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Dose Ranging Study of Pazopanib to Treat Neovascular Age-Related Macular Degeneration

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ClinicalTrials.gov Identifier: NCT01134055
Recruitment Status : Completed
First Posted : May 31, 2010
Results First Posted : January 8, 2018
Last Update Posted : January 8, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The purpose of this study is to determine the safety and efficacy of different dosage regimens of pazopanib eye drops for the treatment of neovascular age-related macular degeneration.

Condition or disease Intervention/treatment Phase
Macular Degeneration Drug: pazopanib eye drops Drug: placebo Biological: ranibizumab intravitreal injection Phase 2

Detailed Description:
MD7110852 is a Phase 2b dose-ranging study designed to demonstrate the 1 year efficacy and safety of pazopanib eye drops for the treatment of neovascular age related macular degeneration (AMD) in subjects whose disease is currently managed with anti-VEGF (vascular endothelial growth factor) injection therapy. Eye drop regimens are double-masked with placebo eye drops and will have access to open-label ranibizumab intravitreal (IVT) injection if needed. The ranibizumab IVT injection every 4 weeks control arm is open-label.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 510 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: MD7110852, A Phase 2b Dose-Ranging Study of Pazopanib Eye Drops Versus Ranibizumab Intravitreal Injections for the Treatment of Neovascular Age-Related Macular Degeneration
Actual Study Start Date : June 1, 2010
Actual Primary Completion Date : October 1, 2012
Actual Study Completion Date : October 1, 2012


Arm Intervention/treatment
Experimental: investigational arm 1
5 mg/mL pazopanib eye drops TID with allowance for as-needed ranibizumab injection
Drug: pazopanib eye drops
A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.
Experimental: investigational arm 2
5 mg/mL pazopanib eye drops QID with allowance for as-needed ranibizumab injection
Drug: pazopanib eye drops
A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.
Experimental: investigational arm 3
10 mg/mL pazopanib eye drops BID with allowance for as-needed ranibizumab injection
Drug: pazopanib eye drops
A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.
Experimental: investigational arm 4
10 mg/mL pazopanib eye drops TID with allowance for as-needed ranibizumab injection
Drug: pazopanib eye drops
A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.
Experimental: investigational arm 5
10 mg/mL pazopanib eye drops QID with allowance for as-needed ranibizumab injection
Drug: pazopanib eye drops
A tyrosine kinase inhibitor of multiple receptors including vascular endothelial growth factor receptors and platelet-derived growth factor receptors.
Placebo Comparator: placebo control arm
Placebo eye drops QID with allowance for as-needed ranibizumab injection
Drug: placebo
placebo eye drops
Active Comparator: active open-label control arm
Ranibizumab intravitreal injection every 4 weeks
Biological: ranibizumab intravitreal injection
Humanized recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A



Primary Outcome Measures :
  1. Change From Baseline in Best-corrected Visual Acuity (BCVA) as Measured by the Number of Letters Read on the Early Treatment of Diabetic Retinopathy Study (ETDRS) Grading Charts at a Starting Distance of 4 Meters at Week 52 [ Time Frame: Day 1 and 52 weeks ]
    BCVA was measured in the study eye using the ETDRS grading charts starting at a test distance of 4 meters. The ETDRS grading chart was of at least 24 to 78 letters. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. There were seven cut off points in change from baseline visual acuity on ETDRS grading chart which are, 15 to 29, 10 to 14, 5 to 9, -4 to 4, -5 to -9, -10 to -14 and -15 to -29 letters. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. If either the baseline or post-randomization value was missing, the change from baseline was set to missing as well. Day 1 values are considered as Baseline in this study.


Secondary Outcome Measures :
  1. Percentage of Ranibizumab Re-injections Received Over 28 and 52 Weeks [ Time Frame: Up to 52 weeks ]
    The investigator interpreted each Week 4 to Week 52 Optical coherence tomography (OCT) scan, BCVA score, and available Fluorescein angiography (FA)/Fundus photography (FP) and re-injected if one or more criteria were met. The criteria were: Evidence of Intraretinal (IR) (with or without cysts) fluid or Subretinal (SR) fluid, a serous retinal pigment epithelial detachment, a notable decline in Visual Acuity, new SR or IR macular hemorrhage that the investigator judges is associated with Choroidal neovascularization, increased lesion size on FA relative to the last angiogram as judged by the investigator or leakage on FA that the investigator judges would benefit from re-injection. Injection rate over 52 weeks was computed by taking the number of injections received divided by the number of visits for the participant. Likewise for 28 weeks it was estimated as the number of post baseline injections received divided by the number of post baseline visits at or before the week 28 visit.

  2. Number of Participants With BCVA Over Time [ Time Frame: Up to Week 52 ]
    BCVA was measured in the study eye using the ETDRS grading charts starting at a test distance of 4 meters. The ETDRS grading chart was of at least 24 to 78 letters. There were seven cut off points in change from baseline visual acuity on ETDRS grading chart which are, 15 to 29, 10 to 14, 5 to 9, -4 to 4, -5 to -9, -10 to -14 and -15 to -29 letters.

