Conditions: Malignant Neoplasm of Breast
Keywords: breast cancer AryoTrust Herceptin® non-Inferiority
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
This is A Phase III, randomized, two-armed, patient-outcome assessor-data analyzer blinded, parallel active controlled non-Inferiority clinical trial study to evaluate efficacy and safety of AryoTrust (Aryogen Trastuzumab in comparison to Herceptin® (Genentech/Roche) in patients with Human Epidermal Growth Factor Receptor 2-Positive breast cancer. The main objective is to verify the non-inferiority of AryoTrust (Aryogen trastuzumab) vs. Herceptin® (Genentech/Roche trastuzumab), both given concomitantly with docetaxel after doxorubicin plus cyclophosphamide in the neoadjuvant setting according to pathological complete response (pCR) as primary objective and objective response (cOR), clinical complete response (cCR), clinical partial response (cPR), clinical stable disease (cSD), clinical progressive disease (cPD), breast conservation rate as Secondary objectives of this study. Evaluating the safety and immunogenicity of AryoTrust vs. Herceptin®, are also the other secondary outcomes. This study has two arms and 108 subjects will participate with a 1:1 allocation and receive mentioned treatment randomly.

Detailed description:
This is A Phase III, randomized, two-armed, patient-outcome assessor-data analyzer blinded, parallel active controlled non-Inferiority clinical trial study to evaluate efficacy and safety of AryoTrust (Aryogen Trastuzumab) in comparison to Herceptin® (Genentech/Roche) in patients with Human Epidermal Growth Factor Receptor 2-Positive breast cancer. Patients who met the following criteria will be recruited. The inclusion criteria are: 18-70 years old female patients, Patients with newly diagnosed stage III (locally advanced) or in-operable stage II (due to sizes larger than 5 cm or high tumor to breast ratio) tumors are candidates for participation, Willing and able to sign an informed consent, Pathological diagnosis of adenocarcinoma of the breast, ECOG status of 0-1, With any ER/PR status, HER2 positive (Immunohistochemical (IHC) 3+ intensity, amplification of the HER2 gene on fluorescence in situ hybridization (FISH+ ) or HER2 positive results of Chromogenic in situ hybridization (CISH)). Exclusion criteria are: Clinical or radiologic evidence of metastatic disease, History of any other malignancy including previous breast cancer, second non-breast malignant disease, History of previous chemotherapy, Left ventricular ejection fraction \[LVEF\] \<55% confirmed by echo cardiogram within 3 months before registration, Any prior myocardial infarction, History of documented congestive heart failure (CHF),Any prior history of arrhythmia or cardiac valvular disease requiring medications or clinically significant, Current use of medications for treatment of angina pectoris, Current uncontrolled hypertension (diastolic \> 100 mmHg or systolic \> 200 mmHg), A severe conduction abnormality (having pacemaker or diagnosed by the ECG) and any other significant cardiovascular disease, Hematologic abnormalities including baseline Absolute Neutrophil Count (ANC) of ≤1,500/µL or platelet count ≤ 100,000/µL, Liver dysfunction including (baseline) Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) ≥ 3 Upper Limit Normal (ULN), Alkaline phosphatase (ALP) ≥3 ͯ ULN, serum total, bilirubin \> 1.5 ULN, Renal dysfunction, defined as serum creatinine ≥2.5 mg/dL, Pregnant, lactating women or women of childbearing potential who are not willing to use adequate contraception.

