Reduction in the Occurrence of Center-Involved Diabetic Macular Edema

Sponsor
Chromaderm, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00090519
Collaborator
(none)
731
84
2
74
8.7
0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if ruboxistaurin can help slow the worsening of an eye disease called macular edema in patients with diabetes.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
731 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Reduction in the Occurrence of Center-Involved Diabetic Macular Edema
Study Start Date :
Feb 1, 2004
Actual Primary Completion Date :
Apr 1, 2010
Actual Study Completion Date :
Apr 1, 2010

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ruboxistaurin

32 milligrams (mg) once daily (QD) oral for up to 36 months

Drug: ruboxistaurin
32 mg once daily (QD) oral for up to 36 months
Other Names:
  • LY333531
  • Arxxant
  • Placebo Comparator: Placebo

    QD oral for up to 36 months

    Drug: placebo
    QD oral for up to 36 months

    Outcome Measures

    Primary Outcome Measures

    1. Mean Duration of Definite Center of Macula-involved Diabetic Macular Edema (DME) [6 Months through 36 Months]

      Duration of center of macula involvement when primary study outcome (DME involvement in center of macula determined by central grading of stereoscopic fundus photographs) was identified at a visit, participant was considered to have had definite center involvement for a specified length of time between the adjacent visits. Total duration of center involvement was calculated. Mean duration was total duration of center involvement divided by total number of participants. Participant durations were summarized, total number of months of center involvement in both treatment groups were displayed.

    2. Occurrence of Sustained Moderate Visual Loss (SMVL) in a Diabetic Retinopathy (DR) Study Eye [Baseline, 36 Months]

      The occurrence of SMVL was defined as ≥15 letter decrease from baseline in best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) in any DR study eye relative to baseline that is sustained for the last 6 months of participation. ETDRS VA: participant starts at the top of the chart containing 5 letters per row and reads down the chart until reaching a row where a minimum of 3 letters on a line cannot be read. Participant is scored by how many letters could be correctly identified. A higher number of letters correctly identified represents better visual acuity.

    Secondary Outcome Measures

    1. Change From Baseline in Visual Acuity by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity (VA) Chart at 36 Months [Baseline, 36 Months]

      ETDRS VA: participant starts at the top of the chart containing 5 letters per row and reads down the chart until reaching a row where a minimum of 3 letters on a line cannot be read. Participant is scored by how many letters could be correctly identified. A higher number of letters correctly identified represents better visual acuity. Results are reported based on the number of diabetic retinopathy (DR) eyes.

    2. First Occurrence of Focal/Grid Photocoagulation [Baseline through 36 Months]

      The first occurrence of focal/grid photocoagulation regardless of diabetic macular edema (DME) distance from the center of the macula.

    3. Change From Baseline in Contrast Sensitivity by Pelli-Robson [Baseline, 36 Months]

      Pelli-Robson chart read from left to right + from top to bottom. Each line has 2 groups, each of 3 letters. Letters in each group have same contrast. Contrast in each successive group is less than the preceding group. Participant reads letters starting with highest contrast, continues until 2 or 3 letters in 1 group are incorrectly named. Scored on key showing all letters at full contrast, gives the log contrast sensitivity corresponding to each group. Score is determined by previous group (last group in which 2 or 3 letters were correctly named). Results reported based on number of DR eyes.

    4. Progression of Nonproliferative Diabetic Retinopathy (DR) by Seven-field Stereo Fundus Photography [Baseline through 36 Months]

      Participants were classified as having experienced progression or no progression of DR by 36-month visit. Progression of DR=3 steps on ETDRS retinopathy severity person scale for participants with both eyes less than proliferative diabetic retinopathy (PDR) at baseline OR 2 steps on ETDRS retinopathy severity eye scale for participants with 1 eye less than PDR at baseline OR application of panretinal laser therapy. Participants were assigned at baseline to ETDRS retinopathy severity scale for persons or individual eyes; determination of no progression/progression was dependent on the scale.

    5. Change From Baseline in Estimated Glomerular Filtration Rate [Baseline, 36 Months]

      The Modification of Diet in Renal Disease (MDRD) study formula used for the estimated glomerular filtration rate (eGFR) determination is: eGFR = 170 X (Serum creatinine concentration [mg/deciliter (dL)])-0.999 X (Age [years]) -0.176 X (0.762 if participant is female) X (1.180 if participant is black) X (Serum urea nitrogen concentration [mg/dL])-0.170 X (Serum albumin concentration [grams (g)/dL])+0.318.

    6. Change From Baseline at Endpoint in Albumin/Creatinine Ratio [36 Months]

    7. Change From Baseline at Endpoint in Visual Function by the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) at 36 Months [36 Months]

      25 vision-targeted questions representing 11 vision-related constructs and a 1-item general health rating question. Measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning and task-oriented domains related to daily visual functioning. Each item is converted to a 0 to 100 scale such that a higher score represents better functioning.

