| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057934 |
| E.1.2 | Term | Diabetic macular edema |
| E.1.2 | System Organ Class | 100000004853 |
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| 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 |
1. To determine the safety and dose-limiting toxicities of a single IVT injection of PF-04523655 in subjects with low vision (Stratum I).
2. To determine the PK of a single IVT injection of PF-04523655 in subjects with low vision (Stratum I).
3. To evaluate the safety and tolerability of PF-04523655 alone and in combination with ranibizumab in subjects with DME (Stratum II).
4. To evaluate the ability of PF-04523655 alone and in combination with ranibizumab to improve visual acuity compared to ranibizumab alone in subjects with DME (Stratum II). |
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| E.2.2 | Secondary objectives of the trial |
| 1. To evaluate the anatomical changes in retina and retinal nerve fiber layer (RNFL) morphology following administration of PF-04523655 alone and in combination with ranibizumab compared to ranibizumab alone by fundus photography (FP) and high resolution optical coherence tomography (HR-OCT) (Stratum II). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Stratum I
1. Visual acuity in the study eye less than or equal to 20/200. This level of visual function should have been stable and consistently low (less than or equal to 20/200), for the entire 6 month period prior to Screening. Stable visual function is defined as the same BCVA score (± 1 line or 5 letters of BCVA at Screening) within 6 months prior to Screening using the same visual acuity test (Snellen or Early Treatment Diabetic Retinopathy Study (ETDRS)).
2. Low visual acuity is the result of an irreversible condition affecting the posterior segment of the study eye. These conditions include, but are not limited to:
a. Diabetic retinopathy except proliferative diabetic retinopathy
b. Age-related macular degeneration
c. Other retinal degeneration
d. Optic neuritis
e. End stage glaucoma
f. Optic nerve atrophy due to any etiology
g. Leber’s hereditary optic neuropathy with onset at least 2 years prior to Screening.
3. Clear ocular media and able to undergo adequate pupil dilation to allow a good fundus examination, and required imaging.
4. Visual acuity in the fellow eye is better than or equal to the study eye at Screening.
5. Males and females aged at least 18 years old or the legal age of consent, where older.
6. Capable of giving written informed consent.
7. Willing and able to comply with the study procedures and visit schedule, including follow-up visits.
8. Female subjects must be one of the following:
a. Post-menopausal (For the purpose of this study, post-menopausal is defined as the absence of menses for at least one year and a serum follicle stimulating hormone (FSH) level ≥ 20 IU/L. Investigators can determine if a serum FSH level is required to prove post-menopausal status.)
b. Surgically sterile (For the purpose of this study, a subject is considered to be surgically sterilized if she has had a bilateral tubal ligation for at least 6 months prior to administration of PF-04523655, bilateral oophorectomy, or complete hysterectomy.)
c. Using an effective means of contraception which will be continued until the Month 3 visit with a negative pregnancy test within 48 hours prior to administration of PF-04523655. (For the purpose of this study, effective means of contraception include use of one of the following: hormonal contraceptives (oral, implant, transdermal patch, or injection) at a stable dose for at least 3 months prior to administration of PF-04523655, barrier (condom with spermicide, diaphragm with spermicide), IUD, or a male subject/partner who has been vasectomized for at least 6 months prior to administration of PF-04523655.)
Male subjects with female partners of childbearing potential must agree to use an effective means of contraception which will be continued until the Month 3 visit.
Stratum II
1. History of diabetes mellitus (Type 1 or Type 2).
2. Serum HbA1c ≤12% at screening (DCCT assay).
3. Stable medication for the management of diabetes within 3 months before randomization and expected to remain stable during the study (see note in protocol).
4. Retinal thickening secondary to the edema caused by diabetes mellitus involving the center of the fovea on clinical examination.
5. Subjects with diabetic macular edema affecting the fovea consisting of retinal thickness on HR-OCT measuring 310 μm or more in the central subfield at Screening (see note in protocol).
6. BCVA using ETDRS visual acuity protocol of 20/40 or worse (letter score of ≤73) and up to 20/320 or better (letter score ≥24) in the study eye at Screening.