  3. Number of Participants Analyzed for Visual Acuity (VA) Response Over Time [ Time Frame: Week 52 ]
    VA was measured in the study eye using the ETDRS grading charts starting at a test distance of 4 meters.The ETDRS grading chart was of at least 24 to 78 letters. There were seven cut off points in change from baseline visual acuity on ETDRS grading chart which are, 15 to 29, 10 to 14, 5 to 9, -4 to 4, -5 to -9, -10 to -14 and -15 to -29 letters. This outcome measure contains the number of participants who were analyzed for VA response.

  4. Change From Baseline in Center Point Thickness (CPT) Over Time [ Time Frame: Baseline and Week 52 ]
    CPT was the inner limiting membrane to the beginning of the retinal pigment epithelium (RPE) inclusive of SR fluid. The outer boundary included the outer segment of the photoreceptors and not included the RPE. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. If either the baseline or post-randomization value was missing, the change from baseline was set to missing as well. Day 1 values are considered as Baseline in this study. In amendment 3, inclusion criterion number 5 was revised to remove the required quantitative OCT component. OCT examination was used to supplement FA findings and provided qualitative (presence of SR and/or IR fluid) and quantitative (a CPT that is at least 250 microns) evidence of an active subfoveal lesion. Hence data for pre and post amendment have been provided separately.

  5. Number of Participants That Met Criteria for Re-injection [ Time Frame: Up to Week 52 ]
    The investigator interpreted each Week 4 to Week 52 Optical coherence tomography (OCT) scan, BCVA score, and available Fluorescein angiography (FA)/Fundus photography (FP) and re-injected if one or more criteria were met. The criteria were: Evidence of Intraretinal (IR) (with or without cysts) fluid or Subretinal (SR) fluid, a serous retinal pigment epithelial detachment, a notable decline in Visual Acuity, new SR or IR macular hemorrhage that the investigator judges is associated with Choroidal neovascularization, increased lesion size on FA relative to the last angiogram as judged by the investigator or leakage on FA that the investigator judges would benefit from re-injection.

  6. Change From Baseline in the Area of Choroidal Neovascularisation (CNV) [ Time Frame: Day 1, Week 28 and Week 52 ]
    Choroidal neovascularisation is progressive worsening of vision that can cause hemorrhage and exudation, and finally disciform scarring and retinal atrophy. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. If either the baseline or post-randomization value was missing, the change from baseline was set to missing as well. Day 1 values are considered as Baseline in this study.

  7. Change From Baseline in the Area of the CNV Lesion Complex (i.e. CNV, Blood, PED, and Fibrosis) [ Time Frame: Day 1, Week 28 and Week 52 ]
    CNV is progressive worsening of vision that can cause hemorrhage and exudation, and finally disciform scarring and retinal atrophy. The change from baseline was calculated by subtracting the baseline values from the individual post-randomization values. If either the baseline or post-randomization value was missing, the change from baseline was set to missing as well. Day 1 values are considered as Baseline in this study.

  8. Change From Baseline in the Area of Fluorescein Leakage [ Time Frame: Day 1, Week 28 and Week 52 ]
    Fluorescein angiograms was performed at the Screening, Week 12, Week 28, and Week 52 Visits. All images, including any that were performed at the investigator's medical discretion, were transferred to the FPRC. Fluorescein was injected intravenously according to usual clinic procedures. Dose response was also examined under different aspects of re-injection, such as time to first injection, the percentage of participants that required an injection by Week 28, as well as the estimation of the probability of reinjection. FA assessments of area of fluorescein leakage, CNV area and area of CNV lesion complex were also examined for dose differentiation.

  9. Change in Area of Serous Sensory Retinal Detachment (SSRD) [ Time Frame: Day 1, Week 28 and Week 52 ]
    This is an Optical coherence tomography (OCT) parameter used to manually measure thickness along any scan. OCT was performed at week 28 and week 52.

  10. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 52 Weeks ]
    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect.

  11. Summary of Potentially Clinically Important Findings for Ophthalmic Examinations [ Time Frame: Up to Week 52 ]
    Opthalmicexaminations were done on Ocular alignment and motility, pupillary function, and visual fields by confrontation. Slit-lamp biomicroscopic examination of the anterior segment structure was performed. Fundus slit-lamp biomicroscopic examination, including use of accessory diagnostic lenses, to view the vitreous, retina (including posterior pole and periphery), macula, vasculature, and optic nerve was also performed. These examinations were performed on the study eye (SE) and the Fellow eye (FE). Participants with abnormal findings are listed here.

  12. Summary of Intraocular Pressure Exam Findings [ Time Frame: Up to week 52 ]
    Intraocular pressure (IOP) measurement was done with Goldmann tonometer. Intraocular pressure was measured prior to dilating the pupil and, to account for diurnal variation, at approximately the same time of day for every visit.

