Trial Outcomes & Findings for (ACORD Study) - A Study of NeoRecormon (Epoetin Beta) in Patients With Early Diabetic Nephropathy (NCT NCT00354341)

Last Updated: 2016-03-31

Results Overview

LVMI (in g/m\^2) = (0.8 \[1.04 {(LVEDD + IVS + PWT)\^3 - (LVEDD)\^3}\] + 0.6) divided by BSA. Here, LVEDD = left ventricular end diastolic diameter (in centimeters \[cm\]); PWT = left ventricular posterior wall thickness in diastole (in cm); IVS = interventricular septal wall thickness in diastole (in cm). Echocardiogram was performed at baseline and Month 15 to interpret LVMI which was expressed in grams per meter square (g/m\^2).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

170 participants

Primary outcome timeframe

Baseline, Month 15

Results posted on

2016-03-31

Participant Flow

Participant milestones

Participant milestones
Measure	Group 1 (Early Epoetin Beta) Along with their standard treatment participants received epoetin beta at a starting dose of 2000 International Units (IU) subcutaneously (SC) once weekly to reach and maintain target hemoglobin (Hb) between 13 and 15 grams per deciliter (g/dL), for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was less than (\<) 10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Overall Study STARTED	88	82
Overall Study COMPLETED	85	75
Overall Study NOT COMPLETED	3	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Group 1 (Early Epoetin Beta) Along with their standard treatment participants received epoetin beta at a starting dose of 2000 International Units (IU) subcutaneously (SC) once weekly to reach and maintain target hemoglobin (Hb) between 13 and 15 grams per deciliter (g/dL), for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was less than (\<) 10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Overall Study Adverse Event	1	0
Overall Study Death	0	2
Overall Study Refused treatment	1	2
Overall Study Failure to return	0	1
Overall Study Other	1	2

Baseline Characteristics

(ACORD Study) - A Study of NeoRecormon (Epoetin Beta) in Patients With Early Diabetic Nephropathy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 1 (Early Epoetin Beta) n=88 Participants Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=82 Participants Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.	Total n=170 Participants Total of all reporting groups
Age, Continuous	56.7 years STANDARD_DEVIATION 13.82 • n=5 Participants	55.6 years STANDARD_DEVIATION 12.64 • n=7 Participants	56.2 years STANDARD_DEVIATION 13.24 • n=5 Participants
Sex: Female, Male Female	43 Participants n=5 Participants	41 Participants n=7 Participants	84 Participants n=5 Participants
Sex: Female, Male Male	45 Participants n=5 Participants	41 Participants n=7 Participants	86 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Month 15

Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Group 1 (Early Epoetin Beta) n=84 Participants Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=79 Participants Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Change From Baseline in Left Ventricle Mass Index (LVMI) at Month 15	0.69 g/m^2 Standard Deviation 26.34	0.10 g/m^2 Standard Deviation 24.25

SECONDARY outcome

Timeframe: Baseline, Months 6 and 15

Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome measure. Here "n"= participants who were evaluable for each category, for respective arm groups.

LVESVI was calculated by dividing left ventricular end systolic volume (LVESV) (in milliliters \[mL\]) with body surface area (BSA) (in meter square \[m\^2\]). LVESVI is presented in milliliter per meter square (mL/m\^2).

Outcome measures

Outcome measures
Measure	Group 1 (Early Epoetin Beta) n=57 Participants Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=56 Participants Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Left Ventricular End Systolic Volume Index (LVESVI) Baseline (n=57, 56)	22.40 mL/m^2 Standard Deviation 6.36	21.04 mL/m^2 Standard Deviation 5.42
Left Ventricular End Systolic Volume Index (LVESVI) Month 6 (n=47, 53)	26.86 mL/m^2 Standard Deviation 8.21	24.54 mL/m^2 Standard Deviation 8.06
Left Ventricular End Systolic Volume Index (LVESVI) Month 15 (n=54, 55)	25.99 mL/m^2 Standard Deviation 9.31	25.03 mL/m^2 Standard Deviation 6.88

SECONDARY outcome

Timeframe: Baseline, Months 6 and 15

LVEDVI was calculated by dividing left ventricular end diastolic volume (LVEDV) (in mL) BSA (in m\^2). LVEDVI was presented in mL/m\^2.