    8. Number of Participants With Adverse Events [Baseline through 36 Months]

      Summaries of serious adverse events (SAEs) and all other non-serious adverse events (AEs) are located in the Reported Adverse Event Module.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Type 1 or Type 2 diabetes

    • 18 years or older

    • Non-clinically significant diabetic macular edema

    • Mild to moderate diabetic retinopathy in the study eye, vitreous hemorrhage in the study eye

    • Relatively good vision (20/30 or better)

    Exclusion Criteria:
    • Surgery or laser treatment in the study eye

    • Glaucoma in the study eye

    • Glycosylated hemoglobin (HbA1c) greater than 11%, or systolic blood pressure greater than 170 millimeters of mercury (mmHg)

    • Liver disease, dialysis or renal transplant

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Artesia California United States 90701
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    81 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Aberdeen Scotland United Kingdom AB25 2ZN
    82 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Birmingham West Midlands United Kingdom B9 5SS
    83 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Bristol United Kingdom BS1 2LX
    84 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. London United Kingdom EC1V 2PD

    Sponsors and Collaborators

    • Chromaderm, Inc.

    Investigators

    • Study Director: Karl Beutner, Chromaderm, Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Chromaderm, Inc.
    ClinicalTrials.gov Identifier:
    NCT00090519
    Other Study ID Numbers:
    • 8211
    • B7A-MC-MBDL
    First Posted:
    Aug 31, 2004
    Last Update Posted:
    Oct 6, 2016
    Last Verified:
    Aug 1, 2016
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Period Title: Overall Study
    STARTED 371 360
    COMPLETED 298 285
    NOT COMPLETED 73 75

    Baseline Characteristics

    Arm/Group Title Ruboxistaurin Placebo Total
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months Total of all reporting groups
    Overall Participants 371 360 731
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    55.20
    (10.85)
    55.15
    (11.18)
    55.17
    (11.01)
    Sex: Female, Male (Count of Participants)
    Female
    138
    37.2%
    137
    38.1%
    275
    37.6%
    Male
    233
    62.8%
    223
    61.9%
    456
    62.4%
    Region of Enrollment (participants) [Number]
    United States
    93
    25.1%
    97
    26.9%
    190
    26%
    Portugal
    15
    4%
    16
    4.4%
    31
    4.2%
    Taiwan
    3
    0.8%
    1
    0.3%
    4
    0.5%
    Spain
    13
    3.5%
    11
    3.1%
    24
    3.3%
    Russian Federation
    28
    7.5%
    24
    6.7%
    52
    7.1%
    United Kingdom
    21
    5.7%
    18
    5%
    39
    5.3%
    Italy
    8
    2.2%
    6
    1.7%
    14
    1.9%
    India
    25
    6.7%
    26
    7.2%
    51
    7%
    France
    11
    3%
    10
    2.8%
    21
    2.9%
    Mexico
    22
    5.9%
    22
    6.1%
    44
    6%
    Canada
    22
    5.9%
    25
    6.9%
    47
    6.4%
    Brazil
    13
    3.5%
    16
    4.4%
    29
    4%
    Poland
    20
    5.4%
    16
    4.4%
    36
    4.9%
    Australia
    20
    5.4%
    17
    4.7%
    37
    5.1%
    Denmark
    26
    7%
    28
    7.8%
    54
    7.4%
    Netherlands
    9
    2.4%
    8
    2.2%
    17
    2.3%
    Germany
    22
    5.9%
    19
    5.3%
    41
    5.6%
    Body Mass Index (BMI) (kilograms/square meters (kg/m^2)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kilograms/square meters (kg/m^2)]
    29.90
    (6.09)
    29.82
    (5.89)
    29.86
    (5.99)
    Blood Pressure (millimeters of mercury (mmHg)) [Mean (Standard Deviation) ]
    Systolic Blood Pressure
    132.90
    (15.25)
    133.50
    (15.58)
    133.20
    (5.99)
    Diastolic Blood Pressure
    77.68
    (8.68)
    77.77
    (9.05)
    77.73
    (8.86)
    Glycosylated hemoglobin (HbA1c) (percent glycosylated hemoglobin) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percent glycosylated hemoglobin]
    8.14
    (1.31)
    8.25
    (1.31)
    8.19
    (1.31)
    Diabetes Type (participants) [Number]
    Type 1
    85
    22.9%
    76
    21.1%
    161
    22%
    Type 2
    286
    77.1%
    284
    78.9%
    570
    78%
    Duration of diabetes (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    15.82
    (8.00)
    15.57
    (7.48)
    15.70
    (7.75)
    Insulin use (participants) [Number]
    Yes
    241
    65%
    228
    63.3%
    469
    64.2%
    No
    130
    35%
    132
    36.7%
    262
    35.8%
    Number of diabetic retinopathy (DR) study eyes per participant (participants) [Number]
    Two
    351
    94.6%
    336
    93.3%
    687
    94%
    One
    20
    5.4%
    24
    6.7%
    44
    6%
    Visual Acuity Score (Letters Correct) (Letters read correctly) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Letters read correctly]
    84.12
    (7.93)
    84.27
    (7.70)
    84.19
    (7.81)
    Diabetic Retinopathy (DR) Level (DR study eyes for each level) [Number]
    <47
    465
    421
    886
    47
    250
    272
    522
    53
    7
    3
    10

