| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Macular Oedema due to Central Retinal Vein Occlusion (CRVO). |
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| E.1.1.1 | Medical condition in easily understood language |
| Swelling of the centre of the retina, the light detecting layer at the back of the eye, due to blockage of a blood vessel that usually drains blood out of this layer. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine if bevacizumab or afilbercept are as effective as ranibizumab in reducing visual loss from MO due to CRVO, whether they have an equivalent side effect profile and whether either could be considered as a recommended NHS treatment based on non-inferior clinical effectiveness and superior cost-effectiveness to ranibizumab. |
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| E.2.2 | Secondary objectives of the trial |
1. To determine any differences in visual loss between the three different treatment groups after one year.
2. To determine any differences in the number of patients in each treatment group who gain vision or those who loose a large amount of vision.
3. To determine the difference between treatment groups in the number of patients who maintain good enough vision to continue driving, or be registered partially or severely visually impaired.
4&5. To determine any differences between treatment groups arms in the anatmical ie structural appearance of the macula at 52 and 100 weeks.
6. To determine any differences between treatment groups in the number of injections performed per patient.
7.& 8. To determine any differences in the quality of daily life, experienced by the patients in the different treatment groups
9. To determine whether patients in one treatment group experience more side effects than patients in another group.
10. To determine whether different numbers of patien |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects of either sex aged ≥ 18 years.
2. Clinical diagnosis of centre-involving macular oedema (MO) due to CRVO
3. CRVO of ≤ 12 months duration.
4. Best corrected visual acuity in the study eye ≥ 19 and ≤ 73 ETDRS letters (approximate Snellen VA 3/60 to VA 6/12).
5. Best corrected visual acuity in the non-study eye ≥ 14 ETDRS letters (approximate Snellen VA ≥ 2/60).
6. SD-OCT central subfield thickness (CST) > 320μm (Spectralis) predominantly due to MO secondary to CRVO in the study eye. See appendix 1 for equivalent CST value for alternative SD-OCT machines.
7. Media clarity, pupillary dilatation and subject cooperation sufficient for adequate fundus imaging of the study eye.
8. In cases of bilateral CRVO, if both eyes are potentially eligible, unless the patient prefers otherwise the worst seeing eye will be recruited.
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| E.4 | Principal exclusion criteria |
The following apply to the study eye only and to the non-study eye only where specifically stated:
1. Macular oedema considered to be due to a cause other than CRVO (e.g. diabetic macular oedema, Irvine-Gass syndrome).
2. An ocular condition is present that, in the opinion of the investigator, might affect macular oedema or alter visual acuity during the course of the study (e.g. vitreomacular traction)
3. Any previously documented diabetic retinopathy or diabetic macular oedema in the study eye.
4. Moderate or severe non proliferative diabetic retinopathy (NPDR) or quiescent, treated or active proliferative diabetic retinopathy (PDR) or macular oedema in the non-study eye. Note: Mild NPDR only is permissible in the non-study eye.
5. History of treatment for MO due to CRVO in the past 90 days with intravitreal or peribulbar corticosteroids or in the last 60 days with anti-VEGF drugs or >3 prior anti-VEGF treatments in the previous 12 months.
6. Active iris or angle neovascularisation, neovascular glaucoma, untreated NVD, NVE and vitreous haemorrhage or treatment for these conditions in the last 3 months.
7. Uncontrolled glaucoma [>30mmHg], either untreated or on anti-glaucoma medication at screening.
8. Any active periocular or intraocular infection or inflammation (e.g. conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis).