Outcome measures

Outcome measures
Measure	Group 1 (Early Epoetin Beta) n=57 Participants Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=56 Participants Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Left Ventricular End Diastolic Volume Index (LVEDVI) Month 15 (n=54, 55)	62.26 mL/m^2 Standard Deviation 16.27	62.07 mL/m^2 Standard Deviation 11.36
Left Ventricular End Diastolic Volume Index (LVEDVI) Baseline (n=57, 56)	61.08 mL/m^2 Standard Deviation 12.69	58.13 mL/m^2 Standard Deviation 10.83
Left Ventricular End Diastolic Volume Index (LVEDVI) Month 6 (n=47, 53)	62.74 mL/m^2 Standard Deviation 15.41	60.40 mL/m^2 Standard Deviation 12.25

SECONDARY outcome

Timeframe: Baseline, Months 6 and 15

Population: ITT population. Here "n"= participants who were evaluable for each category, for respective arm groups.

FS was calculated as: (\[LVEDD - LVESD\] divided by LVEDV) multiplied by 100; where LVEDD = left ventricular end diastolic diameter (in centimeters \[cm\]), LVESD = left ventricular end systolic diameter (in cm), LVEDV = left ventricular end diastolic volume (in mL). FS is expressed in percentage of LVEDV.

Outcome measures

Outcome measures
Measure	Group 1 (Early Epoetin Beta) n=88 Participants Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=82 Participants Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Fractional Myocardial Shortening (FS) Baseline (n=88, 82)	36.45 percentage of LVEDV Standard Deviation 7.80	36.58 percentage of LVEDV Standard Deviation 8.97
Fractional Myocardial Shortening (FS) Month 6 (n=84, 76)	37.80 percentage of LVEDV Standard Deviation 7.40	38.49 percentage of LVEDV Standard Deviation 7.03
Fractional Myocardial Shortening (FS) Month 15 (n=85, 79)	37.58 percentage of LVEDV Standard Deviation 7.01	38.86 percentage of LVEDV Standard Deviation 7.52

SECONDARY outcome

Timeframe: Baseline, Months 6 and 15

LVEF was calculated as (\[LVEDV - LVESV\], divided by LVEDV) multiplied by 100; where LVEDV = left ventricular end diastolic volume (in mL), LVESV = left ventricular end systolic volume (in mL). LVEF is expressed in percentage of LVEDV.

Outcome measures

Outcome measures
Measure	Group 1 (Early Epoetin Beta) n=57 Participants Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=56 Participants Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Left Ventricular Ejection Fraction (LVEF) Baseline (n=57, 56)	63.44 percentage of LVEDV Standard Deviation 5.73	63.84 percentage of LVEDV Standard Deviation 5.44
Left Ventricular Ejection Fraction (LVEF) Month 6 (n=47, 53)	57.22 percentage of LVEDV Standard Deviation 6.87	59.92 percentage of LVEDV Standard Deviation 7.71
Left Ventricular Ejection Fraction (LVEF) Month 15 (n=54, 55)	58.63 percentage of LVEDV Standard Deviation 6.47	59.97 percentage of LVEDV Standard Deviation 6.46

SECONDARY outcome

Timeframe: Week 26 up to Week 64

Population: ITT population. Here, number of participants analyzed = participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Group 1 (Early Epoetin Beta) n=86 Participants Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=81 Participants Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Percentage of Participants With Stable Hb Levels Between 13 to 15 g/dL	75.6 percentage of participants Interval 65.1 to 84.2	9.9 percentage of participants Interval 4.4 to 18.5