The main objective is to verify the non-inferiority of AryoTrust (Aryogen Trastuzumab) vs. Herceptin® (Genentech/Roche Trastuzumab), both given concomitantly with docetaxel after doxorubicin plus cyclophosphamide in the neoadjuvant setting according to pathological, clinical response and immunogenicity assay in patients with Human Epidermal Growth Factor Receptor 2-Positive breast cancer. The primary objective of this study is to verify the non-inferiority of AryoTrust vs. Herceptin®, given concomitantly with docetaxel after doxorubicin plus cyclophosphamide in the neoadjuvant setting according to pathological complete response (pCR) rate. The secondary objectives are to evaluate non-significance between AryoTrust and Herceptin®, given concomitantly with docetaxel after Adriamycin plus cyclophosphamide in the neoadjuvant setting according to clinical objective response (cOR), clinical complete response (cCR), clinical partial response (cPR), clinical stable disease (cSD), clinical progressive disease (cPD), breast conservation rateEvaluating the safety and immunogenicity of AryoTrust vs. Herceptin®, are also the other secondary outcomes. This study has two arms and 108 subjects will participate with a 1:1 allocation and receive AryoTrust vs. Herceptin® randomly given concomitantly with docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide For primary outcome analysis, Treatment differences in proportions will be calculated. A 95% two-sided confidence interval will be constructed and the upper bound to determine non-inferiority with a 2.5% significance level will be used.Frequency and proportions will be calculated for all secondary efficacy endpoints include clinical complete response (cCR), clinical partial response (cPR), clinical stable disease (cSD), clinical progressive disease (cPD), clinical objective response (cOR), breast conservation rate. All safety data will be analyzed descriptively by each treatment group. same protocol and procedures have been implemented by using same SOPs. Regular and strict monitoring visits have been provided to ensure all processes will be carried out in accordance with GCP. Probable variation of eligibility criteria and evaluation criteria are resolved through investigator meetings.

Arms:
arm 1: Trastuzumab (AryoTrust) is given concomitantly with docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide arm 2: Trastuzumab (Herceptin) is given concomitantly with docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide

Interventions: intervention 1: Trastuzumab plus docetaxel (for four 21-day cycles) after four 14-day cycles of Doxorubicin plus cyclophosphamide
Intervention descriptions: intervention 1: Trastuzumab (8 mg/kg IV loading dose at cycle 1, followed by 6 mg/kg at subsequent cycles) is given concomitantly with docetaxel (100 mg/m2 IV) for four 21-day cycles after four 14-day cycles of Doxorubicin (60 mg/m2 IV) plus cyclophosphamide (600 mg/m2 IV)

Protocol document:
Prot_ICF_000.pdf: 
STUDY PROTOCOL
A Phase III, randomized, double blind (patient and assessor blinded), two armed, parallel, active
controlled, non-inferiority clinical trial to compare therapeutic efficacy and safety of AryoTrustTM
(produced by AryoGen Pharmed) and Herceptin® (the reference drug, produced by Roche
Company) as control drug in treating HER2-positive Breast Cancer.
Name of Test Drug:
Phase:
Methodology:
Sponsor:
Sponsor Representatives:
NCT Number:
Protocol Date
AryoTrust
III
Randomized, two-armed, double-blind (patient and assessor
blinded), parallel, active controlled, non-inferiority clinical
trial
AryoGen Pharmed
No.140. Corner of Tajbakhsh Street
24th Kilometer of Tehran-Karaj Makhsous Road, Alborz,
Iran.
Dr. Araz Sabzevari
Orchid Pharmed company CEO
NCT03425656
23 Dec 2017


Table Contents
Table Contents ............................................................................................................................2
Confidential Information.............................................................................................................1
Abbreviations..............................................................................................................................2
Administrative information.........................................................................................................4
Title .................................................................................................................................4
Trial registration..............................................................................................................4
Protocol version ..............................................................................................................4
Funding ...........................................................................................................................4
Roles and Responsibilities ..............................................................................................5
Introduction...............................................................................................................................17
Background ...................................................................................................................17
Objectives..................................................................................................................................20
Main objective...............................................................................................................20
Primary objective ..........................................................................................................20
Secondary objectives.....................................................................................................20
Methods.....................................................................................................................................20
Trial Design...................................................................................................................20
Study setting..................................................................................................................21
Eligibility criteria ......................................................................................................................21
Inclusion criteria: ..........................................................................................................21
Exclusion Criteria..........................................................................................................21
Intervention ...............................................................................................................................22
Pre-treatment considerations.........................................................................................23
Monitoring parameters..................................................................................................23
Dose adjustment for hepatic or renal dysfunction.........................................................24
Pretreatment considerations ..........................................................................................27


