Macular Degeneration
Conditions
Brief summary
This study will evaluate visual improvement in patients treated with Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified (IGIV-C) or placebo who have Age-Related Macular Degeneration (AMD) with occult Choroidal Neovascularization (CNV).
Detailed description
The purpose of this trial is to investigate the effect of IGIV-C in subjects suffering from AMD with occult CNV where fewer treatment options exist for patients with this disease form. This study is designed as a randomized, double-blind, parallel group, placebo-controlled prospective trial. Sixty patients, 30 per treatment group, with newly diagnosed pure occult CNV defined by angiography diagnostic criteria will be enrolled. If a subject has more than one eye affected with occult CNV, the eye with the better vision as measured by visual acuity ( Logarithm of the Minimum Angle of Resolution \[LogMAR\] score) will be entered as the study eye. Patients will be randomized to receive either IGIV-C at a dose of 2 g/kg body weight (bw) over 5 consecutive days or matching placebo. Additional 2 study drug treatment courses (IGIV-C or matching placebo) will be administered every 4 weeks at the same dose of 2 g/kg bw given over 5 days. Subjects' visual acuity will be measured and reported as LogMAR at screening, week 0 (baseline), day 5, week 4, week 8 and week 12. If at anytime during the study the subject's visual acuity worsens by ≥ 2 lines (0.2 on the LogMAR score), then a slit lamp examination will be performed and an angiogram will be conducted; the patient would be discontinued if the worsening is due to some other reason outside of the occult CNV or if the disease has changed from pure occult to the classic or mixed form. Subjects will be evaluated for efficacy (LogMAR score) at endpoint (at week 12 or at last LogMAR assessment at or after week 8, if the subject prematurely discontinues the trial). At the end of the treatment period (week 12), patients will be entered into a 3 month observation period with monthly visual acuity LogMAR score assessments.
Interventions
The dose per infusion cycle was 2 g/kg body weight over 5 consecutive days (= 4 mL/kg body weight/infusion). The infusion duration was approximately 1.5 - 2 h.
Albumin (Human) 20% or 25% will be diluted with 5% glucose to a final concentration of 0.1%.
Sponsors
Grifols Therapeutics LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
51 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The best corrected visual acuity must be in the range of 20/40 to 20/200 on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart (0.5 - 0.1). * Patient complaint of visual loss within the last three months prior to study entry. * Documented visual loss on a visual acuity chart in the 3-month period prior to the beginning of the run-in period. * Signed written informed consent prior to initiation of any study-related procedures.
Exclusion criteria
* Treatment with IGIV within the last 3 months prior to the run-in. * Previous photodynamic therapy (PDT) or vitrectomy or transpupillary thermotherapy (TTT) or any specific pre-treatment of CNV * Subfoveal blood in the study eye if ≥ 1/2 disc diameter as measured by slit lamp during run-in period. * History of anaphylaxis or severe systemic response to immunoglobulin or with a blood product. * Cardiac insufficiency (NYHA III/IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic heart disease, or severe or uncontrolled hypertension (diastolic \> 95 mmHg or systolic \>170 mmHg) * Females, who are pregnant, breast feeding, or if of childbearing potential, unwilling to practice adequate contraception throughout the study. * History of renal insufficiency or serum creatinine levels \> 221 µmol/L (2.5 mg/dL). * Known selective immunoglobulin A (IgA) deficiency * Other investigational drugs received within the past 3 months. * Conditions whose symptoms and effects could alter protein catabolism and/or immunoglobulin (IgG) utilization (e.g. protein-losing enteropathies, nephrotic syndrome). * Known hypercoagulable state. * Patients on continuous systemic steroid treatment * Mentally challenged adult subjects who cannot give independent informed consent. * History of thromboembolic events. * Diabetes mellitus requiring drug treatment. * Known severe hypersensitivity to sodium fluorescein. * Acute or known ocular diseases such as glaucoma, arterial or venous occlusions, acute ischemic optic-neuropathy, impairment of visual acuity due to opacities in the lens (LOCSIII: NO 5-6 or C: 4-5 or P 4-5) or vitreous which may influence the evaluation of the therapeutic effect.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Visual Acuity (Logarithm of the Minimum Angle of Resolution [LogMAR]) Score From Baseline for IGIV-C, 10% Compared to Placebo at Week 12 or at Last LogMAR Assessment (Conducted at or After Week 8 of the Treatment Period) | At Week 12 or, if the Week 12 assessment is not available, at the last LogMAR assessment conducted at or after Week 8 of the Treatment Period | Using the LogMAR score, lower values correspond to higher visual acuity. For example, a visual acuity of 20/20 corresponds to a LogMAR value of zero (0), and a visual acuity of 20/100 corresponds to a LogMAR value of 0.7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Who Improve Visual Acuity From Baseline to Endpoint by ≥ 0.2 LogMAR | Last measurement at or later than Week 8 | — |
