A Double-blind, Randomized, Balanced, Parallel Group, Phase I Study Comparing Pharmacokinetics and Safety of Bevacizumab
Phase: PHASE1
Conditions: Pharmacokinetics, Safety Issues
Sponsor: Laboratorios Richmond S.A.C.I.F.

Juncal 4484 3º Piso - Buenos Aires - Argentina - C1425BAB 
 
Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
  
 
 
 
Clinical Investigation Protocol 
 
Protocol code: 0221 
 
Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab 
 
 
 
 
 
 
Sponsor of the study  
Principal Investigator  
Laboratorios Richmond S.A.C.I.F. 
Dr. Ethel C. Feleder 
Av. Elcano 4938 – C1427CIU 
FP Clinical Pharma S.R.L. 
C.A.B.A. – Bs. As. – Argentina 
Juncal 4484 3º – C1425BAB 
Telephone: (54-11) 5555-1600 
C.A.B.A. – Bs. As. – Argentina 
Fax: (54-11) 5555-1600 
Telephone: (54-11) 4775-2640 y (54-11) 4775-2869 
Fax: (54-11) 4775-2640 y (54-11) 4775-2869 
 
 
Representative of the sponsor  
Clinical center 
of the study 
Unidad de investigación-clínica farmacocinética 
Lic. Elvira Zini 
FP Clinical Pharma en Clínica CIAREC 
Laboratorios Richmond S.A.C.I.F. 
Monroe 4770 – C1431CEF 
Av. Elcano 4938 – C1427CIU 
C.A.B.A. – Bs. As. – Argentina 
C.A.B.A. – Bs. As. – Argentina 
Telephone: (54-11) 5555-1600 
Telephone: (54-11) 4541-5700 
Fax: (54-11) 5555-1600 
Fax: (54-11) 4541-5700 
 
 
 
 
 
 
 
 
 
 
 
This Clinical Investigation Protocol contains confidential information and is the 
property of Laboratorios Richmond S.A.C.I.F. 
 
 
 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
CLINICAL INVESTIGATION PROTOCOL AGREEMENT  
 
I have read this Clinical Investigation Protocol and I agree with its contents as presented herein. I 
shall conduct the study in accordance with the details contained in this document.  
 
Principal Investigator 
 
Name:  Dr. Ethel C. Feleder 
 
Position: Principal investigator  
 
 
Signature: 
 
Date: 
 
 
 
 
 
Representative of the Sponsor 
 
Name: Lic. Elvira Zini 
Position: Legal agent (principal)  
 
 
Signature: 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
TABLE OF CONTENTS  
 
1. 
SUMMARY OF THE STUDY  .................................................................................... 7 
1.1. 
General considerations  .................................................................................................... 7 
1.2. 
Approvals, authorizations, records and notifications  ..................................................... 7 
1.3. 
Study responsible persons  .............................................................................................. 7 
1.3.1. 
Sponsor  ........................................................................................................................... 7 
1.3.2. 
Study coordination, development and organization  ....................................................... 7 
1.3.3. 
Clinical stage  .................................................................................................................. 7 
1.3.3.1.  Clinical center ................................................................................................................. 7 
 
1.3.3.2.  Principal investigator ...................................................................................................... 8 
1.3.4. 
Statistical stage  ............................................................................................................... 8 
1.4. 
Investigation hypothesis  ................................................................................................. 8 
1.5. 
Objectives ........................................................................................................................ 8 
1.6. 
Design  ............................................................................................................................. 9 
1.7. 
Study type  ....................................................................................................................... 9 
1.8. 
Study duration  ................................................................................................................ 9 
1.9. 
Study schedule  ................................................................................................................ 9 
1.10. 
Number of subjects  ....................................................................................................... 10 
1.11. 
Main  inclusion criteria  ................................................................................................. 10 
1.12. 
Products under investigation ......................................................................................... 10 
1.13. 
Pharmacokinetic parameters  ......................................................................................... 10 
1.14. 
Statistical analysis  ........................................................................................................ 11 
1.15. 
Safety parameters  ......................................................................................................... 11 
1.15.1. Safety ............................................................................................................................. 11 
1.15.2. Immunogenicity  ............................................................................................................ 11 
2. 
STUDY HYPOTHESIS  .............................................................................................. 11 
3. 
INTRODUCTION ....................................................................................................... 12 
3.1. 
Pharmacokinetics  .......................................................................................................... 12 
3.1.1. 
Distribution .................................................................................................................... 12 
3.1.2. 
Biotransformation .......................................................................................................... 12 
3.1.3. 
Clearance ....................................................................................................................... 13 
3.2. 
Indications ..................................................................................................................... 13 
3.3. 
Contraindications ........................................................................................................... 15 
3.4. 
Adverse reactions  ......................................................................................................... 15 
 
4. 
OBJECTIVES OF THE STUDY  .............................................................................. 34 
4.1. 
Primary objectives  ........................................................................................................ 34 
4.2. 
Secondary objectives  .................................................................................................... 34 
5. 
ETHICAL CONSIDERATIONS  .............................................................................. 34 
5.1. 
Good clinical practices  ................................................................................................. 34 
5.2. 
Independent Ethics Committee  ..................................................................................... 35 
5.3. 
Informed consent  .......................................................................................................... 35 
5.4. 
Approvals, notifications, authorizations and records  ................................................... 35 
 
 
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Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
6. 
INVESTIGATION PLAN  .......................................................................................... 36 
6.1. 
Study design  ................................................................................................................. 36 
6.2. 
Study phases  ................................................................................................................. 37 
6.3. 
Study duration  .............................................................................................................. 38 
6.4. 
Centers ........................................................................................................................... 38 
6.5. 
Study population  ........................................................................................................... 38 
6.5.1. 
Inclusion criteria  ........................................................................................................... 38 
6.5.2. 
Exclusion criteria  .......................................................................................................... 39 
6.5.3. 
Discontinuation of the treatment by the study subjects  ................................................ 40 
6.5.4. 
Study subject substitution  ............................................................................................. 41 
 
7. 
TREATMENTS  .......................................................................................................... 41 
7.1. 
Treatments of the study  ................................................................................................ 41 
7.1.1. 
Product under investigation  .......................................................................................... 41 
7.1.2. 
Non experimental product  ............................................................................................ 42 
7.1.3. 
Identification .................................................................................................................. 42 
7.1.4. 
Packaging and labeling  ................................................................................................. 43 
7.1.5. 
Handling and delivery  .................................................................................................. 44 
7.1.6. 
Blinding and unblinding procedures  ............................................................................ 44 
7.2. 
Method to assign treatments  ......................................................................................... 44 
7.3. 
Dose selection and schedule for each study subject  ..................................................... 45 
7.4. 
Concomitant treatments  ................................................................................................ 45 
7.4.1. 
Prohibited treatments and/or restricted use  .................................................................. 45 
7.4.2. 
Other restrictions and precautions  ................................................................................ 46 
7.5. 
Treatment adherence ..................................................................................................... 46 
8. 
STUDY EVALUATIONS AND PROCEDURES  .................................................... 47 
8.1. 
Schedule of events  ........................................................................................................ 47 
8.1.1. 
Procedures according to visit  ........................................................................................ 49 
8.1.1.1.  Visit 1: Screening and inclusion (Day -28 a -1) ............................................................ 49 
8.1.1.2.  Visit 2: Dosing, blood draw, 24 hour confinement (Day 1) .......................................... 50 
8.1.1.3.  Visit 3: Outpatient blood draw - hour  48 post-infusion (Day 2) .................................. 51 
8.1.1.4.  Visit 4: Outpatient blood draw - hour  72 post-infusion (Day 3) .................................. 51 
8.1.1.5.  Visit 5: Outpatient blood draw - hour  96 post-infusion (Day 4) .................................. 52 
8.1.1.6.  Visit 6: Outpatient blood draw - hour  120 post-infusion (Day 5) ................................ 52 
8.1.1.7.  Visit 7: Outpatient blood draw - hour  168 post-infusion (Day 7) ................................ 52 
8.1.1.8.  Visit 8: Outpatient blood draw - hour  336 post-infusion (Day 14) .............................. 53 
 
8.1.1.9.  Visit 9: Outpatient blood draw - hour  504 post-infusion (Day 21) .............................. 53 
8.1.1.10. Visit 10: Outpatient blood draw - hour  672 post-infusion (Day 28) ........................... 53 
8.1.1.11. Visit 11: Outpatient blood draw - hour  840 post-infusion (Day 35) ........................... 54 
8.1.1.12. Visit 12: Outpatient blood draw - hour  1008 post-infusion (Day 42) ......................... 54 
8.1.1.13. Visit 13: Outpatient blood draw - hour  1176 post-infusion (Day 49) ......................... 54 
8.1.1.14. Visit 14: Outpatient blood draw - hour  1344 post-infusion (Day 56) ......................... 55 
8.1.1.15. Visit 15: Outpatient blood draw - hour  1512 post-infusion – End of Study Visit………55 
  
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
8.1.2. 
Eating plan  ................................................................................................................. 
56 
8.1.3. 
Blood samples ............................................................................................................. 
56 
8.1.3.1.   PK sampling cronogram…………………………………………………………...... 
56 
8.1.3.2. Extraction .................................................................................................................... 
57 
8.1.3.3. Labeling  ..................................................................................................................... 
57 
8.1.3.4. Volume ....................................................................................................................... 
57 
8.1.3.5. Storage and transportation  ......................................................................................... 
58 
8.1.3.6. Sample rejection  ........................................................................................................ 
58 
8.2. 
Analytical method ...................................................................................................... 
58 
8.3. 
Efficacy evaluations .................................................................................................... 
58 
8.3.1. 
Main efficacy evaluation.............................................................................................. 58 
8.4. 
Immunogenicity evaluation  ........................................................................................ 60 
8.5. 
Safety evaluations  ...................................................................................................... 
60 
8.5.1. 
Blood safety laboratory dashboard, serum detection dashboard and immunogenicity 60 
8.5.1.1.  Blood safety laboratory dashboard for initial safety laboratory tests  .......................... 
60 
9.4.1.1.1 Blood test……………………………………………………………………………. 60 
    9.4.1.1.2 . Serum chemistry ........................................................................................................... 
61 
    9.4.1.1.3 . Clotting time  ................................................................................................................. 61 
    9.4.1.1.4 . Serum detection dashboard  .......................................................................................... 
61 
8.5.1.2.  Blood safety laboratory dashboard for final safety laboratory tests  ............................ 
61 
8.5.1.2.1. Blood test .... ................................................................................................................ 61 
8.5.1.2.2. Serum chemistry .......................................................................................................... 62 
8.5.2. 
Laboratory urine test dashboard for safety  ................................................................... 62 
8.5.2.1. Detecting drugs of abuse  .............................................................................................. 62 
8.5.3. 
Electrocardiogram ......................................................................................................... 62 
8.5.4. 
Measuring blood pressure, heart rate, respiratory rate and axillary temperature…….    62  
8.5.4.1.  Blood pressure, heart rate and respiratory rate .............................................................. 62 
    8.5.4.2.  Axillary temperature ...................................................................................................... 62 
8.5.4.3.  Schedule to measure blood pressure, heart rate, respiratory rate and axillary  
temperature during the study visits ................................................................................ 63 
8.5.5. 
Further evaluations ........................................................................................................ 63 
8.5.5.1. Body weight, size and body mass index (BMI) ……………………………………… 63 
8.5.5.2. Physical examination ..................................................................................................... 63 
9. 
ADVERSE EVENTS  ................................................................................................... 63 
9.1. 
Definitions  .................................................................................................................... 63 
9.1.1. 
Adverse event ................................................................................................................ 63 
9.1.2. 
Serious adverse event .................................................................................................... 64 
9.1.3. 
Unexpected adverse event ……………………………………………………………. 64 
9.1.4. 
Adverse drug reactions  ................................................................................................. 64 
9.1.5. 
Serious and unexpected adverse drug reaction (SUADR)……………………………. 65 
9.2. 
Collection ........................................................................................................................ 65 
 
 
 
 
 
 
 
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           Juncal 4484 3º Piso - Buenos Aires - Argentina - C1425BAB 
 
Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
9.3. 
Evaluation ...................................................................................................................... 65 
9.3.1. 
Evaluating the severity  ................................................................................................. 65 
9.3.2. 
Evaluating the seriousness ............................................................................................. 66 
9.3.3. 
Evaluating the biological plausibility  ........................................................................... 66 
9.3.4. 
Evaluating causality  ...................................................................................................... 67 
9.4. 
Records  ......................................................................................................................... 67 
9.5. 
Adverse event reporting ................................................................................................ 68 
9.5.1. 
Reporting non-serious adverse events  .......................................................................... 68 
9.5.2. 
Reporting serious adverse events  ................................................................................. 68 
9.6. 
Adverse event follow up  ............................................................................................... 70 
 
9.7. 
Abnormal results in laboratory tests  ............................................................................. 70 
9.8. 
Overdosing  ................................................................................................................... 70 
10. 
STATISTICAL CONSIDERATIONS  ...................................................................... 71 
10.1. 
Determining the sample size ......................................................................................... 71 
10.2. 
Population analysis  ....................................................................................................... 71 
10.3. 
Statistical analysis  ........................................................................................................ 71 
10.4. 
Bioavailability acceptance criteria  ............................................................................... 72 
10.5. 
Outsiders and missing samples  ..................................................................................... 72 
10.6. 
Software used for efficacy analysis  .............................................................................. 72 
11. 
ADMINISTRATIVE SECTION  ............................................................................... 72 
11.1. 
Compliance  ................................................................................................................... 72 
11.1.1. Compliance with the Clinical Investigation Protocol and its revisions  ........................ 72 
11.1.2. Monitoring ..................................................................................................................... 73 
11.2. 
Record keeping  ............................................................................................................. 73 
11.2.1. Clinical data forms  ....................................................................................................... 74 
11.2.2. Records of the product under investigation  .................................................................. 74 
11.3. 
Return and destruction of the product under investigation ........................................... 74 
11.3.1. Return of the product under investigation  .................................................................... 74 
11.3.2. Destruction of the product under investigation  ............................................................ 74 
11.4. 
Confidentiality statement  .............................................................................................. 75 
11.5. 
Publications ................................................................................................................... 75 
12. 
LIST OF ABBREVIATIONS  .................................................................................... 75 
13. 
REFERENCES ............................................................................................................ 78 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
1. 
SUMMARY OF THE STUDY  
 
1.1. General considerations 
 
Study Sponsor: Laboratorios Richmond S.A.C.I.F. 
 
Study title: Double blind, randomized, balanced, parallel group, Phase I Study comparing 
pharmacokinetics and safety of Bevacizumab.   
 
Protocol code: 0221 
 
Version of the clinical investigation protocol: 2 
 
Date: 08 January 2019 
 
1.2. Approvals, authorizations, records and notifications 
 
 Clinical Investigation Ethics Committee (CEIC) 
 
 Teaching and clinical investigation committee, CIAREC 
 Medical director of CIAREC 
 
 National Administration for Drugs, Food and Medical Technology 
 Argentine Ministry of Health (Registro Nacional de Investigaciones en Salud- ReNIS)  
 Central Ethics Committee of the City of Buenos Aires  
 
1.3. Study responsible persons  
 
1.3.1. Sponsor 
 
Legal agent: Lic. Elvira Zini 
 
1.3.2. Study coordination, development and organization 
 
FP Clinical Pharma S.R.L. 
 
1.3.3. Clinical stage 
 
1.3.3.1. 
Clinical center  
 
Unidad de investigación-clínica farmacocinética FP Clinical Pharma en Clínica CIAREC 
 
 
 
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Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
1.3.3.2. Principal investigator 
 
M.D.: Ethel C. Feleder 
 
1.3.4. Statistical stage 
 
FP Clinical Pharma S.R.L. 
Dr. Ethel C. Feleder 
 
1.4. Investigation hypothesis 
 
The test formulation containing Bevacizumab - Bevacizumab Richmond Hetero- bulk product 
manufactured by Hetero Biopharma Limited, transported in bulk from India and dosed and packaged 
in Laboratorios Richmond S.A.C.I.F (Test Product 1) presents a bioavailability of bevacizumab 
measured in the amount and speed of the drug absorbed similar to that of product Avastin®-
Bevacizumab from Productos Roche S.A.Q. e I. (Reference Product). 
 
The test formulation containing bevacizumab - Cizumab®- Bevacizumab from Hetero Biopharma 
Limited manufactured and dosed in India (Test Product 2) presents a bioavailability of bevacizumab 
measured in the amount and speed of the drug absorbed similar to that of product Avastin®-
Bevacizumab from Productos Roche S.A.Q. e I. (Reference Product). 
 
The test formulation containing bevacizumab - Bevacizumab Richmond-Hetero- bulk product 
manufactured by Hetero Biopharma Limited, transported in bulk from India and dosed and packaged 
in Laboratorios Richmond S.A.C.I.F (Test Product 1) presents a bioavailability of bevacizumab 
measured in the amount and speed of the drug absorbed (since it is the same bulk used) similar to 
that of product Cizumab®- Bevacizumab from Hetero Biopharma Limited, manufactured and dosed 
in India (Test Product 2). 
 
The process of transportation / local filling of the product Bevacizumab Richmond Hetero (Test 
Product 1) does not affect the pharmacokinetic profile or the safety profile of the molecule in 
comparison with Cizumab® (Test Product 2). Therefore, it is expected that the clinical response be 
similar in the three products under investigation. 
 
 
1.5. Objectives 
 
To evaluate the pharmacokinetics and safety profile of Bevacizumab after administering the following 
investigation products: 
 
 A single IV dose of 1 mg/kg of the test product Bevacizumab-Richmond-Hetero [Test Product 1 local 
primary packaging]
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 

 A single IV dose of 1 mg/kg of Avastin® [Local Reference Product]

 A single IV dose of 1 mg/kg of Cizumab® [Test Product 2 manufactured and packaged by Hetero in 
India]
 
The products are administered to male volunteer study subjects.  
 
1.6. Design 
 
The study to be conducted is a double blind, randomized, balanced, parallel group Phase I study 
comparing pharmacokinetics and safety with a single dose in healthy male volunteers. 
 
1.7. Study type  
 
This study is a clinical pharmacokinetics and safety comparison study belonging to the Phase 1 of the 
clinical studies.   
 
1.8. Study duration 
 
The duration of the participation of each subject in the study, in its clinical stage, is approximately 91 
days.  
 
