in Group B (28 and 33 in the 0.3 and 0.5 mg dose groups, respectively) as shown in Table 1. In Group A, a total of seven patients were not discontinued in the extension phase. Two patients in the 0.3 mg dose group withdrew from the study, as their condition did not further require the study drug. In Group B, 22 patients in the 0.3 mg dose group and 21 patients in the 0.5 mg dose groups were not discontinued in the extension phase. Six patients in the 0.3 mg dose group and 12 patients in the 0.5 mg dose group withdrew from the extension study. The maximum number of patients discontinued as they did not require the study drug because of improvement in VA (n = 9, two in the 0.3 mg dose group and seven in the 0.5 mg dose group); other reasons being AEs (n = 4, two in each dose group), withdrawal of consent (n = 4, one in the 0.3 mg dose group and three in the 0.5 mg dose group) and protocol violation (n = 1, one in the 0.3 mg dose group). None of the AEs leading to study discontinuation was thought to be related to the study drug.

Table 1.   Patient disposition in the extension phase.
Disposition/patients studiedGroup A Ranibizumab 0.3 mgGroup A Ranibizumab 0.5 mgGroup B Ranibizumab 0.3 mgGroup B Ranibizumab 0.5 mg
Patients (n%)
 Enrolled3 (100.0)6 (100.0)28 (100.0)33 (100.0)
 Not discontinued1 (33.3)6 (100.0)22 (78.6)21 (63.6)
 Discontinued2 (66.7)0 (0.0)6 (21.4)12 (36.4)
Main cause of discontinuation
 Adverse event (s)0 (0.0)0 (0.0)2 (7.1)2 (6.1)
 Patient’s condition does not requires study drug2 (66.7)0 (0.0)2 (7.1)7 (21.2)
 Protocol violation0 (0.0)0 (0.0)1 (3.6)0 (0.0)
 Patient withdrew consent0 (0.0)0 (0.0)1 (3.6)3 (9.1)
Mean duration, years, of the extension phase (SD)1.70 (0.35)1.93 (0.09)1.45 (0.33)1.36 (0.39)

The mean duration of treatment (standard deviation, SD) during the extension phase was 1.70 (0.35) years in the 0.3 mg group and 1.93 (0.09) years in the 0.5 mg dose group in Group A (Table 1). In Group B patients, the mean duration of treatment was 1.45 (0.33) years and 1.36 (0.39) years in the 0.3 and 0.5 mg dose groups, respectively.

The baseline demographic and ocular characteristics of enrolled patients at the start of the extension phase are given in Table 2. The mean (SD) BCVA score of the study eye at the start of the extension phase was 59.1 (11.69) letters and 59.8 (15.07) letters in the 0.3 and 0.5 mg dose groups of Group B, respectively. Overall, approximate Snellen equivalent VA of almost all patients was better than 20/200 except for two patients in the 0.5 mg dose group.

Table 2.   Baseline demographics of enrolled patients and ocular characteristics (study eye) at the start of the extension phase.
CharacteristicCategory/statisticGroup A Ranibizumab 0.3 mg N = 3Group A Ranibizumab 0.5 mg N = 6Group B Ranibizumab 0.3 mg N = 28Group B Ranibizumab 0.5 mg N = 33
  1. Data of ocular characteristics are based on Month 11 visit in Group A and Month 12 visit in Group B.

  2. N = number of enrolled patients, n = number of patients.

Gender –n (%)Male3 (100.0)5 (83.3)19 (67.9)28 (84.8)
Female0 (0.0)1 (16.7)9 (32.1)5 (15.2)
Age, yearsMean (SD)68.0 (10.15)72.0 (4.82)69.8 (8.72)70.2 (7.83)
Race (%)Asian3 (100.0)6 (100.0)28 (100.0)33 (100.0)
Best-corrected visual acuity scoreMean (SD)72.0 (4.58)58.5 (15.66)59.1 (11.69)59.8 (15.07)
Range68–7742–7739–8036–85
Approximate Snellen equivalent n (%)Median40.070.071.563.0
20/200 or worse0 (0.0)0 (0.0)0 (0.0)2 (6.1)
Better than 20/200 but worse than 20/401 (33.3)3 (50.0)20 (71.4)20 (60.6)
20/40 or better2 (66.7)3 (50.0)8 (28.6)11 (33.3)
Intraocular pressure (mmHg)Mean (SD)13.3 (1.53)14.2 (3.06)13.5 (2.92)13.7 (3.09)
Range12–159–188–209–23