Monitoring parameters..................................................................................................28
Suggested dose alterations for toxicity .........................................................................28
Pre-treatment considerations.........................................................................................31
Monitoring parameters..................................................................................................32
Dose adjustment for hepatic or renal dysfunction.........................................................32
Pretreatment considerations ..........................................................................................35
Monitoring parameters..................................................................................................36
Suggested dose alterations for toxicity .........................................................................36
Dose adjustment for hepatic or renal dysfunction.........................................................36
Outcomes ..................................................................................................................................38
Primary outcomes..........................................................................................................38
Secondary outcomes......................................................................................................38
Safety Outcomes ...........................................................................................................38
Immunogenicity ............................................................................................................39
Termination policy....................................................................................................................39
Participant timelines..................................................................................................................40
Description of study's visits ......................................................Error! Bookmark not defined.
Visit 0: Evaluation and selection of the patients (week -3 up to 0)Error! Bookmark not
defined.
Visit 1 (week 1).............................................................Error! Bookmark not defined.
Visit 2 (week 3):............................................................Error! Bookmark not defined.
Visit 3 (week 5):............................................................Error! Bookmark not defined.
Visit 4 (week 7):............................................................Error! Bookmark not defined.
Visit 5 (week 9):............................................................Error! Bookmark not defined.
Visit 6 (week 10):..........................................................Error! Bookmark not defined.
Visit 7 (week 13):..........................................................Error! Bookmark not defined.
Visit 8 (week 16):..........................................................Error! Bookmark not defined.
Visit 9 (week 19):..........................................................Error! Bookmark not defined.
Visit 10 (week 21):........................................................Error! Bookmark not defined.
Visit 11 (week 23):........................................................Error! Bookmark not defined.
Visit 12 (week 26):........................................................Error! Bookmark not defined.


Sample size................................................................................................................................41
Recruitment...............................................................................................................................41
Randomization ..............................................................................................................41
Allocation (concealment process).................................................................................42
Blinding.....................................................................................................................................42
Treatment compliance...............................................................................................................42
Treatment discontinuation.........................................................................................................42
Data management......................................................................................................................44
Data collection methods................................................................................................44
Data management..........................................................................................................44
Data monitoring ............................................................................................................45
Statistical methods & Statistical Analyses................................................................................45
Monitoring ................................................................................................................................47
Site initiation visit .........................................................................................................47
Site monitoring visit......................................................................................................47
Study closeout...............................................................................................................47
Adverse events ..........................................................................................................................48
Auditing ....................................................................................................................................54
Ethics and dissemination...........................................................................................................54
Research ethics approval...............................................................................................54
Consent..........................................................................................................................55
Confidentiality ..............................................................................................................55
Amendment...................................................................................................................56
Declaration of interests .................................................................................................56
Funding organization ....................................................................................................56
Access to data................................................................................................................56
Ancillary and post-trial care..........................................................................................56
Dissemination policy.....................................................................................................56
Appendix 1: Informed consent materials..................................................................................57
Appendix 2: breast cancer staging ............................................................................................62
References.................................................................................................................................63




Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Confidential Information
The confidential information in the following document is provided to you as an investigator,
auditor, and sponsor for review by you, your staff and an ethics committee and food and drug
administration. By accepting this document, you agree that the information contained herein will
not be disclosed to others without written authorization from AryoGen Pharmed Co., except to the
extent necessary to obtain informed consent from those persons to whom the products may be
administered. By signing below, the investigator agrees to adhere to the protocol as outlined and
agrees that any changes to the protocol must be approved by AryoGen Pharmed Co., prior to
seeking approval from the Independent Ethics Committee (IEC).
This study will be conducted in accordance with Good Clinical Practices (GCPs), the Declaration of
Helsinki, local, ethical, and legal requirements.
Chief Investigator: Dr. Seyed Reza Safaeinodehi, Tehran University of Medical Sciences
Signature: ……………………………………………………………….
Date: ……/………. /………
Sponsor Representative: Dr. Araz Sabzevari, Orchid Pharmed company CEO
Signature: ……………………………………………………………………….
Date: ……/………. /… ……
CRO Trial Representative: Dr. Hamed Hosseini, Tehran University of Medical Sciences
Signature: ……………………………………………………………………….
Date: ……/………. /… ……
Confirmed
Conditionally confirmed
Not Confirmed
Comments:
ARYOGEN Pharmed Co
Clinical Trial Center
1


