| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PF-04634817 is a small molecule chemokine CCR2/5 receptor antagonist that is being developed for the treatment of diabetic nephropathy and diabetic macular edema. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diabetic nephtopathy and diabetic macular edema (DME) |
|
| 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 | 18.0 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061835 |
| E.1.2 | Term | Diabetic nephropathy |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| 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 |
| Evaluate whether the clinical efficacy of PF-04634817 is non-inferior to ranibizumab, as measured by change from baseline in best corrected visual acuity after 12 weeks of treatment in subjects with diabetic macular edema (DME). |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of PF-04634817 following 12 weeks of treatment.
- To evaluate the effects of PF-04634817 on macular edema (central retinal thickness and vascular leakage) and retinopathy.
- To evaluate the systemic exposure of PF-04634817 in subjects with type 1 or type 2 diabetes and macular edema. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document
indicating that the subject (or a legal representative) has been informed
of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits,
treatment plan, laboratory tests, and other study procedures.
3. Female subjects of non-childbearing potential ≥18 years and male
subjects ≥18 years. A subject is of childbearing potential if, in the
opinion of the investigator, he/she is biologically capable of having
children and is sexually active.
4. Clinical diagnosis of diabetes mellitus (type 1 or type 2).
5. Stable medication for the management of diabetes (for those subjects
on anti-diabetes medication) for at least 3 months before randomization
and expected to remain stable during the study.
6. Serum HbA1c ≤10.5% at the screening visit.
7. Diabetic macular edema affecting the fovea in the study eye,
consisting of central retinal thickness on OCT measuring 250 μm or more
at the screening visit and a diagnosis of DME confirmed by fluorescein
angiography.
8. Reduced visual acuity resulting from retinal thickening involving the
center of the fovea and a BCVA, using ETDRS visual acuity protocol of
20/32 or worse (letter score of ≤78) and up to 20/320 or better (letter
score ≥24) in the study eye at the screening visit.
9. Visual acuity score in the non-study eye of 20/400 or better (letter
score of ≥19) at the screening visit.
10. Subjects who have not been treated with anti-angiogenic therapy,
including pegaptanib sodium, bevacizumab, ranibizumab or aflibercept,
or intra/peri-ocular steroids in either
eye within 3 months of the screening visit and who, from a clinical
perspective, are considered suitable for the withholding of treatment for
diabetic macular edema, including laser photocoagulation, for the
duration of the study following enrolment (at least 90 days).
11. Ocular media and adequate pupillary dilation to allow good quality
OCT and fundus photography.
12. If both eyes meet the inclusion criteria for this study, the most
severely affected eye will become the study eye. If both eyes are
affected equally, then the investigator and the
subject will select the study eye. |
|
| E.4 | Principal exclusion criteria |
1. Subjects (subs) who are investigational site staff members directly
involved in the conduct of the trial and their family members, site staff
members otherwise supervised by the Investigator, or subs who are
Pfizer employees directly involved in the conduct of the trial.
2. Participation in other studies involving investigational drug(s) (Ph. 1-4)
during study participation or within the prev. 60 days or 5 half-lives
preceding the 1st dose of study medication whichever is longer. 3. Other
severe acute or chronic med or psychiatric condition or lab abnormality
that may incr the risk associated with study participation or
investigational product (IP) administration or may interfere with the
interpretation of study results and, in the judgment of the investigator,
would make the subject inappro. for entry into this study. 4. Females of
childbearing potential or who are pregnant or breastfeeding. 5. Males of
childbearing potential who are unwilling or unable to use a highly
effective method of contraception as outlined in this protocol for the
duration of the study and for at least 28 days after the last dose of IP. 6.
Known history of HIV based on documented history with + serological
test, or + HIV serological test at screening. 7. Any history of prev.
untreated or current evidence of active or untreated latent infection with
Mycobacterium tuberculosis (TB). 8. Family history of prolonged QT
syndrome, or who themselves have a QTC >450 msec for males or >470
msec for females, a QRS >120 msec, or PR interval ≥300 msec, whether
considered clinically significant or not, should not be incl. in study. Any
clinically-significant ischemic changes as assessed by the investigator by
12-lead ECG at screening. The ECG should be repeated two more times
and the av. of 3 QTc, QRS or PR values should be used to determine the
subject's eligibility. QT should be corrected using Fridericia's correction.