1.9. Study schedule  
 
 Visit 1: Screening and inclusion (Day -28 through -1) 
 
 Visit 2: Dosing, blood draw, 24 hours confinement (Day 1) 
 
 Visit 3: Outpatient blood draw- hour 48 post-infusion (Day 2) 
 
 Visit 4: Outpatient blood draw- hour 72 post-infusion (Day 3) 
 
 Visit 5: Outpatient blood draw- hour 96 post-infusion (Day 4) 
 
 Visit 6: Outpatient blood draw- hour 120 post-infusion (Day 5) 
 
 Visit 7: Outpatient blood draw- hour 168 post-infusion (Day 7) 
 
 Visit 8: Outpatient blood draw- hour 336 post-infusion (Day 14) 
 
 Visit 9: Outpatient blood draw- hour 504 post-infusion (Day 21) 
 
 Visit 10: Outpatient blood draw- hour 672 post-infusion (Day 28) 
 
 Visit 11: Outpatient blood draw- hour 840 post-infusion (Day 35) 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
  
 Visit 12: Outpatient blood draw- hour 1008 post-infusion (Day 42) 
 
 Visit 13: Outpatient blood draw- hour 1176 post-infusion (Day 49) 
 
 Visit 14: Outpatient blood draw- hour 1344 post-infusion (Day 56) 
 
 Visit 15: Outpatient blood draw- hour 1512 post-infusion - End of study visit (Day 63) 
 
The blood sampling times were as follows:  
 
 Pre-infusion: 0.00 hours 
 
 During the infusion: 0.33, 0.50, 1.00, 1.50 hours 
 
 Post-infusion: 20 min, 40 min, 1.00, 2.00, 4.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00, 
168.00, 336.00, 504.00, 672.00, 840.00, 1008.00, 1176.00, 1344.00 and 1512.00 hours. 
 
1.10.  Number of subjects 
 
The study will be conducted with 90 volunteer subjects. 
 
1.11.  Main inclusion criteria 
 
Volunteer healthy, adult, male subjects.  
 
1.12.  Products under investigation  
 
 Test 1: Bevacizumab Richmond-Hetero, manufactured by Hetero Biopharma Limited, India, 
transported in bulk from India and dosed and packaged in Laboratorios Richmond S.A.C.I.F, 
Argentina.  
 
 Reference: Avastin® Bevacizumab Productos Roche S.A.Q. e I. 
 
 Test 2: Cizumab® Bevacizumab from Hetero Biopharma Limited, manufactured and dosed in 
India.  
 
 
1.13.  Pharmacokinetic parameters  
 
Serum profiles shall be presented for bevacizumab using blood concentration-time curves.  
 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
The following main variables will be calculated: Cmax, AUC0-t, AUC0-inf, Tmax, λz, T1/2, systemic 
clearance, volume of distribution, individual and descriptive statistics.  
 
1.14.  Statistical analysis  
 
Descriptive statistics of concentrations 
Descriptive statistics of pharmacokinetic parameters 
Statistical inference 
Non-compartmental and/or compartmental analysis  
Variance analysis  
 
Calculation of point estimates and confidence intervals  
 
1.15.  Safety parameters 
 
1.15.1. Safety 
 
Anamnesis, 
general 
physical 
examination, 
vital 
signs, 
adverse 
event 
collection 
and 
electrocardiogram.  
 
1.15.2. Immunogenicity  
 
Serum anti-bevacizumab antibodies.  
 
 
2. 
STYDY HYPOTHESIS  
 
The test formulation containing Bevacizumab - Bevacizumab Richmond Hetero- bulk product 
manufactured by Hetero Biopharma Limited, transported in bulk from India and dosed and packaged 
in Laboratorios Richmond S.A.C.I.F (Test Product 1) presents a bioavailability of bevacizumab 
measured in the amount and speed of the drug absorbed similar to that of product Avastin®-
Bevacizumab from Productos Roche S.A.Q. e I. (Reference Product). 
 
The test formulation containing bevacizumab - Cizumab®- Bevacizumab from Hetero Biopharma 
Limited manufactured and dosed in India (Test Product 2) presents a bioavailability of bevacizumab 
measured in the amount and speed of the drug absorbed similar to that of product Avastin®-
Bevacizumab from Productos Roche S.A.Q. e I. (Reference Product). 
 
The test formulation containing bevacizumab - Bevacizumab Richmond-Hetero- bulk product 
manufactured by Hetero Biopharma Limited, transported in bulk from India and dosed and packaged 
in Laboratorios Richmond S.A.C.I.F (Test Product 1) presents a bioavailability of bevacizumab 
measured in the amount and speed of the drug absorbed (since it is the same bulk used) similar to 
that of product Cizumab®- Bevacizumab from Hetero Biopharma Limited, manufactured and dosed 
in India (Test Product 2). 
 
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The process of transportation / local filling of the product Bevacizumab Richmond Hetero (Test 
Product 1) does not affect the pharmacokinetic profile or the safety profile of the molecule in 
comparison with Cizumab® (Test Product 2). Therefore, it is expected that the clinical response be 
similar in the three products under investigation. 
 
 
3. 
INTRODUCTION   
 
3.1. Pharmacokinetics  
 
Bevacizumab pharmacokinetic data stem from 10 clinical studies made on patients with solid 
malignancies who received bevacizumab as IV infusion. The infusion rate was established based on 
the tolerability, with a 90 minutes duration for the initial administration. Bevacizumab 
pharmacokinetics was linear in a dose interval of 1 to 10 mg/Kg (Avastin® Insert, Revision 2016, 
approved by ANMAT 17/02/2017). 
 
As observed with other antibodies, bevacizumab pharmacokinetic data are described by a two-
compartment model. In general terms and in all clinical studies, bevacizumab clearance was 
characterized by a slow clearance, a distribution volume limited to the central compartment, and a 
long mean clearance half life. These parameters ensure the presence of stable bevacizumab 
therapeutic levels in plasma, with a wide range of administration schemes (such as once every 2 or 3 
weeks) (Avastin® Insert, Revision 2016, approved by ANMAT 17/02/2017). 
 
In the pharmacokinetic population meta analysis no significant differences were observed in 
bevacizumab pharmacokinetics with respect to race, when considering the body weight or based on 
the age (no correlation between bevacizumab clearance and the age of patients [the age median was 
59 years and percentiles 5 and 95 of 37 and 76 years of age, respectively] was observed) (Avastin® 
Insert, Revision 2016, approved by ANMAT 17/02/2017). 
 
3.1.1. Distribution 
 
The mean value of the central volume was 2.73 liters in women and 3.28 liters in men, which are 
within the range described for IgG and other monoclonal antibodies. When bevacizumab was 
administered together with antineoplastic agents, the mean value of the peripheral volume was 1.69 
liters in women and 2.35 liters in men. After the correction based on body weight, men showed a 
higher central volume (+20%) than women. (Avastin® Insert, Revision 2016, approved by ANMAT 
17/02/2017). 
 
3.1.2. Biotransformation 
 
 
 
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The evaluation of bevacizumab metabolism in rabbits after the administration of a single IV dose of 
125I-bevacizumab showed that the metabolic profile is similar to the profile expected for a native IgG 
not binding to the VEGF. Bevacizumab metabolism and clearance are similar to those of the 
endogenous IgG, namely, the catabolism is made mainly by proteolysis in all the organism, including 
endothelial cells and does not depend mainly on the elimination through the liver and kidneys. 
Binding to the FcRn receptor protects the IgG from the cell metabolism, which results in a long 
terminal clearance half life. (Avastin® Insert, Revision 2016, approved by ANMAT 17/02/2017). 
 
3.1.3. Clearance 
 
Bevacizumab pharmacokinetics is linear in doses ranging between 1.5 and 10 mg/kg/week. The 
clearance value is 0.188 and 0.220 l/day on average for women and men, respectively. After the 
correction based on the body weight, men showed a higher bevacizumab clearance (+17%) than 
women. According to the two-compartmental model, the average clearance half life is 18 days for an 
average female patient and 20 days for an average male patient. Low albumin levels and a high 
tumor load are general indicators of the disease gravity. Bevacizumab clearance was approximately 
30% faster in patients with low serum albumin levels and 7% faster in those patients with a high 
tumor load when compared with a patient with average values of albumin and tumor load. (Avastin® 
Insert, Revision 2016, approved by ANMAT 17/02/2017).  
 
3.2. Indications 
 
 
 Metastatic carcinoma of the colon or rectum (CCRm)
 
Bevacizumab is indicated in combination with fluoropyrimidine-based chemotherapy for the 
treatment of adult patients with metastatic carcinoma of the colon or rectum. 
 
 Metastatic breast cancer (CMm)
 
Bevacizumab is indicated with paclitaxel for first line treatment in adult patients with metastatic 
breast cancer. 
 
Bevacizumab is indicated in combination with capecitabine as a first line treatment in adult patients 
with metastatic breast cancer, for which the treatment with other chemotherapy options including 
taxanes or anthracyclines are not considered appropriate. Patients with treatment regimens containing 
taxanes and anthracyclines in the adjuvant environment in the past 12 months shall be excluded from 
bevacizumab treatment in combination with capecitabine. 
 
 Non-small cell lung cancer (NSCLC)
 
 
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pharmacokinetics and safety of Bevacizumab  
 
 
Bevacizumab associated with platinum-based chemotherapy is indicated as a first line treatment in 
adult patients with advanced unresectable metastatic or recurring non-microcytic lung cancer, with 
the exception of those having a histology type with squamous cells. 
 
Bevacizumab is indicated in combination with erlotinib as the first line treatment in adult patients 
with advanced unresectable metastatic or recurring non-squamous non-microcytic lung cancer with 
mutations activating the receptor of the epidermal growth factor. 
  
 Advanced and/or metastatic renal cell cancer (CRm)
 
Bevacizumab is indicated in combination with interferon Alpha-2a as a first line treatment of adult 
patients with advanced and/or metastatic renal cell cancer. 
  
 Glioblastoma (Grade IV according to the WHO)
 
Bevacizumab is indicated as a monotherapy for the treatment of patients with relapse of glioblastoma 
(Grade IV according to the WHO) after a previous therapy with temozolomide. 
  
 Epithelial ovarian cancer, Fallopian tube or primary peritoenal cancer
 
Bevacizumab is indicated in combination with carboplatin and paclitaxel as the first line treatment of 
adult patients with advanced (stages IIIB, IIIC and IV according to the International Federation of 
Gynecology and Obstetrics) epithelial ovarian cancer, Fallopian tube or primary peritoneal cancer. 
 
Bevacizumab is indicated in combination with carboplatin and gemcitabine for the treatment of adult 
patients with epithelial ovarian cancer, Fallopian tube carcinoma or primary peritoneal carcinoma 
sensitive to platin after the first relapse, who have not received prior treatment with bevacizumab, 
other vascular endothelial growth factor (VEGF) inhibitors or agents targeting VEGF receptors. 
 
Bevacizumab is indicated in combination with paclitaxel, topotecan or pegylated liposomal 
doxorubicin for the treatment of adult patients with epithelial ovarian cancer, Fallopian tube 
carcinoma or primary recurring peritoneal carcinoma resistant to platinum, who have not received 
more than two prior chemotherapy regimens or prior treatment with bevacizumab, other vascular 
endothelial growth factor (VEGF) inhibitors or agents targeting VEGF receptors. 
  
 Cervical cancer
 
 
 
 
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Bevacizumab is indicated in combination with paclitaxel and cisplatin or carboplatin, or paclitaxel 
and topotecan for the treatment of adult patients with persistent, recurring or metastatic cervical 
cancer. 
 
The information included in this section was extracted from (Avastin® Insert, Revision 2016, 
approved by ANMAT 17/02/2017). 
 
3.3. Contraindications 
 
Hypersensitivity to the active ingredient or to any of its excipients, hypersensitivity to products 
derived from Chinese hamster ovary (CHO) cells or other human or humanized recombinant 
antibodies, pregnancy and nursing. 
 
3.4. Adverse reactions  
 
Summary of the safety profile  
 
Avastin's global safety profile is based on data of approximately 5,400 patients with various types of 
cancer, treated mostly with Avastin in combination with chemotherapy in clinical studies. 
 
The most serious adverse events were: 
 
 Gastrointestinal perforations 
 
 Hemorrhage, including pulmonary hemorrhage/hemoptisis, more frequent in patients with 
non-microcytic lung cancer  
 
 Arterial thromboembolism 
 
In clinical studies the most frequent adverse reactions observed globally in patients treated with 
Avastin were: hypertension, fatigue or asthenia, diarrhea and abdominal pain. 
 
The analysis of clinical safety data suggests that the incidence of hypertension and proteinuria during 
Avastin therapy may probably be dose dependent. 
 
Table of adverse reactions 
 
The adverse reactions listed in this section are classified according to the frequency in the following 
categories: Very Common (≥1/10); Frequent (≥1/100 and <1/10), Uncommon (≥1/1.000 and 
<1/100); rare (≥1/10.000 and <1/1.000); very rare (<1/10.000); and unknown frequency (estimation 
is not possible from the data available). 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Tables 1 and 2 list the adverse reactions associated with the use of Avastin in combination with 
different chemotherapy regimes in multiple indications. 
 
Table 1 shows adverse reactions classified according to frequency. It was determined that they had a 
causal relationship with Avastin through: 
 
- Relative incidences observed among the treatment groups of the clinical study (at least with a 10% 
difference of reactions NCI-CTCAE Grades 1-5, or at least with a 2% difference of reactions NCI-
CTCAE Grades 3–5). 
 
- Post-authorization safety studies  
 
- Spontaneous reporting  
 
- Epidemiologic/non-interventional studies or observational studies  
 
- The evaluation of the reporting of individual cases  
 
Table 2 shows the frequency of the serious adverse reactions. They are defined as adverse events 
with at least a 2% difference in comparison with the control group in clinical studies for reactions 
NCI-CTCAE Grades 3-5. Table 2 also includes adverse reactions considered by Roche as clinically 
significant or serious. 
 
Tables 1 and 2 include post-marketing adverse reactions, as appropriate. The detailed information 
regarding reporting post marketing is shown in Table 3. 
 
The adverse reactions are included in the appropriate frequency category, in the following tables 
according to the highest incidence observed in any indication. 
 
The adverse reactions are listed in decreasing order of severity within each frequency bracket. Some 
are frequently observed in the chemotherapy; however, Avastin may also exacerbate these 
manifestation when used in combination with chemotherapy agents. The examples include palmar 
plantar erythrodysesthesia with pegylated liposomal dosorubicin or capecitabine, sensory peripheral 
neuropathy with paclitaxel or oxaliplatin, alterations in nails or alopecia with paclitaxel and 
paronychia with erlotinib. 
 
Table 1. Adverse reactions according to frequency 
 
 
 
 
 
 
 
 
 
 
 
 
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System 
Organ 
Class  
Very Common  
Frequent  
Uncommon  Rare  
Very Rare  
Unknown 
Frequency 
Infections 
and 
infestations  
Paronychia  
Sepsis  
Abscessb,d, 
Cellulite 
Infection  
Urinal tract infection  
 
Necrotizing 
fascitiisa 
 
 
Blood and 
Lymphatic 
System 
Disorders  
Febrile neutropenia  
Leukopenia 
Netropeniab 
Thrombocytopenia  
Anemia  
Lynphocytopenia  
 
 
 
 
Immune 
System 
Disorders  
 
Hypersensitivity 
Reactions to the 
infusiona,b,d 
 
 
 
 
Metabolism 
and 
Nutrition 
Disorders  
 Anorexia 
Hypomagnesemia 
Hyponatremia 
Dehydration  
Hyponatremia  
 
 
 
 
Nervous 
System 
Disorders  
Sensory peripheral 
neuropathyb 
Dysarthria  
Headache  
Dysgeusia   
 
Stroke  
Syncope  
Drowsiness  
 
 
Posterior 
Reversible 
Encephalopathy 
a,b,d 
 
Hypertensive 
encephalopathy 
 
Eye 
disorders  
Eye disorder 
Lachrimation 
increased 
 
 
 
 
 
Cardiac 
Disorders  
 
Congestive heart 
failureb,d 
Supraventricular 
tachycardia  
 
 
 
 
Vascular 
Disorders  
Hypertensionb,d 
(venous) 
Thromboembolismb,d, 
(arterial) 
Thromboembolismb,d 
Hemorrhageb,d 
Deep vein 
thrombosis  
 
 
 
Renal thrombotic 
microangio-
pathya,b  
 
 
 
Table 1. Adverse reactions classified according to frequency (Continued) 
 
 
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pharmacokinetics and safety of Bevacizumab  
 
 
 
 
System Organ 
Class  
Very Common  
Frequent  
Uncommon  
Rare  
Very 
Rare  
Unknown Frequency 
Respiratory, 
Thoracic and 
Mediastinal 
Disorders  
Dyspnea 
Rhynitis  
Cough 
Pulmonary hemorrhage / 
homoptisisb,d 
Pulmonary embolism 
Hipoxia 
Epistaxis  
Dysphoniaa 
 
 
 
Pulmonay 
hypertensiona 
Nasal septum 
perforationa 
Gastrointestinal 
Disorders  
Rectal 
hemorrhage  
Estomatitis 
Constipation 
Diarrhea 
Nausea  
Vomiting 
Abdominal pain 
Gastrointestinal 
perforationb,d   
Intestinal perforation 
Ileus  
Intestinal obstruction  
Rectovaginal fistulad,e 
Gastrointestinal disorder 
Proctalgia  
 
 
 
Gastrointestinal ulcera 
 
Hepatobiliary 
disorders  
 
 
 
 
 
Perforation of the 
gallbladderb,c  
Skin and 
subcutaenous 
tissue disorders  
 Complications in 
wound healingb, d 
Exfoliative 
dermatitis 
Dry skin 
Discoloration of 
the skin   
 
Palmar plantar 
erythrodysesthesic 
syndrome  
 
 
 
 
Musculoskeletal 
and Connective 
Tissue Disorder  
Arthralgia 
 
Fistulab,d 
Myalgia 
Muscle weakness 
Back pain  
 
 
 
Mandibular 
osteonecrosisa,b 
Non-mandibular 
osteonecrosisa,f 
 
 
 
 
Table 1. Adverse reactions according to frequency (Continued) 
 
 
 
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System Organ 
Class  
Very Common  
Frequent  
Uncommon  
Rare  
Very 
Rare  
Unknown Frequency 
Renal and Urinary 
Disorders  
Proteinuriab,d 
 
 
 
 
 
Reproductive 
system and breast 
disorders  
Ovarian 
insufficiencyb,c,d 
Pelvic pain  
 
 
 
 
Congenital, family 
and genetic 
disorders  
 
 
 
 
 
Fetal anomaliesa,b 
General disorders 
and 
administration site 
conditions  
Asthenia  
Fatigue 
Fever 
Pain 
Mucosa 
inflammation  
 