Systemic exclusion criteria:
9. Uncontrolled blood pressure defined as a systolic value > 170mmHg and diastolic value > 110mmHg.
10. Myocardial infarction, stroke, transient ischaemic attack, acute congestive cardiac failure or any acute coronary event < 3 months before randomisation
11. Women of child bearing potential unless using effective methods of contraception throughout the study and for 6 months after their last injection for the trial. Effective contraception is defined as one of the following:
a. Barrier method: condoms or occlusive cap with spermicides.
b. True abstinence: When it is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
c. Have had tubal ligation or bilateral oophorectomy (with or without hysterectomy).
d. Male partner sterilisation. The vasectomised male partner should be the only partner for the female participant.
e. Use of established oral, injected or implanted hormonal methods of contraception and intrauterine device
12. Pregnant or lactating women.
13. Males who do not agree to an effective form of contraception for the duration of the study and for 6 months after their last injection for the trial.
14. Hypersensitivity to the active ingredients aflibercept, bevacizumab or ranibizumab or any of the excipients of these drugs.
15. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
16. A condition that, in the opinion of the investigator, would preclude participation in the study.
17. Participation in an investigational trial involving an investigational medicinal product within 90 days of randomisation |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Change in mean best corrected visual acuity from baseline to 100 weeks in the study eye measured in ETDRS letter score at 4 metres: difference in means between bevacizumab arm versus ranibizumab arm.
2. Change in best corrected visual acuity from baseline to 100 weeks in the study eye measured in ETDRS letter score at 4 metres: difference in means between aflibercept arm versus ranibizumab arm.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to 100 weeks (4 weekly maximally) and at the point of withdrawal. |
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| E.5.2 | Secondary end point(s) |
Visual Acuity and Clinical Outcomes
1. 1. Difference between arms in mean change in best corrected visual acuity at 52 weeks.
2. Difference between arms in the proportion of participants with ≥ 15 ETDRS letter improvement (appreciable visual gain), ≥ 10 letter improvement, <15 letter loss and ≥ 30 ETDRS letter loss (severe visual loss) at 52 and 100 weeks.
3. Difference between arms in the proportion of participants with ≥73 ETDRS letters or better than 6/12 Snellen equivalent (ie approximate driving visual acuity), ≤58 ETDRS letters (≤6/24) and ≤ 19 letters (≤3/60)(CVI partial and severe visual impairment) at 52 and 100 weeks.
4. Difference between arms in the mean change in OCT CST and macular volume at 52 and 100 weeks.
5. Difference between arms in the proportion of participants with OCT CST < 320μm (Spectralis or refer to appendix 1)at 52 and 100 weeks (key guide to subsequent NHS clinical practice).
6. Differences between arms in the mean number of injections performed per participant.
7. Differences between arms in changes in area of non-perfusion at 100 weeks.
8. Differences between arms in OCT anatomical features at 52 and 100 weeks.
Patient reported and cost-effectiveness outcomes
1. The relative effectiveness of the investigational treatments and comparator on quality of life (VFQ25 composite score, distance and near subscales, and EQ-5D with and without vision ‘bolt-on’) at 0, 12, 24, 52, 76 and 100 weeks.
2. The relative effectiveness of the investigational treatments and standard care on resource utilization (Client Service Receipt Inventories) at 0, 12, 24, 52, 76 and 100 weeks.
Safety and tolerability.
1. Prevalence of local and systemic side effects
2. To determine differences between arms in the proportion i. of persistent non-responders (see Section 8.14.78.14.7) ii. of participants that develop a change in week 100 retinal non-perfusion compared to screening iii. of participants that develop anterior and posterior segment neovascularisation
Pre-specified sub-group analyses
1. To determine differences between arms in mean change in best corrected visual acuity across subgroup variables defined by i) baseline visual acuity stratified as ≤38 letters, 39-58 letters, 59-73 letters, ii) duration of disease stratified as: <3 months, 3-6 months and > 6 months, iii) treatment stratified as naïve vs previous treatment iv) quantity of retinal ischaemia ( <10 , ≥10 and < 30, and ≥ 30 DA of non-perfusion).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients will be seen 4 weekly (maximally) from the point of screening until week 100 when they complete the trial and at the point of withdrawal. The endpoints will be performed according to the schedule in the protocol. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 40 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 0 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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