A Study of the Long-term Safety and Efficacy of Adalimumab in Subjects With Intermediate-, Posterior-, or Pan-uveitis

Uveitis Clinical Trial

— VISUAL III  

Official title:

A Multicenter Open-Label Study of the Long-term Safety and Efficacy of the Human Anti-TNF Monoclonal Antibody Adalimumab in Subjects With Non-infectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01148225
• Other study ID #: M11-327
• Secondary ID: 2009-016196-29
• Status: Completed
• Phase: Phase 3
• Start date: November 23, 2010
• Est. completion date: May 21, 2018

Study information

• Verified date: July 2021
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the long term efficacy and safety of adalimumab participants with non-infectious intermediate-, posterior- or pan-uveitis.

Description:

This study was initially planned to run for 78 weeks but was extended for ethical reasons, to avoid leaving participants untreated who had responded well to adalimumab treatment, so that participants were allowed to remain in the study until regulatory and/or reimbursement approval for the treatment of uveitis in adults was obtained for their respective countries. Data were collected through Week 366 (maximum), but because of decreasing sample size that became too small toward the end of the study to allow for meaningful conclusion, data cut off for efficacy analyses (intent to treat [ITT] population) occurred at Week 246, as less than 10% of participants in the ITT set had visits beyond this timepoint.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 424
• Est. completion date: May 21, 2018
• Est. primary completion date: May 21, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participant must have successfully enrolled in either study M10-877 or M10-880 and either met the endpoint of "Treatment Failure" or completed the study

Exclusion Criteria:

• A participant will be excluded from this study if the participant discontinued from study M10-877 or M10-880 for any reasons other than having a Treatment Failure event
• Participant with corneal or lens opacity that precludes visualization of the fundus or that likely requires cataract surgery during the duration of the trial
• Participants with intraocular pressure of >= 25 mmHg and on >= 2 glaucoma medications or evidence of glaucomatous optic nerve injury
• Participant with proliferative or severe non-proliferative diabetic retinopathy or clinically significant macular edema due to diabetic retinopathy
• Participant with neovascular/wet age-related macular degeneration
• Participant with abnormality of vitreo-retinal interface (i.e., vitreomacular traction, epiretinal membranes, etc.) with the potential for macular structural damage independent of the inflammatory process
• Participant with a systemic inflammatory disease that requires therapy with a prohibited immunosuppressive agent at the time of study entry

Related Conditions & MeSH terms

• Panuveitis
• Uveitis

Intervention

Drug:
• adalimumab
Adalimumab, pre-filled syringe, administered by SC injection

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

References & Publications (1)