Lethargy  
 
 
 
 
 
Complementary 
explorations  
Weight loss  
 
 
 
 
 
 
 
 
When events were observed in clinical studies, be they as adverse reactions of all the Grades or 
belonging only to Grade 3-5, the highest frequency reported in patients was informed. The data are 
not adjusted according to the different treatment times.    
 
a) For further information about adverse reactions reported in the post-marketing experience, refer 
to Table 3. 
 
b) Terms representing a group of adverse events describing a medical concept instead of a single 
condition or MedDra (Medical Dictionary for Regulatory Activities) reference term. This set of 
medical terms may imply the same underlying physiopathology (for example, grouping of arterial 
thromboembolic reactions, including stroke, myocardial infarction, transient ischemic attack and 
other arterial thromboembolic reactions). 
 
c) Based on a sub-study of study AVF3077s (NSABP C-08) with 295 patients. 
 
d) For further details see "Description of selected serious adverse reactions". 
e) Recto-vaginal fistulas are the most common fistulas in the category of GI-vaginal fistulas. 
f) Observed only in pediatric population. 
 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Table 2. Serious adverse reactions classified according to frequency 
 
 
 
System Organ 
Class  
Very Common  
Frequent  
Uncommon  Rare  
Very Rare  
Unknown 
Frequency 
Infections and 
infestations  
 
Sepsis  
Cellulite 
Abscessa, b, 
Infection  
Urinary tract 
infection  
 
 
 
Necrotizing 
fascitiisa 
Blood and 
Lymphatic 
System 
Disorders  
Febrile neutropenia  
Leukopenia 
Netropeniaa 
Thrombocytopenia  
Anemia  
Lynphocytopenia  
 
 
 
 
Immune 
System 
Disorders  
 
 
 
 
 
Hypersensitivity 
Reactions to the 
infusion 
Metabolism 
and Nutrition 
Disorders  
  
Dehydration  
 
 
 
 
Nervous 
System 
Disorders  
Sensory peripheral 
neuropathyb 
 
Stroke  
Syncope  
Drowsiness  
Headache  
 
 
Hypertensive 
encephalopathy a 
Posterior 
Reversible 
Encephalopathy 
a,b,c 
Hypertensive 
encephalopathy  
Cardiac 
Disorders  
 
Congestive heart 
failurea,b 
Supraventricular 
tachycardia  
 
 
 
 
Vascular 
Disorders  
Hypertensionb,d 
 
(arterial) 
Thromboembolisma,b 
Hemorrhageb,d 
(venous) 
Thromboembolisma,b 
Deep vein 
thrombosis  
 
 
 
Renal thrombotic 
microangiopathyb,c  
 
 
 
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Table 2. Serious adverse reactions classified according to frequency (Continued) 
 
 
 
System Organ 
Class  
Very Common  
Frequent  
Uncommon  Rare  
Very Rare  
Unknown 
Frequency 
Respiratory, 
Thoracic and 
Mediastinal 
Disorders  
 
Pulmonary 
hemorrhage / 
homoptisisa,b 
Pulmonary 
embolism  
Epistaxis 
Dyspnea 
Hypoxia 
 
 
 
Pulmonay 
hypertensionc 
Nasal septum 
perforationa 
Gastrointestinal 
Disorders  
Diarrhea 
Nausea  
Vomiting 
Abdominal pain 
Intestinal 
perforation 
Ileus  
Intestinal 
obstruction  
Rectovaginal 
fistulac,d 
Gastrointestinal 
disorder 
Estomatitis 
Proctalgia  
 
 
 
Gastrointestinal 
perforationa,b 
Gastrointestinal 
ulcerc 
Rectal 
hemorrhage  
Hepatobiliary 
disorders  
 
 
 
 
 
Perforation of the 
gallbladderb,c  
Skin and 
subcutaenous 
tissue disorders  
  
Complications in 
wound healinga,b 
Palmar plantar 
erythrodysesthesic 
syndrome  
 
 
 
 
Musculoskeletal 
and Connective 
Tissue Disorder  
 
Fistulab,d 
Myalgia 
Arthralgia 
Muscle weakness 
Back pain  
 
 
 
Mandibular 
osteonecrosisb,c 
 
Renal and 
Urinary 
Disorders  
 
Proteinuriaa,b 
 
 
 
 
 
 
 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
 
Table 2. Serious adverse reactions classified according to frequency (Continued) 
 
 
 
 
System Organ 
Class  
Very Common  
Frequent  
Uncommon  Rare  
Very Rare  
Unknown 
Frequency 
Reproductive 
system and 
breast 
disorders  
 
Pelvic pain  
 
 
 
Ovarian 
insufficiencya,b 
Congenital, 
family and 
genetic 
disorders  
 
 
 
 
 
Fetal anomaliesa,b 
General 
disorders and 
administration 
site conditions  
Asthenia  
Fatigue 
  
Lethargy  
Mucosa 
inflammation  
 
 
 
 
 
 
 
Table 2 shows the frequency of the serious adverse reactions. These are defined as adverse events 
with a 2% difference in comparison with the control group in clinical studies for reactions NCI-
CTCAE Grades 3-5. Table 2 also includes adverse reactions considered by Roche to be clinically 
significant or serious. These clinically significant adverse reactions were reported in the clinical 
studies, but those of Grades 3-5 did not reach the threshold of at least 2% of difference in comparison 
with the control group. 
 
Table 2 also includes clinically significant adverse reactions observed only after the product was on 
the market, therefore, the frequency and the NCI-CTCAE grade is unknown. Consequently, these 
clinically significant reactions have been included in Table 2 in the column with heading "Unknown 
Frequency". 
 
a) Terms representing a group of adverse events describing a medical concept instead of a single 
condition or MedDra (Medical Dictionary for Regulatory Activities) reference terms. This set of 
medical terms may imply the same underlying physiopathology (for example, grouping of arterial 
thromboembolic reactions, including stroke, myocardial infarction, transient ischemic attack and 
other arterial thromboembolic reactions). 
 
b) For further details, see the "Description of selected serious adverse reactions".  
 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
c) For further details about adverse reactions reported in the post-marketing experience, refer to 
Table 3. 
 
d) Recto-vaginal fistulas are the most common fistulas in the category of GI-vaginal fistulas.  
 
Description of selected serious adverse reactions 
 
Gastro-intestinal (GI) perforations and Fistulas (see Warnings and Precautions) 
 
The use of Avastin was associated with serious cases of gastro-intestinal perforation. 
 
Cases of gastro-intestinal perforations have been reported in clinical studies with an incidence of less 
than 1% in patients with non-microcytic lung cancer, of up to 1.3% in patients with metastatic breast 
cancer, of up to 2% in metastatic renal cell cancer, with a recent diagnosis of glioblastoma or with 
ovarian cancer, and of up to 2.7% in patients with metastatic colorectal cancer (including gastro-
intestinal fistula and abscesses). Cases of gastrointestinal perforations were also observed in patients 
with relapsed glioblastoma. 
 
In a clinical study of patients with persistent, recurring or metastatic cervical cancer (GOG-0240), 
gastrointestinal perforations (all the Grades) were observed in 3.2% of patients, all of whom had a 
history of prior pelvic radiation. 
 
A difference in the type and severity of these reactions was observed, ranging from the presence of 
free air detected in a normal abdominal X-ray, which was resolved without the need of treatment up 
to the intestinal perforation with abdominal abscess and a fatal outcome. Some cases already 
presented an underlying intra-abdominal inflammation as a consequence of gastric ulcer, tumor 
necrosis, diverticulitis or chemotherapy associated colitis. 
 
A fatal outcome was reported in approximately a third of the severe cases of gastrointestinal 
perforations, which accounts for between 0.2% and 1% of all patients treated with Avastin. 
 
In clinical studies with Avastin, cases of gastrointestinal fistula (of all Grades) were informed, with 
an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, and also 
(although with a lower frequency) in those patients with other types of cancer.    
 
GI-Vaginal fistulas in study GOG-240 
 
In a study with patients presenting persistent, recurring or metastatic cervical cancer, the incidence of 
GI-vaginas fistulas was 8.3% in patients treated with Avastin and 0.9% in control patients, all of 
whom had history of prior pelvic radiation. The frequency of GI-vaginal fistulas in the group treated 
with Avastin + chemotherapy was higher in patients with a recurrence of the disease within the 
previously radiated field (16.7%) in comparison with those with a recurrence of the disease outside 
the previously radiated field (3.6%). The frequencies corresponding to the control group who 
received only chemotherapy was 1.1% in comparison with 0.8% respectively. Those patients who 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
developed GI-vaginal fistulas may have intestinal obstructions and require surgical intervention, as 
well as ostomy. 
 
Non-gastrointestinal (GI) fistulas (Refer to Warnings and Precautions) 
 
The use of Avastin was associated with severe cases of fistulas, including reactions with fatal 
outcomes. 
 
In a clinical study in patients with persistent, recurring or metastatic cervical cancer (GOG-0240), 
1.8% of patients treated with Avastin and 1.4% of control patients reported having non-gastro 
intestinal fistulas: vaginal or vesical fistulas, or fistulas in the female genital tract. 
 
Uncommon cases (≥0.1% and <1%) of fistulas with involvement of other parts of the body different 
from the gastro-intestinal tract (for example, bronchopleural and biliary fistulas) were observed in 
various indications. Fistulas were also reported during the post-marketing experience. 
 
The reactions were reported at different moments of the treatment, ranging from the first week until 
past the first year since beginning the treatment with Avastin. Most of the cases were observed 
within the first six-month period of the treatment. 
 
Wound Healing (Refer to Warnings and Precautions)  
 
Because Avastin can have a negative impact in the healing of wounds, patients who had major 
surgery in the past 28 days were excluded from Phase III clinical studies. 
 
In clinical studies in patients with metastatic carcinoma of the colon or rectum, patients who had 
undergone major surgery between the 28 and 60 day period before starting the therapy with Avastin 
did not show an increase in the risk of post-operative hemorrhage or complications in the healing of 
the wounds. It was observed that if patients were subject to treatment with Avastin at the moment of 
the surgery, they had a higher risk of post-operative hemorrhage or wound healing problems in the 
60 days after the major surgery. The incidence ranged between 10% (4/40) and 20% (3/15). 
 
Severe complications in the healing of wounds have been reported, including complications related 
to anastomosis, some of them with fatal outcomes. 
 
In studies in patients with locally recurring and metastatic breast cancer, complications in wound 
healing (Grades 3-5) were observed in up to 1.1% of patients treated with Avastin compare to up to 
0.9% in the control arms (NCI-CTCAE v.3). 
 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
In study AVF3708g in patients with relapsed glioblastoma, the incidence of post-operative wound 
healing complications (including wound dehiscence in the location of the craneotomy and loss of 
cerebrospinal fluid) was 3.6% in patients treated with Avastin as a single agent and 1.3% in patients 
receiving Avastin plus irinotecan. 
 
In clinical studies in patients with ovarian cancer, wound healing complications (Grade 3-5) were 
observed in up to 1.2% of patients in the bevacizumab arm compared to 0.1% of the control arm 
(NCI-CTCAE v.3). 
 
In study BO21990 in patients with recent diagnosis of glioblastoma, the incidence of post-operative 
wound healing complications Grade 3-5 (including those which presented themselves after the 
craneotomy) was 3.3% in patients treated with Avastin in combination with chemotherapy and 
radiotherapy, and 1.6% in those receiving only chemotherapy and radiotherapy. 
 
Hypertension (Refer to Warnings and Precautions) 
 
In clinical studies, with the exception of study JO25567, the global incidence of hypertension (all the 
Grades) was of up to 42.1% in patients treated with Avastin in comparison with up to 14% in patients 
receiving the comparator. The global incidence NCI-CTC of hypertension Grades 3 and 4 occurred 
in 0.4% through 17.9% of patients treated with Avastin. Grade 4 hypertension (hypertensive crisis) 
occurred in up to 1.0% of patients treated with Avastin and chemotherapy in comparison with up to 
0.2% of patients receiving the same single chemotherapy. 
 
In study JO25567, all the Grades of hypertension were observed in 77.3% of patients who received 
bevacizumab in combination with erlotinib as first line of treatment for non-squamous CPNM with 
EGFR activating mutations, in comparison with 14.3% of patients treated with only erlotinib. Grade 
3 hypertension occurred in 60.0% of patients treated with bevacizumab in combination with erlotinib 
in comparison with 11.7% of patients receiving only erlotinib. No Grade 4 or 5 hypertension events 
occurred. 
 
In general, hypertension was adequately controlled with oral antihypertensive drugs, such as 
angiotensin-converting enzyme, diuretics and calcium channel blockers. Only rarely was it necessary 
to discontinue the treatment with Avastin or hospitalization. 
 
Very rare cases of hypertensive encephalopathy have been reported, some of them were fatal. 
 
There is no correlation between the risk of hypertension associated with Avastin treatment and the 
baseline characteristics of patients, the underlying disease or the concomitant therapy. 
 
Posterior Reversible Ecephalopathy Syndrome (Refer to Warnings and Precautions) 
 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Some rare cases have been reported of patients treated with Avastin who develop signs and 
symptoms coinciding with the Posterior Reversible Encephalopathy Syndrome (PRES), a rare case of 
neurological disorder. Its manifestation can include seizures, headache, altered mental status, visual 
alterations or cortical blindness, with or without associated hypertension. The clinical features of 
PRES are frequently unspecific and therefore the diagnosis requires confirmation using cerebral 
imaging techniques, preferably a magnetic resonance imaging (MRI). 
 
In patients developing PRES, an early awareness of the symptoms is recommended, with a timely 
treatment of the specific symptoms, including control of the hypertension (if associated with 
uncontrolled severe hypertension), in addition to discontinuing bevacizumab administration. 
Symptoms generally resolve or improve in the days after the treatment discontinuation, although 
some patients have experienced some neurologic sequelae. The safety of resuming Avastin therapy in 
patients who had previously experienced PRES is unknown. 
 
As a result of the clinical studies, 8 cases of PRES were reported. Two of the eight cases did not have 
a radiological confirmation using MRI. 
 
Proteinuria (Refer to Warnings and Precautions)    
 
In clinical studies, proteinuria cases were reported in a bracket ranging from 0.7% to 54.7% of 
patients treated with Avastin. 
 
The proteinuria severity varied from the clinically asymptomatic, transitory, indication of proteinuria 
up to nephrotic syndrome, with most cases being Grade 1 (NCI-CTCAE v. 3) proteinuria. Grade 3 
proteinuria was observed in up to 8.1% of treated patients. Grade 4 proteinuria (nephrotic syndrome) 
was observed in up to 1.4% of treated patients. 
 
Patients with known history of hypertension may have a higher risk of proteinuria during Avastin 
treatment. Some data suggest that Grade 1(NCI-CTCAE v. 3) may be related with the dose of 
Avastin. It is recommended to run proteinuria tests before starting with Avastin treatment. In most of 
the clinical studies where the protein levels in urine were ≥2 g/24 hours, the treatment with Avastin 
was discontinued until levels of <2 g/24 hours were recovered. 
 
Hemorrhage (Refer to Warnings and Precautions) 
 
In clinical studies in all indications, the overall incidence of hemorrhagic reactions Grade 3-5 
according to scale NCI-CTCAE v.3, ranged from 0.4% to 6.9% in patients treated with Avastin, 
compared to up to 4.5% of the chemotherapy control group. 
 
In clinical study (GOG-0240) in patients with persistent, recurring or metastatic carcinoma of the 
cervix, hemorrhagic reactions Grade 3-5 were reported in up to 8.3% of patients treated with 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Avastin in combination with paclitaxel and topotecan, in comparison with up to 4.6% of patients 
receiving paclitaxel and topotecan. 
 
The hemorrhagic reactions observed in the clinical studies were mostly hemorrhages associated with 
the tumor, and minor mucocutaneous hemorrhages (for example, epistaxis). 
  
Tumor-associated hemorrhages (Refer to Warnings and Precautions)  
 
Severe or massive pulmonary hemorrhage / hemoptisis was observed mainly in studies in patients 
with non-microcytic lung cancer. The possible risk factors include histology of squamous cells, 
treatment with anti-rheumatic/anti-inflammatory drugs or anticoagulant drugs, prior radiotherapy, 
treatment with Avastin, prior medical history of atherosclerosis, localization of the central tumor and 
cavitation of tumors before or during the treatment. The only variables that showed a statistically 
significant correlation with the hemorrhage were Avastin treatment and squamous cell histology. 
Patients with CPNM diagnosed with a histological type of squamous cells or with a histology of a 
mixed cell type with predominance of squamous cells were excluded from later Phase III studies, 
whereas patients with an unknown tumor histology were included. 
 
In patients with non-microcytic lung cancer, excluding patients who had a histology with a 
predominance of squamous cells, reactions of all Grades were observed, with a frequency of up to 
9.3% in patients treated with Avastin plus chemotherapy in comparison with up to 5% of patients 
receiving only chemotherapy. Grade 3-5 reactions were observed in up to 2.3% of patients treated 
with Avastin plus chemotherapy in comparison with <1% with chemotherapy alone (NCI-CTCAE v. 
3). Severe or massive pulmonary hemorrhage / hemoptisis may occur suddenly and up to two thirds 
of serious pulmonary hemorrhages had a fatal outcome. 
 
In patients with colorectal cancer, gastrointestinal hemorrhages were reported, including rectal 
hemorrhage and melena. They were evaluated as associated to the tumor. 
 
Rare cases of hemorrhages linked to the tumor in other tumor types and locations were observed, 
including cases in the central nervous system (CNS) in patients with CNS metastasis (Refer to 
Warnings and Precautions) and in patients with glioblastoma. 
 
No prospective evaluation in randomized clinical studies were conducted to assess the incidence of 
hemorrhage in the CNS in patients with untreated metastases located in the CNS who received 
bevacizumab. In a retrospective exploratory analysis of data from 13 randomized studies completed 
in patients with different types of tumors, 3 of 91 (3.3%) with brain metastasis experienced CNS 
hemorrhage (all Grade 4) when treated with bevacizumab versus 1 case (Grade 5) of 96 (1%) who 
did not receive bevacizumab. In two later studies in patients with treated brain metastases (including             
approximately 800 patients), when the interim safety analysis was conducted, one Grade 2 case was 
reported with hemorrhage in the CNS (1.2%) of the 83 patients administered with bevacizumab 
(NCI-CTCAE v.3). 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Intracranial hemorrhage may occur in patients with relapsed glioblastoma. In study AVF3708g, CNS 
hemorrhage was reported in 2.4% (2/84) of Avastin only patients (Grade 1), and in 3.8% (3.79%) of 
patients treated with Avastin plus irinotecan (Grades 1, 2 and 4). 
  
