A Phase 2, Multi-Center Study To Compare The Efficacy And Safety Of A Chemokine CCR2/5 Receptor Antagonist With Ranibizumab In Adults With Diabetic Macular Edema

• ClinicalTrials.gov Identifier: NCT01994291
• Recruitment Status: Terminated
• First Posted: November 25, 2013
• Results First Posted: October 17, 2016
• Last Update Posted: October 17, 2016
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: November 8, 2013
• First Posted Date: November 25, 2013
• Results First Submitted Date: July 5, 2016
• Results First Posted Date: October 17, 2016
• Last Update Posted Date: October 17, 2016
• Study Start Date: November 2013
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 23, 2016)

Mean Letter Change From Baseline at Week 12 in Best Corrected Visual Acuity (BCVA) [ Time Frame: Baseline (Day 0) and Week 12 ]

Refraction and visual acuity were assessed through the BCVA obtained using the retro illuminated early treatment diabetic retinopathy study (ETDRS) charts. Distance visual acuity was expressed as an ETDRS score (number of letters correctly read).

• Original Primary Outcome Measures (submitted: November 19, 2013): Mean Change from Baseline in the Best Corrected Visual Acuity Score [ Time Frame: Baseline, 12 weeks ]

Current Secondary Outcome Measures (submitted: August 23, 2016)

• Proportion of Subjects Gaining 15 ETDRS Letters in BCVA From Baseline at Week 12 [ Time Frame: Baseline (Day 0) and Week 12 ]
  Refraction and visual acuity were assessed through the BCVA obtained using the retro illuminated ETDRS charts. Distance visual acuity was expressed as an ETDRS score (number of letters correctly read).
• Mean Change From Baseline in Central Subfield Retinal Thickness in the Study Eye at Week 12 [ Time Frame: Baseline (Day 0) and Week 12 ]
  A central reading center was used for the evaluation. A photographer or technician pre certified ("study certified") by the Central Reading Center ought to perform all optical coherence tomography (OCT) imaging. Use of a Spectralis or Cirrus OCT was acceptable.
• Mean Change From Baseline in The Area of Fluorescein Leakage in the Study Eye at Week 12 [ Time Frame: Baseline (Day 0) and Week 12 ]
  Fluorescein Angiography (FA) using certified digital systems was taken by a photographer who had been pre-certified ("study-certified") by the Central Reading Center. They were evaluated by the Central Reading Center.
• Mean Change From Baseline in Steps of Diabetic Retinopathy Step (ETDRS Severity Scale) in the Study Eye at Week 12 [ Time Frame: Baseline (Day 0) and Week 12 ]
  Stereo color fundus photographs using certified digital systems were taken by a photographer who had been pre-certified ("study certified") by the Central Reading Center. They were evaluated by the Central Reading Center.
• Plasma Concentration of PF-04634817 up to Week 12 [ Time Frame: Week 0, Week 4, Week 8, and Week 12 ]

Original Secondary Outcome Measures (submitted: November 19, 2013)

• Proportion of participants gaining 15 ETDRS letters in BCVA from baseline [ Time Frame: Baseline, 12 Weeks ]
• Mean changes in central subfield retinal thickness from baseline as assessed by optical coherence tomography (OCT) [ Time Frame: Baseline, 12 Weeks ]
• Mean changes in the area of fluorescein leakage from baseline by scheduled study visit as assessed by fluorescein angiography (FA) [ Time Frame: Baseline, 12 Weeks ]
• Mean change in steps of diabetic retinopathy (ETDRS severity scale) from baseline as assessed by digital fundus photography (FP) [ Time Frame: Baseline, 12 Weeks ]
• The systemic exposure of PF-04634817 in participants with diabetes and macular edema [ Time Frame: 12 Weeks ]
  PK samples will be taken pre-dose and 2 hours (+15 mins) post-dose for all randomized subjects from Visit 2 to Visit 4 and during Visit 5. The systemic exposure of PF-04634817 will be evaluated at the above mentioned time points. Summary statistics for exposure at different time points will be presented.

Current Other Pre-specified Outcome Measures (submitted: August 23, 2016)

• Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Week 0 to Week 16 ]
  An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
• Number of Participants With Potentially Clinically Important Post-Baseline Vital Signs [ Time Frame: Week -5 to Week 16 ]
  Number of participants who met the categorical summary of post-baseline criteria at any time point, defined as: supine pulse rate <40 beats per minute (bpm) or >120 bpm; supine systolic blood pressure (SBP) ≥30 millimeters of mercury (mmHg) change from baseline in same posture; supine diastolic BP (DBP) ≥20 mmHg change from baseline in same posture; supine SBP <90 mmHg; supine DBP <50 mmHg.
• Number of Participants With Laboratory Abnormalities [ Time Frame: Week -5 to Week 16 ]
  The following laboratory parameters were analyzed for abnormalities at any time point: hematology (hemoglobin, hematocrit, red blood cell count (RBC), white blood cell count (WBC) with differential, and platelet count); blood chemistry (sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, albumin, calcium, total, direct and indirect bilirubin, gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), alkaline phosphatase, creatine phosphokinase (CPK), uric acid, amylase and lipase); follicle-stimulating hormone (FSH) (Weeks -5 to 0 only, for postmenopausal women who have been amenorrheic for at least 12 consecutive months prior to screening visit).
• Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings [ Time Frame: Week -5 to Week 16 ]
  ECG parameters included PR interval, QRS interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval greater than or equal to (>=)300 milliseconds (msec) or >=25% increase when baseline is greater than (>)200 msec and >=50% increase when baseline is less than or equal to (≤)200 msec; QRS interval >=200 msec or >=25% increase when baseline is greater than (>)200 msec and >=50% increase when baseline is less than or equal to (≤)200 msec; QT interval >=500 msec; and QTcF >=450 msec or >=30 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.
• Number of Participants With Changes in the Anterior Segment of the Study Eye at Week 12 [ Time Frame: Week -5 to Week 16 ]
  The anterior biomicroscopy exam was done undilated in order to assess whether there was any anterior segment inflammation caused either by ranibizumab or PF-04634817.
• Maximum Increase of Intraocular Pressure (IOP) From Baseline in Study Eye [ Time Frame: Week -5 to Week 16 ]
  IOP was measured using Goldmann applanation tonometry. To maintain consistency, it was recommended that the same examiner ought to measure IOP with the same tonometer at each visit for a given subject. Intraocular pressure ought to be measured in the study eye approximately 30 minutes after intravitreal injection or masked sham therapy (performed by unmasked study team member).
• Number of Participants With Change in Ophthalmoscopy Examination Results in Study Eye After Administration of Ranibizumab or Masked Sham Therapy at Week 8 [ Time Frame: Week -5 to Week 16 ]
  Ophthalmoscopy ought to be performed after pupillary dilation to examine the vitreous body, optic nerve head, macular and peripheral retina. All findings, including the presence or absence of vitreous inflammation, ought to be documented. All post-dose ophthalmoscopy assessments ought to be made immediately following the administration of ranibizumab or masked sham therapy.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 2, Multi-Center Study To Compare The Efficacy And Safety Of A Chemokine CCR2/5 Receptor Antagonist With Ranibizumab In Adults With Diabetic Macular Edema
• Official Title: A Phase 2, Randomized, Double-Masked, Placebo-Controlled, Parallel Group, Multi-Center Study To Compare The Efficacy And Safety Of A Chemokine CCR2/5 Receptor Antagonist (PF-04634817) With That Of Ranibizumab In Adult Subjects With Diabetic Macular Edema
• Brief Summary: The study hypothesis under test is that administration of the CCR2/5 antagonist has the potential to be as effective as the current treatment options for subjects with diabetic macular edema. The current treatment option for these subjects is an injection directly into the eye, while this CCR2/5 antagonist would be an oral drug which has the potential to be just as effective. This CCR2/5 antagonist also has a broader anti-inflammatory potential and might be able to provide an alternative mechanism to treat Diabetic Macular Edema.
• Detailed Description: Study recruitment was stopped on April 9, 2015. This decision was taken for business reasons due to changes in the prioritization of the drug development portfolio. This decision was not as a result of any evolving safety, efficacy issue or changes in the risk:benefit assessment of this product or regulatory interactions.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Macular Edema, Diabetic

Intervention

• Drug: Ranibizumab

  Intravitreal Injection supplied as:

  • 10 mg/mL in a 0.2 mL vial with instructions on preparation and administration of the 0.5 mg (0.05 mL) dose.
  • 6 mg/mL in a single use vial with instructions on preparation and administration of the 0.3 mg (0.05 mL) dose.
  • Adminstered once a month for 12 weeks
• Drug: Placebo

  Oral Placebo is provided in tablet form to match the 50mg dose of PF-04634817.

  Dose is 4 tablets each day for 12 weeks

• Drug: PF-04634817
  Four 50mg tablets PF-04634817 once a day for 12 weeks.
• Drug: Masked Sham Therapy
  Empty, needle-less syringe is used by the unmasked team once a month.

Study Arms

• Active Comparator: Arm 1
  Intravitreal administration of ranibizumab (either 0.3 or 0.5 mg, given monthly, as detailed in the prescribing information and label content approved for the country governing the study site) plus an oral placebo.
  Interventions:

  • Drug: Ranibizumab
  • Drug: Placebo
• Experimental: Arm 2
  Oral PF-04634817 200 mg, once daily plus a masked sham therapy (given monthly).
  Interventions:

  • Drug: PF-04634817
  • Drug: Masked Sham Therapy

• Publications *: Gale JD, Berger B, Gilbert S, Popa S, Sultan MB, Schachar RA, Girgenti D, Perros-Huguet C. A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2659-2669. doi: 10.1167/iovs.17-22731.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 23, 2016): 199
• Original Estimated Enrollment (submitted: November 19, 2013): 200
• Actual Study Completion Date: August 2015
• Actual Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients with Diabetes Mellitus (Type 1 or Type 2) Showing Diabetic Macular Edema in the Eye
• Reduced visual acuity resulting from retinal thickening
• Female subjects of non-childbearing potential ≥18 years and male subjects greater than or equal to 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.

• Female subjects who are not of childbearing potential must meet at least one of the following criteria:

  • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
  • Have medically confirmed ovarian failure; or
  • Achieved post-menopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females.

Exclusion Criteria:

• Severe Impaired Renal Function
• Any intraocular condition or previous surgery in either eye that would likely require medical or surgical intervention during the study duration or if allowed to progress untreated for the 16 weeks of study duration, would likely contribute to a reduction in visual acuity.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Czech Republic, Germany, Hungary, Israel, Moldova, Republic of, Poland, Romania, United States

Administrative Information

• NCT Number: NCT01994291
• Other Study ID Numbers: B1261009; 2013-003147-27 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: August 2016