| Mean Change in LogRAD Score From Baseline to Endpoint (RADNER Test) | Last measurement at or later than Week 8 | The RADNER test gives not only information about the subject's reading performance, but also about the reading speed (life quality) and the faults while reading. The RADNER reading charts (1, 2, and 3) contain sentences in paragraphs having a range of print sizes starting with the largest print at the top.The subject was randomly assigned one of the RADNER charts, and the charts were different between consecutive visits. The reading distance was 25 cm. The subject's score was corrected for reading speed and errors. The range of possible logRAD scores was from 2.0 (could not read the first paragraph) to -0.2, with higher scores indicating lower reading acuity and lower scores indicating higher reading acuity. |
| Proportion of Subjects Who Improve Visual Acuity From Baseline to Endpoint by ≥ 0.1 LogMAR | Last measurement at or later than Week 8 | — |
| Presence of Fibrosis and Location Assessed by Slit-lamp | Last measurement at or later than Week 8 | — |
| Mean Change From Baseline to Endpoint in Size of Lesion (Largest Dimension Relative to Disk Diameter) Assessed by Central Fluorescein Angiogram Reading Center | At end of treatment (12 weeks) | — |
| Proportion of Subjects With an Increase ≥ 2 or More Points in Lens Opacity Classification System (LOCS III) for Nuclear Opalescence, Nuclear Color, Cortical Cataract or Posterior Subcapsular Cataract Categories | Last measurement at or later than Week 8 | The LOCS III scale for cortical cataract and posterior subcapsular cataract opacity ranged from 1.0 to 5.0. The LOCS III scale for nuclear opalescence and for nuclear color was 1.0 to 6.0. For all scales, higher values indicate higher opacity, opalescence, or color. |
Countries
Germany
Participant flow
Recruitment details
A total of 96 subjects were enrolled (signed the informed consent and screened) in this study at 6 German study centers.
Pre-assignment details
Of the 96 enrolled subjects, 14 subjects withdrew their consent for participation before randomization and an additional 25 subjects were withdrawn before randomization because of violations of inclusion/exclusion criteria or because their angiograms were rejected by the central reading site as not meeting the pre-specified criteria.
Participants by arm
| Arm | Count |
|---|---|
| IGIV-C 10% Immune Globulin Intravenous \[Human\], 10% Caprylate/Chromatography Purified | 29 |
| Placebo Albumin (Human) 25%, United States Pharmacopeia (USP) | 24 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Develop. of choroidal neovascularization | 3 | 8 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | IGIV-C 10% | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 20 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Continuous | 74.724 years STANDARD_DEVIATION 8.417 | 74.042 years STANDARD_DEVIATION 10.217 | 74.415 years STANDARD_DEVIATION 9.189 |
| Logarithm of the Minimum Angle of Resolution (LogMAR) of the Study Eyes | 0.581 LogMAR STANDARD_DEVIATION 0.209 | 0.533 LogMAR STANDARD_DEVIATION 0.153 | 0.559 LogMAR STANDARD_DEVIATION 0.186 |
| Region of Enrollment Germany | 29 participants | 24 participants | 53 participants |
| Sex: Female, Male Female | 20 Participants | 17 Participants | 37 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 16 Participants |
| Visual Acuity Score (VAS) of the Study Eyes | 55.9 units on a scale STANDARD_DEVIATION 10.4 | 58.4 units on a scale STANDARD_DEVIATION 7.7 | 57.0 units on a scale STANDARD_DEVIATION 9.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 30 | 15 / 27 |
| serious Total, serious adverse events | 1 / 30 | 5 / 27 |
Outcome results
Primary
Mean Change in Visual Acuity (Logarithm of the Minimum Angle of Resolution [LogMAR]) Score From Baseline for IGIV-C, 10% Compared to Placebo at Week 12 or at Last LogMAR Assessment (Conducted at or After Week 8 of the Treatment Period)
Using the LogMAR score, lower values correspond to higher visual acuity. For example, a visual acuity of 20/20 corresponds to a LogMAR value of zero (0), and a visual acuity of 20/100 corresponds to a LogMAR value of 0.7.