    Outcome Measures

    1. Primary Outcome
    Title Mean Duration of Definite Center of Macula-involved Diabetic Macular Edema (DME)
    Description Duration of center of macula involvement when primary study outcome (DME involvement in center of macula determined by central grading of stereoscopic fundus photographs) was identified at a visit, participant was considered to have had definite center involvement for a specified length of time between the adjacent visits. Total duration of center involvement was calculated. Mean duration was total duration of center involvement divided by total number of participants. Participant durations were summarized, total number of months of center involvement in both treatment groups were displayed.
    Time Frame 6 Months through 36 Months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population including all randomized participants analyzed according to the treatment group to which they were originally assigned by random allocation even if the participant does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 349 346
    Mean (Standard Deviation) [months per participant]
    1.72
    (4.95)
    1.69
    (4.41)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.969
    Comments
    Method ANOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.714 to 0.686
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline in Visual Acuity by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity (VA) Chart at 36 Months
    Description ETDRS VA: participant starts at the top of the chart containing 5 letters per row and reads down the chart until reaching a row where a minimum of 3 letters on a line cannot be read. Participant is scored by how many letters could be correctly identified. A higher number of letters correctly identified represents better visual acuity. Results are reported based on the number of diabetic retinopathy (DR) eyes.
    Time Frame Baseline, 36 Months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population including all randomized participants analyzed according to the treatment group to which they were originally assigned by random allocation even if the participant does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 371 360
    Measure DR study eyes 722 695
    Baseline (letters correct) (n=722, 695)
    84.12
    (7.93)
    84.27
    (7.70)
    Change from baseline (n=687,670)
    -1.14
    (7.38)
    -2.30
    (9.21)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.015
    Comments P-value is for change from baseline.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 1.09
    Confidence Interval (2-Sided) 95%
    0.21 to 1.97
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title First Occurrence of Focal/Grid Photocoagulation
    Description The first occurrence of focal/grid photocoagulation regardless of diabetic macular edema (DME) distance from the center of the macula.
    Time Frame Baseline through 36 Months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population including all randomized participants analyzed according to the treatment group to which they were originally assigned by random allocation even if the participant does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 371 360
    Yes
    32
    8.6%
    27
    7.5%
    No
    339
    91.4%
    333
    92.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.577
    Comments P-value is for first occurrence of focal/grid photocoagulation yes versus no.
    Method Chi-squared
    Comments
    4. Secondary Outcome
    Title Change From Baseline in Contrast Sensitivity by Pelli-Robson
    Description Pelli-Robson chart read from left to right + from top to bottom. Each line has 2 groups, each of 3 letters. Letters in each group have same contrast. Contrast in each successive group is less than the preceding group. Participant reads letters starting with highest contrast, continues until 2 or 3 letters in 1 group are incorrectly named. Scored on key showing all letters at full contrast, gives the log contrast sensitivity corresponding to each group. Score is determined by previous group (last group in which 2 or 3 letters were correctly named). Results reported based on number of DR eyes.
    Time Frame Baseline, 36 Months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: all randomized participants analyzed according to treatment group to which they were originally assigned by random allocation even if they did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 371 360
    Measure DR Study Eyes 718 689
    Baseline (letters correct) (n=718,689)
    33.54
    (3.33)
    33.71
    (3.54)
    Change from baseline (n=685,664)
    -0.54
    (3.84)
    -1.06
    (4.68)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.041
    Comments P-value is for change from baseline.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 0.45
    Confidence Interval (2-Sided) 95%
    0.02 to 0.87
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Progression of Nonproliferative Diabetic Retinopathy (DR) by Seven-field Stereo Fundus Photography
    Description Participants were classified as having experienced progression or no progression of DR by 36-month visit. Progression of DR=3 steps on ETDRS retinopathy severity person scale for participants with both eyes less than proliferative diabetic retinopathy (PDR) at baseline OR 2 steps on ETDRS retinopathy severity eye scale for participants with 1 eye less than PDR at baseline OR application of panretinal laser therapy. Participants were assigned at baseline to ETDRS retinopathy severity scale for persons or individual eyes; determination of no progression/progression was dependent on the scale.
    Time Frame Baseline through 36 Months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population including all randomized participants analyzed according to the treatment group to which they were originally assigned by random allocation even if the participant does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 371 360
    No progression
    328
    88.4%
    312
    86.7%
    Progression
    43
    11.6%
    48
    13.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.475
    Comments P-value is for progression of nonproliferative diabetic retinopathy (DR) by seven-field stereo fundus photography progression versus no progression.
    Method Chi-squared
    Comments
    6. Secondary Outcome
    Title Change From Baseline in Estimated Glomerular Filtration Rate
    Description The Modification of Diet in Renal Disease (MDRD) study formula used for the estimated glomerular filtration rate (eGFR) determination is: eGFR = 170 X (Serum creatinine concentration [mg/deciliter (dL)])-0.999 X (Age [years]) -0.176 X (0.762 if participant is female) X (1.180 if participant is black) X (Serum urea nitrogen concentration [mg/dL])-0.170 X (Serum albumin concentration [grams (g)/dL])+0.318.
    Time Frame Baseline, 36 Months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population including all randomized participants analyzed according to the treatment group to which they were originally assigned by random allocation even if the participant does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 368 358
    Baseline (n=368,358)
    85.35
    (22.24)
    87.27
    (23.44)
    Change from baseline (n=340,328)
    -5.55
    (15.70)
    -7.92
    (17.31)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.211
    Comments P-value is for change from baseline.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 1.52
    Confidence Interval (2-Sided) 95%
    -0.87 to 3.92
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Change From Baseline at Endpoint in Albumin/Creatinine Ratio
    Description
    Time Frame 36 Months