Of the 61 patients in Group B, approximately 90% (25/28 and 27/33 in the 0.3 mg and the 0.5 mg dose groups, respectively, Table 3) completed Month 24 from the baseline of the multiple-injection phase of the study, i.e., these patients received treatment of ranibizumab with PRN for 12 months in the extension phase. The duration of treatment of each patient in the extension phase varied with respect to the study entry and the longest was 35 months from baseline for the 0.3 mg dose group (n = 1). For the 0.5 mg dose group, the longest was 34 months (n = 1), as shown in Fig. 2.

Table 3.   Summary of patient exposure to ranibizumab for 12 months (from Month 12 to Month 24) in the extension phase (Group B, enrolled patients).
Cumulative number of injectionsRanibizumab 0.3 mg (N = 28)Ranibizumab 0.5 mg (N = 33)
  1. The number of injections per year is calculated as: 365.25 × total number of injections/duration of the pro re nata (PRN) regimen.

  2. Number of injections per year is calculated for total group, not per patient.

  3. Duration of the PRN regimen: date of last potential treatment visit − date of Month 11 visit + 1.

  4. N = number of enrolled patients, n = number of patients.

Month 24
n2527
Mean (SD)4.1 (4.12)3.9 (4.63)
Range0–130–13
079
1–238
3–692
7–923
10–1234
1311
Number of injections per Year4.194.27
image

Figure 2.  Mean change from Month 12 (the start of Extension phase) in best-corrected visual acuity score (±SE) of study eye by visit during extension phase (Group B patients).

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The exposure to ranibizumab in the extension phase of Group B is shown in Table 3. At Month 24, the patients had been treated with the PRN regimen for 12 months in the extension phase, and hence the maximum achievable number of injections by this visit was 13. The injection frequency of ranibizumab for individual patient varied from 0 to 13 times for this 12 months in the extension phase. The estimated number of injections per year in the extension phase was 4.19 and 4.27 in the 0.3 and 0.5 mg dose groups in Group B, respectively.

Efficacy

The mean change (SD) from Month 12 in BCVA score of the study eye to the last visit in the extension phase was −3.6 (14.82) letters in the 0.3 mg group and −2.2 (7.92) letters in the 0.5 mg group of Group B using the PRN regimen (Table 4). Furthermore, the mean change (SD) from baseline in BCVA score of the study eye to the last visit in the extension phase was 7.5 (19.12) letters in the 0.3 mg group and 7.7 (13.02) letters in the 0.5 mg group (p = 0.0475 for the 0.3 mg dose group and p = 0.0019 for the 0.5 mg dose group) (Table 4). Overall, the improvement in BCVA score at Month 12 by monthly ranibizumab injection was sustained throughout the extension phase with the PRN regimen (Fig. 2).

Table 4.   Mean change from baseline in best-corrected visual acuity score of the study eye at the last visit in the extension phase (Group B, enrolled patients).
Visual acuity (letters)Ranibizumab 0.3 mg N = 28Ranibizumab 0.5 mg N = 33
  1. Observed values are presented. Patients must have values at both Month 12 and last visit to be included. Baseline value is defined as the last available measurement prior to the first injection in the multiple-injection phase of the study. End of study differed between the patients and this was more evident from Month 30. Month 35 was the longest analysis point.

  2. N = number of enrolled patients.

  3. * Derived from t-distribution.

  4. Derived from paired t-test.

Baseline
 Mean (SD)47.9 (12.59)50.0 (10.38)
Month 12 (start of extension phase)
 Mean (SD)59.1 (11.69)59.8 (15.07)
Last visit
 Mean (SD)55.4 (17.14)57.6 (15.36)
Change from baseline
 Mean (SD)7.5 (19.12)7.7 (13.02)
 95% CI of the mean*  0.1, 14.9  3.0, 12.3
 p-value  0.0475  0.0019
Change from Month 12
 Mean (SD)−3.6 (14.82)−2.2 (7.92)
 95% CI of the mean*−9.4, 2.1−5.0, 0.6
 p-value  0.2042  0.1186

Table 5 shows the proportion of patients with respect to VA outcome at the last visit in the extension phase. The proportion of patients who lost <15 letters from baseline in BCVA in the study eye was 85.7% (24/28) and 97.0% (32/33) in the 0.3 and 0.5 mg dose groups, respectively. Nine patients each in the 0.3 mg (32.1%) and 0.5 mg (27.3%) dose groups gained ≥15 letters from the baseline. One patient each in the 0.3 mg (3.6%) and 0.5 mg (3.0%) dose groups lost ≥30 letters from the baseline. The proportion of patients with approximate Snellen equivalent of 20/200 or worse was 14.3% (4/28) and 6.1% (2/33) in the 0.3 and 0.5 mg groups, respectively.