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Date:
Abbreviations
Abbreviation
IEC
GCP
IRCT
CRF
Stand for
Independent Ethics Committee
Good Clinical Practices
Iranian Registry of Clinical Trial
Case Report Form
ICH
International
Conference
on
Harmonization
TSC
Trial Steering Committee
HER2
Human epidermal growth factor receptor
2
FISH
Fluorescence In Situ Hybridization
IHC
Immunohistochemistry
AC
Adriamycin, cyclophosphamide
pCR
pathologic Complete Response
cCR
clinical Complete Response
cPR
clinical Partial Response
cNC
clinically No Change
cPD
clinical Progressive Disease
cOR
clinical Objective Response
SOPs
Standard Operating Procedures
ER
Estrogen Receptor
ECG
Electrocardiography
LVEF
Left Ventricular Ejection Fraction
AST
Aspartate Aminotransferase
ULN
Upper Limit of Normal
ICF
Informed Consent Form
2


Clinical Trial Protocol
SIL
AE
CBC
Plt
CRO
PI
AryoTrust vs. Herceptin®: a non-inferiority study
Subject Identification Log
Adverse Effect
Complete Blood Count
Platelet
Contract Research Organization
Principal Investigator
3


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Administrative information
Title
A Phase III, randomized, two-armed, patient-outcome assessor-data analyzer blinded, parallel active
controlled non-Inferiority clinical trial study of AryoTrust (AryoGen Pharmed Trastuzumab) efficacy
and safety in Human Epidermal Growth Factor Receptor 2–Positive breast cancer in comparison to
Herceptin® (Genentech/Roche) control.
Trial registration
It is planned to register this protocol to Iranian Registry of Clinical Trial (IRCT) http://IRCT.ir
Registration code in IRCT: IRCT201606226135N7
Ethics committee code has been received in 1395/04/01 from Tehran University of Medical Sciences
with the number of IR.TUMS.REC.1395.2730.
Ethics committee code has been received in 1395/04/27 from Isfahan University of Medical Sciences
with the number of IR.MUI.REC.1395.4.041.
Clinical Trial Authorization (CTA) from Iran food and drug administration of Iran with the number
of 665/65516 in 1395/04/19.
Protocol version
Version 4.3, Date: 2017/12/23
Funding
AryoTrust (AryoGen Pharmed) will be manufactured by AryoGen Pharmed Company and
Herceptin® will be provided by AryoGen Pharmed Company. All trial costs will be provided by
AryoGen Pharmed Company.
4


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Roles and Responsibilities
Sponsor:
AryoGen Pharmed Company
Contact address: AryoGen Pharmed, No. 140, Corner of Tajbakhsh St., 24th Km Tehran-Karaj Makhsous
Road, Alborz, Iran
Tel: 0098 26 36106480-4
Fax: 0098 26 36104644
Zip Code: 3164819711
Sponsor representative: Dr. Araz Sabzvari
Contact address: Orchid Pharmed company, No 2, Khorasani dead-end, Derakhti St., Dadman Blvd.,
Shahrak Gharb, Tehran, Iran.
Telephone: 00982143473000
Extension: 400
Role:
·
Preparing final draft of study protocol
·
Obtaining necessary approvals from external organizations for the conduct of study
·
Providing standard operational procedures (SOP) for principle investigators in participating
centers
·     Providing quality controlled drugs to be used in the trial and delivery to participating centers
·     Funding provision for all activities foreseen in study protocol via signing contracts with
principal investigator
·
Providing compensation for patients who may be adversely affected by participating in the
trial
·
Providing insurance coverage for all study participants
·
Providing necessary training for staff
·
Recruiting necessary workforce to conduct monitoring of the trial
·
All expenses will be the responsibility of the sponsor.
5