During the clinical studies, mucocutaneous hemorrhage was observed in up to 50% of patients 
treated with Avastin. The most frequent cases were Grade 1 epistaxis according to the scale (NCI-
CTCAE v.3) lasting less than 5 minutes, and which resolved without the need of medical treatment 
and did not require any change in the regime with Avastin. Safety clinical data suggest that the 
incidence of minor mucocutaneous hemorrhages (for example, epistaxis) may be dose-dependent. 
 
Likewise, but with a lesser frequency, cases of minor mucocutaneous hemorrhage were observed in 
other locations, such as gingival or vaginal hemorrhage. 
 
Thromboembolism (Refer to Warnings and Precautions) 
 
Arterial thromboembolism 
 
An increase in the incidence of arterial thromboembolic reactions was observed in patients treated 
with Avastin in all the indications. These included stroke, myocardial infarction, transient ischemic 
attacks and other arterial thromboembolic reactions. 
 
In clinical studies the overall incidence of arterial thromboembolic reactions was of up to 3.8% in the 
arms including Avastin in comparison with up to 2.1% in the control chemotherapy arms. Fatal 
outcomes were reported in 0.8% of patients treated with Avastin, compared with 0.5% of patients 
who were treated only with chemotherapy. Strokes were informed (including transient ischemic 
attacks) in up to 2.7% of patients treated with Avastin in combination with chemotherapy in 
comparison with up to 0.5% of patients who received only chemotherapy. Myocardial infarction was 
reported in up to 1.4% of patients treated with Avastin in combination with chemotherapy, versos up 
to 0.7% of patients receiving only chemotherapy. 
 
In a clinical study to evaluate Avastin in combination with 5-fluorouracil/folinic acid, AVF2192g, 
patients with metastatic colorectal cancer who were not candidates for irinotecan treatment were 
included. In this study, arterial thrombo encephalic reactions were observed in 11% (11/100) of 
patients vs. 5.8% (6/104) in the control chemotherapy group. In non-controlled clinical study 
AVF3708g in patients with relapsing glioblastoma, arterial thromboembolic events were observed in 
up to 6.3% (5/79) of patients receiving Avastin in combination with irinotecan, versos up to 4.8% 
(4/84) who received only Avastin. 
 
Venous thromboembolism  
 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
The incidence of venous thromboembolic reactions in clinical studies was similar in patients treated 
with Avastin in combination with chemotherapy versus patients receiving only control 
chemotherapy. Venous thromboembolic reactions include deep vein thrombosis, pulmonary 
embolism and thromboflebitis. 
 
In clinical studies in all indications, the overall incidence of venous thromboembolic reactions ranged 
from 2.8% to 17.3% of patients treated with Avastin versus 3.2% to 15.6% in the control groups. 
 
Grade 3-5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% of 
patients treated with chemotherapy plus bevacizumab in comparison with up to 4.9% in patients who 
received only chemotherapy (in all indications, excluding persistent, recurring or metastatic cervical 
cancer). 
 
In a clinical study (GOG-0240) in patients with persistent, recurring or metastatic carcinoma of the 
cervix, Grade 3-5 venous thromboembolic events were reported in up to 15.6% of patients treated 
with Avastin in combination with paclitaxel and cisplatin compared to up to 7.0% of patients 
receiving paclitaxel and cisplatin. 
 
Patients who suffered a venous thromboembolic reaction may have a higher risk of recurrence with 
Avastin in combination with chemotherapy, than with only chemotherapy. 
 
In clinical study BO21990, Grade 3-5 venous thromboembolic events were observed in 7.6% of 
patients recently diagnosed with glioblastoma, treated with Avastin in combination with 
chemotherapy and radiotherapy, versus 8.0% of patients receiving only chemotherapy and 
radiotherapy. 
 
Congestive heart failure 
 
In Avastin clinical studies, congestive heart failure was observed in all the indications of cancer 
studied so far, although there was a preponderance in patients with metastatic breast cancer. In four 
Phase III studies in patients with metastatic breast cancer (AVF2119g, E2100, BO17708 and 
AVF3694g), up to 3.5% of patients treated with Avastin in combination with chemotherapy reported 
Grade 3 or higher (NCI-CTCAE v. 3) congestive heart failure versus up to 0.9% in the control arms. 
In the patients of study AVF3694g receiving anthracyclines concomitantly with bevacizumab, the 
incidences of Grade 3 or higher congestive heart failure in the control arms and with bevacizumab 
were similar to those of other metastatic breast cancer studies: 2.9% in the anthracycline plus 
bevacizumab arm and 0% in the anthracycline plus placebo arm. Additionally, in study AVF3694g 
the incidences of congestive heart failure of any grade were similar in the anthracycline plus Avastin 
arm (6.2%) and the anthracycline plus pacebo arm (6.0%). 
 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
After the adequate clinical therapy, an improvement in the symptoms and/or the left ventricular 
function was observed in most patients who developed congestive heart failure during the metastatic 
breast cancer studies. 
 
In most of clinical studies with Avastin, patients with pre-existing congestive heart failure Grade II-
V according to the NYHA (New York Heart Association) were excluded, therefore, no information is 
available related with the risk of worsening of the congestive heart failure in this population. 
 
The previous exposure to anthracyclines and/or prior radiation on the chest wall may be a likely risk 
factor to develop congestive heart failure. 
 
In a clinical study in patients with diffuse large B-cell lymphoma, an increase in the incidence of 
congestive heart failure was observed when patients received bevacizumab with a cumulative dose of 
doxorubicin 
in 
excess 
of 
300 
mg/m2. 
This 
Phase 
III 
clinical 
study 
compared 
rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) plus bevacizumab with 
R-CHOP without bevacizumab. While the incidence of congestive heart failure was in both groups 
higher than the incidence observed previously for the doxorubicin therapy, the rate was higher in the 
R-CHOP group plus bevacizumab. These results suggest that a close clinical observation should be 
considered with adequate heart evaluations in patients exposed to cumulative doxorubicin doses in 
excess of 300 mg/m2 when used in combination with bevacizumab. 
 
Hypersensitivity reactions / reactions to the infusion (Refer to Warnings and Precautions, and 
Adverse Reactions, Post Marketing Experience) 
 
In some clinical studies, anaphylactic reactions and anaphylactoid like reactions with higher 
frequency in patients who had received Avastin in combination with chemotherapy versus patients 
treated only with chemotherapy. The incidence of these reactions in some clinical studies with 
Avastin is frequent (up to 5% in patients receiving bevacizumab). 
 
Infections 
 
In clinical study (GOG-0240) in patients with persistent, recurring or metastatic carcinoma of the 
cervix, Grade 3-5 infections were reported in up to 24% of patients treated with Avastin in 
combination with paclitaxel and topotecan, versus up to 13% of patients who received paclitaxel and 
topotecan. 
 
In randomized, double blind placebo controlled, multicenter Phase III clinical study BO21990 of 
Avastin in combination with chemotherapy plus radiotherapy for the treatment of patients with recent 
diagnosis of glioblastoma, the incidence of infections of all Grades was 54.4% and 12.8% for Grade 
3-5 infections in the bevacizumab plus chemotherapy and radiotherapy arm, versus 39.1% and 7.8% 
in the chemotherapy plus radiotherapy only, respectively. 
 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Ovarian insufficiency / Fertility (Refer to Warnings and Precautions) 
 
In Phase III study NSABP C-08 of Avastin for the adjuvant treatment of patients with colon cancer, 
the incidence of new cases of ovarian insufficiency, defined as amenorrhea lasting 3 months or more, 
level FSH  ≥ 30 MUI/ml and a negative value of β-HCG for the pregnancy test, was evaluated in 295 
premenopausal women. New cases of ovarian insufficiency were reported in 2.6% of patients in the 
mFOLFOX-6 group compared to 39% of the Mfolfox-6 plus bevacizumab group. In 86.2% of the 
women evaluated, the ovarian function was recovered after discontinuing bevacizumab. The long 
term effect of bencizumab treatment on the fertility is unknown. 
 
Abnormal laboratory findings 
 
The decrease in the neutrophil count and white cells, and the presence of proteins in the urine may be 
associated with the treatment with Avastin. 
 
As a result of clinical studies, patients treated with Avastin showed the following Grade 3 and 4 
(NCI-CTCAE v.3) abnormal laboratory findings with at least 2% of difference in comparison with 
the corresponding control 
groups: hyperglycemia, decreased hemoglobin, hypokalemia, 
hyponatremia, decreased white cell count, and an increase in the International Normalized Ratio 
(INR). 
 
The clinical tests showed that transitory increases in serum creatinine (ranging between 1.5 and 1.9 
times the base line level), with and without proteinuria, are associated with Avastin use. The increase 
observed in serum creatinine was not linked with a higher incidence of clinical manifestation of renal 
insufficiency in patients treated with Avastin. 
 
Other special populations 
 
Elderly patients 
 
In randomized clinical studies, an age or more than 65 years was associated with an increase of 
arterial thromboembolic reactions, including stroke, transient ischemic attacks and myocardial 
infactions. Other reactions during the Avastin treatment observed with a higher frequency in patients 
older than 65 years were leukopenia and thrombocytopenia Grades 3-4 (NCI-CTCAE v.3); and 
neutropenia, diarrhea, headache and fatigue of all Grades in comparison with patients younger than 
65 years of age (Refer to Adverse reactions, and Warnings and Precautions, Thromboembolism). In a 
clinical study, the incidence of Grade ≥3 hypertension was twice higher in patients older than 65 
years of age than in the younger group (less than 65 years of age). 
 
In a study in patients with recurring platinum-resistant ovarian cancer cases of alopecia, 
inflammation of the mucous membranes, sensory peripheral neuropathy, proteinuria and 
 
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Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
hypertension, which occurred with a rate of at least 5% higher in the QT + BV group in female 
patients of 65 years of age or older treated with bevacizumab in comparison with patients younger 
than 65 years of age equally treated. 
 
No increase in the incidence of other reactions was observed, including gastrointestinal perforation, 
wound healing complications, congestive heart failure and hemorrhage in elderly patients (older than 
65 years) treated with Avastin in comparison with patients younger than 65 years equally treated. 
 
Pediatric population 
 
The safety of Avastin in children and adolescents younger than 18 years of age has not been 
established. Avastin is not approved for use in patients younger than 18 years of age. Some 
publications indicate that some cases of non-mandibular osteonecrosis in patients younger than 18 
years of age treated with Avastin were observed. 
 
Post-marketing experience 
 
Table 3. Adverse reactions reported during the post-marketing experience 
 
 
 
System Organ 
Class  
Reactions (frequency*)  
Infections and 
infestations  
Necrotizing fascitiis, in general, secondary to wounds resulting from 
complications in the wound healing, gastrointestinal perforations or formation 
of fistula (rare) (See Warnings and Precautions)   
Immune system 
disorders 
Hypersensitivity reactions and reactions to the infusion (unknown), with the 
following possible co-manifestations: dyspnea/breathing difficulty, 
flushing/redness/rash, hypotensionn or hypertension, oxygen desaturation, 
throacic pain, chills and nausea/vomiting (see Warnings and Precautions; 
Adverse Reactions, Hypersensitivity Reactions/reactions to the infusion).  
Nervous system 
disorders  
Hypertensive encephalopathy (very rare) (See Warnings and Precautions, and 
Adverse Reactions, hypertension).  
 
Posterior reversible encephalopathy syndrome (rare) (see Warnings and 
Precautions)   
Vascular disorders  Renal thrombotic microangiopathy, which could present itself clinically as 
proteinuria (unknown) with and without the concomitant use of sunitinib (See 
Warnings and Precautions and Adverse reactions, proteinuria).   
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
Table 3. Adverse reactions reported during the post-marketing experience (Continued) 
 
 
 
 
System Organ 
Class  
Reactions (frequency*)  
Respiratory, 
Thoracic and 
Mediastinal 
Disorders 
Perforation of the nasal septum (unknown) 
 
Pulmonary hypertension (unknown) 
 
Dysphonia (frequent)  
Gastrointestinal 
disorders  
Gastrointestinal ulcer (unknown) 
Hepatobiliary 
disorders  
Gallbladder perforation (unknown) 
Musculoskeletal 
and Connective 
Tissue Disorder 
Cases of maxilar osteonecrosis have been observed in patients treated with 
Avastin, most of which occurred in those which had risk factors identified in 
the maxilar osteonecrosis, concretely the intravenous exposure to 
bisphosphonate and/or history of dental disease which required invasive dental 
processes (see Warnings and Precautions).  
 
Cases of non-mandibular osteonecrosis have been observed in pediatric 
patients treated with Avastin (see Adverse Reactions, Pediatric Population).   
Congenital, family 
and genetic 
disorders 
Fetal anomanies were observed in women treated with bevacizumab alone or 
in combination with known embryotoxis chemotherapeutic agents (See 
Warnings and Precautions; Fertility, pregnancy and lactation).  
 
 
* If indicated, the frequency was obtained from clinical study data. 
 
The information described in this section was extracted from Avastin® Insert, Revision 2016, 
approved by ANMAT 17/02/2017. 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
4. 
OBJECTIVES OF THE STUDY  
 
4.1. Primary objectives  
 
The primary objective of this Study was to evaluate the pharmacokinetics and safety profile of 
Bevacizumab after administering the following investigation products: 
 
 A single IV dose of 1 mg/kg of the test product Bevacizumab-Richmond-Hetero [Test Product 1 local 
packaging]


 A single IV dose of 1 mg/kg of Avastin® [Local Reference Product]

 A single IV dose of 1 mg/kg of Cizumab® [Test Product 2 manufactured and packaged by Hetero in 
India]
 
The products will be administered to volunteer healthy male subjects.   
 
4.2. Secondary objectives  
 
Report the nature and the incidence of adverse events and the eventual discontinuation or drop out in the study 
or the participation of a subject in the study. 
 
Evaluate the immunogenic potential of the products under investigation. 
 
Evaluate if the transportation / local filling of the product Bevacizumab Richmond Hetero (Test 
Product 1) affects the pharmacokinetic profile and the safety profile of the molecule with respect to 
Cizumab® (Test Product 2). 
 
 
 
 
5. 
ETHICAL CONSIDERATIONS  
 
5.1. Good clinical practices  
 
This Clinical Investigation Protocol will be carried out according to the "Guide for investigations in 
human beings" issued by the Ministry of Health (Ministry of Health resolution number 1480/11), the 
Good Clinical Practice Regime for clinical pharmacology studies of the National Administration for 
Drugs, Food and Medical Technology (ANMAT Provision number 6677/10), good clinical practices 
standards (as defined in the Guidelines for Good Clinical Practices of the ICH, and in keeping with 
the Helsinki Declaration " Ethical Principles for Medical Research Involving Human Subjects" of the 
World Medical Association. 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
The study will be carried out in compliance with the Clinical Investigation Protocol. The Clinical 
Investigation Protocol, its amendment(s) and the informed consent of the study subject will receive 
the approval/favorable opinion of the Independent Ethics Committee (CEI) before starting with the 
study.   
 
5.2. Independent Ethics Committee 
 
Before the study begins, the Investigator shall obtain the approval/favorable opinion by the CEI in 
writing of the Clinical Investigation Protocol, the consent form, the materials/process to include the 
subjects in the study (for example, announcements), and any other written information to be 
delivered to the study subjects. The Investigator or the sponsor shall provide the CEI with the 
necessary documents for the ethical evaluation of the Clinical Investigation Protocol, according to 
the descriptions included in their standard operating procedures.    
 
The Investigator or the sponsor shall provide the CEI with reports, updates and any other information 
(for example, safety expedited reporting, amendments, administrative letters, study completion 
report, etc.) according to the local regulatory requirements and the standard operating procedures.  
 
5.3. Informed consent  
 
The Investigator shall ensure that the study subjects, or in the situations in which the consent cannot 
be given by the study subjects, their legally acceptable representative, have been informed clearly 
and comprehensively about the study purpose, potential risks and any other critical issues involving 
the Clinical Investigation Protocol in which the individual volunteers participate. The informed 
consent of each study subject shall be obtained in writing and shall be delivered willingly by said 
subject or by the legally acceptable representative if the subject is not in condition to do it, before 
their participation in the Clinical Investigation Protocol, including the informed consent to conduct 
any selection procedure to establish the eligibility condition of the study subject for the Clinical 
Investigation Protocol.     
 
The study subject shall sign two (2) copies of the consent document (Section 2 - Signature Page), of 
which one copy shall be kept by the study subject and the remaining copy shall be filed in the 
investigator's file.  
 
5.4. Approvals, notifications, authorizations and records  
 
The following approvals, notifications, authorizations and records of the Clinical Investigation 
Protocol and the informed consent shall be processed:   
 
• Clinical Investigation Ethics Committee (CEIC) 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Larrea 1381 3º A – C1117ABK 
C.A.B.A. – Bs. As. – Argentina 
Telephone number: (54-11) 4826-3962 
 
• Comité de Docencia e Investigación de Clínica (Teaching and Clinical Investigation Committee) 
CIAREC 
 
Monroe 4770 – C1431CEF 
C.A.B.A. – Bs. As. – Argentina 
Telephone number: (54-11) 
4541-5700 
 
• Dirección Médica de Clínica (Medical Director's Office) CIAREC 
 
Monroe 4770 – C1431CEF 
C.A.B.A. – Bs. As. – Argentina 
Telephone number: (54-11) 4541-5700 
 
The following authorization shall be processed:  
 
• Administración Nacional de Medicamentos, Alimentos y Tecnología Médica 
(ANMAT) Av. de Mayo 869 – C1084AAD 
 
C.A.B.A. – Bs. As. – Argentina 
Telephone number: (54-11) 
4340-0800 
 
The following registration shall be processed:  
 
• Ministerio de Salud de la Nación 
 
Registro Nacional de Investigaciones en Salud (ReNIS) 
Av. 9 de Julio 1925 – C1073ACA C.A.B.A. – Bs. As. 
– Argentina, Telephone number: (54-11) 4379-9000 
 
 
The following notification shall be processed:  
 
• Comité de Ética Central de la C.A.B.A.  
Monasterio 480 – C1284AEJ  
C.A.B.A. – Bs. As. – Argentina  
Telephone number: (54-11) 4123-3160/61/62/63 
 
6. 
INVESTIGATION PLAN  
 
6.1. 
Study design  
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
A double blind, randomized, parallel group, balanced, Phase 1 study comparing pharmacokinetics and 
safety in healthy volunteer male subjects shall be conducted.  
 