9. Severely impaired renal function as defined by an eGFR of <30
mL/min/1.73m2 calculated using the CKDEPI eqn. at screening. 10. Any
relevant, clinically-significant abnormalities on physical examination or
clinically-significant lab tests, including subs with mod. liver function
test abnormalities >1.5 times the upper limit of normal. 11. Pan retinal
photocoagulation or macular photocoagulation performed in either eye
within 3 mo. of the screening visit. 12. Any intraocular condition or prev.
surgery in either eye that, in the opinion of the investigator, would
either (a) likely require medical or surgical intervention during the 16
wk duration of the study to prevent or treat visual loss that might result
from that condition, or (b) if allowed to progress untreated, would likely
contribute to loss of at least 2 ETDRS lines of BCVA over a 16 wk period,
or (c) may affect macular edema or reduce visual acuity during the
course of the study. 13. Ocular or peri-ocular infection in the study eye.
14. Cataract surgery in either eye within 60 days prior to study
enrolment. 15. High risk proliferative diabetic retinopathy (PDR) in
either eye. Inactive fibrosed neovascularization following pan retinal
photocoagulation (PRP) laser therapy and non high risk PDR with no
evidence of vitreous hemorrhage is permitted. 16. Structural damage to
the center of the macula in either eye likely to preclude improvement in
visual acuity following the resolution of macular edema, including but
not limited to persistent DME involving the foveal center of more than 2
yrs in duration, atrophy of the retinal pigment epithelium, subretinal
fibrosis, macular ischemia as def. by an enlarged foveal avascular zone
(FAZ >1000 μm on fundus fluorescein angiography), laser scar(s),
organized hard exudative plaque, visually-significant vitreomacular
traction, epiretinal membrane evident on ophthalmic examination or by
OCT. 17. Uncontrolled glaucoma with IOP ≥30 mm Hg and/or advance disc
cupping with glaucomatous visual field loss. 18. Inability to tolerate
fluorescein angiography. 19. Subs currently experiencing any clinically
significant or unstable medical condition that might limit their ability to
complete the study, or to comply with the requirements of the protocol,
including: dermatologic, hematologic, pulmonary, hepatic,
gastrointestinal, genitourinary, cardiovascular, endocrine, neurological
or psychiatric disease. 20. Any malignancy not considered cured (except
basal cell carcinoma and squamous cell carcinoma of the skin). A sub is
considered cured if there has been no evidence of cancer recurrence in
the previous 5 years. 21. Blood donation in the previous 4 wks, or stated intention to donate
blood or blood products during the period of the study or within 1 mo.
following completion of the study. 22. Subs receiving or likely to receive
during the study any moderate-strong inhibitors or inducers of
cytochrome P450 3A4 23. Signif. allergy or known intolerance to
ranibizumab, CCR2 or CCR5 inhibitors or any ingredient in the
formulation of PF-04634817. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean letter change from baseline (Day 0) at Week 12 in best corrected visual acuity (BCVA), as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity protocol (ETDRS-BCVA),12 of PF-04634817 compared to ranibizumab. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- The proportion of subjects gaining 15 ETDRS letters in BCVA from baseline at Week 12.
- Mean changes in central subfield retinal thickness from baseline at Week 12 as assessed by optical coherence tomography (OCT).
- Mean changes in the area of fluorescein leakage from baseline by scheduled study visit up to Week 12, as assessed by fluorescein angiography (FA).
- Mean change in steps of diabetic retinopathy (ETDRS severity scale) from baseline at Week 12, as assessed by digital fundus photography (FP).
- The systemic exposure of PF-04634817 in subjects with diabetes and macular edema. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Bulgaria |
| Czech Republic |
| Germany |
| Hungary |
| Israel |
| Moldova, Republic of |
| Poland |
| Romania |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Last Subject Last Visit (LPLV) |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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