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Audit of study sites to review the process of conducting the study and report the cases of
violations from the protocol.
Representatives of the sponsor to conduct an audit to monitor the quality of the study:
Name: Dr. Somayeh Amini, Pharmacist, Medical Department Manager
Contact address: Orchid Pharmed company, No 2, Khorasani dead-end, Derakhti St., Dadman Blvd.,
Shahrak Gharb, Tehran, Iran.
Telephone: 00982143473000
Extension: 211
Signature:
Name: Dr. Nasim Anjidani, Pharmacist, Clinical Trial department Manager
Contact address: Orchid Pharmed company, 5th floor, No 74, Hafezi St., Farahzadi Blvd., Shahrak Gharb,
Tehran, Iran.
Telephone: 00982143473000
Extension: 510
Signature:
Name: Dr. Sahar Pedram, Pharmacist, Clinical Research Associate
Contact address: Orchid Pharmed company, 5th floor, No 74, Hafezi St., Farahzadi Blvd., Shahrak Gharb,
Tehran, Iran.
Telephone: 00982143473000
Extension: 530
Signature:
Name: Mrs. Elham Farhang, Clinical Research Coordinator
Contact address: Orchid Pharmed company, 5th floor, No 74, Hafezi St., Farahzadi Blvd., Shahrak Gharb,
Tehran, Iran.
Telephone: 00982143473000
Roles:
6


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Visiting study sites to review the process of the protocol and ensure that the study is conducted in
accordance with the protocol and GCP principles (at least one or two of these persons will attend
each visit).
·
Check the site's facilities for the performance and continuation of the clinical trials and take the
necessary measures to provide them (to ensure that enough drugs are available to continue the study,
to ensure that enough CRF and consent forms are met, and other requirements for the performance of
the study).
·
Persistent training of site personnel for protocol performance.
·
Checking CRFs and matching them with source data and filling out the query for noncompliance and
reminding them to correct them.
·
Provide reports of non-compliances and facilities required by the site and submit it to the company's
managers.
Representative of the sponsor for external monitoring on quality control of the study:
Name: CRO Trial
CRO representative: Dr. Hamed Hosseini, Tehran university of medical sciences
Contact address: Tehran university of medical sciences, Institute of Research and Research Centers,
Keshavarz Blvd., North Kargar St., Tehran, Iran.
Telephone: 00982188963546
Signature:
CRO monitor: Dr. Ayat Ahmadi, Tehran university of medical sciences
Contact address: Tehran university of medical sciences, Institute of Research and Research Centers,
Keshavarz Blvd., North Kargar St., Tehran, Iran.
Telephone: 00982188963546
Signature:
Roles:
·
Preparing a randomization file
7


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Conducting a 70% monitoring in all of the sites participating in the study according to GCP
Guidelines, 108 patients were diagnosed in patient recruitment centers.
·
Supervision over the study and Data Management
·
Performing Statistical analysis and Preparing or approving the project either in middle or the end of
the study
·
Cooperation with company to perform Monitoring visits
·
Cooperation for answering the methodology queries
·
Regular visiting of all patient sites of Tehran
8


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Chief investigator:
Name: Dr. Seyed Reza Safaeinodehi
Contact Address: Imam Khomeini Hospital Complex, Tehran, IRAN.
Telephone: 00982166581593
Role:
ü Conducting the study according to the agreed protocol
ü Setting up a team for this purpose
ü All clinical examinations
ü Filling out the CRF
ü Responsible for conducting trial according to ICH-GCP in sites.
ü Organizing training events for their existing and newly recruited team members wherever
necessary
ü Provision of suitable storage and delivery for drugs used in the trial
ü Cooperation with monitors during the conduct of the study
ü No part of this trial could be published without the prior agreement with sponsor.
(This agreement must be signed by PI and sponsor before the study initiation.)
ü Responsible to provide training for staff at the study site
ü Patients care
ü Notification of AEs and ADRs to sponsor and regulatory according to the protocol schedule
and regulatory requirements.
Signature:
9