    Outcome Measure Data

    Analysis Population Description
    The completer population includes participants who completed all 36 months of the treatment phase.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 270 261
    Baseline (n=270,261)
    123.53
    (507.93)
    152.61
    (623.98)
    Change from baseline (n=267,253)
    135.90
    (865.34)
    72.69
    (720.35)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.365
    Comments P-value is for change from baseline.
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 63.22
    Confidence Interval (2-Sided) 95%
    -73.68 to 200.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Change From Baseline at Endpoint in Visual Function by the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) at 36 Months
    Description 25 vision-targeted questions representing 11 vision-related constructs and a 1-item general health rating question. Measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning and task-oriented domains related to daily visual functioning. Each item is converted to a 0 to 100 scale such that a higher score represents better functioning.
    Time Frame 36 Months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population including all randomized participants analyzed according to the treatment group to which they were originally assigned by random allocation even if the participant does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 351 342
    Baseline (n=351,342)
    67.86
    (8.25)
    67.56
    (7.85)
    Change from baseline (n=314,309)
    0.17
    (6.21)
    -1.36
    (8.56)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.009
    Comments P-value is for change from baseline.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 1.52
    Confidence Interval (2-Sided) 95%
    0.38 to 2.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Number of Participants With Adverse Events
    Description Summaries of serious adverse events (SAEs) and all other non-serious adverse events (AEs) are located in the Reported Adverse Event Module.
    Time Frame Baseline through 36 Months

