| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Exudative Age Related Macular Degeneration (AMD) | |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10025411 | |
| 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 the safety , efficacy and pharmacokinetics of intravitreous injections of pegaptanib sodium compared to sham injections for 30 weeks in patients with recent vision loss due to macular edema secondary to CRVO.
The primary objective is to compare visual acuity (measured by ETDRS protocol) in eyes administered pegaptanib sodium 1mg or 0.3mg vs. sham when given every 6 weeks for 5 doses. The primary endpoint is at 30 weeks after 5 treatments. The final study visit is at 52 weeks
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Ophthalmic Criteria CRVO
1.CRVO must have occurred within 6 months from Baseline. The date of occurrence is defined as the date of first visual symptoms leading to a diagnosis of CVRO. The study site will collect evidence documenting the date of first visual symptoms from the referring clinic or ophthalmologist for inclusion in the patient site chart. Evidence may be an Emergency Room sheet or clinical note.
2.CRVO patients must have macular edema determined by OCT. Central retinal thickness is measured by the center point value, and must equal or exceed 250µm at Baseline and Day 0. In order to assure reasonable quality, the standard deviation for the center point value must be ≤10% of the center point value. For instance, if the center point value is 250µm, the standard deviation must be ≤ 25 µm for the value to have reliability.
3.Best corrected visual acuity in the study eye, using ETDRS protocol, must be between 65 and 20 letters inclusive on the ETDRS chart (corresponding to between approximately 20/50 to 20/400 Snellen equivalents), and better than , or equal to 35 letters (approx. 20/200) in the fellow eye.
General Criteria
1.Clear ocular media and adequate pupillary dilatation to permit good quality stereoscopic fundus photography, angiography, and APD assessment.
2.Intraocular pressure of 21mm Hg, or less. Patients with stable glaucoma or ocular
hypertension treated with no more than 2 medications may be enrolled as long as the baseline IOP is 21 mmHg or less. The medication regimen must be stable for 3 months prior to enrollment.
3.Patients without systemic hypertension or with stable, treated systemic hypertension are permitted to enter the study. The resting, sitting blood pressure (BP) must be ≤140 systolic AND ≤90 diastolic. The medication regimen for stable systemic hypertension should be unchanged for the past 30 days. RVO may also be the first sign of systemic hypertension. Patients with untreated systemic hypertension may enter the study once they have been stabilized on anti-hypertensive medication for 30 days, and their resting, sitting BP is ≤140 systolic and ≤90 diastolic.
4.Performance Status ≤2 according to the Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) scale. Limited vision should not be used as a criteria for determining performance status.
5.Normal electrocardiogram (ECG), or clinically non-significant changes.
6.Women must be using effective contraception, be post-menopausal for at least 12 months prior to study entry, or surgically sterile. All women of childbearing potential must have a negative serum pregnancy test at baseline and negative urine pregnancy tests immediately prior to each injection and use two effective forms of contraception during the study and for at least 60 days following the last dose of pegaptanib sodium.
7.Adequate haematological function: haemoglobin ≥ 10g/dl; platelet count ≥ 130 x 109/l; WBC ≥3.8 x 109/l.
8.Adequate liver function: serum bilirubin ≤ 1.5 mg/dl; SGOT/ALT, SGPT/AST, GGT and alkaline phosphatase within 2 x ULN.
9.Adequate renal function: serum creatinine ≤ 2.5 mg/dl, BUN within 2.5 x ULN.
10.Written informed consent.
11.Ability to return for all study visits.
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| E.4 | Principal exclusion criteria | Patients will not be eligible for the study if any of the following criteria are presented systemically, or in the study eye:
1.Presence of signs of old BRVO or CRVO in the study eye or any other retinal vascular disease including diabetic retinopathy.
2.Brisk APD in the study eye is excluded. APD and vision less than 20/400 are associated with ischemic CRVO, in which vision may not improve despite resolution of macular edema or capillary non-perfusion.
3.Vitreous hemorrhage except breakthrough hemorrhage from intraretinal hemorrhage.
4.The investigator should be confident that central vision is not limited by macular intaretinal hemorrhage, but us limited by macular edema.
5.Evidence of any neovascularization involving the iris, disc or retina.
6.Prior PRP or sector scatter photocoagulation. (Prophylactic scatter or PRP is not permitted. PRP is allowed on study for newly developing iris neovascularization of ≥2 clock hours, any angle neovascularization, or any retinal neovascularization that the investigator feels must be treated with panretinal or sector photocoagulation). Investigators are urged to use the CVOS protocol for criteria and methods for panretinal photocoagulation.