Table 5.   Best-corrected visual acuity (BCVA) of the study eye at the last visit in Group B (Enrolled patients).
BCVARanibizumab 0.3 mg (N = 28)Ranibizumab 0.5 mg (N = 33)
  1. * Derived from the exact confidence interval. Baseline value is defined as the last available measurement prior to the first injection in the multiple dose phase of the study; N = number of enrolled patients; n = number of patients.

Loss of <15 letters from baseline
 n (%)24 (85.7)32 (97.0)
 95% CI of %*67.3, 96.084.2, 99.9
Gain of ≥15 letters from baseline
 n (%)9 (32.1)9 (27.3)
 95% CI of %*15.9, 52.413.3, 45.5
Loss of ≥30 letters from baseline
 n (%)1 (3.6)1 (3.0)
 95% CI of %*0.09, 18.30.08, 15.8
Visual acuity <34 letters
 n (%)3 (10.7)1 (3.0)
 95% CI of %*2.27, 28.20.08, 15.8
Approximate Snellen equivalent of 20/200 or worse
 n (%)4 (14.3)2 (6.1)
 95% CI of %*4.03, 32.70.74, 20.2
Approximate Snellen equivalent better than 20/200 but worse than 20/40
 n (%)18 (64.3)20 (60.6)
 95% CI of %*44.1, 81.442.1, 77.1
Approximate Snellen equivalent of 20/40 or better
 n (%)6 (21.4)11 (33.3)
 95% CI of %*8.30, 41.018.0, 51.8

The mean time to first retreatment in the extension phase since Month 11 of the multiple-injection phase (when the last monthly injection was done) in Group B was 218.5 days (range: 29–512 days) for the 0.3 mg group and 255.6 days (range: 29–571 days) for the 0.5 mg group.

Safety

In Group A patient population (n = 9), two of three (66.7%) patients in the 0.3 mg dose group and three of six (50.0%) patients in the 0.5 mg dose group experienced at least one ocular AE in the study eye during the extension phase. In Group B, 20 of 28 (71.4%) patients in the 0.3 mg dose group and 18 of 33 (54.5%) patients in the 0.5 mg dose group experienced at least one ocular AE in the study eye during the extension phase. The most common ocular AE in the study eye in Group B was conjunctival haemorrhage. Other frequent ocular AEs included retinal haemorrhage, retinal detachment and increased intraocular pressure (Table 6). Two patients in the 0.3 mg dose group of Group B experienced Grade 3 targeted AEs (intraocular inflammation, reduced VA, increased intraocular pressure, vitreous haemorrhage, retinal tear or detachment, and retinal haemorrhage). One patient experienced retinal detachment, retinal haemorrhage and vitreous haemorrhage in the study eye, and the other patient experienced retinal haemorrhage in the fellow eye.

Table 6.   Summary of ocular and nonocular adverse events during the extension phase.
Preferred termGroup A: Ranibizumab, 0.3 mg N = 3Group A: Ranibizumab, 0.5 mg N = 6Group B: Ranibizumab, 0.3 mg N = 28Group B: Ranibizumab 0.5 mg N = 33
  1. N = number of enrolled patients; n = number of patients.

  2. * Five incidences in Group B (2 from 0.3 mg; 3 from 0.5 mg) are suspected to be study-drug related.

  3. #Serous retinal detachment in all cases.