    Outcome Measure Data

    Analysis Population Description
    Safety population: all randomized participants who received at least one dose of study drug.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 371 360
    Serious adverse events
    93
    25.1%
    82
    22.8%
    Adverse events
    298
    80.3%
    299
    83.1%
    10. Primary Outcome
    Title Occurrence of Sustained Moderate Visual Loss (SMVL) in a Diabetic Retinopathy (DR) Study Eye
    Description The occurrence of SMVL was defined as ≥15 letter decrease from baseline in best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) in any DR study eye relative to baseline that is sustained for the last 6 months of participation. ETDRS VA: participant starts at the top of the chart containing 5 letters per row and reads down the chart until reaching a row where a minimum of 3 letters on a line cannot be read. Participant is scored by how many letters could be correctly identified. A higher number of letters correctly identified represents better visual acuity.
    Time Frame Baseline, 36 Months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) population: all randomized participants with at least 1 eligible study eye analyzed according to the treatment group to which they were originally assigned by random allocation even if the participant does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol.
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    Measure Participants 342 331
    Yes
    8
    2.2%
    16
    4.4%
    No
    334
    90%
    315
    87.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Ruboxistaurin, Placebo
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.081
    Comments P-value is for occurrence of sustained moderate visual loss (SMVL) in a diabetic retinopathy (DR) study eye yes versus no.
    Method Chi-squared
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.47
    Confidence Interval (2-Sided) 95%
    0.20 to 1.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Ruboxistaurin Placebo
    Arm/Group Description 32 mg once daily (QD) oral for up to 36 months QD oral for up to 36 months
    All Cause Mortality
    Ruboxistaurin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Ruboxistaurin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 93/371 (25.1%) 82/360 (22.8%)
    Blood and lymphatic system disorders
    Anaemia 3/371 (0.8%) 4 0/360 (0%) 0
    Thrombocytopenia 1/371 (0.3%) 1 0/360 (0%) 0
    Cardiac disorders
    Acute myocardial infarction 2/371 (0.5%) 3 5/360 (1.4%) 5
    Angina pectoris 4/371 (1.1%) 14 1/360 (0.3%) 1
    Angina unstable 3/371 (0.8%) 4 2/360 (0.6%) 2
    Aortic valve stenosis 1/371 (0.3%) 1 0/360 (0%) 0
    Arteriosclerosis coronary artery 1/371 (0.3%) 10 0/360 (0%) 0
    Atrial fibrillation 2/371 (0.5%) 5 1/360 (0.3%) 2
    Atrial flutter 1/371 (0.3%) 4 1/360 (0.3%) 1
    Atrioventricular block 1/371 (0.3%) 1 0/360 (0%) 0
    Cardiac arrest 2/371 (0.5%) 2 0/360 (0%) 0
    Cardiac failure 0/371 (0%) 0 1/360 (0.3%) 8
    Cardiac failure congestive 1/371 (0.3%) 4 2/360 (0.6%) 9
    Cardiogenic shock 0/371 (0%) 0 1/360 (0.3%) 1
    Cardiovascular disorder 1/371 (0.3%) 1 0/360 (0%) 0
    Cor pulmonale 1/371 (0.3%) 4 0/360 (0%) 0
    Coronary artery disease 3/371 (0.8%) 9 5/360 (1.4%) 16
    Coronary artery occlusion 0/371 (0%) 0 2/360 (0.6%) 2
    Ischaemic cardiomyopathy 1/371 (0.3%) 2 0/360 (0%) 0
    Left ventricular failure 1/371 (0.3%) 1 0/360 (0%) 0
    Myocardial infarction 6/371 (1.6%) 6 4/360 (1.1%) 4
    Myocardial ischaemia 0/371 (0%) 0 1/360 (0.3%) 1
    Stress cardiomyopathy 1/371 (0.3%) 1 0/360 (0%) 0
    Tachycardia 1/371 (0.3%) 1 1/360 (0.3%) 1
    Ear and labyrinth disorders