  13. Number of Participants With Vital Sign Values Outside of Clinical Concern Range [ Time Frame: Up to Week 52 ]
    Vital signs including systolic and diastolic blood pressure and heart rate were measured throughout the study. Number of participants with vital signs outside of clinical concern Range were summarized. 'High' denotes above normal range and 'Low' denotes below normal range for all the categories. The potential clinical importance ranges (low and high) of the vital sign parameters were for systolic blood pressure (<85 and >160 millimeter of mercury [mmHg]), diastolic blood pressure (<45 and >100 mmHg) and heart rate (<40 and >110 beats per minute). Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important vital parameter findings at any visit were reported.

  14. Summary of Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Week 4, Week 28, Week 44 and Week 52 ]
    12-Lead ECGs were performed in triplicate and were obtained on Weeks 4 to Week 28 and Week 52. The on-treatment ECGs were used to ascertain any risk of QTc interval prolongation at extremely low pazopanib exposures compared to what was routinely observed in participants with cancer. The on-treatment ECG data collected from participants assigned to one of the control arms also provided ECG background rate data for participants not exposed to pazopanib. Participants with Clinically significant abnormal ECGs are included here.

  15. Summary of Hematology and Clinical Chemistry Parameters Data of Clinical Concern [ Time Frame: Up to Week 52 ]
    The Laboratory Parameters included Alanine Amino Transferase (ALT), Albumin, Alkaline Phosphatase, Aspartate Amino Transferase (AST), Calcium, Bicarbonate, Creatinine, Glucose, Hemoglobin, Lymphocytes, Platelet count, Potassium, Sodium, Thyroid Stimulating Hormone (TSH), Total Bilirubin, Total Neutrophils, Blood Urea Nitrogen (BUN) and White Blood Cell count (WBC). Number of participants with Laboratory outside of clinical concern Range were summarized here. Data of high and low from the clinical concern range has been provided here. Here 'High' denotes above normal range and 'Low' denotes below normal range for all the categories.

  16. Number of Participants With Laboratory Data of Clinical Concern for Urine Protein [ Time Frame: Day 1 to Week 28 and Week 52 ]
    Urine Samples were collected from Day 1 to Week 28 and Week 52 for analyses. In this dipstick test, the level of protein in urine samples was recorded as negative (Neg), trace (tr), 1+, 2+, and 3+ (the plus sign increases with a higher level of proteins in the urine: 1+=slightly positive, 2+=positive, 3+=high positive). Neg indicated no proteinuria and 3+(high positive) indicated worst proteinuria.

  17. Plasma Concentrations of Pazopanib [ Time Frame: Week 4, Week 24 and Week 52 ]
    All participants in the eye drop containing arms had a single blood sample drawn for assessment of pazopanib plasma concentration at the Week 4, Week 24 and Week 24. The sample was drawn without restriction for the time interval between blood draw and the last dose of IP eye drops.



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women aged ≥50 years.
  • Active subfoveal choroidal neovascularization (CNV) lesion secondary to AMD in study eye: Total lesion area ≤12 disc areas with CNV ≥50% total lesion area.
  • Anti-Vascular endothelial growth factor (VEGF) intravitreal injection experienced and in need of re-treatment.
  • Best-corrected visual acuity of at least 24 letters (equates to approximately 20/320 Snellen equivalents or better).

Exclusion Criteria:

  • Prior ocular investigational drug/device for choroidal neovascularization, photodynamic therapy, radiation, subfoveal or juxtafoveal focal laser photocoagulation.
  • Prior failure to anti-VEGF intravitreal injection therapy.
  • Recent ocular investigational drug/device for non-CNV condition.
  • Prior ocular surgeries (vitrectomy, scleral buckle, or glaucoma filtering/shunt surgery). Cataract surgery permitted if ≥3 months and has posterior chamber intraocular lens.
  • Center-fovea involvement of any of the following: fibrosis, atrophy, serous retinal pigment epithelial detachment, or retinal pigment epithelial tear.
  • CNV in either eye due to other causes.
  • Clinical evidence of diabetic retinopathy or diabetic macular edema.
  • Recent myocardial infarction or cerebrovascular accident.
  • Uncontrolled hypertension in spite of antihypertensive medications.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01134055


  Show 77 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01134055     History of Changes
Other Study ID Numbers: 110852
First Posted: May 31, 2010    Key Record Dates
Results First Posted: January 8, 2018
Last Update Posted: January 8, 2018
Last Verified: December 2017

Keywords provided by GlaxoSmithKline:
ranibizumab
wet AMD
MD7110852
age related macular degeneration
age-related macular degeneration
macular degeneration
pazopanib

Additional relevant MeSH terms:
Macular Degeneration
Wet Macular Degeneration
Retinal Degeneration
Retinal Diseases
Eye Diseases
Ranibizumab
Endothelial Growth Factors
Ophthalmic Solutions
Tetrahydrozoline
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Pharmaceutical Solutions
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Nasal Decongestants
Vasoconstrictor Agents
Respiratory System Agents