7. Decreased BCVA due to diabetic macular edema and not other causes, in the opinion of the Investigator
8. Visual acuity score in the fellow eye of 20/400 or better (letter score of ≥19) at Screening. Note: Only one eye will be treated (study eye). In the event both eyes are eligible for study entry, the eye with the worse VA will be chosen as the study eye, unless subject’s choice is the fellow eye, and Investigator agrees with the subject’s choice. If the VA is the same in both eyes, and the subject has no preference, then the study eye will be randomly chosen.
9. Standard of care treatment for diabetic macular edema (including but not limited to anti-VEGF treatment, and laser photocoagulation) can be withheld for at least 90 days after the subject has enrolled in the study (study eye only).
10. Clear ocular media and able to undergo adequate pupil dilation to allow a good fundus examination, and required imaging.
11. Capable of giving written informed consent.
12. Willing and able to comply with the study procedures and visit schedule, including follow-up visits.
13. Males and females aged at least 18 years old or the legal age of consent, where older.
14. See section 8 of stratum I |
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| E.4 | Principal exclusion criteria |
Stratum I
History of: (1) vitrectomy, (3) vitreous hemorrhage, (5) retinal detachment, (6) invasive trauma (all - study eye only)
2 IVT injection (study eye only) within last 6 months
4 History of uveitis or endophthalmitis in either eye
7 Any active inflammatory condition (e.g. conjunctivitis) (study eye only)
8 Received any drugs known to cause optic nerve or retinal toxicity within 14 days prior to dosing (see protocol)
9 Any medical condition, concomitant therapy or previous incisional or laser surgery that, in the opinion of the Investigator, would preclude IVT injection in the study eye
10 Intraocular pressure in either eye ≥25 mmHg on maximal medication
11 Cataract surgery and laser corneal surgery (i.e. LASIK) within 3 months prior to dosing and glaucoma laser surgery (i.e. laser iridotomy, laser iridoplasty, and laser trabeculoplasty) performed within 1 month prior to dosing in the study eye and all other intraocular surgeries at any time
12 Clinically significantly abnormal ECG, suggesting ischemic heart disease, clinically significant cardiac arrhythmias, atrioventricular block and/or congestive heart failure as determined by a physician at Screening. If a clinically significant abnormality is identified at Screening, the ECG should be re-assessed at baseline to determine eligibility
13 Women who are pregnant or lactating
14 Any uncontrolled medical condition (see protocol for details)
15 Participating in a concurrent interventional study with the last intervention occurring within 30 days prior to planned dosing with PF-04523655
Stratum II
1 Any history of panretinal photocoagulation within 6 months or macular laser photocoagulation within 3 months of prior to dosing in the study eye
2 Any intravitreal injection therapy performed in the study eye within 3 months prior to dosing
3 Concomitant intravitreal therapy in the fellow eye within 7 days prior to dosing
4 Any concurrent intraocular condition in the study eye or previous surgery (eg, cataract) that, in the opinion of the investigator, could either (a) require medical or surgical intervention during the 6-month study period to prevent or treat visual loss that might result from that condition, or (b) if allowed to progress untreated, could likely contribute to loss of at least 1 ETDRS line of best corrected visual acuity over a 6-month period (c) may affect macular edema or reduce visual acuity during the course of the study eg, uveitis/ocular inflammatory disease, vein occlusions, Irvine-Gass syndrome
5 Iris neovascularization, vitreous hemorrhage, tractional retinal detachment, vitreomacular traction, clinically significant epiretinal membrane or clinically significant preretinal fibrosis involving the macula in the study eye
6 History of vitreoretinal surgery or incisional glaucoma surgery in the study eye
7 In the opinion of the Investigator, any concomitant conditions in the study eye that could prevent improvement in visual acuity following study treatment
8 Prior intraocular surgery (i.e. cataract surgery) or corneal laser surgery (i.e. LASIK), performed within 3 months prior to dosing in the study eye, and prior glaucoma laser surgery (i.e. laser iridotomy, laser iridoplasty, and laser trabeculoplasty) performed within 1 month prior to dosing in the study eye
9 (section 8, Stratum I)
10 (section 9, Stratum I)