Suhler EB, Jaffe GJ, Fortin E, Lim LL, Merrill PT, Dick AD, Brezin AP, Nguyen QD, Thorne JE, Van Calster J, Cimino L, Adan A, Goto H, Kaburaki T, Kramer M, Vitale AT, Kron M, Song AP, Liu J, Pathai S, Douglas KM, Schlaen A, Muccioli C, Van Velthoven MEJ, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent Change in Left Eye in Central Retinal Thickness (1 mm Subfield) From Baseline to Each Study Time Point Relative to Baseline for Participants Who Had Inactive Uveitis at Study Entry Over Time	Central retinal thickness was measured using optical coherence tomography (OCT) and assessed by a central reader. Percent change in left eye from baseline (Week 0) to each study time point relative to baseline for participants who had inactive uveitis at study entry is presented.	Baseline (Week 0) and Weeks 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Percent Change in Right Eye in Central Retinal Thickness (1 mm Subfield) From Baseline to Each Study Time Point Relative to Baseline for Participants Who Had Inactive Uveitis at Study Entry Over Time	Central retinal thickness was measured using optical coherence tomography (OCT) and assessed by a central reader. Percent change in right eye from baseline (Week 0) to each study time point relative to baseline for participants who had inactive uveitis at study entry is presented.	Baseline (Week 0) and Weeks 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Percent Change in Left Eye of Central Retinal Thickness (1 mm Subfield) at Each Study Time Point Relative to Week 8 for Participants Who Had Active Uveitis at Study Entry Over Time	Central retinal thickness was measured using OCT and assessed by a central reader. Percent change in left eye at each study time point relative to Week 8 (baseline) for participants who had active uveitis at study entry is presented.	Baseline (Week 8) and Weeks 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Percent Change in Right Eye of Central Retinal Thickness (1 mm Subfield) at Each Study Time Point Relative to Week 8 for Participants Who Had Active Uveitis at Study Entry Over Time	Central retinal thickness was measured using OCT and assessed by a central reader. Percent change in right eye at each study time point relative to Week 8 (baseline) for participants who had active uveitis at study entry is presented.	Baseline (Week 8) and Weeks 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Percentage of Participants With Grade =0.5+ in Anterior Chamber (AC) Cells in Both Eyes on Slit Lamp Exam According to Standardization of Uveitis Nomenclature (SUN) Criteria Over Time	Slit lamp examinations were conducted at each visit to assess AC cell count. The number of AC cells observed within a 1 mm * 1 mm slit beam was used to determine the grade according to the Standardization of Uveitis Nomenclature (SUN) criteria: Grade 0: ? 1 cell; Grade 0.5+: 1 - 5 cells; Grade 1+: 6 - 15 cells; Grade 2+: 16 - 25 cells; Grade 3+: 26 - 50 cells; and Grade 4+: = 50 cells.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Percentage of Participants Achieving a =50% Reduction in Immunosuppression Load Relative to Baseline Over Time Among Participants With Inactive Uveitis at Study Entry	Immunosuppression load was assessed using a weighted semiquantitative scale, applying grades ranging from 0 to 9 for each immunosuppressive agent on a scale for the total daily dose in milligrams per kilogram per day or per week if dosed weekly. A higher score indicating a higher immunosuppression load and a lower or decreased score indicated improvement or less need for immunosuppressive therapy. The grading scheme was used to accommodate the simultaneous use of multiple agents and provided a combined, single numeric score for the total immunosuppression load per unit body weight per day at each visit. For participants receiving multiple medications, the sum of the grading scores for each drug was used to calculate a total immunosuppression score at each visit. Data not presented after Week 234 as no participants remained on study as of Week 234.	Weeks 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, and 234
Other	Percentage of Participants Achieving a =50% Reduction in Immunosuppression Load Relative to Week 8 Over Time Among Participants With Active Uveitis at Study Entry	Immunosuppression load was assessed using a weighted semiquantitative scale, applying grades ranging from 0 to 9 for each immunosuppressive agent on a scale for the total daily dose in milligrams per kilogram per day or per week if dosed weekly. A higher score indicating a higher immunosuppression load and a lower or decreased score indicated improvement or less need for immunosuppressive therapy. The grading scheme was used to accommodate the simultaneous use of multiple agents and provided a combined, single numeric score for the total immunosuppression load per unit body weight per day at each visit. For participants receiving multiple medications, the sum of the grading scores for each drug was used to calculate a total immunosuppression score at each visit.	Weeks 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Percentage of Participants With No New Active, Inflammatory Chorioretinal or Inflammatory Retinal Vascular Lesion in Both Eyes Relative to Baseline Over Time Among Participants With Inactive Uveitis at Study Entry	Percentage of participants at each study time point with no new active, inflammatory chorioretinal or inflammatory retinal vascular lesion in both eyes relative to Baseline for participants who had inactive uveitis when they entered the study.	Weeks 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Percentage of Participants With No New Active, Inflammatory Chorioretinal or Inflammatory Retinal Vascular Lesion in Both Eyes Relative to Week 8 Over Time Among Participants With Active Uveitis at Study Entry	Percentage of participants at each study time point with no new active, inflammatory chorioretinal or inflammatory retinal vascular lesion in both eyes relative to Week 8 for participants who had active uveitis when they entered the study.	