    Hearing impaired 0/371 (0%) 0 1/360 (0.3%) 11
    Vertigo 1/371 (0.3%) 1 1/360 (0.3%) 1
    Endocrine disorders
    Goitre 1/371 (0.3%) 8 0/360 (0%) 0
    Eye disorders
    Cataract 0/371 (0%) 0 2/360 (0.6%) 7
    Ocular myasthenia 1/371 (0.3%) 4 0/360 (0%) 0
    Retinal detachment 1/371 (0.3%) 1 0/360 (0%) 0
    Visual disturbance 1/371 (0.3%) 1 0/360 (0%) 0
    Gastrointestinal disorders
    Colitis 0/371 (0%) 0 1/360 (0.3%) 1
    Diarrhoea 1/371 (0.3%) 2 1/360 (0.3%) 1
    Faecal incontinence 1/371 (0.3%) 2 1/360 (0.3%) 1
    Gastritis 0/371 (0%) 0 1/360 (0.3%) 1
    Gastrointestinal ulcer haemorrhage 1/371 (0.3%) 1 0/360 (0%) 0
    Lower gastrointestinal haemorrhage 0/371 (0%) 0 1/360 (0.3%) 1
    Mouth ulceration 0/371 (0%) 0 1/360 (0.3%) 1
    Oesophageal ulcer 0/371 (0%) 0 1/360 (0.3%) 1
    Pancreatitis 0/371 (0%) 0 1/360 (0.3%) 1
    Pancreatitis acute 0/371 (0%) 0 1/360 (0.3%) 1
    Umbilical hernia 1/371 (0.3%) 1 0/360 (0%) 0
    Vomiting 0/371 (0%) 0 1/360 (0.3%) 1
    General disorders
    Calcinosis 1/371 (0.3%) 3 0/360 (0%) 0
    Chest discomfort 1/371 (0.3%) 1 1/360 (0.3%) 2
    Chest pain 3/371 (0.8%) 3 1/360 (0.3%) 1
    Death 0/371 (0%) 0 3/360 (0.8%) 3
    Impaired healing 0/371 (0%) 0 1/360 (0.3%) 4
    Pyrexia 1/371 (0.3%) 1 0/360 (0%) 0
    Hepatobiliary disorders
    Cholecystitis 1/371 (0.3%) 1 1/360 (0.3%) 1
    Cholecystitis acute 0/371 (0%) 0 1/360 (0.3%) 1
    Cholelithiasis 0/371 (0%) 0 1/360 (0.3%) 1
    Immune system disorders
    Anaphylactic reaction 0/371 (0%) 0 1/360 (0.3%) 1
    Infections and infestations
    Appendicitis 0/371 (0%) 0 1/360 (0.3%) 1
    Bacteraemia 0/371 (0%) 0 1/360 (0.3%) 1
    Cystitis 1/371 (0.3%) 2 0/360 (0%) 0
    Dengue fever 0/371 (0%) 0 1/360 (0.3%) 1
    Diarrhoea infectious 0/371 (0%) 0 1/360 (0.3%) 1
    Endocarditis 1/371 (0.3%) 1 0/360 (0%) 0
    Gastroenteritis 2/371 (0.5%) 2 2/360 (0.6%) 2
    Gastroenteritis viral 0/371 (0%) 0 1/360 (0.3%) 1
    Herpes zoster 1/371 (0.3%) 1 0/360 (0%) 0
    Liver abscess 1/371 (0.3%) 2 0/360 (0%) 0
    Lobar pneumonia 1/371 (0.3%) 1 0/360 (0%) 0
    Localised infection 2/371 (0.5%) 2 0/360 (0%) 0
    Osteomyelitis 1/371 (0.3%) 1 0/360 (0%) 0
    Perirectal abscess 0/371 (0%) 0 1/360 (0.3%) 1
    Pneumonia 3/371 (0.8%) 3 1/360 (0.3%) 1
    Pyelonephritis 0/371 (0%) 0 2/360 (0.6%) 2
    Pyelonephritis acute 1/371 (0.3%) 1 0/360 (0%) 0
    Sepsis 0/371 (0%) 0 1/360 (0.3%) 1
    Subcutaneous abscess 1/371 (0.3%) 1 0/360 (0%) 0
    Urinary tract infection 0/371 (0%) 0 2/360 (0.6%) 2
    Urinary tract infection fungal 1/371 (0.3%) 1 0/360 (0%) 0
    Wound infection 0/371 (0%) 0 1/360 (0.3%) 1
    Injury, poisoning and procedural complications
    Ankle fracture 3/371 (0.8%) 6 0/360 (0%) 0
    Cerebral haemorrhage traumatic 1/371 (0.3%) 1 0/360 (0%) 0
    Chest injury 1/371 (0.3%) 1 0/360 (0%) 0
    Concussion 1/371 (0.3%) 1 0/360 (0%) 0
    Device occlusion 0/371 (0%) 0 1/360 (0.3%) 1
    Fall 3/371 (0.8%) 5 0/360 (0%) 0
    Foot fracture 1/371 (0.3%) 1 0/360 (0%) 0
    Head injury 1/371 (0.3%) 1 0/360 (0%) 0
    Hip fracture 2/371 (0.5%) 2 0/360 (0%) 0
    Jaw fracture 1/371 (0.3%) 1 0/360 (0%) 0
    Pelvic fracture 1/371 (0.3%) 2 0/360 (0%) 0
    Road traffic accident 1/371 (0.3%) 1 0/360 (0%) 0
    Spinal fracture 1/371 (0.3%) 1 0/360 (0%) 0
    Subdural haemorrhage 1/371 (0.3%) 1 0/360 (0%) 0
    Therapeutic agent toxicity 0/371 (0%) 0 1/360 (0.3%) 1
    Wound 1/371 (0.3%) 1 0/360 (0%) 0
    Wrist fracture 1/371 (0.3%) 2 0/360 (0%) 0
    Investigations
    Blood glucose increased 1/371 (0.3%) 1 0/360 (0%) 0
    Colonoscopy 0/371 (0%) 0 1/360 (0.3%) 1
    Electrocardiogram abnormal 0/371 (0%) 0 1/360 (0.3%) 1