  4. One incident in 0.5 mg (Group B) is suspected to be study-drug related.

  5. Full list provided in Table S1.

Ocular
 Total, n (%)2 (66.7)3 (50.0)20 (71.4)18 (54.5)
 Asthenopia1 (33.3)0 (0.0)0 (0.0)0 (0.0)
 Cataract0 (0.0)0 (0.0)1 (3.6)0 (0.0)
 Conjunctival haemorrhage1 (33.3)3 (50.0)12 (42.9)11 (33.3)
 Conjunctival hyperaemia0 (0.0)0 (0.0)2 (7.1)1 (3.0)
 Conjunctivitis0 (0.0)0 (0.0)0 (0.0)1 (3.0)
 Conjunctivitis allergic0 (0.0)1 (16.7)0 (0.0)1 (3.0)
 Dry eye1 (33.3)0 (0.0)0 (0.0)1 (3.0)
 Eye pain0 (0.0)0 (0.0)2 (7.1)0 (0.0)
 Glaucomatocyclitic crisis0 (0.0)0 (0.0)1 (3.6)0 (0.0)
 Injection site discomfort0 (0.0)0 (0.0)0 (0.0)1 (3.0)
 Intraocular pressure increased*0 (0.0)0 (0.0)2 (7.1)4 (12.1)
 Iritis0 (0.0)0 (0.0)1 (3.6)0 (0.0)
 Maculopathy0 (0.0)0 (0.0)1 (3.6)0 (0.0)
 Myodesopsia0 (0.0)1 (16.7)0 (0.0)2 (6.1)
 Ocular hypertension0 (0.0)0 (0.0)1 (3.6)0 (0.0)
 Punctate keratitis0 (0.0)0 (0.0)1 (3.6)1 (3.0)
 Retinal detachment#0 (0.0)1 (16.7)3 (10.7)4 (12.1)
 Retinal haemorrhage1 (33.3)2 (33.3)8 (28.6)8 (24.2)
 Retinal oedema0 (0.0)0 (0.0)1 (3.6)0 (0.0)
 Visual acuity reduced0 (0.0)0 (0.0)1 (3.6)0 (0.0)
 Vitreous haemorrhage0 (0.0)0 (0.0)1 (3.6)0 (0.0)
Nonocular (>5% in any group)
 Total2 (66.7)2 (33.3)19 (67.9)24 (72.7)
 Colonic polyp0 (0.0)1 (16.7)0 (0.0)0 (0.0)
 Cough0 (0.0)0 (0.0)0 (0.0)2 (6.1)
 Dental caries0 (0.0)0 (0.0)1 (3.6)2 (6.1)
 Diabetes mellitus0 (0.0)0 (0.0)3 (10.7)0 (0.0)
 Fall0 (0.0)0 (0.0)1 (3.6)2 (6.1)
 Gastroenteritis1 (33.3)0 (0.0)0 (0.0)0 (0.0)
 Hypertension0 (0.0)0 (0.0)3 (10.7)1 (3.0)
 Nasopharyngitis1 (33.3)1 (16.7)5 (17.9)8 (24.2)

One patient in the 0.3 mg dose group of Group B experienced iritis in the study eye among the ocular AEs defined under the group of intraocular inflammation (iritis, iridocyclitis, vitritis, uveitis, hypopyon and anterior chamber inflammation). Two kinds of ocular AEs in six patients of Group B were suspected to be study-drug related: increased intraocular pressure (two patients in the 0.3 mg dose group and three patients in the 0.5 mg dose group) and retinal haemorrhage (one patient in the 0.5 mg dose group).

Nonocular AEs were observed in four patients (44.4%) in Group A (two each in the 0.3 and 0.5 mg dose groups), 19 patients (67.9%) in the 0.3 mg group and 24 patients (72.7%) in the 0.5 mg group in Group B. Nasopharyngitis was the most common AE in Group B patients (Table 6).

Adverse events potentially related to systemic VEGF inhibition were observed in four patients (14.3%) and two patients (6.1%) in the 0.3 and 0.5 mg dose groups of Group B, respectively. One patient in each dose group experienced cerebral infarction; three patients (0.3 mg dose group) and one patient (0.5 mg dose group) experienced hypertension. In Group A, AEs potentially related to systemic VEGF inhibition were observed in two patients in the 0.3 mg dose group (blood pressure increased and haematuria in one patient and hypertension in another patient).

Nonocular AEs suspected to be related to study drug were cerebral infarction, dementia and hypertension (one patient each) in 0.3 mg group, cerebral infarction and malaise (one patient each) in 0.5 mg dose group.