Weeks 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Percentage of Participants With Grade =0.5+ in VH in Both Eyes on Indirect Ophthalmoscopy According to NEI/SUN Criteria Over Time	Vitreous haze was measured using dilated indirect ophthalmoscopy (DIO) and assessed by the Investigator according to NEI and SUN criteria: Grade 0: No evident vitreous haze; Grade 0.5+: Slight blurring of the optic disc margin because of the haze; normal striations and reflex of the nerve fiber layer cannot be visualized; Grade 1+: Permits a better definition of both the optic nerve head and the retinal vessels (compared to higher grades); Grade 2+: Permits better visualization of the retinal vessels (compared to higher grades); Grade 3+: Permits the observer to see the optic nerve head, but the borders are quite blurry; Grade 4+: Optic nerve head is obscured.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Change in National Eye Institute (NEI) Visual Functioning Questionnaire (VFQ-25) Score at Each Study Time Point Relative to Baseline for Participants Who Had Inactive Uveitis at Study Entry Over Time	The National Eye Institute (NEI) Visual Functioning Questionnaire (VFQ-25) is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning.The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The overall composite score ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning. Baseline was defined as Week 0 for participants with inactive uveitis.	Weeks 0, 8, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Other	Change in NEI VFQ-25 Score at Each Study Time Point Relative to Week 8 for Participants Who Had Active Uveitis at Study Entry Over Time	The National Eye Institute (NEI) Visual Functioning Questionnaire (VFQ-25) is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning.The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The overall composite score ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning. Baseline was defined as Week 8 for participants with active uveitis.	Weeks 0, 8, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Primary	Number of Participants With Adverse Events	An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs/TESAEs) are defined as any event with an onset date on or after the first dose of study drug and up to 70 days after the last dose. See the Adverse Event section for details.	Baseline to Final Visit (up to 366 weeks)
Primary	Hematology: Number of Participants With Potentially Clinically Significant (PCS) Values	PCS laboratory values were defined as Common Toxicity Criteria (CTC) according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) v3.0 = Grade 3. Abbreviations used include g=grams; L=liters.	Baseline to Final Visit (Up to 366 weeks)
Primary	Chemistry: Number of Participants With PCS Values	PCS laboratory values were defined as Common Toxicity Criteria (CTC) according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) v3.0 = Grade 3. Abbreviations include ALT/SGPT=alanine aminotransferase/serum glutamate pyruvate transaminase; AST/SGOT=aspartate aminotransferase/serum glutamate oxaloacetate transaminase; g/L=grams/liter; mmol/L=millimoles/liter; ULN=upper limit of normal.	Baseline to Final Visit (Up to 366 weeks)
Primary	Pulse (Sitting): Mean Change (Beats Per Minute) From Baseline To Final Visit	Heart rate (beats per minute) was measured while the participant was sitting.	Baseline to Final Visit (Up to 366 weeks)
Primary	Respiratory Rate (Sitting): Mean Change (Respirations Per Minute) From Baseline To Final Visit	Respiratory rate (respirations per minute) was measured while the participant was sitting.	Baseline to Final Visit (Up to 366 weeks)
Primary	Temperature (Sitting): Mean Change (Centigrade) From Baseline To Final Visit	Temperature was measured while the participant was sitting.	Baseline to Final Visit (Up to 366 weeks)
Primary	Diastolic and Systolic Blood Pressure (Sitting): Mean Change (mmHg) From Baseline To Final Visit	Blood pressure was measured while the participant was sitting. Abbreviations used include mmHg=millimeters of mercury.	Baseline to Final Visit (Up to 366 weeks)
Secondary	Percentage of Participants in Quiescence Over Time	Quiescence is defined as no active inflammatory lesions and anterior chamber (AC) cell grade = 0.5+ and vitreous haze (VH) grade =0.5+. Participants with active uveitis at study entry could have been in quiescence at Week 0 because all participants were evaluated for uveitis status at the Final/Early Termination visit of the lead-in study and the Week 0 visit could have occurred up to 28 days later during which time the participant's disease status may have changed.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Percentage of Participants With Uveitis Flare Among Participants With Inactive Uveitis at Study Start	Uveitis flare is defined as no quiescence (active inflammatory lesions and AC cell grade > 0.5+ and/or VH grade >0.5+).	366 Weeks
Secondary	Percentage of Participants With Uveitis Flare From Week 8 Through Last Visit Among Participants With Active Uveitis at Study Start	Uveitis flare is defined as no quiescence (active inflammatory lesions and AC cell grade > 0.5+ and/or VH grade >0.5+).	Weeks 8 to 246 (238 Weeks)
Secondary	Percentage of Participants With New Active Inflammatory Lesions or Grade =2 in Anterior Chamber (AC) Cells or Grade =2 in Vitreous Haze (VH) Over Time	Dilated indirect ophthalmoscopy is performed to determine both vitreous haze grading and the absence/presence of inflammatory chorioretinal and/or inflammatory retinal vascular lesions. The number of AC cells observed within a 1 mm * 1 mm slit beam was recorded for each eye and this number was used to determine the grade according to Standardization of Uveitis Nomenclature (SUN) criteria. Grading of VH was based on the National Eye Institute (NEI) publication which was adapted by the SUN working group. The percentage of participants with new active inflammatory lesions or grade =2 in AC cells or grade =2 in VH are presented.	Weeks 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Percentage of Participants With Steroid-free Quiescence Over Time	Steroid-free quiescence is defined as no active inflammatory lesions and AC cell grade = 0.5+ and VH grade =0.5+ and no uveitis-related corticosteroids on the day of assessment.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Percentage of Participants in Non-quiescence (With/Without Change in Concomitant Medications Within 5 Days and With/Without Quiescence at Next Visit at Least 8 Weeks After Non-quiescence) Among Participants With Inactive Uveitis at Study Start	Percentage of participants, without quiescence, with/without change in concomitant medications within 5 days after non-quiescence and with/without quiescence at next visit at least 8 weeks after non-quiescence among participants with inactive uveitis at study start. Quiescence is defined as no active inflammatory lesions and AC cell grade = 0.5+ and VH grade =0.5+. Abbreviations used are as follows: CM=concomitant medications; NQ=non-quiescence.	366 Weeks