Adverse Events

Group 1 (Early Epoetin Beta)

Serious events: 21 serious events

Other events: 21 other events

Deaths: 0 deaths

Group 2 (No/Late Epoetin Beta)

Serious events: 20 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Group 1 (Early Epoetin Beta) n=88 participants at risk Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=82 participants at risk Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Vascular disorders Hypertension	15.9% 14/88 • up to 30 days after last study drug administration (35 months)	9.8% 8/82 • up to 30 days after last study drug administration (35 months)
General disorders Edema peripheral	9.1% 8/88 • up to 30 days after last study drug administration (35 months)	11.0% 9/82 • up to 30 days after last study drug administration (35 months)
Renal and urinary disorders Renal impairment	5.7% 5/88 • up to 30 days after last study drug administration (35 months)	4.9% 4/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Nasopharyngitis	5.7% 5/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Group 1 (Early Epoetin Beta) n=88 participants at risk Along with their standard treatment participants received epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain target Hb between 13 and 15 g/dL, for 15 months. Epoetin beta doses were adjusted according to individual participant's Hb level. Standard treatment was as per investigator discretion.	Group 2 (No/Late Epoetin Beta) n=82 participants at risk Participants received their standard treatment for 15 months but no treatment for anemia correction unless Hb level was \<10.5 g/dL on 2 consecutive visits of 2 weeks interval or the Hb level was \<10 g/dL on a single determination. In such cases participants could receive epoetin beta at a starting dose of 2000 IU SC once weekly to reach and maintain a target Hb level of 10.5 to 11.5 g/dL. Standard treatment was as per investigator discretion.
Renal and urinary disorders Renal Impairment	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	3.7% 3/82 • up to 30 days after last study drug administration (35 months)
Renal and urinary disorders Renal failure chronic	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Renal and urinary disorders Proteinuria	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Renal and urinary disorders Renal failure	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Renal and urinary disorders Urinary retention	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Pneumonia	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	2.4% 2/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Abscess limb	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Cellulitis	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Diabetic gangrene	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Erysipelas	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Gastroenteritis	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Perianal abscess	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Pyelonephritis acute	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Infections and infestations Respiratory tract infection	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Cardiac disorders Cardiac failure congestive	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Cardiac disorders Myocardial infarction	2.3% 2/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Cardiac disorders Angina unstable	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Cardiac disorders Atrial fibrillation	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Cardiac disorders Cardiac failure acute	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Vascular disorders Hypertension	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Vascular disorders Atherosclerosis	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Vascular disorders Deep vein thrombosis	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Vascular disorders Vasculitis	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Eye disorders Cataract	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Eye disorders Diabetic retinopathy	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Eye disorders Eye hemorrhage	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Eye disorders Vitreous hemorrhage	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
General disorders Generalized edema	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
General disorders Chest pain	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
General disorders Pyrexia	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Gastrointestinal disorders Abdominal pain upper	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Gastrointestinal disorders Gastrointestinal hemorrhage	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Gastrointestinal disorders Vomiting	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Hepatobiliary disorders Cholangitis acute	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Hepatobiliary disorders Hepatitis	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Hepatobiliary disorders Jaundice	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bile duct cancer	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colorectal cancer	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm malignant	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Respiratory, thoracic and mediastinal disorders Pulmonary edema	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Surgical and medical procedures Cataract operation	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Surgical and medical procedures Toe amputation	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Endocrine disorders Hyperthyroidism	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Nervous system disorders Cerebral infarction	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Nervous system disorders Hypertensive encephalopathy	1.1% 1/88 • up to 30 days after last study drug administration (35 months)	0.00% 0/82 • up to 30 days after last study drug administration (35 months)
Reproductive system and breast disorders Testicular pain	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/88 • up to 30 days after last study drug administration (35 months)	1.2% 1/82 • up to 30 days after last study drug administration (35 months)