There were no deaths during the extension phase. Serious adverse events were reported for one of three (33.3%) patients in the 0.3 mg dose group and one of six (16.7%) patients in the 0.5 mg dose group in Group A, four patients (14.3%) in the 0.3 mg dose group and seven patients (21.2%) in the 0.5 mg dose group of Group B. Summary of ocular and nonocular SAEs is shown in Table 7. Of the SAEs, cerebral infarction (one patient each in the 0.3 and 0.5 mg dose groups of Group B) was suspected to be related to study drug and resolved with medical treatment in both patients. Four patients (two patients each from both dose groups) in Group B discontinued from the study because of SAEs. These SAEs that led to discontinuation were, however, not suspected to be study-drug related.

Table 7.   Serious adverse events (SAEs) observed during the extension phase.
 Group A Ranibizumab 0.3 mg N = 3Group A Ranibizumab 0.5 mg N = 6Group B Ranibizumab 0.3 mg N = 28Group B Ranibizumab 0.5 mg N = 33
  1. Both of gastric cancer and small cell lung cancer stage unspecified occurred in same patient of the 0.5 mg dose group.

  2. N = number of enrolled patients; n = number of patients.

  3. * SAE resolved by the last visit of the study.

  4. SAE led to discontinuation.

Total, n (%)1 (33.3)1 (16.7)4 (14.3)7 (21.2)
Ocular SAE of study eye1 (33.3)0 (0.0)2 (7.1)0 (0.0)
Glaucomatocylitic crisis0 (0.0)0 (0.0)1 (3.6)*0 (0.0)
Macular degeneration1 (33.3)0 (0.0)0 (0.0)0 (0.0)
Retinal detachment0 (0.0)0 (0.0)1 (3.6)0 (0.0)
Vitreous haemorrhage0 (0.0)0 (0.0)1 (3.6)0 (0.0)
Ocular SAE of fellow eye0 (0.0)0 (0.0)0 (0.0)1 (3.0)
Visual acuity reduced0 (0.0)0 (0.0)0 (0.0)1 (3.0)
Nonocular SAE0 (0.0)1 (16.7)2 (7.1)6 (18.2)
Abscess neck0 (0.0)0 (0.0)0 (0.0)1 (3.0) *
Cerebral infarction0 (0.0)0 (0.0)1 (3.6)*1 (3.0)*
Colon cancer0 (0.0)0 (0.0)1 (3.6)0 (0.0)
Colon polyp0 (0.0)1 (16.7)*0 (0.0)0 (0.0)
Depression0 (0.0)0 (0.0)0 (0.0)1 (3.0)
Emphysema0 (0.0)0 (0.0)0 (0.0)1 (3.0)
Enterocele0 (0.0)0 (0.0)1 (3.6)*0 (0.0)
Gastric cancer0 (0.0)0 (0.0)0 (0.0)1 (3.0)
Gastric polyps0 (0.0)0 (0.0)0 (0.0)1 (3.0)*
Small cell lung cancer stage unspecified0 (0.0)0 (0.0)0 (0.0)1 (3.0)
Spondylitic myelopathy0 (0.0)0 (0.0)0 (0.0)1 (3.0)*
SAEs causing discontinuation from study drug/study0 (0.0)0 (0.0)2 (7.1)2 (6.1)
Ocular SAE of study eye0 (0.0)0 (0.0)1 (3.6)0 (0.0)
Ocular SAE of fellow eye0 (0.0)0 (0.0)0 (0.0)0 (0.0)
Nonocular SAE0 (0.0)0 (0.0)1 (3.6)2 (6.1)

During the extension phase, immunoreactivity to ranibizumab (antiranibizumab antibodies) was not detected in patients of Group A; however, it was detected in two patients in the 0.3 mg dose group and one patient in the 0.5 mg dose group of Group B in the extension phase. In one patient in the 0.3 mg dose group, immunoreactivity to ranibizumab was detected at Month 12 (for the first time) and at study completion visit, but not at Month 24. In another patient in the 0.3 mg dose group, immunoreactivity to ranibizumab was detected at Month 24 (for the first time) and at study completion visit. In the 0.5 mg dose group, immunoreactivity to ranibizumab was detected in one patient at Month 12 (for the first time), Month 24 and at study completion visit. Of the three patients, AEs were reported in two patients. One patient in the 0.3 mg dose group experienced mild iritis as ocular AE and moderate glaucomatocyclitic crises as ocular SAE in the study eye as well as mild back injury and fall as nonocular AE. Iritis, back injury and fall were resolved without treatment and glaucomatocyclitic crises were resolved with medical treatment. One patient in the 0.5 mg dose group experienced both of conjunctival hyperaemia and intraocular pressure increased in the study eye, and both events were mild and resolved without treatment. All these events, except for intraocular pressure increased, were not suspected to be study-drug related.

