Clinical Trials Register

Summary
EudraCT Number:	2005-001460-32
Sponsor's Protocol Code Number:	EOP 1013
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-03-08
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Portugal - INFARMED

A.2

EudraCT number

2005-001460-32

A.3

Full title of the trial

A Phase 2/3 Randomized, Controlled, Double-Masked, Multi-Center, Comparative Dose-Finding Trial, in Parallel Groups, to Compare the Safety and Efficacy of Intravitreous Injections of 0.3, 0.03 or 0.003 mg Pegaptanib Sodium (MacugenÒ), Given as Often as Every 6 Weeks for 3 years, to Sham Injections, in Subjects with Diabetic Macular Edema (DME) Involving the Center of the Macula.

A.4.1

Sponsor's protocol code number

EOP 1013

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Macugen
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Macugen
D.3.2	Product code	EYE001
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravitreal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pegaptanib Sodium
D.3.9.2	Current sponsor code	EYE001
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Diabetic Macular Edema (DME)

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objectives of this trial will be to confirm the safety and compare the efficacy of pegaptanib sodium when given as intravitreous injections of 0.3 mg/eye, 0.03 mg/eye or 0.003 mg/eye versus sham injections in a 2:2:1:2 ratio, respectively, as often as every 6 weeks for 3 years, in subjects with diabetic macular edema involving the center of the macula associated with vision loss not due to ischemia.

E.2.2

Secondary objectives of the trial

Secondary (at 1, 2 and 3 years unless specified):·

The proportion of subjects with a ≥15 letter improvement at 1 year and 2 years.
The proportion of eyes experiencing a change in the degree of retinopathy by 2 or more steps.
Changes in mean visual acuity over time.
The proportion of subjects with a ≥10 letter improvement.
The proportion of subjects requiring focal or grid laser

Other: Additional efficacy, safety and health related outcomes endpoints will be included.

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

OPHTHALMIC CRITERIA

1. Subjects must have macular edema that involves the center of the macula with corresponding leakage on fluorescein angiogram. Leakage will be confirmed retrospectively by the IRC.
2. Foveal thickness of at least 300 microns (OCT center point thickness), with a standard deviation of the center point of <10%, an OCT signal strength of ≥5, and properly drawn ILM and RPE borders. As well, the initial OCT must be confirmed by repeat measurement on the same day, with the center point thicknesses being within 10% of each other. In cases that the OCT image software fails to properly draw ILM and RPE borders, if the IRC obtains a manual estimate of OCT center point thickness of at least 300 microns, then the patient will be considered eligible.
3. Best corrected distance visual acuity in the study eye must be a letter score between 65 and 35 inclusive (20/50 to 20/200 Snellen equivalents).
4.Clear ocular media and adequate pupillary dilatation to permit good quality stereoscopic fundus photography.
5.Intraocular pressure of 21 mmHg, or less.
6.The treating ophthalmologist should be comfortable that focal laser (direct and grid as needed) can be deferred for at least 18 weeks in the study eye, even though focal or grid laser is indicated.

GENERAL CRITERIA

1. Type I, or Type II diabetic subjects as defined by the WHO criteria, of either gender, and aged ≥18 years
2. Performance Status ≤2 according to the Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) scale.
3. Normal electrocardiogram (ECG), or clinically non-significant changes as determined by an internist.
4. Women must be using effective contraception, be post-menopausal for at least 12 months prior to trial 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 trial and for at least 60 days following the last dose of pegaptanib sodium.
5. Adequate hematological function: hemoglobin ≥10 g/dL; platelet count ≥130 x 109/l; WBC ≥3.8 x 109/l.
6. Adequate liver function: serum bilirubin ≤1.5 mg/dL; SGOT/ALT, SGPT/AST, GGT and alkaline phosphatase within 2 x ULN.
7. Adequate renal function: serum creatinine ≤ 2.5 mg/dL and BUN within 2.5 x ULN.
8. Ability to provide written informed consent.
9. Ability to return for all trial visits.