6.2. Study phases  
 
For each study subject, the Clinical Investigation Protocol includes 15 visits with an IV perfusion 
administration regimen during 90 minutes once only according to the following detail:  
 
Visit 1: Screening and inclusion (Day -28 a -1) 
 
Visit 2: Dosing, blood draw, 24 hours confinement (Day 1) 
 
Visit 3: Outpatient blood draw- hour 48 post-infusion (Day 2) 
 
Visit 4: Outpatient blood draw- hour 72 post-infusion (Day 3) 
 
Visit 5: Outpatient blood draw- hour 96 post-infusion (Day 4) 
 
Visit 6: Outpatient blood draw- hour 120 post-infusion (Day 5) 
 
Visit 7: Outpatient blood draw- hour 168 post-infusion (Day 7) 
 
Visit 8: Outpatient blood draw- hour 336 post-infusion (Day 14) 
 
Visit 9: Outpatient blood draw- hour 504 post-infusion (Day 21) 
 
Visit 10: Outpatient blood draw- hour 672 post-infusion (Day 28) 
 
Visit 11: Outpatient blood draw- hour 840 post-infusion (Day 35) 
 
Visit 12: Outpatient blood draw- hour 1008 post-infusion (Day 42) 
 
Visit 13: Outpatient blood draw- hour 1176 post-infusion (Day 49) 
 
Visit 14: Outpatient blood draw- hour 1344 post-infusion (Day 56) 
 
Visit 15: Outpatient blood draw- hour 1512 post-infusion - End of study visit (Day 63) 
 
 
Table 6.2.1. Study phases  
 
 
 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
14 
15 
Description Screening / 
Dosing 
Follow up 
Follow up 
Follow up 
Follow up 
Follow up Follow up 
Follow up 
Follow up 
Follow up 
Follow up 
Follow up 
Follow up 
End of 
inclusion 
Study
Day 
-28 to -1 
1 
2 
3 
4 
5 
7 
14 
21 
28 
35 
42 
49 
56 
63 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
6.3.  Study duration  
 
The estimated duration of the study, for each subject during the clinical stage from recruitment 
through Visit 15 - End of study- is expected to be approximately 91 days.  
 
6.4.  Centers 
 
The screening, inclusion, control, clinical follow up, blood draws and confinement/hospitalization of 
the study subjects shall be carried out at Unidad de Investigation-clínica farmacocinética FP Clinical 
Pharma en Clínica CIAREC. The biological study samples shall be transferred to the Analytical 
center using a transportation system to conduct the quantification of bevacizumab and the 
determination of antibodies.    
 
 
6.5. Study population 
 
To be included in the Clinical Investigation Protocol, the following criteria must be met.  
 
6.5.1. Inclusion criteria  
 
1) Written and signed informed consent  
 The subjects in the study were willing and able to provide their informed consent in 
writing  
 
2) Target population  
 Study subjects, volunteers, healthy, adults  
 
 Study subjects whose laboratory test results for safety and complementary tests were 
within the normal values, or that at the discretion of the Investigator did not present a 
clinical significance: complete blood count, erythrocyte sedimentation rate, 
hepatogram, urea, creatinine, glucose, coagulogram, serology for HIV, hepatitis B, 
hepatitis C, urinalysis, detection of drugs of abuse in urine and electrocardiogram 
 
 Body mass index between 19 and 27 kg/m2 at the screening visit. 
 Preferably non-smoker subjects. 
 
3) Age and gender  
 Men, 21 through 55 years of age. 
 
 Men in a relationship with a child bearing age spouse agreed to having their spouse use 
an adequate contraceptive method before entering the study and during at least three 
months after the study completion. The participants understood that" adequate  
  
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
contraceptive method" means any hormonal contraceptive or intra uterine device 
(placed before the beginning of the study) and the use of a spermicidal as a barrier 
method. The use of a barrier method alone or sexual abstinence was not considered 
adequate. 
 
 Subjects agreed to not donate sperm during the study and for at four months after the 
treatment. 
 
6.5.2. Exclusion criteria  
 
1) Medical history and concurrent diseases  
 History of the following diseases/conditions: pulmonary, gastrointestinal, hepatic, 
renal, hematologic, endocrine-metabolic, neurologic or psychiatric origin conditions 
(especially depressive disorder) at the moment of the anamnesis and the physical 
examination during the first visit of the Clinical Investigation Protocol. 
 
 History of gastro-intestinal surgery (with the exception of uncomplicated 
appendectomy at least three months before the study) 
 
 History of major surgery, surgical biopsy and/or history of significant trauma within 
one month of the screening visit. 
 
 Specifically, preexisting gastrointestinal conditions such as abdominal fistulas, 
gastrointestinal perforation within the 6 months of the screening visit.   
 
Specifically, preexisting gastrointestinal conditions such as acute or sub-acute intestinal 
occlusion.  
 
Specifically, history of intestinal inflammatory disease.  
 
History of hemorrhagic diseases and/or coagulopathies and/or thromboembolic events. 
 
History of cardiac and vascular diseases: specifically, myocardial infarction, unstable 
angina, stroke, uncontrolled blood hypertension and cardiac arrhythmias.  
 
History or current occurrence or alcohol or drug abuse.  
 
Donating blood within the three months prior to screening.   
 
Administration of any drug under investigation or participation in a clinical investigation 
study within the three months prior to the scheduled participation in this Clinic 
Investigation Protocol.  
 
History or current occurrence of clinically significant diseases or disorders, which, at the 
discretion of the Investigator, may prevent the participation of the subject in the study due 
to safety reasons or because they may influence the study results, as well as the capacity of 
the study subject to participate in the Clinical Investigation Protocol.  
 
History of hypersensitivity to bevacizumab and/or any of the excipients.  
     
 
2) Physical findings in laboratory test results  
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Following diseases/conditions: cardiac, pulmonary, gastrointestinal, hepatic, renal, 
hematologic, endocrine-metabolic, neurological or conditions of a psychiatric origin 
(especially depressive disorders).  
 Evidence of ulcers, unhealed wounds or bone fractures.  
 Clinically significant abnormalities in any of the laboratory test results and 
electrocardiograms.  
 Positive serology for HIV, hepatitis B, hepatitis C.  
 Positive result in the immunogenicity test (anti-bevacizumab serum antibodies).   
 
  
4) Allergies or adverse drug reactions  
 Subjects of the study who presented contraindications to the therapy.  
 
5) Prohibited treatments and/or therapies  
 Subjects of the study who received (two weeks prior) or are currently receiving aspirin 
or clopidogrel.  
 The study subjects must have discontinued possible pharmacological treatments at least 
two weeks prior to the beginning of this Clinical Investigation Protocol.  
 
 
6) Other exclusion criteria  
 Uncooperative subjects.  
 Subjects of the study who are employees of the Investigator or the Clinical-
Pharmacokinetic Investigation Unit, with a direct participation in the clinical protocol 
or other clinical protocols directed by the Investigator or the Clinical-Pharmacokinetic 
Investigation Unit.  
 
 
The eligibility criteria for this Clinical Investigation Protocol have been considered to guarantee the 
safety of the study subjects and ensure that the results can be used.  
 
6.5.3. Discontinuation of the treatment by the study subjects 
 
The subjects MUST discontinue the product under investigation (and the non-experimental product, 
at the discretion of the Investigator) due to any of the following reasons:  
 Withdrawal of the informed consent (the decision of the subject to withdraw for whatever 
reason).  
 Any clinical adverse event, abnormal laboratory test results or intercurrent disease, which, 
at the discretion of the Investigator, indicates that the participation in the study is not the 
best option for the study subject. 
 Medical contraindication to continue receiving the product under investigation.   
  
 
The subjects of the study may have the therapy of the Clinical Investigation Protocol discontinued 
and/or removed from the Clinical Investigation Protocol due to the following reasons:  
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Incapacity to comply with the Clinical Investigation Protocol.  
 Significant lack of adherence by the study subject.  
 Investigator's discretion.  
 Need to take prohibited medications.  
 Unavoidable administrative or scientific reasons.  
 
 
Efforts must be made so that all the study subjects who discontinue the treatment of the Clinical 
Investigation Protocol comply with the end of study procedures specified in the Clinical 
Investigation Protocol described in Section 8.1.1.15.  
 
The only exception to this pre-requisite is when the study subject withdraws his/her consent for all 
the procedures of the Clinical Investigation Protocol or loses his/her capacity to grant the consent 
freely.   
 
6.5.4. Study subject substitution  
 
Study subjects who dropped out cannot be substituted.  
 
 
7. 
TREATMENTS  
 
7.1. Treatments of the study  
 
All the products under investigation and non experimental products included in the Clinical 
Investigation Protocol are considered products under investigation.  
 
7.1.1. Product under investigation  
 
A product under investigation is defined as follows:  
 
A pharmaceutical form of an active ingredient or placebo that is being evaluated or used as a 
reference in a Clinical Investigation Protocol, including products that already have a free sale 
authorization but are used or presented (as to the formulation or the packaging) in a different form 
than the pharmaceutical form authorized, or used for an indication not approved, or when they are 
used to obtain more information about the approved pharmaceutical form.  
 
In this Clinical Investigation Protocol the products under investigation are:  
 Test Product 1: Bevacizumab Richmond-Hetero, manufactured by Hetero Biopharma Limited, 
India; transported in bulk and dosed and packaged in Laboratorios Richmond S.A.C.I.F., 
Argentina 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
  
 Reference product: Avastin® Bevacizumab Productos Roche S.A.Q. e I. 
 
 Test Product 2: *Cizumab® Bevacizumab de Hetero Biopharma Limited, manufactured and 
packaged in India 
 
 
* Product Cizumab® from Hetero Biopharma Limited is the same product in bulk that Richmond 
doses/fills in Argentina, Bevacizumab Richmond-Hetero. Cizumab® is approved to be sold in India 
since 13 May 2016. This approval is based on a series of comparability studies among which is found a 
Phase III study "Prospective, randomized, multi-dose, multicenter, parallel comparative study to 
evaluate the efficacy, safety and immunogenicity and pharmacokinetics of a Bevacizumab IV infusion 
(Test Product, Hetero) and the medicinal reference product (Reference product, Roche) administered in 
combination with standard chemotherapy in patients with metastatic colorectal cancer" (version in 
English and Spanish), registry number of the Clinical Trials Registry - India (CTRI): 
CTRI/2015/05/005757, non inferiority study which was completed as of the date in which a total of 
137 patients with metastatic colorectal cancer were evaluated.     
 
7.1.2. Non-experimental product  
 
Other medications used in the Clinical Investigation Protocol as support medication or escape 
mediation as prevention, diagnosis medications or resulting from therapeutic reasons, as components 
of the standard treatment for a given diagnosis are considered non-experimental products.   
 
Not applicable to this Clinical Investigation Protocol.  
 
7.1.3. Identification 
 
Table 7.1.3.1. Description of the products under investigation  
 
API 
Bevacizumab 
Bevacizumab 
Trade name  
Bevacizumab Richmond-Hetero 
Cizumab® 
Treatment  
Test 1 
Test 2 
Treatment code  
T1 
T2 
Pharmaceutical form  
Solution for IV infusion  
Solution for IV infusion  
Route of administration  
IV- perfusion  
IV- perfusion 
Presentations 
100 mg/4 ml 
100 mg/4 ml 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Dosing regime  
1 mg/kg in 90 minutes 
1 mg/kg in 90 minutes 
Total dose  
1 mg/kg 
1 mg/kg 
Frequency 
Single dose  
Single dose  
Origin 
Manufactured by Hetero Biopharma 
Hetero Biopharma Limited, 
Limited, India; Transported in bulk  
manufactured and packaged 
in India 
from India and filled and packaged  
in Laboratorios Richmond 
S.A.C.I.F., Argentina 
API  
Bevacizumab 
Trade name 
Avastin® 
Treatment 
Reference 
Treatment code  
R 
Pharmaceutical form  
Solution for IV infusion  
Route of 
administration  
IV- perfusion 
Presentation 
100 mg/4 ml 
Dosing regime  
1 mg/kg in 90 minutes 
Total dose 
1 mg/kg 
Frequency 
Single dose 
Origin 
Productos Roche S.A.Q. e I. 
 
 
7.1.4. Packaging and labeling      
 
The packaging and labeling of the products under investigation is the responsibility of the Sponsor of 
the Clinical Investigation Protocol.  
 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
The containers shall have a label showing the name of the company, domicile, Clinical Investigation 
Protocol code, name of the drug, concentration, information about storage conditions and an 
investigation warning statement. Additional statements shall be added on the label(s) according to 
local regulations.    
 
The reference products shall be provided by the Sponsor in the manufacturer's original packaging.   
 
7.1.5. Handling and delivery 
 
The drug of the Clinical Investigation Protocol shall be provided by the Sponsor to the Investigator 
and it shall be stored in a safe location according to the local regulations. The Investigator shall be 
responsible for ensuring that the products under investigation are delivered only to the study subjects. 
The products under investigation shall be distributed only in the clinical center of the Clinical 
Investigation Protocol by the authorized personnel, according to local regulations.   
 
The investigator shall ensure that the products under investigation are stored in line with the 
established ambient conditions (temperature, light and humidity). Bevacizumab must be stored in 
accordance with the specifications which shall be provided by Laboratorios Richmond S.A.C.I.F. If 
doubts arise as to the quality or appearance of the experimental product, then the product shall not be 
administered and the Sponsor shall be advised.  
 
See Section 11.2.2 for information about the conservation of the records of the product under 
investigation, and Section 11.3 for instructions to return and destroy the product under investigation.  
 
7.1.6. Blinding and unblinding procedures  
 
This Clinical Investigation Protocol is a double blind study.  
 
The study subjects, the investigators, the sponsor, the monitor, the analytical center and the data 
analyst will not know the treatments assigned.  
 
Each product in its original primary packaging shall be packaged in a blinding secondary package 
and labeled with the fantasy name "Product A", "Product B" or "Product C".  
 
The link between "Product A, B or C" with Test Product 1, 2, or Reference Product, shall be kept in 
two independent copies in a sealed envelope. One copy shall remain in the possession of the Sponsor 
and the other envelope shall be delivered to the Principal Investigator. The envelope may only be 
opened if there is a medical emergency. The Investigator shall follow the study randomization 
procedures and shall make sure that the code is only broken according to the protocol. The 
Investigator shall document and give a brief explanation to the sponsor if the identity of the product 
under investigation is revealed (be it accidentally or due to a serious adverse event).    
 
7.2. Method to assign treatments  
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Each study subject included in the Clinical Investigation Protocol shall be assigned a randomization 
number at the moment the Investigator conducts the dosing visit. The randomization number is 
created using a specific software which generates a treatment assignment randomized list 
(randomization scheme), so that each randomization number is linked to a single treatment each 
study subject shall receive.   
 
Table 7.2.1. Treatment assignment  
 
Ninety (90) subjects shall be randomized to the three treatments under investigation in a 1:1:1 ratio. 
Then N=90 [total N], and n=30 [n per treatment]. The study subjects shall receive a number from 01 
to 90 at random, each number corresponds to the assignment of a single treatment under 
investigation.   
 
The investigator shall receive a randomization list which shall be kept filed in the investigator's file.  
 
The treatment assignment scheme is included below:  
 
 
 
 
n=30 Bevacizumab Richmond-Hetero 
  
Visit 2 
Randomization 
Dosing 
 
n=30 Avastin® 
 
 
 
 
n=30 Cizumab® 
 
 
 
7.3. Dose selection and schedule for each study subject  
 
According to studies published involving bevacizumab in healthy volunteers a 30 minutes infusion at 
a dose of 1 mg/kg of body weight is considered safe for a healthy population (Hettema W, 2017; 
Tajima N, 2017; Knight B, 2016). 
 
7.4. Concomitant treatments  
 
7.4.1. Prohibited treatments and/or restricted use  
 
The study subjects are not allowed to receive any medication different from the medications of the 
Clinical Investigation Protocol during the study period.  
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Once the study subjects are included, they shall not start any treatment with any systemic therapy 
during the duration of this Clinical Investigation Protocol. The study subjects requiring a systemic 
therapy shall be analyzed by the Investigator before starting the therapy, whenever this is possible.   
 
The study subjects shall abstain from consuming products containing caffeine, xanthines and alcohol 
starting 72 hours prior to the confinement/hospitalization visit and during the whole of the Clinical 
Investigation Protocol.   
 
7.4.2. Other restrictions and precautions  
 
The study subjects shall be warned that any new therapy with prescribed or over the counter 
medication, or herbs-based / nutritional medication must be discussed in detail with the Investigator 
before it is started, since the concomitant use may cause significant events interfering with the 
objectives of this Clinical Investigation Protocol.    
 
The study subjects shall abstain from consuming drinks and foods containing xanthines, and foods 
which are difficult to digest within 72 hours prior to the confinement/hospitalization visit, and during 
said visit.  
 
During the confinement/hospitalization visit, the study subjects shall only ingest the meals provided 
by the center. Subjects shall remain in a fasting condition for 10 hours prior to the administration of 
the medication under study and up to 4 hours after said administration. The study subject shall not 
consume any snack in-between the meals provided. Only water shall be allowed (with the exception 
of 1 hour prior and up to 2 hours after the administration of the treatments).  
 
The study subjects shall avoid extenuating exercise, contact sports and sunbathing during the 72 
hours prior to the confinement/hospitalization visit and during said visit.  
 
7.5. Treatment adherence  
 
The study subjects shall receive 1 single dose of the test 1, 2 or reference treatments. The treatments 
shall be administered by IV infusion as a 90 minutes perfusion.  
 
To ensure treatment adherence, the Investigator (or the person appointed), shall verify the 
intravenous infusion.  
 