11 High risk (in the opinion of the investigator) proliferative diabetic retinopathy (PDR) in the study eye
12 Current infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye
13 Monocular subjects, defined as having only one eye
14 History of idiopathic or autoimmune uveitis in either eye
15 Aphakia or absence of the posterior capsule in the study eye.
Previous Yttrium Aluminum Garnet (YAG) capsulotomy performed 2 months or more prior to study entry associated with posterior intraocular lens implant is permitted
16 Structural damage to the center of the macula in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema(for details see protocol)
17 Uncontrolled glaucoma in either eye (see protocol for definition) and/or advanced disc cupping with glaucomatous visual field loss in the study eye
18 Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia
19 (section 14, Stratum I)
20 Blood pressure >160/100 mmHg at Screening. (see protocol for details)
21 History of stroke within 6 months
22 Renal failure requiring dialysis or history of renal transplant
23 (section 12, Stratum I)
24 (section 15, Stratum I)
25 Use of corticosteroids that, in the Investigator’s opinion, may change the status of the subject’s diabetic retinopathy in the study eye
26 History of allergy to anti-VEGF injection
27 (section 13, Stratum I) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for Stratum I is safety outcomes determined from treatment emergent adverse events (TEAEs) and ophthalmic and laboratory assessments. An additional primary endpoint is the characterization of PF-04523655 PK at doses evaluated.
The primary safety endpoint for Stratum II is safety and tolerability of PF-04523655 in DME determined from TEAEs and ophthalmic and laboratory assessments.
The primary efficacy endpoint for Stratum II is mean change from baseline (Day 0) to Month 6 in the best corrected visual acuity (BCVA) score, as measured by ETDRS visual acuity protocol.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stratum I
Treatment emergent adverse events (TEAEs): Day 0, Day 1, Week 1, Week 2, Month 1, Month 2, Month 3, Month 6 (ocular only)
Ophthalmic and laboratory assessments: Screening, Day 0, Day 1, Week 1, Week 2, Month 1, Month 2, Month 3, Month 6
PK: Day 0, Day 1, Week 1, Week 2
Stratum II
Treatment emergent adverse events (TEAEs): Day 0, Day 1, Week 1, Week 2, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6
Ophthalmic and laboratory assessments: Screening, Day 0, Day 1, Week 1, Week 2, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6
Best Corrected Visual Acuity (BCVA) score: Screening, Day 0, Day 1, Week 1, Week 2, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6 (the primary efficacy endpoint for Stratum II is mean change from baseline (Day 0) to Month 6)
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| E.5.2 | Secondary end point(s) |
Stratum II
1. Incidence and severity of ocular adverse events, as identified by ophthalmic examination and/or spontaneously reported.
2. Incidence and severity of systemic adverse events, changes in vital signs, clinical laboratory abnormalities and/or spontaneously reported.
3. Percent of subjects gaining ≥15 letters in the BCVA score from baseline by scheduled study visit up to Month 6, as measured by the number of letters read correctly per ETDRS visual acuity protocol.
4. Percent of subjects gaining ≥10 letters in the BCVA score from baseline by scheduled study visit up to Month 6, as measured by the number of letters read correctly per ETDRS visual acuity protocol.
5. Percent of subjects losing ≥15 letters in BCVA score from baseline by scheduled study visit up to Month 6, as measured by the number of letters read correctly per ETDRS visual acuity protocol.
6. Percent of subjects losing ≥10 letters in BCVA score from baseline by scheduled study visit up to Month 6, as measured by the number of letters read correctly per ETDRS visual acuity protocol.
7. Mean changes in BCVA score from baseline by scheduled study visit up to Month 6, as measured by the number of letters read correctly per ETDRS visual acuity protocol.
8. Mean changes in central subfield retinal thickness from baseline by scheduled study visit up to Month 6, as assessed by HR-OCT.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Adverse events: Day 0, Day 1, Week 1, Week 2, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6
Best Corrected Visual Acuity (BCVA) score: Screening, Day 0, Day 1, Week 1, Week 2, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6
High resolution optical coherence tomography (HR-OCT): Screening, Day 0, Day 1, Week 1, Week 2, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6
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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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Stratum I-Open-Label Dose Escalation Study; Stratum II-randomised, double-blind, controlled |
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| 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 | 10 |
| 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 | 33 |
| 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 | No |
| 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 |
| Israel |
| Poland |
| United Kingdom |
| United States |
| Czech Republic |
| Germany |
| Belgium |
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| 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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| The study ends when the last data element is available from the last subject’s last study visit in Stratum II. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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