Discussion

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methodology
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

EXTEND-I was the first study with ranibizumab in Japanese patients with primary or recurrent subfoveal CNV secondary to AMD. The 6-month results indicated that monthly ranibizumab treatment significantly improved BCVA scores at Month 6 compared with baseline; the mean change (SD) observed was of +8.1 (12.65) letters and +9.0 (9.62) letters in BCVA score in the 0.3 and 0.5 mg dose groups, respectively. The improved BCVA scores at Month 6 were maintained until Month 12 by monthly treatment; the mean change (SD) observed was of +9.5 (12.79) letters and +10.5 (11.14) letters in BCVA score in the 0.3 and 0.5 mg dose groups, respectively. Monthly intravitreal injections of ranibizumab were shown to be safe and well tolerated over 12 months in Japanese patient population (Tano & Ohji 2010).

In the extension phase, the efficacy and safety of individualized flexible interval regimen (PRN regimen) of ranibizumab was assessed. In other words, the study consecutively investigated 12 monthly injections in the multiple-injection phase followed by the extension phase with PRN regimen guided by monthly BCVA score and by other ophthalmic examinations, such as slit-lamp examination, ophthalmoscopy, fundus photography, fluorescein angiography and optical coherence tomography.

The estimated number of ranibizumab injections per year in the extension phase was approximately four injections in both the dose groups, which is equivalent to one-third of the maximally possible number of injections per year. The actual injection interval during the extension phase was not fixed and varied among patients and even in individual subject. Consequently, the PRN regimen with monthly monitoring resulted in considerably less frequent injections than a monthly regimen in this study. This seems to suggest that fixed monthly injection of ranibizumab is not necessary for all patients to maintain the improved VA gained through the initial monthly injections.

Results from the extension phase show a slight, but not significant, decrease in BCVA score when the regimen was switched from monthly injections to the PRN regimen. Thus, based on the mean change in BCVA scores in both the multiple-injection phase and the extension phase, the monthly regimen seems to be more effective in obtaining the best treatment outcome in VA than PRN regimen. However, continuous monthly injections are not feasible for many patients because of the physical and psychological burden and risk of AEs such as eye infections associated with the invasive intravitreal injection procedure.

Based on the results of the pivotal randomized Phase III studies, MARINA, ANCHOR and PIER, a drug and disease model with good agreement with study data was developed to simulate BCVA outcomes by individualized flexible VA-guided regimen following the initial three consecutive monthly injections of ranibizumab (Holz et al. 2010). Individualized flexible VA-guided regimen (administered if BCVA decreased by >5 letters) is suggested to sustain initial BCVA gains following the initial three consecutive monthly injections of ranibizumab. According to the model prediction, it was recommended that patients should be monitored with monthly visits and further treatment should be considered if BCVA decreased by >5 letters.

As discussed in the modelling and simulation study and as observed in the present study, slight decrease in BCVA was noted during the PRN regimen in the extension phase unlike the monthly treatment regimen. Because the concept of the PRN regimen is to treat in case of deterioration, especially a decrease in BCVA score, a corresponding decline in the BCVA curve over time is expected, i.e., the observed decline in BCVA during the extension phase is imminent to the PRN regimen concept.