7.Presence of any abnormality that is likely to confound assessment of visual acuity improvement in eyes in which macular edema resolves, or improves, such as:
- Epiretinal membrane
- Signs of vitreoretinal traction confirmed by OCT, or seen clinically within 1 disc
diameter of the center of the macula.
- Presence of chorioretinal or retinal pigment epithelial atrophy involving the
center of the macula.
- Hard exudates at the center of the macula severe enough to preclude
improvement in visual acuity even withy resolution of macular edema (a large plaque or organized mound of hard exudate).
8.Patients who have received systemic, intravitreous, or subtenons’s corticosteroids for ophthalmic conditions are excluded.
9.Any prior treatment with an investigational agent or procedure to treat RVO in the study eye, i.e. hemodilution, choroidoretinal anastomosis, radial optic neurotomy, anticoagulation with heparin, streptokinase or tPA.
10.Treatment with investigational agents for any condition during the past 60 days for any other condition.
11.Significant media opacities, including cataract, which might interfere with visual acuity, assessment of toxicity or fundus photography. Patients should not be entered if there is likelihood that they will require cataract surgery within the following 1 year.
12.Any intraocular surgery with the exception of cataract surgery within 12 months of study entry. Cataract surgery is excluded within 3 months of study entry. YAG posterior capsulotomy is excluded within 3 months of study entry.
13.Previous posterior vitrectomy or scleral buckling surgery.
14.History of retinal detachment or surgery for retinal detachment.
15.Myopia of >8 diopters, or axial length > 25mm.
16.Intraocular pressure exceeding 21 mm Hg at baseline in the study eye.
17.Any of the following underlying systemic diseases including:
- History or evidence of severe cardiac disease, e.g NYHA Functional Class III or
IV, clinical or medical history of unstable angina, acute coronary syndrome,
myocardial infraction, or revasularization procedure within 6 months prior to
baseline, or ventricular tachyarrythmias requiring ongoing treatment.
- History (previous surgery or amputation), or evidence (symptoms of claudication) of clinically significant peripheral vascular disease.
- Clinically significant impaired renal function (serum creatinine > 2.5 mg/dl or post renal transplant or receiving dialysis).
- Clinically significant impaired hepatic function.
- Stroke (within 12 months of study entry).
- Chronic or recurrent ocular ot periocular infection (including any history of ocular Herpes Simplex or Herpes Zoster infection).
- Acute infection of ocular or peri-ocular adnexa in past 3 months.
- Any major surgical procedure within one month of study entry.
18.Previous radiation to the head in the region of the study eye.
19.Known serious allergies to the fluorescein dye used in angiography, or to the components of pegaptanib sodium formulation.
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| E.5 End points |
| E.5.1 | Primary end point(s) | The primary efficacy endpoint is:
1.The proportion of treated eyes gaining ≥15 letters of visual acuity from baseline up to 30 weeks for each dose group.
Secondary vision related efficacy endpoints are:
1. Mean change in VA from baseline up to week 30 for each dose group.
2. VA data over time – a repeated measure analysis which utilizes all the VA data over time will be preformed to compare between sham and each dose group.
3. The proportion of treated eyes losing ≥ 15 letters of visual acuity from baseline up to 30 weeks for each dose group.
4. The proportion of treated eyes with vision better than or equal to 65 letters (better than approximately 20/50) at 30 weeks for each dose group.
5. The proportion of treated eyes with vision better than or equal to 35 letters (better than approximately 20/200) at 30 weeks for each dose group.
Other endpoints are:
1. Difference in change from baseline mean OCT center point value between sham and 0.3 mg at 30 weeks and between sham and 1 mg at 30 weeks.
2. OCT data over time – a repeated measure analysis which utilizes all of the OCT center point values over time will be performed to compare between sham and each dose group.
3. The proportion of eyes developing retinal or iris neovascularization post baseline before week 30 for each dose group.
4. The proportion of eyes requiring laser photocoagulation at any time post baseline before week 30 for each dose group.
5. The change in mean area of macular edema determined from fluorescein angiography at 30 weeks for each dose group.
6. The change in mean are of capillary non-perfusion determined from fluorescein angiography at 30 weeks for each dose group.
7. The change in mean center point retinal thickness as determined by grading of the colour photographs for each dose group.
8. Population pharmacokinetics will be assessed in patients participating in this trial
The most important measure of macular edema determined by OCT is the center point value. In addition, a center subfield value will also be calculated, which measures thickness in a regional area, rather than at the point of fixation. Descriptive statistics will be used to evaluate the effect of pegaptanib sodium or sham on center point and center subfield values. Safety assessments will include clinical and laboratory adverse events, and will be analyzed in terms of their incidence, severity, type and relationship to the study drug.
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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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description | |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