The Investigator (or the person appointed) shall record the process in the source documents of the 
study.  
 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
8. 
STUDY EVALUATIONS AND PROCEDURES  
 
8.1. Schedule of events  
 
Refer to Table 8.1.1. Schedule of events on the following page.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing pharmacokinetics and safety of 
Bevacizumab  
 
 
Phase 
Screening & 
Dosing 
Follow up  
End of 
inclusion 
Study 
Day 
-28 to -1 
1 
2 
3 
4 
5 
7 
14 
21 
28 
35 
42 
49 
56 
63 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Explaining the features and scope of the participation  
X 
in the Clinical Protocol  
Obtaining the informed consent  
X 
Reviewing and confirming eligibility  
X 
Obtaining the comprehensive medical record  
X 
Conducting physical check up  
X 
X 
Vital signs (Including: blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
Respiratory rate, axillary temperature)1 
Other evaluations (Including: body weight, size and  
X 
body mass index) 
History and review of concomitant medications  
X 
(Blood) sample for initial safety laboratory test 
X 
results2 
(Blood) sample for serological detection dashboard3 
X 
(Blood) sample for immunogenicity4 
X 
X 
Sample for urinalysis  
X 
X 
Drugs of abuse in urine  
X 
X 
Electrocardiogram 
X 
X 
X 
X 
X 
X 
Instructions with indications and restrictions for the  
X 
subject of the study  
Study subject randomization  
X 
24-hour confinement / hospitalization  
X 
Measuring body weight  
X (pre-dose) 
Administration of the product under investigation  
X 
IV infusion during 90 minutes) 
Obtaining samples for PK5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Blood) sample for final safety laboratory test results6 
X 
Food 
X 
Discharge 
X 
Anamnesis about compliance with diet, fasting   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication, restrictions and contraception  
Evaluation and adverse event recording  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1= At the times and conditions described in Section 8.5.4.1    2= Including: CBC, erythrocyte sedimentation rate, hepatogram (alkaline phosphatase, TGO, TGP, direct and indirect total bilirubin), urea, creatinine, glucose, coagulogram (prothrombin time, KPTT) 
3= Including: 
HIV, hepatitis B (HBsAg) and C (Anti HCV) 
4= Immunogenicity (anti-bevacizumab antibodies)    5= Pre-infusion: 0.00; During infusion: 0.33-0.50-1.00-1.50 hours; Post-infusion: 20 min, 40 min, 1.00, 2.00, 4.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00, 
168.00, 336.00, 504.00, 672.00, 840.00, 1008.00, 1176.00, 1344.00 & 1512.00 hours 
6= Including: CBC, erythrocite sedimentation rate, hepatogram (alkaline phosphatase, TGO, TGP, direct and indirect total bilirubin), urea, creatinine, glucose 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
8.1.1. Procedures according to visit  
 
The visits scheduled in the Clinical Investigation Protocol are as follows:  
 
Visit 1: Screening and inclusion (Day -28 to -1) 
 
Visit 2: Dosing, blood draw, 24 hours confinement (Day 1) 
 
Visit 3: Outpatient blood draw- hour 48 post-infusion (Day 2) 
 
Visit 4: Outpatient blood draw- hour 72 post-infusion (Day 3) 
 
Visit 5: Outpatient blood draw- hour 96 post-infusion (Day 4) 
 
Visit 6: Outpatient blood draw- hour 120 post-infusion (Day 5) 
 
Visit 7: Outpatient blood draw- hour 168 post-infusion (Day 7) 
 
Visit 8: Outpatient blood draw- hour 336 post-infusion (Day 14) 
 
Visit 9: Outpatient blood draw- hour 504 post-infusion (Day 21) 
 
Visit 10: Outpatient blood draw- hour 672 post-infusion (Day 28) 
 
Visit 11: Outpatient blood draw- hour 840 post-infusion (Day 35) 
 
Visit 12: Outpatient blood draw- hour 1008 post-infusion (Day 42) 
 
Visit 13: Outpatient blood draw- hour 1176 post-infusion (Day 49) 
 
Visit 14: Outpatient blood draw- hour 1344 post-infusion (Day 56) 
 
Visit 15: Outpatient blood draw- hour 1512 post-infusion - End of Study Visit (Day 63) 
 
 
8.1.1.1. Visit 1: Screening and inclusion (Day -28 to -1)    
 
The study subjects shall be evaluated with respect to their participation in the Clinical 
Investigation Protocol, and the eligibility shall be determined by evaluating the inclusion and 
exclusion criteria listed in Sections 6.5.1 and 6.5.2. 
 
The procedures to be performed during this visit include:  
 
 Oral explanation to the subject of the features and scope of the subject's participation in the 
Clinical Investigation Protocol  
 Obtaining the written informed consent before performing any procedure of the Clinical 
Investigation Protocol   
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Review and confirmation of the subject eligibility, according to the inclusion and exclusion 
criteria listed in Sections 6.5.1 and 6.5.2. 
 
 Obtaining the full medical record  
 Physical examination  
 Obtaining vital signs (blood pressure [sitting position after 5 minutes at rest] heart rate, 
respiratory rate, axillary temperature).   
 Obtaining other safety evaluations (body weight, size and calculation of body mass index) 
 Obtaining history and review of concomitant medications 
 Obtaining (blood) sample for safety laboratory test results  
 Obtaining (blood) sample for serologic detection dashboard 
 Obtaining (blood) sample for immunogenicity  
 Obtaining urine sample for full urinalysis 
 Tests to determine drugs of abuse  
 12-channel electrocardiogram.  
 Delivery of written instructions containing indications and restrictions to study subject  
 
 
   The study subject shall be considered included when the informed consent form is signed.  
 
After the inclusion, the subject shall be contacted to inform them of their inclusion/exclusion in 
this Clinical Investigation Protocol. At the moment of confirming the inclusion of the study 
subject, the scheduling of the following visits included in this Clinical Investigation Protocol shall 
be performed.  
 
The study medical team shall inform the study subject of their inclusion or not inclusion in this 
study.    
 
If changes in the health status of the subject are detected impeding the subject's participation in this 
study, the medical team shall then inform the subject of this situation, shall provide advice as to the 
medical follow up and shall refer the subject to the clinician or hospital medical service, as 
appropriate.   
 
The inclusion shall be made in a period of not more than 4 weeks after the signature of the 
informed consent.  
 
8.1.1.2. Visit 2: Dosing, blood draw, 24 hours confinement (Day 1) 
 
The procedures to be performed during this visit include:  
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a fasting 
condition (at least 10 hour fasting)  
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, adverse 
events and contraception  
 Obtaining a (urine) sample to determine drugs of abuse  
 Performing 12 channel electrocardiogram 
 Measuring body weight [prior to the administration of the product under investigation] 
 Obtaining vital signs (blood pressure, heart rate, respiratory rate, axillary temperature) prior to 
the administration of the product under investigation and at the times described in Section 
8.5.4.3 
 Randomization of the study subject 
 Placing a peripheral line in a forearm vein, preferably 
 IV administration of the product under investigation according to the randomization scheme of 
the Clinical Investigation Protocol 
 Obtaining samples for PK according to the extraction schedule [Pre-infusion; during the 
infusion; post infusion (up to hour 24:00)]   
 Evaluation and recording of adverse events 
 Supervision of the intake of food and water provided during the confinement/hospitalization 
 Reviewing with the study subject of the fasting requirements (at least 10 hours); indications 
and restrictions for follow up visits before the next scheduled follow up visit.  
 Discharge of the subject at 24 hours post dose  
  
8.1.1.3. 
Visit 3: Outpatient blood draw- hour 48 post-infusion (Day 2) 
 
The procedures to be performed in this visit include:  
 
Admission of the study subject to Unidad de investigación clínica-farmacocinética in a fasting 
condition (at least 10 hour fasting) 
 
Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, adverse 
events and contraception 
 
Obtaining sample for PK corresponding to hour 48 post infusion  
 
Evaluation and recording of adverse events 
 
Reviewing with the study subject of the fasting requirements (at least 10 hours); indications and 
restrictions for follow up visits before the next scheduled follow up visit.  
 
 
8.1.1.4. 
Visit 4: Outpatient blood draw- hour 72 post-infusion (Day 3) 
 
The procedures to be performed in this visit include:  
 
 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, adverse 
events and contraception 
 Obtaining sample for PK corresponding to hour 72 post infusion 
 Evaluation and recording of adverse events 
 
 
8.1.1.5. 
Visit 5: Outpatient blood draw- hour 96 post-infusion (Day 4) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, adverse 
events and contraception 
 Obtaining vital signs (blood pressure, heart rate, respiratory rate and axillary temperature) 
 Obtaining sample for PK corresponding to hour 96 post infusion 
 Evaluation and recording of adverse events 
 
 
 
8.1.1.6. 
Visit 6: Outpatient blood draw- hour 120 post-infusion (Day 5) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, adverse 
events and contraception 
 Performing 12 channel electrocardiogram 
 Obtaining sample for PK corresponding to hour 120 post infusion 
 Evaluation and recording of adverse events 
  
 
 
8.1.1.7. 
Visit 7: Outpatient blood draw- our 168 post-infusion (Day 7) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
 Obtaining sample for PK corresponding to hour 168 post infusion 
 Evaluation and recording of adverse events 
 
 
8.1.1.8. 
Visit 8: Outpatient blood draw- hour 336 post-infusion (Day 14) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
 Obtaining vital signs (blood pressure, heart rate, respiratory rate and axillary 
temperature) 
 Obtaining sample for PK corresponding to hour 336 post infusion 
 Evaluation and recording of adverse events 
 
 
8.1.1.9. 
Visit 9: Outpatient blood draw- hour 504 post-infusion (Day 21) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
 Performing 12 channel electrocardiogram  
 Obtaining sample for PK corresponding to hour 504 post infusion 
 Evaluation and recording of adverse events 
 
 
8.1.1.10.  Visit 10: Outpatient blood draw- hour 672 post-infusion (Day 28) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
  
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Obtaining vital signs (blood pressure, heart rate, respiratory rate and axillary 
temperature) 
 Obtaining sample for PK corresponding to hour 672 post infusion 
 Evaluation and recording of adverse events 
 
 
8.1.1.11.  Visit 11: Outpatient blood draw- hour 840 post-infusion (Day 35) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
 Obtaining sample for PK corresponding to hour 840 post infusion 
 Evaluation and recording of adverse events 
 
 
8.1.1.12.  Visit 12: Outpatient blood draw- hour 1008 post-infusion (Day 42) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
 Obtaining vital signs (blood pressure, heart rate, respiratory rate and axillary 
temperature) 
 Performing 12 channel electrocardiogram 
 Obtaining sample for PK corresponding to hour 1008 post infusion 
 Evaluation and recording of adverse events 
 
 
 
8.1.1.13.  Visit 13: Outpatient blood draw- hour 1176 post-infusion (Day 49) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
  
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Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Obtaining sample for PK corresponding to hour 1176 post infusion 
 Evaluation and recording of adverse events 
 
 
8.1.1.14.  Visit 14: Outpatient blood draw- hour 1344 post-infusion (Day 56) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
 Obtaining sample for PK corresponding to hour 1344 post infusion 
 Evaluation and recording of adverse events 
 
 
8.1.1.15. Visit 15: Outpatient blood draw- hour 1512 post-infusion – End of Study visit  
(Day 63) 
 
The procedures to be performed in this visit include: 
 
 Admission of the study subject to Unidad de investigación clínica-farmacocinética in a 
fasting condition (at least 10 hour fasting) 
 Anamnesis about compliance with diet, fasting, concomitant medication, restrictions, 
adverse events and contraception 
 Performing physical examination  
 Obtaining vital signs (blood pressure, heart rate, respiratory rate and axillary 
temperature) 
 Obtaining immunogenicity (blood) sample 
 Obtaining a urine sample for full urinalysis 
 Performing 12 channel electrocardiogram  
 Obtaining sample for PK corresponding to hour 1512 post infusion 
 Obtaining (blood) sample for final safety laboratory test results 
 Evaluation and recording of adverse events  
 
 
If an adverse event occurred, irrespective of the causal relationship with the product under 
investigation, this shall be notified according to Section 9.5. Adverse Event Reporting  
 
If no adverse event occurred, Visit 15 shall be considered as End of Study Visit for each study 
subject.  
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
8.1.2. Eating plan      
 
This corresponds to the eating plan included for Visit 2. The remaining of the study visits were 
outpatient visits. The study subjects shall have a balanced diet.   
 
Standardized meals and/or menus shall be provided. The hours the meals shall be served are as 
follows:   
 
Breakfast 
 
 No breakfast shall be provided. This clinical investigation protocol requires a fasting period of 
at least 10 hours. 

Lunch 

 Approximately 4 hours after the administration of the medication 
Snack
 Approximately 8 hours after the administration of the medication 

Dinner 

 Approximately 12 hours after the administration of the medication 
 
 
All meals shall be ingested in the space of 30 minutes. The subject shall try to ingest all the food. 
The starting and end time of food intake shall be recorded in the source documents, as well as the 
percentage of food consumed.  
 
Regarding water drinking, the morning of the hospitalization visit subjects are not allowed to 
drink water during the previous half hour to the administration of the medication. Water 
drinking is allowed at request after two hours past the medication administration.  
 
8.1.3. Blood samples  
 
8.1.3.1. 
PK blood sampling schedule  
 
In Visit 2 through Visit 15, a total of 26 venous blood samples shall be obtained from every subject 
according to the following schedule:  
 
 Pre-infusion: 0.00 hours 
 
 During the infusion: 0.33, 0.50, 1.00, 1.50 hours 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 Post-infusion: 20 min, 40 min, 1.00, 2.00, 4.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 
120.00, 168.00, 336.00, 504.00, 672.00, 840.00, 1008.00, 1176.00, 1344.00 and 1512.00 
hours 
 
 
The exact hours of all blood draws shall be recorded in the source documents of the Clinical 
Investigation Protocol.  
 
8.1.3.2. 
Extraction 
 
With the subject lying down on the bed, at an angle of approximately 45 degrees, in a dorsal 
decubitus position, a line or Abbocath type catheter shall be placed in a permeable peripheral 
venous access. This line shall remain placed (if possible) until the completion of the 
confinement/hospitalization of each period, in order to avoid multiple punctures.   
 
This line will be constantly purged with physiological saline solution. The total volume of the 
physiological saline solution the subject receives shall be recorded in the nurse's source 
documents.  
 
If the line becomes non operational, it may be replaced with a new one on another vein of the same 
arm or the other arm.  
 
If this inconvenience occurs near the hour in which the sample must be obtained, the sample may 
be obtained by direct puncture and then place a new line during the timeframe before the next 
extraction.    
 
8.1.3.3. 
Labeling  
 
The labeling of the tubes shall be agreed with the Analytical Laboratory.  
 
8.1.3.4. 
Volume  
 
During Visit 1 and after signing the informed consent, a first sample containing approximately 10 
ml of blood shall be obtained as outpatient in order to run the initial safety and immunogenicity 
tests (pre-study).  
 
From Visit 2 through Visit 15, twenty-six (26) samples will be obtained from each study subject 
containing approximately 10 ml of blood each. The total amount of blood to be drawn in these 
Visits will be approximately 260 ml [including final safety analysis and immunogenicity (post-
study) corresponding to Visit 15].  
 
For each sample, approximately 10 ml of blood shall be drawn, with a total of 270 ml of blood 
drawn along the study (including samples to run the initial safety and immunogenicity analysis   
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
(pre-study of Visit 1 and post-study of Visit 15). 
 
8.1.3.5. 
Storage and transportation  
 
The samples obtained from each study subject, for each sampling time shall be stored according to 
the specifications of the analytical method of the Unidad de investigación clínica-farmacológica up 
to the moment they are transported to the Analytical Center.  
 
The form "Biological Sample Shipment" shall be filled out each time the samples are transported 
from Unidad de investigación clínica-farmacocinética to the Analytical Center. 
 
The original copy of the form shall be filed in the investigator's file.  
 
The samples shall be packaged for transportation by skilled staff trained for that task, using 
adequate thermal containers fitted with refrigerating material to keep the cold chain at all times.   
 
The transportation is the responsibility of the Analytical Center and it shall comply with Good 
Practices regarding transportation and storage of samples, according to current regulations.  
 
8.1.3.6. 
Sample rejection  
 
The criterion to reject samples shall be the one defined in the validation report of the analytical 
method.  
 
8.2. Analytical method  
 
Bevacizumab levels shall be determined using a validated ELISA method. Samples shall be 
quantified in Syngene International Ltd. Biocon Park, SEZ, Bommasandra Industrial Area - Phase-
IV, Bommasandra-Jigani Link Road, Bangalore 560 099 India. 
 
 
8.3. Efficacy evaluations  
 
8.3.1. Main efficacy evaluation  
 
Bioavailability shall be evaluated from the quantification of bevacizumab in the samples obtained 
from the study subjects.  
 
The primary analysis shall consist in calculating the pharmacokinetic parameters from the 
individual concentrations at each sampling time using the non-compartmental and/or 
compartmental model.  
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
The pharmacokinetic parameters calculated shall include, but are not limited to, the following:  
 
 Cmax: Peak serum concentration obtained directly from the serum concentration-time curve 
[Day 1 through Day 63] 
 
 AUC0-t: Area under the serum concentration-time curve from time 0 to the last experimental 
point, calculated using the trapezoidal rule [Day 1 through Day 63]  
 
 AUC0-inf: Area under the serum concentration-time curve from time zero to infinity 
 
 Tmax: Time to reach serum peak concentration, which is obtained directly from the serum 
concentration-time curve.  
 
 λz: Elimination constant calculated using a linear regression analysis of the semi-logarithmic 
curve.   
 
 T1/2 λz: Elimination half life  
 Systemic clearance  
 
 Volume of distribution  
 
The pharmacokinetic parameters described shall be calculated for the test product and for the 
reference products.  
 
The results shall be presented as follows:  
 
 Individual data: Unit of measure, value at each time, sequence, treatment received.  
 
 Concentration/time data: arithmetic mean, median, standard deviation, percent coefficient of 
variation, minimum value, maximum value.    
 
 Serum concentration-time curves for every subject, with non-transformed data.  
 
 Serum concentration-time curves compared for test and reference products with average values 
for each sampling time, for non-transformed data.  
 
 Pharmacokinetic parameters: individual data and descriptive statistic including: arithmetic 
mean, median, geometric mean, standard deviation, percent coefficient of variation, minimum 
value, maximum value.  
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
The analysis shall be made using Phoenix® WinNonlin® software, version 7.0 from Certara USA, 
Inc. The software is authorized by license granted to F.P. Clinical Pharma S.R.L. 
 
8.4. Immunogenicity evaluation  
 
The immunogenic potential shall be evaluated by the presence of anti-bevacizumab serum 
antibodies in the serum samples obtained from the study subjects.  
 
The immunogenic potential shall be evaluated for each treatment, in Visits 1 and 15.  
 
8.5. Safety evaluations  
 
Anamnesis, physical examination, clinical laboratory tests (initial-final safety laboratory 
dashboard, serologic detection dashboard, immunogenicity) and electrocardiogram shall be 
performed. Blood pressure, heart rate, respiratory rate and axilliary temperature shall be measured.  
 
8.5.1. Blood safety laboratory dashboard, serum detection dashboard and 
immunogenicity  
 
All the clinical laboratory samples shall be retrieved in the morning after the study subject has 
fasted for at least 10 hours before the blood draw.  
 
Additional blood and urine samples may be obtained at specific time points to run laboratory tests.  
 