As a guidance for retreatment during the PRN regimen, in this study, BCVA decrease by >5 letters between two consecutive scheduled visits (including the current visit) was applied, so that the decision of retreatment at the current visit was made on the basis of changes calculated between BCVA scores of the last and current scheduled visit, taking the other ophthalmic conditions into account. On the other hand, in SAILOR and SUSTAIN, although the applied retreatment criterion of BCVA was the same as adopted in this study, the starting point of calculation was any previous visit wherein the BCVA score was the highest, especially in SUSTAIN the previous visit was limited to the first three months (Mitchell et al. 2010). Therefore, the decrease of BCVA score by >5 letters was less likely to occur in this study than in both SAILOR and SUSTAIN. From this perspective, if the retreatment criterion based on the previous highest score is applied, it is speculated that both the number of injection and the BCVA score are apt to increase in comparison with the criterion based on the two consecutive scheduled visits. In both this study and SUSTAIN, monitoring of BCVA scores and other ophthalmic examinations was performed monthly in the same manner; the decline of the BCVA score in the 0.3 mg dose group from Month 12 in this study and from Month 3 in SUSTAIN was almost the same (decrease of 2–3 letters) on an average. Furthermore, in SUSTAIN, the number of retreatments in 9 months of maintenance phase with PRN regimen after three consecutive monthly injection was 2.7 on average, which translates into approximately four times per year. This estimated number of retreatments per year in the SUSTAIN study is roughly the same as the estimated number of injections per year in the extension phase with the PRN regimen of this study. Thus, the influence of the starting point to calculate the decrease in BCVA score for retreatment criterion on the stabilization of BCVA score may not be so large. Apart from the difference in the starting point for the PRN regimen, the duration of consecutive monthly injection before start of PRN regimen in this study and SUSTAIN was different, i.e., 12 and 3 months, respectively, and the duration of the extension phase in this study (about one and half year) and that of maintenance phase in SUSTAIN (9 months) were also different, so that it seems to be difficult to simply compare the mean change in BCVA score between these two studies. Although the starting point to calculate the decrease of BCVA for retreatment criterion still remains to be investigated, it can be argued that a more stringent retreatment criterion may lead to better results, taking into consideration the best treatment outcome obtained by monthly injection.

Recently, based on the evidence available from prospective, multicentre studies evaluating different ranibizumab treatment schedules (ANCHOR, MARINA, PIER, PrONTO, SUSTAIN and EXCITE), it was summarized that the treatment initiation with three consecutive monthly injections of ranibizumab, followed by continued monthly injections, has provided the best VA outcomes in pivotal clinical studies (Mitchell et al. 2010). Furthermore, Mitchell et al. (2010) recommended that if continued monthly injections are not feasible after initiation, a flexible regimen may be adopted with monthly monitoring of lesion activity. The results from the extension phase with PRN regimen in EXTEND-I study are consistent with these clinical recommendations on ranibizumab treatment.

Regarding safety, the comparison between the multiple-injection phase and the extension phase is difficult as there were substantial differences between these two phases with regard to the duration, the number of patients and the number of injections. Although the mean duration of observation in the extension phase was longer than 12 months (1.45 and 1.36 years in the 0.3 and 0.5 mg dose groups, respectively), the incidence rate of ocular AEs appears to be lower than those during the 12-month multiple-injection phase (Tano & Ohji 2010). As the incidence rate of conjunctival haemorrhage, conjunctival hyperaemia and eye pain in the study eye appears to be lower in the extension phase than those in the multiple-injection phase, these AEs are likely to be related to the intravitreal injection of ranibizumab and subconjunctival anaesthesia. Because the estimated number of ranibizumab injections per year was reduced by about one-third because of the PRN regimen in comparison with monthly regimen, there appears to be a relationship between the lower incidence of ocular AEs and reduction of number of injections. On the other hand, the incidence rate of nonocular AEs appears to be similar to those in the multiple-injection phase.

In conclusion, given the efficacy and safety profile observed in the extension phase, an individualized flexible interval regimen (PRN regimen) of ranibizumab, guided by monthly monitoring of BCVA score and other ophthalmic examinations, appears sufficiently effective and feasible in sustaining BCVA gained by consecutive monthly treatment and helps reducing the number of injections and treatment burden. Ranibizumab administered over the extension phase in Japanese patients with subfoveal CNV secondary to AMD was safe and well tolerated.

Acknowledgements

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methodology
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

The authors acknowledge principal investigators for multiple-injection phase, Dr Yuichiro Ogura (Nagoya City University Hospital), Dr Nagahisa Yoshimura (Kyoto University Hospital) and Dr Shinobu Takeuchi and Dr Fumihiko Yagi (Toho University Ohashi Medical Center), latter principle investigator, Dr Nobuyuki Ohguro (Osaka University Medical School) and Dr Takashi Tokoro (Tokyo Medical and Dental University) for their contribution to the study protocol and clinical study report. The authors acknowledge medical writing assistance from Ajithkumar Vasudevan, PhD, and Aditi Gandhe, PhD, Novartis Healthcare Pvt Ltd. This study was funded by Novartis Pharma.

The extension phase of EXTEND-I study was presented at APVRS 2009 meeting as a luncheon seminar.

References

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  2. Abstract.
  3. Introduction
  4. Methodology
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methodology
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Table S1. Number (%) of patients with non-ocular adverse events by preferred term in Part B (Enrolled patients).

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