Time frame: At Week 12 or, if the Week 12 assessment is not available, at the last LogMAR assessment conducted at or after Week 8 of the Treatment Period
Population: The Intent-to-Treat (ITT) Population consisted of all randomized subjects who received any amount of study medication and had at least one evaluation of the primary efficacy variable (LogMAR score) at Week 8 or later and at Baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IGIV-C 10% | Mean Change in Visual Acuity (Logarithm of the Minimum Angle of Resolution [LogMAR]) Score From Baseline for IGIV-C, 10% Compared to Placebo at Week 12 or at Last LogMAR Assessment (Conducted at or After Week 8 of the Treatment Period) | Baseline | 0.581 LogMAR | Standard Deviation 0.209 |
| IGIV-C 10% | Mean Change in Visual Acuity (Logarithm of the Minimum Angle of Resolution [LogMAR]) Score From Baseline for IGIV-C, 10% Compared to Placebo at Week 12 or at Last LogMAR Assessment (Conducted at or After Week 8 of the Treatment Period) | End of treatment (EOT) Week 12 or last assessment | 0.646 LogMAR | Standard Deviation 0.309 |
| IGIV-C 10% | Mean Change in Visual Acuity (Logarithm of the Minimum Angle of Resolution [LogMAR]) Score From Baseline for IGIV-C, 10% Compared to Placebo at Week 12 or at Last LogMAR Assessment (Conducted at or After Week 8 of the Treatment Period) | Change End of treatment (EOT) minus Baseline | 0.064 LogMAR | Standard Deviation 0.22 |
| Placebo | Mean Change in Visual Acuity (Logarithm of the Minimum Angle of Resolution [LogMAR]) Score From Baseline for IGIV-C, 10% Compared to Placebo at Week 12 or at Last LogMAR Assessment (Conducted at or After Week 8 of the Treatment Period) | Baseline | 0.533 LogMAR | Standard Deviation 0.153 |
| Placebo | Mean Change in Visual Acuity (Logarithm of the Minimum Angle of Resolution [LogMAR]) Score From Baseline for IGIV-C, 10% Compared to Placebo at Week 12 or at Last LogMAR Assessment (Conducted at or After Week 8 of the Treatment Period) | End of treatment (EOT) Week 12 or last assessment | 0.557 LogMAR | Standard Deviation 0.244 |
| Placebo | Mean Change in Visual Acuity (Logarithm of the Minimum Angle of Resolution [LogMAR]) Score From Baseline for IGIV-C, 10% Compared to Placebo at Week 12 or at Last LogMAR Assessment (Conducted at or After Week 8 of the Treatment Period) | Change End of treatment (EOT) minus Baseline | 0.024 LogMAR | Standard Deviation 0.182 |
Comparison: The primary efficacy comparison for the change in LogMAR from baseline to endpoint was a two-way analysis of variance (ANOVA) with treatment group and center as fixed factors (main effect model).p-value: 0.49ANOVA
Secondary
Mean Change From Baseline to Endpoint in Size of Lesion (Largest Dimension Relative to Disk Diameter) Assessed by Central Fluorescein Angiogram Reading Center
Time frame: At end of treatment (12 weeks)
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IGIV-C 10% | Mean Change From Baseline to Endpoint in Size of Lesion (Largest Dimension Relative to Disk Diameter) Assessed by Central Fluorescein Angiogram Reading Center | 0.074 Disk Diameter | Standard Deviation 0.209 |
| Placebo | Mean Change From Baseline to Endpoint in Size of Lesion (Largest Dimension Relative to Disk Diameter) Assessed by Central Fluorescein Angiogram Reading Center | 0.173 Disk Diameter | Standard Deviation 0.298 |
Secondary
Mean Change in LogRAD Score From Baseline to Endpoint (RADNER Test)
The RADNER test gives not only information about the subject's reading performance, but also about the reading speed (life quality) and the faults while reading. The RADNER reading charts (1, 2, and 3) contain sentences in paragraphs having a range of print sizes starting with the largest print at the top.The subject was randomly assigned one of the RADNER charts, and the charts were different between consecutive visits. The reading distance was 25 cm. The subject's score was corrected for reading speed and errors. The range of possible logRAD scores was from 2.0 (could not read the first paragraph) to -0.2, with higher scores indicating lower reading acuity and lower scores indicating higher reading acuity.