8.5.1.1. Blood safety laboratory dashboard for initial safety laboratory tests  
 
The blood clinical laboratory tests to evaluate the initial safety of the study subjects shall be made 
at Visit 1.   
 
8.5.1.1.1. 
Blood test 
 
Complete Blood Count (CBC)  
 
 Red cells, leukocytes, hemoglobin, hematocrit 
 
Relative leukocyte formula  
 
 Segmented neutrophils, eosinophils, basophils, lymphocytes, monocytes 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Hematimetric indices  
 
 MCV (Mean corpuscular volume), MCH (Mean corpuscular hemoglobin), MCHC  
(Mean corpuscular hemoglobin concentration) 
 
Erythrocyte sedimentation rate  
 
8.5.1.1.2. 
Serum chemistry  
 
Uremia, creatinine, blood sugar level 
 
Hepatogram 
 
 Alkaline phosphatase - FAL, TGO/AST, TGP/ALT, total bilirubin, direct bilirubin, 
indirect bilirubin 
 
8.5.1.1.3. 
Clotting time  
 
Prothrombin time and concentration, KPTT 
 
8.5.1.1.4. 
Serum detection dashboard  
 
HIV, Hepatitis B (HBsAg), Hepatitis C (Anti HCV)    
 
8.5.1.2. Blood safety laboratory dashboard for final safety laboratory tests 
 
The blood clinical laboratory tests to evaluate the final safety of the study subjects shall be made at 
Visit 15.    
 
8.5.1.2.1. 
Blood test 
 
Complete blood count  
 
 Red cells, leukocytes, hemoglobin, hematocrit  
 
Relative leukocyte formula 
 
 Segmented neutrophils, eosinophils, basophils, lymphocytes, monocytes 
 
Hematimetric indices 
 
 MCV (Mean corpuscular volume), MCH (Mean corpuscular hemoglobin), MCHC  
(Mean corpuscular hemoglobin concentration) 
 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
Erythrocyte sedimentation rate 
 
8.5.1.2.2. 
Serum chemistry  
 
Uremia, creatinine, blood sugar level 
Hepatogram 
 
 Alkaline phosphatase - FAL, TGO/AST, TGP/ALT, total bilirubin, direct bilirubin, 
indirect bilirubin  
 
8.5.2. Laboratory urine test dashboard for safety 
 
The clinical urine laboratory tests to evaluate the safety of the study subjects shall be made at Visit 
1. The following determinations shall be made:  
 
Color, appearance, density, pH, albumin, hemoglobin, glucose, ketonuria, bile pigments, bile salts, 
urobilin.   
 
Microscope examination: cells, leukocytes, pyocytes, red cells, cylinders.  
 
8.5.2.1. Detecting drugs of abuse  
 
The detection of drugs of abuse [marijuana, cocaine, opiates and benzodiazepines] by means of a 
urine reactive dashboard at Visits 1 and 2.  
 
8.5.3. Electrocardiogram 
 
A 12-channel ECG shall be made at Visits 1, 2, 6, 9, 12 and 15.  
 
8.5.4. Measuring blood pressure, heart rate, respiratory rate and axillary temperature 
 
 
8.5.4.1. Blood pressure, heart rate and respiratory rate.  
 
The measurements of blood pressure, heart rate and respiratory rate shall be made at Visits 1, 2, 5, 
8, 10, 12 and 15 
 
8.5.4.2. Axillary temperature  
 
The measurement of axillary temperature shall be made at Visits 1, 2, 5, 8, 10, 12 and 15. 
 
 
 
 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
8.5.4.3.   Schedule to measure blood pressure, heart rate, respiratory rate and axillary 
temperature during the study Visits 
 
The measurements of blood pressure, heart rate, respiratory rate and axillary temperature at Visits 
1, 5, 8, 10, 12 and 15 shall be performed after the study subject has remained in a sitting position, 
at rest, for approximately 5 minutes.  
 
The measurements of blood pressure, heart rate, respiratory rate and axillary temperature at Visit 2 
shall be prior to the administration of the product under investigation and after the PK sample 
draws of  hours 2.00, 4.00, 8.00, 12.00 and 24.00 post dose.  
 
8.5.5. Further evaluations  
 
8.5.5.1. 
Body weight, size and body mass index (BMI)  
 
The measurements for body weight, size and calculation of the body mass index shall be made at 
Visit 1.  
 
The weight shall be checked at Visit 2 prior to the administration of the product under 
investigation.  
 
8.5.5.2. 
Physical examination  
 
A physical examination shall be conducted at Visits 1 and 15. It shall include the following: 
general appearance, head, eyes, ears, nose, throat, neck, cardiovascular system, lungs, abdomen, 
lymph nodes, extremities, neurologic system, skin and muscular-skeletal system.  
 
 
9. 
ADVERSE EVENTS  
 
9.1. Definitions  
 
9.1.1.  Adverse event 
 
An Adverse Event (AE) is defined as any adverse medical occurrence in a patient or subject of a 
clinical study of a product involving the health, or a therapeutic procedure and which does not 
have a necessary causal relationship with this treatment. An adverse event may be any unfavorable 
and unintended sign, including abnormal laboratory test results, symptoms or diseases temporarily 
associated with the use of the product under investigation, whether they are related or unrelated.     
 
Some examples of adverse events include, but are not limited to:  
 
Clinically significant symptoms and signs 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Abnormal findings in clinically significant supplementary tests 
 
Changes in the findings of the physical examination 
 
Hypersensitivity  
 
Progression/worsening of an underlying disease  
 
Additionally, some signs and symptoms resulting from:  
 
Lack of efficacy  
 
Overdosing 
 
Abandoning the medication  
 
Misuse, abuse of the drug 
 
Drug interactions 
 
Drug dependence  
 
Extravasation 
 
9.1.2. Serious Adverse Event  
 
A Serious Adverse Event (SAE) is defined as any unfavorable occurrence during the duration and 
in the context of an investigation of a product or a diagnostic or therapeutic procedure which 
results in the death, threat to the life, requires hospitalization or prolonging the existing 
hospitalization, results in persistent or significant incapacity or disability or is a congenital 
anomaly or birth defect or is medically significant according to the medical opinion: those events, 
that in the opinion of the investigator may harm the subject and/or require medical or surgical 
intervention to prevent any of the conditions mentioned above. The above also applies without the 
presumption of the existence of a causal link between the application of the product or treatment 
and the adverse event.      
 
9.1.3. Unexpected Adverse Event  
 
An Unexpected Adverse Event is defined as any adverse event which was not previously 
documented, from the perspective of previously observed and not on the basis of what could be 
anticipated from the pharmacological properties of a drug, that is, the nature or the severity is not 
consistent with the information in the corresponding source document(s) such as the investigator's 
brochure or product insert.  
 
9.1.4. Adverse Drug Reaction  
 
An Adverse Drug Reaction (ADR) is defined as a harmful and unintended response to a medicinal 
product related with any dose. In the clinical experience before the approval of a new medicinal 
product or new uses, especially when the therapeutic dose cannot be established, any adverse drug 
reaction is considered to be any reaction that implies a causal relationship between a medicinal 
product and an adverse event as a reasonable possibility, that is, that the relationship cannot be 
ruled out. In approved medicinal products that are sold on the market, an ADR is the harmful and  
 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
unintended response to a drug, harmful and unintended which occurs at doses normally used in 
humans for prophylaxis, diagnosis or therapeutics of the diseases or modification of physiological 
functions.   
    
9.1.5. Serious and Unexpected Adverse Drug Reaction (SUADR)   
 
A Serious and Unexpected Adverse Drug Reaction (SUADR) is defined as an adverse reaction 
resulting in death, threat to life, requires hospitalization or prolonging the existing hospitalization 
or causes persistent or significant incapacity or disability, and whose nature or severity is not 
consistent with the product information described in the investigator's brochure for a non approved 
product under investigation, or in the insert of an approved medicinal product.   
 
9.2. Collection 
 
All the adverse events observed or voluntarily reported by the study subject shall be collected 
during the course of the investigation study, irrespective of the treatment group or of the suspicion 
of a causal relationship with the product(s) under investigation.  
 
The study subject is informed by the IP about their responsibility of reporting all the physical 
changes occurring during the investigation study.  
 
For all adverse events, the IP or the staff appointed shall use their best efforts to obtain the 
adequate information regarding the beginning and end of the adverse event and its characteristics, 
which will enable a determination of its severity and causality, as well as evaluating if the event 
meets the classification criteria for a serious adverse event.   
 
9.3. Evaluation 
 
9.3.1. Evaluating the severity  
 
The IP or the staff appointed shall determine the severity of the adverse event using the following 
categories: "mild, moderate, severe". These categories are required in the adverse event reporting form 
of the Clinical Data Form (FDC - CDF). For consistency purposes, the degrees of severity are defined 
as follows. Mild: It does not interfere with the subject's normal activity; moderate: It somehow 
interferes with the subject's normal activity; severe: It significantly interferes with the subject's normal 
activity. When applicable, the severity categories established by the Common Terminology Criteria for 
Adverse Events (CTCAE)   
  
Grade 1 (mild): Asymptomatic or mild symptoms, clinical or diagnostic observations only, 
intervention not indicated. 
 
 
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Grade 2 (Moderate): minimal, local or noninvasive intervention indicated, limiting age-
appropriate instrumental activities of the daily living, for example: preparing meals, 
shopping for groceries, using the telephone, managing money, etc.  
 
Grade 3 (severe or medically significant but not immediately life-threatening); 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
activities of the daily living, for example bathing, dressing and undressing, feeding self, 
using the toilet, taking medication and not bedridden.   
 
Grade 4 (life threatening consequences): urgent intervention indicated.  
 
Grade 5 (lethal): Death related to the adverse event. It must be noted that not all grades of 
this scale are appropriate for all adverse events, therefore, some adverse events may have 
fewer than 5 grades.  
 
9.3.2. Evaluating the seriousness  
 
The IP or staff appointed shall determine the seriousness of the adverse event. The adverse event 
shall be considered "serious" if it meets any of the characteristics described in the definition of 
serious adverse event.  
 
Note the difference between severity and seriousness of an adverse event. A severe adverse event 
is not necessarily a serious adverse event. For example: a headache may be severe (it significantly 
interferes with the subject's normal daily activity), but it would not be classified as serious unless it 
meets one of the criteria of serious events listed above.  
 
9.3.3. Evaluating the biological plausibility  
 
The IP or staff appointed shall determine the biological plausibility by evaluating the consistency 
of the information of the adverse event with the safety information of the product described in the 
investigator's brochure or in the product insert. An adverse event is considered to be "unexpected" 
if the adverse event meets the characteristics described in the definition of unexpected adverse 
event. To that end, the following source document(s) or special circumstances are considered:  
 
-Source document(s): For those medicinal products that are not approved to be sold in the country, 
the source document is the Investigator's Brochure of the medicinal product. For the medicinal 
products already approved for sale in the country, or comparator product, the latest version of the 
updated insert of the product sold in the country is used. For medicinal product having more than 
one presentation form (different formulations, doses, etc.) or having more than one use (different 
indications, populations, etc.) we check that the source document(s) consulted correspond to the 
same form of presentation of the medicinal product. If the adverse event is not listed in this/these 
source document(s), it is considered "unexpected".   
 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
-Special circumstances: The adverse events that add significant information about the specificity or 
the severity of an already documented adverse event are also considered as "unexpected" adverse 
events. In this way, a more specific or more severe adverse event than the one described in the 
Investigator's Brochure or insert of the medicinal product is considered "unexpected". Specific 
examples are (a) "acute renal insufficiency" as a documented adverse event with a new adverse 
event of "interstitial nephritis" and (b) "hepatitis" as a documented adverse event with a new 
adverse event of fulminant hepatitis.  
 
9.3.4. Evaluating causality  
 
The IP or staff appointed shall determine the causality of the adverse event by determining the 
existence of a reasonable possibility that the product under investigation has caused it or 
contributed to cause it. To evaluate the causality, the IP or staff appointed shall use Naranjo 
algorithm whereby the points obtained determine if the adverse event is related with the suspected 
product under investigation (point 1 or higher), in which case it is considered as an "ADR", or 
alternatively if it is not related with the medicinal product (point 0 or lower) in which case it is 
considered as an "unrelated adverse event".    
 
If the causality cannot be determined by the Investigator, and the Investigator does not know 
whether the product under investigation caused the event or not, then the event is considered as 
"related with the product under investigation" for the purposes of the report. If the investigator 
considers that the causality "is not related with the product under investigation", then said 
evaluation shall be documented in the study records. 
 
For the adverse events that have a causal relationship with the products under investigation, 
especially those serious or unexpected adverse events, follow up by the Investigator is required 
until the moment the event or its sequelae resolve or stabilize towards a condition that is 
considered acceptable by the investigator.   
 
9.4. Records 
 
All serious and non serious events shall be documented and their evolution described in the 
subject's clinical record by the IP or by duly delegated staff from the moment of the occurrence 
until its final resolution. The following shall be documented: beginning and end date and time, 
dose and actions taken with respect to the product under investigation, biological plausibility, 
causality, and seriousness and severity of the adverse event.   
 
All serious and non-serious adverse events are recorded in the FDC by the IP or by staff duly 
delegated on the adverse event reporting page designed to that end. The events described in the 
FDC must be consistent with the ones described in the clinical record and further source 
documents.    
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
The term "reasonable causal relationship" in general means that there are facts (for example, 
evidence such as the discontinuation or the reinstatement of the drug under study) or other 
arguments suggesting a positive causal relationship.    
 
9.5. Adverse event reporting  
 
9.5.1. Reporting non-serious adverse events  
 
Non-serious adverse events are reported by the IP, or duly delegated staff, to the Sponsor of the 
study within the framework of the final report.  
 
Non-serious adverse events are reported by the IP to the CEI and CODeI in the framework of the 
End of Study reports.  
 
In the case of long term investigation studies, the adverse events are communicated to the CEI with 
a minimum frequency of once a year in the report sent to the CEI.   
 
9.5.2. Reporting serious adverse events  
 
In the case of a serious adverse event (SAE), the IP or delegated staff drafts a written report to be 
sent immediately to the Sponsor. When available, all the additional information shall be provided 
to determine the relationship of the SAE with the product under investigation. The initial reports 
are followed by follow up reports. Both the initial reports as well as follow up reports shall identify 
the subject using a single code. In the event of death, the IP shall provide the Sponsor, the CEI and 
the Regulatory Body any additional information required (for example: autopsies, medical reports, 
etc.). A CIOMS type form is used to report SAE; in the event that the Sponsor establishes its own 
SAE form, then that form shall be used.   
 
The SAE report to the CEI shall be submitted in the due time and manner established in it. The 
CEI is requested to confirm reception, which will be filed in the Investigator's File.  
 
The SAE report to the CODeI shall be submitted in the due time and manner established in it. 
The CODeI is requested to confirm reception, which will be filed in the Investigator's File.  
 
Likewise, all SAE (with the exception of SUADR) occurred during the investigation study are 
recorded by the IP in the periodic report / final report of the study, using the appropriate form, in 
compliance with the national regulatory framework in force, with a minimum yearly frequency 
starting from the date of ANMAT authorization and at the end of the study, which shall be sent to 
the Sponsor.   
 
 
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Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
The sponsor is responsible for reporting SAEs to the National Regulatory Authorities or to other 
applicable authorities.   
 
For the case of SUADR reporting, the availability of the minimum required information is verified 
to have a swift reporting, namely: a) an identifiable volunteer, b) name of the suspicious 
medication, c) a source of information with personal identification, d) an event or a result that can 
be identified as a serious or unexpected, and for which there is a causal relationship of reasonable 
suspicion. In the case of a SUADR that does not comply with any of the criteria above, efforts 
shall be made to obtain the information as soon as possible.   
 
All the SUADR related with the product under investigation, reported by the IP of the study, are 
reported by the sponsor expeditiously to the National Regulatory Authority (ANMAT) within 10 
administrative working days as from the moment they became aware of the event.  
 
The SUADRs related with a comparator product already registered with ANMAT for sale in the 
country or those related with placebo are communicated by the sponsor only to ANMAT 
Pharmacovigilance System within 7 running days after the initial reception of the information by 
the sponsor in case the outcome of the SUADR is death or a threat to life, or within 15 running 
days after the reception of the information for all other severity categories.   
 
Likewise, all SUADRs occurring during the investigation study shall be entered by the IP in the 
presentation of the Periodic Report / Final Report, in the appropriate form in compliance with the 
national regulatory framework in force, with a annual minimum frequency starting from the date 
ANMAT granted the authorization, which is sent to the sponsor.   
 
The sponsor is responsible for reporting SUADRs to the National Regulatory Authorities or other 
applicable authorities.  
 
In blinded treatment studies, when the sponsor receives a SAE report, it shall check the treatment 
the patient receives to establish whether it is indeed a SUADR as defined, however the blinding 
shall remain for the investigator or the persons in charge of the data analysis and interpretation.  
 
The sponsor shall communicate the SUADRs related with a product under investigation to all the 
investigators and to all studies in progress with the product within a 14 day period after 
becoming aware of them, in compliance with the national regulatory framework in force. The 
investigators shall inform these SUADR to the corresponding CEI in the timeframes established.  
 
COMMUNICATION OF SAEs:  
 
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Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
Dr. Myriam Rozenberg 
Laboratorios Richmond S.A.C.I.F. 
Av. Elcano 4938 – C1427CIU 
C.A.B.A. – Bs. As. – Argentina 
Telephone number: (54-11) 5555-1600 
Fax: (54-11) 5555-1600 
 
9.6. Adverse event follow up  
 
The IP or staff delegated shall adopt diagnostic and therapeutic measures required when the 
evolution of an eventual serious or non-serious adverse event so requires. The IP is responsible for 
ensuring the compliance with all the necessary procedures to address the medical emergencies 
arising during the course of the study.   
 
The sponsor and the investigator shall ensure access to the necessary contraceptive methods to the 
participants during the course of the study.  
 
9.7. Abnormal results in laboratory tests  
 
All the results of the laboratory tests collected as part of the Clinical Investigation Protocol shall be 
recorded in the appropriate pages for the laboratory test results of the FDC. Additionally, the 
following abnormalities in laboratory tests shall also be recorded in the Adverse Events page of the 
FDC (hard copy or electronic):     
 
 Any result of a laboratory test that is clinically significant or fits the definition of SAE.  
 
 Any abnormal laboratory test result requiring the study subject to discontinue or interrupt the 
product under investigation. 
 
 Any abnormal laboratory test result requiring the study subject to receive specific corrective 
therapy.  
 