Secondary	Percentage of Participants in Non-quiescence (With/Without Change in Concomitant Medications Within 5 Days and With/Without Quiescence at Next Visit at Least 8 Weeks After Non-quiescence) Among Participants With Active Uveitis at Study Start	Percentage of participants, without quiescence, with/without change in concomitant medications within 5 days after non-quiescence and with/without quiescence at next visit at least 8 weeks after non-quiescence, among participants with active uveitis at study start. Quiescence is defined as no active inflammatory lesions and AC cell grade = 0.5+ and VH grade =0.5+. Abbreviations used include: CM=concomitant medications, NQ=non-quiescence.	366 Weeks
Secondary	Percentage of Participants Who Started Uveitis-related Systemic Corticosteroids During the Study	Percentage of participants who started uveitis-related systemic corticosteroids during the study.	366 Weeks
Secondary	Mean Daily Dose in Milligrams (mg) of Uveitis-related Systemic Corticosteroids in Participants With Active Uveitis Over Time	Corticosteroid doses were converted into prednisone equivalents. Participants with uveitis-related systemic corticosteroid that could not be converted to prednisone equivalents were excluded. Individual mean daily doses were calculated within the respective visit windows. For Week 0, only uveitis-related systemic corticosteroids at Baseline (Day 1 for all participants) were considered. Baseline was defined as Week 0 for all participants.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Mean Daily Dose (mg) of Uveitis-related Systemic Corticosteroids in Participants With Inactive Uveitis Over Time	Corticosteroid doses were converted into prednisone equivalents. Participants with uveitis-related systemic corticosteroid that could not be converted to prednisone equivalents were excluded. Individual mean daily doses were calculated within the respective visit windows. For Week 0, only uveitis-related systemic corticosteroids at Baseline (Day 1 for all participants) were considered. Baseline was defined as Week 0 for all participants.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Percent Change in Mean Daily Dose of Uveitis-related Systemic Corticosteroids Relative to Week 0 in Participants With Inactive Uveitis Using Systemic Corticosteroids at Week 0 Over Time	Corticosteroid doses were converted into prednisone equivalents. Participants with uveitis-related systemic corticosteroid that could not be converted to prednisone equivalents were excluded. Individual mean daily doses were calculated within the respective visit windows. For Week 0, only uveitis-related systemic corticosteroids at Baseline (Day 1 for all participants) were considered. Baseline was defined as Week 0 for all participants. Data not presented after Week 198 as no participants remained on study as of Week 198.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, and 198
Secondary	Percent Change in Mean Daily Dose of Uveitis-related Systemic Corticosteroids Relative to Week 0 in Participants With Active Uveitis Using Systemic Corticosteroids at Week 0 Over Time	Corticosteroid doses were converted into prednisone equivalents. Participants with uveitis-related systemic corticosteroid that could not be converted to prednisone equivalents were excluded. Individual mean daily doses were calculated within the respective visit windows. For Week 0, only uveitis-related systemic corticosteroids at Baseline (Day 1 for all participants) were considered. Baseline was defined as Week 0 for all participants.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Percentage of Participants Not Using Systemic Corticosteroids Over Time	Corticosteroid doses were converted into prednisone equivalents. Participants with uveitis-related systemic corticosteroid that could not be converted to prednisone equivalents were excluded. Individual mean daily doses were calculated within the respective visit windows. For Week 0, only uveitis-related systemic corticosteroids at Baseline (Day 1 for all participants) were considered. Baseline was defined as Week 0 for all participants. Data presented for participants not using systemic corticosteroids at each timepoint.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Percentage of Participants Without Worsening of Best Corrected Visual Acuity (BCVA) by =15 Letters on Early Treatment Diabetic Retinopathy Study (ETDRS) in Both Eyes Relative to Baseline Over Time Among Participants Who Had Inactive Uveitis at Study Entry	Percentage of participants at each study time point without a worsening of Best Corrected Visual Acuity (BCVA) by =15 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) in both eyes relative to Baseline for participants who had inactive uveitis when they entered the study.	Weeks 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Percentage of Participants Without Worsening of BCVA by =15 Letters on the ETDRS in Both Eyes Relative to Week 8 Over Time Among Participants With Active Uveitis at Study Entry	Percentage of participants at each study time point without a worsening of BCVA by =15 letters on the ETDRS in both eyes relative to Week 8 for participant who had active uveitis when they entered the study.	Weeks 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246
Secondary	Mean of Both Eyes of the Logarithm of the Minimum Angle of Resolution (LogMAR) BCVA Over Time	Using corrective lenses based on that visit's refraction testing, participant's BCVA was measured using an ETDRS logMAR chart. On the logMAR scale, 0 is equivalent to 20/20 visual acuity, the range of normal vision is considered to be from -0.2 to 0.1; higher values indicate visual impairment. Data presented includes the mean of both eyes for all participants (active or inactive uveitis) for all study time points.	Weeks 0, 2, 4, 8, 12, 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138, 150, 162, 174, 186, 198, 210, 222, 234, and 246

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