AFLIBERCEPT AVE0005

Any untoward medical occurrence in a participant who received investigational medicinal product (IMP) was considered an adverse event (AE) without regard to possibility of causal relationship with this treatment. A serious AE (SAE): Any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs. National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Version 4.03 was used to assess severity (Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling) of AEs.

Abnormal hematological parameters included: anaemia, thrombocytopenia, leukopenia and neutropenia. Number of participants with each of these parameters were analyzed by grades (All Grades and Grades 3-4 as per NCI CTCAE (Version 4.03), where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4.

The INR is a derived measure of the prothrombin time. The INR is the ratio of a participant's prothrombin time to a normal control sample. Normal range (without anti coagulation therapy): 0.8-1.2; Targeted range (with anti coagulation therapy) 2.0-3.0.

Abnormal electrolytes parameters included: hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypokalemia, and hyperkalemia. Number of participants with each of these parameters were analyzed by grades ( All Grades and Grades 3-4 as per NCI CTCAE Version 4.03, where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4.

Renal and liver function parameters included: creatinine, hyperbilirubinemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase. Number of participants with each of these parameters were analyzed by grades (All Grades and Grades 3-4) as per NCI CTCAE version 4.03, where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4.

Creatinine clearance is a measure of kidney function. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Creatinine clearance can be measured directly or estimated using established formulas. For this study, the creatinine clearance was calculated using the Cockroft-Gault or Modification of Diet in Renal Disease (MDRD).

Other abnormal biochemistry parameters included: hypoglycemia, hyperglycemia and hypoalbuminemia. Number of participants with each of these parameters were analyzed by grades (All Grades and Grades 3-4) as per NCI CTCAE Version 4.03, where Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4.

Non-gradeable biochemistry parameters included; chloride, urea, total protein, blood urea nitrogen (BUN) and lactate dehydrogenase (LDH). Number of participants with \<lower limit of normal ranges (LLN) and \>upper limit of normal ranges (ULN) for each of these parameters were reported.

Proteinuria is defined as the ratio of protein to creatinine. Number of participants with proteinuria were analyzed by grades (Grades 1, 2, 3 ,4) as per NCI CTCAE Version 4.03 where Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling.

Proteinuria is defined as the ratio of protein to creatinine. Number of participants with proteinuria grade \>=2 (graded as per NCI CTCAE Version 4.03), where Grade\>=2 represents moderate to life-threatening/disabling event.

Urinary protein creatinine ratio (UPCR) corresponds to the ratio of the urinary protein and urinary creatinine concentration (expressed in mg/dL). This ratio provides an accurate quantification of 24-hours urinary protein excretion. There is a high correlation between morning UPCR and 24-hour proteinuria in participants with normal or reduced renal functions. Normal ratio is \< or = 1.

Proteinuria is defined as the presence of excess proteins in the urine (assessed either by spot sample, dipstick/ urine protein or 24 hour urine collection). Hematuria is defined as the presence of blood in urine (positive dipstick for RBC or reported AE). Number of participants with proteinuria grade \>=2 (graded as per NCI CTCAE Version 4.03), where Grade\>=2 represents moderate to life-threatening/disabling event. Hypertension (high blood pressure) is defined as having a blood pressure reading of more than 140/90 mmHg over a number of weeks.

A theoretical cycle is a 2 week period i.e. 14 days. A cycle is delayed if duration of previous cycle is greater than 14+2 days ; dose modification includes dose reduction and dose omission.