    Metabolism and nutrition disorders
    Dehydration 1/371 (0.3%) 1 2/360 (0.6%) 2
    Diabetes mellitus inadequate control 5/371 (1.3%) 9 6/360 (1.7%) 6
    Diabetic foot 0/371 (0%) 0 2/360 (0.6%) 7
    Diabetic ketoacidosis 1/371 (0.3%) 1 0/360 (0%) 0
    Fluid retention 0/371 (0%) 0 1/360 (0.3%) 1
    Hyperglycaemia 1/371 (0.3%) 1 1/360 (0.3%) 1
    Hypoglycaemia 3/371 (0.8%) 3 2/360 (0.6%) 2
    Hypokalaemia 1/371 (0.3%) 1 0/360 (0%) 0
    Hyponatraemia 1/371 (0.3%) 1 0/360 (0%) 0
    Obesity 2/371 (0.5%) 10 0/360 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthritis 0/371 (0%) 0 1/360 (0.3%) 1
    Back pain 1/371 (0.3%) 1 1/360 (0.3%) 2
    Cervical spinal stenosis 0/371 (0%) 0 1/360 (0.3%) 3
    Dupuytren's contracture 1/371 (0.3%) 1 0/360 (0%) 0
    Foot deformity 1/371 (0.3%) 10 0/360 (0%) 0
    Intervertebral disc protrusion 1/371 (0.3%) 1 1/360 (0.3%) 1
    Lumbar spinal stenosis 0/371 (0%) 0 1/360 (0.3%) 4
    Osteitis 0/371 (0%) 0 1/360 (0.3%) 1
    Osteoarthritis 0/371 (0%) 0 2/360 (0.6%) 11
    Rhabdomyolysis 1/371 (0.3%) 1 0/360 (0%) 0
    Spinal osteoarthritis 1/371 (0.3%) 1 0/360 (0%) 0
    Spondylolisthesis 0/371 (0%) 0 1/360 (0.3%) 1
    Tendonitis 1/371 (0.3%) 14 0/360 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angioimmunoblastic t-cell lymphoma 1/371 (0.3%) 1 0/360 (0%) 0
    Bladder transitional cell carcinoma 0/371 (0%) 0 1/360 (0.3%) 1
    Breast cancer 0/371 (0%) 0 1/360 (0.3%) 4
    Colon adenoma 0/371 (0%) 0 1/360 (0.3%) 1
    Colon cancer 0/371 (0%) 0 1/360 (0.3%) 1
    Colorectal cancer 1/371 (0.3%) 1 0/360 (0%) 0
    Gastric cancer stage iii 0/371 (0%) 0 1/360 (0.3%) 1
    Meningioma 0/371 (0%) 0 1/360 (0.3%) 5
    Pancreatic carcinoma 2/371 (0.5%) 2 1/360 (0.3%) 1
    Prostatic adenoma 1/371 (0.3%) 1 0/360 (0%) 0
    Renal cancer metastatic 0/371 (0%) 0 1/360 (0.3%) 1
    Small intestine carcinoma 0/371 (0%) 0 1/360 (0.3%) 1
    Squamous cell carcinoma of skin 0/371 (0%) 0 1/360 (0.3%) 1
    Thyroid cancer 1/371 (0.3%) 3 0/360 (0%) 0
    Nervous system disorders
    Balance disorder 1/371 (0.3%) 1 0/360 (0%) 0
    Carotid artery stenosis 2/371 (0.5%) 4 0/360 (0%) 0
    Carpal tunnel syndrome 1/371 (0.3%) 4 0/360 (0%) 0
    Cerebral ischaemia 1/371 (0.3%) 7 0/360 (0%) 0
    Cerebrovascular accident 4/371 (1.1%) 5 2/360 (0.6%) 3
    Coma hepatic 1/371 (0.3%) 1 0/360 (0%) 0
    Coordination abnormal 0/371 (0%) 0 1/360 (0.3%) 1
    Cubital tunnel syndrome 1/371 (0.3%) 1 0/360 (0%) 0
    Diabetic hyperglycaemic coma 1/371 (0.3%) 1 0/360 (0%) 0
    Dysarthria 1/371 (0.3%) 1 0/360 (0%) 0
    Facial palsy 1/371 (0.3%) 1 0/360 (0%) 0
    Grand mal convulsion 1/371 (0.3%) 9 0/360 (0%) 0
    Ischaemic stroke 2/371 (0.5%) 7 0/360 (0%) 0
    Loss of consciousness 1/371 (0.3%) 1 0/360 (0%) 0
    Peripheral sensory neuropathy 0/371 (0%) 0 1/360 (0.3%) 1
    Sciatica 1/371 (0.3%) 1 0/360 (0%) 0
    Simple partial seizures 1/371 (0.3%) 1 0/360 (0%) 0
    Syncope 1/371 (0.3%) 1 0/360 (0%) 0
    Transient ischaemic attack 2/371 (0.5%) 2 0/360 (0%) 0
    Psychiatric disorders
    Anxiety 0/371 (0%) 0 1/360 (0.3%) 5
    Confusional state 1/371 (0.3%) 1 0/360 (0%) 0
    Conversion disorder 1/371 (0.3%) 1 0/360 (0%) 0
    Depression 1/371 (0.3%) 12 0/360 (0%) 0
    Suicidal ideation 1/371 (0.3%) 4 0/360 (0%) 0
    Renal and urinary disorders
    Diabetic nephropathy 2/371 (0.5%) 7 0/360 (0%) 0
    Dysuria 1/371 (0.3%) 1 0/360 (0%) 0
    Nephrolithiasis 1/371 (0.3%) 1 0/360 (0%) 0
    Pelvi-ureteric obstruction 0/371 (0%) 0 1/360 (0.3%) 9
    Renal artery arteriosclerosis 1/371 (0.3%) 1 0/360 (0%) 0
    Renal failure 3/371 (0.8%) 11 0/360 (0%) 0
    Renal failure acute 0/371 (0%) 0 1/360 (0.3%) 1