E.4

Principal exclusion criteria

EXCLUSION CRITERIA

Subjects will not be eligible for the trial if any of the following criteria are present systemically, or in the study eye:

1. Eyes with prior scatter (panretinal) photocoagulation or eyes in which scatter (panretinal) photocoagulation is needed now or is likely to be needed within the next 9 months (e.g. eyes with DRS high risk PDR not already adequately treated with photocoagulation).
2. 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 non-perfusion for >1 disc area involving the foveal avascular zone (FAZ - involving 2 or more quadrants centered around the foveal avascular zone), epiretinal membrane associated with signs of contraction and/or significant opacification (i.e. striae within 1 disc diameter of the foveal center), or presence of chorioretinal atrophy involving the center of the macula.
3. Vitreomacular traction determined clinically and/or by OCT, which, in the investigator’s opinion, contributes to the macular edema (or causes associated foveal detachment), and would preclude improvement with pegaptanib sodium or sham treatment.
4. Any other cause of macular edema such as vitreous extension, or entrapment to anterior segment wound, or any retinal vein occlusion involving the macula.
5. Atrophy/scarring/fibrosis involving the center of the macula, including evidence of laser treated atrophy within 200 microns of FAZ.
6. Any subfoveal hard exudates, or RPE atrophy; or any present evidence, or past documentation of a foveal cyst (by fundus examination, FA or OCT).
7. Subjects who have received panretinal photocoagulation, YAG laser, or peripheral retinal cryoablation (for retinal tears only), or focal or grid photocoagulation, within the previous 16 weeks, or more than one prior focal or grid laser.
8. Significant media opacities, including cataract, which might interfere with visual acuity, assessment of toxicity or fundus photography. Subjects should not be entered if there is likelihood that they will require cataract surgery within the following 1 year.
9. Any intraocular surgery within 6 months of trial entry.
10. Previous vitrectomy.
11. HbA1C level ≥10% or recent signs of uncontrolled diabetes (3 or more episodes of severe hypoglycemia by DCCT (Diabetes Control and Complications Trial) definition [10] within 3 months of baseline, or 2 or more episodes of ketoacidosis within 1 year of baseline, or an episode of ketoacidosis within 3 months of baseline).
12. 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 infarction, or revascularization 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
s/p renal transplant or receiving dialysis).
Clinically significant impaired hepatic function.
Stroke (within 12 months of trial entry).
Any major surgical procedure within one month of trial entry
13. Previous radiation to the head in the region of the study eye.
14. Any prior treatment with an investigational agent for DME (including intravitreal, subconjunctival or subtenons corticosteroids) at any time, or during the past 90 days for any other condition.
15. Known serious allergies to the fluorescein dye used in angiography, or to the components of pegaptanib sodium formulation.
16. Systolic BP >160 (2 different readings) or diastolic BP >100 (2 different readings).
17. Acute ocular or periocular infection.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the proportion of subjects who experience a ≥ 15 letter (or 3-line) improvement in vision (ETDRS) from baseline. This endpoint will be assessed at 3 years to test the significance of the comparison of the proportions of 3-line improvement in each dose group versus sham. The 3 year endpoint is the primary endpoint, while the 1 and 2 year endpoints will be secondary endpoints. The primary endpoint will be tested in a stepwise fashion . An interim analysis (IA) will be performed by the Independent Data Safety Monitoring Committee (IDMC) in consultation with the independent holder of the database on all subjects who have completed the one year time point or have dropped out . The purpose of this IA is to determine if pegaptanib sodium is efficacious for subjects with DME after one year of therapy.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Information not present in EudraCT

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.5

The trial involves multiple Member States

Yes

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

Information not present in EudraCT

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

150 weeks (3 years)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Information not present in EudraCT

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-03-08.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

340

F.4.2.2

In the whole clinical trial

900

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

As expected for normal treatment of this condition

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2007-01-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-02-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2011-07-15

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