9.8. Overdosing  
 
Overdosing is defined as the accidental or intentional intake or infusion of any dose of a product 
which is considered to be excessive and medically important. All the cases of overdosing shall be 
reported as SAE (See Section 9.5 "Adverse event reporting" to obtain details about reporting).   
 
 
 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
10. STATISTICAL CANSODERATIONS  
 
10.1. 
Determining the sample size  
 
The sample size was established as 90 subjects; with n being 30 for each treatment.  
 
10.2. 
Population analysis  
 
All the subjects in the study receiving at least one dose of the medication under study shall be 
included in the safety population analysis. All the data of the samples coming from study subjects 
receiving the study formulations shall be analyzed statistically.  
 
10.3. 
Statistical analysis  
 
 Descriptive statistics: The primary statistical analysis is defined by the descriptive statistics 
of the concentrations and the pharmacokinetic parameters introduced above in item 8.3.1. 
Main efficacy evaluation which will be calculated and presented for the study formulations.  
 
 Inferential statistics: The statistical analysis includes the following pair-based comparisons 
between the products under investigation:  
 
a) Test Product 1 vs. Reference Product  
b) Test Product 2 vs. Reference Product  
c) As supplementary information, Test Product 1 vs. Test Product 2 shall also be compared.  
 
For each pair-based comparison, variance analysis for a linear model of mixed effects shall be 
performed, considering the following null hypothesis:    
 
H0: µT = µR  y H1: µT ≠ µR 
 
For each pair-based comparison, the variance analysis shall include the terms of the fixed effects 
of sequence, period, treatment and random subject, embedded inside the sequence. The degrees of 
freedom, the sum of the squares, the mean squares, the F statistic value and the corresponding p 
values shall all be specified.    
 
For the pair-based comparison, the results of the percentages of inter and intra-individual 
variation coefficients for the following parameters: Cmax, AUC0-t and AUC0-inf shall be presented. 
The point estimator and the 90% confidence intervals shall be calculated for the ratio of the 
geometric means for parameters Cmax, AUC0-t and AUC0-inf to compare treatments, as follows:     
 
For each pair-based comparison, the t test of Schuirmann and Hauck Anderson shall be 
performed.  
 
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Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
10.4. 
Bioavailability acceptance criteria  
 
The comparable bioavailability between Test Product 1 vs. Reference, and Test Product 2 vs. 
Reference is established if the ratios of the geometric means of the µT/µR ratios for Cmax and 
AUC0-t  are within the acceptance bracket [0.80 y 1.25]. 
 
10.5. 
Outsiders and missing samples  
 
Those study subjects with a differing behavior (remarkable difference of their results versus those 
of the rest) in the bioequivalence parameters, in comparison with the remaining subjects of the 
study shall be considered outsiders.  
 
Their exclusion in the calculations shall be justified and the results of the pharmacokinetic 
parameters shall be submitted with and without the inclusion of their data.  
 
10.6. 
Software used for efficacy analysis  
 
The analysis shall be made using software Phoenix® WinNonlin® version 7.0 from Certara USA, 
Inc. The software is authorized by license granted to F.P. Clinical Pharma S.R.L. 
 
 
11. ADMINISTRATIVE SECTION  
 
11.1. 
Compliance  
 
11.1.1. Compliance with the Clinical Investigation Protocol and its revisions 
 
The study shall be conducted as described in the approved Clinical Investigation Protocol. All the 
revisions of the Clinical Investigation Protocol shall be discussed with Laboratorios Richmond 
S.A.C.I.F. The Investigator is not authorized to make any changes in the Clinical Investigation Protocol 
without the prior review and approval/favorable opinion documented by the CEI regarding an 
amendment, with the exception of when it is necessary to eliminate an immediate risk to the study 
subjects. Any significant deviation shall be documented in the FDC.    
 
If a deviation or change is implemented in a Clinical Investigation Protocol to eliminate an 
immediate risk before obtaining the approval/favorable opinion of the CEI, said deviation or 
change shall be promptly notified to:  
 
 Laboratorios Richmond S.A.C.I.F.; 
 The CEI to be reviewed and grant their approval/favorable opinion; 
 The regulatory authorities, when required by local regulations.  
 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
If a change substantially alters the design of the Clinical Investigation Protocol or increases the 
potential risk for the study subject: (1) the consent form shall be revised, which shall be submitted to 
the CEI for review and approval/favorable opinion, (2) the revised form shall be used to obtain the 
consent of the study subjects currently included in the Clinical Investigation Protocol if they are 
affected by the amendment, and (3) the new form shall be used to obtain the consent of new study 
subjects before they are included.  
 
11.1.2. Monitoring 
 
During the performance of the study, Laboratorios Richmond S.A.C.I.F may perform monitoring 
visits to ensure that the Clinical Investigation Protocol is executed in compliance with the Good 
Clinical Practices.  
 
The Unidad de investigación clínica-farmacocinética where the study is conducted may be subject 
to reviews by the CODeI/CEI and/or quality assurance audits conducted by Laboratorios 
Richmond S.A.C.I.F and/or inspections by the local Regulatory Authority.   
 
All the data referring to the participation of the study subject shall be documented in the subject's 
clinical record (independently of the FDC). The clinical record will be considered the source 
document. The case report forms, the progress reports, etc. shall always be available for inspection 
by Laboratorios Richmond S.A.C.I.F.   
 
The Sponsor monitor may review all the FDS, clinical records, source documents and signed 
written informed consent forms. The monitor shall verify that the Clinical Investigation Protocol is 
conducted, in all its aspects, in full compliance with the Clinical Investigation Protocol.  
 
11.2. 
Record keeping  
 
The Investigator shall keep all the records regarding the disposal of the product under investigation 
(provided by the Sponsor or provided by the Investigator), the copies of the FDC (or electronic 
files) and the source documents for the maximum period established in the regulations and 
applicable guides, or in compliance with the procedures of the Unidad de investigación clínica-
farmacocinética; or else during the period specified by the Sponsor, whichever is longer. The 
Investigator shall consult Laboratorios Richmond S.A.C.I.F before destroying any record related 
with the Clinical Investigation Protocol.  
 
If the investigator withdraws from the Clinical Investigation Protocol (for example due to a 
position change or retirement), the records shall be delivered to a person appointed agreed with 
Laboratorios Richmond S.A.C.I.F. The notification of the information transfer shall be delivered in 
writing to Laboratorios Richmond S.A.C.I.F. 
 
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Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
11.2.1. Clinical data forms     
 
The Investigator shall prepare and keep adequate and accurate clinical records. The data recorded 
in the FDC, derived from the source documents, shall be consistent with said documents, or, in the 
case of discrepancies, these shall be explained.  
 
One FDC shall be provided for each study subject included and randomized. The forms shall be 
filled out electronically. The Investigator shall ensure that all the data provided to the Sponsor in 
the FDC and in all the necessary reports are completed and accurate, legible and submitted in due 
time.   
 
The confidentiality of the records which may identify the study subjects shall be protected, in order 
to respect the subject's intimacy and the confidentiality rules according to the applicable regulatory 
requirements.   
 
The Investigator is responsible for ensuring the completeness, review and approval of all FDCs.  
 
The FDCs shall be signed by the investigator or by an authorized member of his/her team. These 
signatures serve as an attestation that the information contained in FDC is true and that it can be 
checked against the source documents. During all the stages of the Clinical Investigation Protocol, 
the Investigator shall have the final responsibility for the accuracy and authenticity of all the 
clinical data and laboratory results entered in the FDC.  
 
11.2.2. Records of the product under investigation  
 
The Investigator is responsible for ensuring that an updated record is kept of the disposal of the product 
under investigation (provided by the Sponsor) in the Unidad de investigación clínica-farmacocinética 
where the product under investigation is inventoried and arranged. The records or notes shall comply 
with the appropriate regulations and guidelines.  
 
11.3. 
Return and destruction of the product under investigation  
 
11.3.1. Return of the product under investigation  
 
Once the Clinical Investigation Protocol is deemed completed or finalized, the product under 
investigation which was not used and/or which was partially used shall be returned Laboratorios 
Richmond S.A.C.I.F. 
 
11.3.2. Destruction of the product under investigation  
 
Not applicable. 
 
 
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Tel/Fax: 4775-2640 y 4775-2869 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
11.4. 
Confidentiality statement  
 
The information regarding the data of the study subject obtained in this study is considered 
confidential information and its disclosure to third parties is expressly prohibited.  
 
The confidentiality of the identity of the study subjects shall be kept using personal identification 
codes.  
 
The medical information of each volunteer subject may be provided to the subject's individual 
clinician.  
 
The data generated in this protocol shall be available for inspection upon request of FP. Clinical 
Pharma S.R.L., Laboratorios Richmond S.A.C.I.F monitors, the Ethics Committee and the 
Regulatory Health Authority.  
 
11.5. 
Publications 
 
The data collected during this Clinical Investigation Protocol are confidential and property of the 
Sponsor. The publication conditions of the results are defined in the contract between the parties.  
 
 
12. LIST OF ABBREVIATIONS 
 
AUC0-t 
Area under the concentration-time curve from time 0 to hour t 
 
AUC0-inf 
Area under the concentration-time curve from time 0 to infinity  
 
ANMAT 
National Administration for Drugs, Food and Medical Technology  
Anti HCV 
Hepatitis C virus antibody  
ALT 
Alanine amino transferase  
AST 
Aspartate transaminase 
C.A.B.A. 
Autonomous city of Buenos Aires  
CCRm 
Metastatic carcinoma of the colon or rectum 
CMm 
Metastatic breast cancer  
CPNM 
Non-microcytic lung cancer  
CRm 
Advanced or metastatic renal cell cancer  
CEI 
Independent Ethics Committee 
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Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
CEIC 
Clinical Investigation Ethics Committee 
CHCM 
Mean corpuscular hemoglobin concentration (MCHC)  
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum serum concentration  
CODeI 
Teaching and Institutional Investigation Committee  
EA 
Adverse event (AE)  
EAS 
Serious adverse event  (SAE) 
ECG 
Electrocardiogram 
FIGO 
International Federation of Gynecology and Obstetrics  
FDA 
Food and Drug Administration 
FDC 
Clinical Data Form (CDF)  
FSH 
Follicle-stimulating hormone  
g 
Grams 
h 
Hour 
HBsAg 
Hepatitis B surface antigen  
HCM 
Mean corpuscular hemoglobin  
HIV 
Human Immunodeficiency Virus  
IC 
Confidence Interval (CI)  
ICC 
Congestive heart failure  
ICH 
International Conference on Harmonization  
IFA 
Active Pharmaceutical Ingredient (API) 
IgG 
Immunoglobulin G 
IMC 
Body mass index (BMI)  
IV 
Intravenous 
IP 
Principal Investigator  
kg 
Kilogram 
KPTT 
Kaolin activated partial thromboplastin time  
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
l 
Liter 
m2 
Square meter  
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram 
ml 
Milliliter 
mmHg 
Milliliter of mercury  
NYHA 
New York Heart Association 
OMS 
World Health Organization (WHO)  
pH 
Ratio indicating the degree of acidity  
PK 
Pharmacokinetics  
RAM 
Adverse drug reaction  (ADR)  
RAMSI 
Serious and unexpected adverse reaction (SUADR) 
ReNIS 
Registro Nacional de Investigaciones en Salud 
RM 
Magnetic Resonance Imaging (MRI) 
SNC 
Central Nervous System (CNS)  
SEPR 
Posterior reversible encephalopathy syndrome  
TGO 
Glutamic oxalacetic transaminase (GOT) 
| 
TGP 
Glutamic-pyrufic transaminase (SGPT) 
T1/2 
Elimination half life   
Tmax 
Time to reach the maximum concentration 
µg 
Microgram 
VCM 
Mean corpuscular volume 
VEGF 
     Vascular endothelial growth factor 
VIH 
Human immunodeficiency virus 
vs. 
Versus 
λz 
Elimination constant 
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Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
13. REFERENCES 
 
A Trial to Demonstrate the Equivalent Pharmacokinetic Properties of HD204 and Bevacizumab 
(Avastin®) in Healthy Male Subjects. 
(Available from: 
https://clinicaltrials.gov/ct2/show/NCT03390673?term=bevacizumab&gndr=Male&age=1&hlth= 
Y&rank=5) 
Accessed: 14/Dic/2018 
 
ANMAT. Disposición Nº 6677/10. Régimen de Buena Práctica Clínica para Estudios de 
Farmacología Clínica, 2010. 
 
ANMAT. Disposición Nº 1746/07. Se sustituye el Anexo I de la Disposición ANMAT Nº 5040/06 
por el Anexo I de la presente Disposición, 2007. 
 
ANMAT. Disposición Nº 5040/06. Régimen de Buenas Prácticas para la realización de Estudios 
de Biodisponibilidad/Bioequivalencia, 2006. 
 
Hetero Drugs Limited. Bevacizumab Hetero- Prospecto. 
 
 
Hettema W, Wynne C, Lang B, Altendorfer M, Czeloth N, Lohmann R, Athalye S, Schliephake D. 
A randomized, single-blind, Phase I trial (INVICTAN-1) assessing the bioequivalence and safety 
of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects. Expert Opin Investig 
Drugs, 26(8):889-896, 2017. 
 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Guideline for Good Clinical Practice E6. ICH Harmonised 
Tripartite Guideline, 1996. 
 
 
Knight B, Rassam D, Liao S, Ewesuedo R. A phase I pharmacokinetics study comparing PF-
06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers. Cancer 
Chemother Pharmacol, 77(4):839-846, 2016. 
 
Ministerio de Salud de la Nación. Resolución Nº 1480/11. Guía para investigaciones con seres 
humanos. Boletín Oficial, 2011. 
 
Productos Roche S.A.Q.e I. Avastin® Prospecto, Revisión 2016, aprobado por ANMAT 17/02/2017 
 
 
Tajima N, Martinez A, Kobayashi F, He L, Dewland P. A phase 1 study comparing the proposed 
biosimilar BS-503a with bevacizumab in healthy male volunteers. Pharmacol Res Perspect, 
20;5(2):e00286, 2017. 
 
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Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
 
14. ANNEXES 
 
14.1. 
Annex I- Indications and restrictions for the study subject  
 
 
Clinical Investigation Protocol Code: 0221 
 
Study title: 
Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
Sponsor Laboratory: Laboratorios Richmond S.A.C.I.F. 
 
 
-RESTRICTIONS FOR THE 72 hours PRIOR TO THE CONFINEMENT / 
HOSPITALIZATION VISIT  
 
1. 
Do not drink beverages containing caffeine (coca-colas, coffee, tea, mate infusion) 
2. 
Do not drink alcohol  
3. 
Do not eat chocolate  
4. 
Do not ingest any type of citrus (As fruit, juice or condiment) 
5. 
Do not eat fried food or spicy sauces  
6. 
Avoid extenuating exercises and contact sports  
7. 
Do not sunbathe  
 
 
- INDICATIONS FOR THE NIGHT PRIOR TO THE CONFINEMENT / 
HOSPITALIZATION VISIT  
 
- Dinner: To be ingested until 9:00 pm of the day prior to hospitalization. The 
meal should be light and in a moderate quantity.  
Option 1: 
1 serving of roasted meat  
1 serving of lettuce, tomato, carrot, pod salad dressed with oil and salt  
1 piece of season fruit: apple, pear, etc.  
Liquid: still or carbonated water, at ease  
 
Option 2: 
1 serving of roasted chicken 
1 serving of mashed pumpkin with oil and salt  
 
1 vanilla custard, no toppings  
Liquid: still or carbonated water, at ease 
 
Option 3: 
1 serving of pasta with oil and salt  
1 serving of lettuce, tomato, carrot pod salad dressed with oil and salt  
1 piece of season fruit: apple, pear, etc.  
Liquid: still or carbonated water, at ease  
 
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Juncal 4484 3º Piso - Buenos Aires - Argentina - C1425BAB 
Tel/Fax: 4775-2640 y 4775-2869 
Email: info@fpclinicalpharma.com.ar 
Web site: www.fpclinicalpharma.com.ar 
 
 
Clinical Investigation Protocol - Protocol code: 0221 – Double blind, randomized, parallel group, Phase 1 study comparing 
pharmacokinetics and safety of Bevacizumab  
 
 
- 
INDICATIONS FOR THE CONFINEMENT / HOSPITALIZATION VISIT AND 
OUTPATIENT VISITS:   
- 
For a more comfortable stay at Unidad de Investigación, reading material, radio or individual 
music players are allowed.  
- 
On hospitalization day, present yourself wearing comfortable clothing.   
 
- 
You are not allowed to ingest liquids starting 1 hour prior until 2 hours after the administration 
of the medication.  
- 
You are not allowed to lie down until 2 hours after the administration of the medication.  
- 
Breakfast will not be provided. This clinical investigation protocol requires fasting of at least 
10 hours. A standardized diet will be provided for lunch (4 hours post dose approximately), 
snack (8 hours post dose approximately and dinner (12 hours post dose approximately). You 
are not allowed to ingest any other food that the standardized diet.  
- 
For lunch/dinner you may receive:  
 
a) A serving of chicken with baked potatoes and pumpkin and a tomato, carrot and lettuce 
salad, salt and oil as dressing, one portion of custard, 2 pieces of bread, and mineral 
water freely.   
or 
 
b) A serving of roasted meat with potatoes and pumpkin and tomato, carrot and lettuce salad, salt and 
oil as dressing, a piece of fruit (for example, peach preserve), 2 pieces of bread, and mineral water 
freely.  
 
- 
As a snack you will receive 5 crackers, cheese spread, 1 vanilla yogurt, mineral water freely.  
 
- 
GENERAL RESTRICTIONS: 
 
- 
If your partner is of child bearing age, she must use an adequate contraceptive method before 
you enter the study and for at least 3 months after the study ends (any hormone-based or intra 
uterine device and the use of spermicide as barrier). The use of a barrier method alone or 
sexual abstinence are not considered adequate methods.    
 
- 
You must not donate sperm during the study and for 4 months after the treatment.  
 
 
 
YOU ARE NOT ALLOWED TO TAKE ANY MEDICATION 2 WEEKS PRIOR OR  
DURING THE DEVELOPMENT OF THE STUDY UNTIL ITS COMPLETION.  
 
 
 
 
 
 
 
 
Clinical 
Creation date: 
Issue date: 
Page No.: 
Created by: 
Reviewed by: Approved by: 
Server\Regulatory\Richmond\0221\ 
Investigation 
08/Jan/2019 
08/Jan/2019 
80 of 80 
LFD 
EZ/LFD/CAS 
ECF 
Protocol-FCI-FDC 
Protocol-0221-V2