    Renal failure chronic 1/371 (0.3%) 4 0/360 (0%) 0
    Renal impairment 0/371 (0%) 0 1/360 (0.3%) 1
    Urge incontinence 0/371 (0%) 0 1/360 (0.3%) 1
    Urinary retention 1/371 (0.3%) 4 0/360 (0%) 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 1/371 (0.3%) 4 2/360 (0.6%) 15
    Ovarian cyst 0/371 (0%) 0 1/360 (0.3%) 1
    Pelvic pain 0/371 (0%) 0 1/360 (0.3%) 1
    Priapism 0/371 (0%) 0 1/360 (0.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/371 (0%) 0 1/360 (0.3%) 8
    Dyspnoea 0/371 (0%) 0 3/360 (0.8%) 3
    Epistaxis 1/371 (0.3%) 1 0/360 (0%) 0
    Hypoxia 1/371 (0.3%) 1 0/360 (0%) 0
    Obstructive airways disorder 0/371 (0%) 0 1/360 (0.3%) 2
    Pulmonary embolism 0/371 (0%) 0 1/360 (0.3%) 1
    Sleep apnoea syndrome 1/371 (0.3%) 4 1/360 (0.3%) 4
    Skin and subcutaneous tissue disorders
    Diabetic neuropathic ulcer 1/371 (0.3%) 1 0/360 (0%) 0
    Idiopathic urticaria 0/371 (0%) 0 1/360 (0.3%) 1
    Skin necrosis 1/371 (0.3%) 1 0/360 (0%) 0
    Skin ulcer 1/371 (0.3%) 1 0/360 (0%) 0
    Surgical and medical procedures
    Cholecystectomy 0/371 (0%) 0 1/360 (0.3%) 1
    Splenectomy 0/371 (0%) 0 1/360 (0.3%) 1
    Thyroidectomy 1/371 (0.3%) 1 0/360 (0%) 0
    Tooth extraction 0/371 (0%) 0 1/360 (0.3%) 1
    Vascular disorders
    Aortic stenosis 1/371 (0.3%) 13 0/360 (0%) 0
    Arteriosclerosis 1/371 (0.3%) 1 0/360 (0%) 0
    Circulatory collapse 1/371 (0.3%) 1 0/360 (0%) 0
    Deep vein thrombosis 1/371 (0.3%) 4 0/360 (0%) 0
    Haemorrhage 0/371 (0%) 0 1/360 (0.3%) 3
    Peripheral arterial occlusive disease 1/371 (0.3%) 1 0/360 (0%) 0
    Peripheral ischaemia 0/371 (0%) 0 1/360 (0.3%) 1
    Peripheral vascular disorder 2/371 (0.5%) 11 2/360 (0.6%) 5
    Subclavian artery stenosis 1/371 (0.3%) 1 0/360 (0%) 0
    Vasculitis 0/371 (0%) 0 1/360 (0.3%) 1
    Other (Not Including Serious) Adverse Events
    Ruboxistaurin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 298/371 (80.3%) 299/360 (83.1%)
    Gastrointestinal disorders
    Diarrhoea 38/371 (10.2%) 90 32/360 (8.9%) 108
    Nausea 17/371 (4.6%) 23 21/360 (5.8%) 60
    Vomiting 19/371 (5.1%) 22 17/360 (4.7%) 25
    General disorders
    Oedema peripheral 16/371 (4.3%) 60 24/360 (6.7%) 86
    Pyrexia 15/371 (4%) 18 19/360 (5.3%) 19
    Infections and infestations
    Bronchitis 19/371 (5.1%) 28 16/360 (4.4%) 23
    Influenza 47/371 (12.7%) 67 36/360 (10%) 58
    Nasopharyngitis 65/371 (17.5%) 135 59/360 (16.4%) 121
    Sinusitis 24/371 (6.5%) 54 13/360 (3.6%) 20
    Upper respiratory tract infection 17/371 (4.6%) 25 20/360 (5.6%) 34
    Urinary tract infection 20/371 (5.4%) 42 18/360 (5%) 40
    Metabolism and nutrition disorders
    Hypercholesterolaemia 28/371 (7.5%) 129 29/360 (8.1%) 131
    Musculoskeletal and connective tissue disorders
    Arthralgia 27/371 (7.3%) 89 35/360 (9.7%) 144
    Back pain 29/371 (7.8%) 93 36/360 (10%) 105
    Musculoskeletal pain 16/371 (4.3%) 56 24/360 (6.7%) 83
    Pain in extremity 32/371 (8.6%) 82 22/360 (6.1%) 99
    Nervous system disorders
    Headache 37/371 (10%) 102 44/360 (12.2%) 129
    Respiratory, thoracic and mediastinal disorders
    Cough 38/371 (10.2%) 73 46/360 (12.8%) 85
    Pharyngolaryngeal pain 21/371 (5.7%) 36 24/360 (6.7%) 36
    Vascular disorders
    Hypertension 43/371 (11.6%) 229 49/360 (13.6%) 282

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title info@chroma-derm.com
    Organization Chromaderm
    Phone
    Email info@chroma-derm.com
    Responsible Party:
    Chromaderm, Inc.
    ClinicalTrials.gov Identifier:
    NCT00090519
    Other Study ID Numbers:
    • 8211
    • B7A-MC-MBDL
    First Posted:
    Aug 31, 2004
    Last Update Posted:
    Oct 6, 2016
    Last Verified:
    Aug 1, 2016