Time frame: Last measurement at or later than Week 8
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IGIV-C 10% | Mean Change in LogRAD Score From Baseline to Endpoint (RADNER Test) | 0.164 LogRAD | Standard Deviation 0.343 |
| Placebo | Mean Change in LogRAD Score From Baseline to Endpoint (RADNER Test) | 0.159 LogRAD | Standard Deviation 0.371 |
p-value: 0.995% CI: [-0.21, 0.19]ANOVA
Secondary
Presence of Fibrosis and Location Assessed by Slit-lamp
Time frame: Last measurement at or later than Week 8
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGIV-C 10% | Presence of Fibrosis and Location Assessed by Slit-lamp | 1 participants |
| Placebo | Presence of Fibrosis and Location Assessed by Slit-lamp | 3 participants |
p-value: 0.74Cochran-Mantel-Haenszel
Secondary
Proportion of Subjects Who Improve Visual Acuity From Baseline to Endpoint by ≥ 0.1 LogMAR
Time frame: Last measurement at or later than Week 8
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGIV-C 10% | Proportion of Subjects Who Improve Visual Acuity From Baseline to Endpoint by ≥ 0.1 LogMAR | 24.1 percentage of participants |
| Placebo | Proportion of Subjects Who Improve Visual Acuity From Baseline to Endpoint by ≥ 0.1 LogMAR | 20.8 percentage of participants |
p-value: 0.76Cochran-Mantel-Haenszel
Secondary
Proportion of Subjects Who Improve Visual Acuity From Baseline to Endpoint by ≥ 0.2 LogMAR
Time frame: Last measurement at or later than Week 8
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGIV-C 10% | Proportion of Subjects Who Improve Visual Acuity From Baseline to Endpoint by ≥ 0.2 LogMAR | 3.4 percentage of participants |
| Placebo | Proportion of Subjects Who Improve Visual Acuity From Baseline to Endpoint by ≥ 0.2 LogMAR | 16.7 percentage of participants |
p-value: 0.13Cochran-Mantel-Haenszel
Secondary
Proportion of Subjects With an Increase ≥ 2 or More Points in Lens Opacity Classification System (LOCS III) for Nuclear Opalescence, Nuclear Color, Cortical Cataract or Posterior Subcapsular Cataract Categories
The LOCS III scale for cortical cataract and posterior subcapsular cataract opacity ranged from 1.0 to 5.0. The LOCS III scale for nuclear opalescence and for nuclear color was 1.0 to 6.0. For all scales, higher values indicate higher opacity, opalescence, or color.
Time frame: Last measurement at or later than Week 8
Population: Intent to Treat subjects with cataract
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGIV-C 10% | Proportion of Subjects With an Increase ≥ 2 or More Points in Lens Opacity Classification System (LOCS III) for Nuclear Opalescence, Nuclear Color, Cortical Cataract or Posterior Subcapsular Cataract Categories | 0 participants |
| Placebo | Proportion of Subjects With an Increase ≥ 2 or More Points in Lens Opacity Classification System (LOCS III) for Nuclear Opalescence, Nuclear Color, Cortical Cataract or Posterior Subcapsular Cataract Categories | 0 participants |