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Principal Investigators:
Roles:
·
Conducting the study according to the agreed protocol
·
Setting up a team for this purpose
·
Organizing training events for their existing and newly recruited team members whenever
necessary
·
Provision of suitable venues for patients admission
·
Provision of suitable storage for drugs used in the trial
·
Cooperation with monitors during the conduct of the study
·
All medical documents related to the trial should be sent to AryoGen Pharmed Company at
the end of the trial. A copy may be kept by principle investigator
·
No part of this trial could be published without the prior agreement of AryoGen Pharmed
Company.
In all of these centers, patient recruitment is performed.
·
Emam Khomeini Hospital
Principal Investigator:
- Dr. Farhad Shahi, Tehran University of Medical Sciences
- Dr. Mehrzad Mirzania, Tehran University of Medical Sciences
- Dr. Farahnaz Vafaeizadeh, Tehran University of Medical Sciences
Contact Address: Hematology and oncology center, Valiasr hospital, Imam Khomeini Therapeutic
Complex, Keshavarz blvd., Tehran, Iran.
Telephone: 00982166581593
·
Mehrad Hospital
Principal Investigator: Dr. Jahangir Rafaat, Tehran University of Medical Sciences.
Contact Address: Miremad St. Mottahari St., Tehran, Iran.
Telephone: 00982188747401
10


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Masoud Clinic
Principal Investigator: Dr. Masoud Iravani, Tehran University of Medical Science
Contact Address: No. 144., 19th St., after Jalal Al Ahmad Highway, North Kargar St., Tehran,
Iran.
Telephone: 00982188336300
·
Jahad Daneshgahi Clinic
Principal Investigator: Dr. Safa Najar Najafi, Tehran University of Medical Sciences.
Contact Address: No. 45., West Shahid Nazari St. Aboureyhan St., Enghelab St., Tehran, Iran.
Telephone: 00982166404050
·
Hazrate Rasoul Hospital
Principal Investigator: Dr. Nafiseh Ansarinejad, Iran University of Medical Sciences
Contact Address: Niayesh St., Satarkhan St., Tehran, Iran.
Telephone: 00982166515001
·
Emam Reza Hospital
Principal Investigator: Dr. Abolghasem Allahyari, Mashhad University of Medical Sciences.
Contact Address: Emam Reza square, Ebne Sina St., Mashhad, Khorasan Razavi.
Telephone: 00985138543031
·
Dr. Mehrdad Payandeh Clinic
Principal Investigator: Dr. Mehrdad Payandeh, Kermanshah University of Medical Sciences.
Contact Address: No 101, Fakhr Razi Alley, Shahrdari square, Modares St., Kermanshah, Iran.
Telephone: 00983837282400
11


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Dr. Mohammadreza Mortazavi Zadeh Clinic
Principal Investigator: Dr. Mohammadreza Mortazavi Zadeh, Yazd University of Medical Sciences.
Contact Address: No 25, Shahid haj Mohammadi Alley, Yazd, Iran.
Telephone: 00983537250044
·
Shahid Faghihi Hospital
Principal Investigator: Dr. Shirin Haghighatju, Shiraz University of Medical Sciences.
Contact Address: Karim Khan Zand St., Shiraz, Iran.
Telephone: 00987132351087
·
Shafa Hospital
Principal Investigator:
- Dr. Mehran Hosseinzadeh, Ahwaz University of Medical Sciences.
- Dr. Mohammad Segholeslami, Ahwaz University of Medical Sciences.
- Dr. Ahmad Ahmad Zadeh Deilami, Ahwaz University of Medical Sciences.
Contact Address: Golestan St., Ahwaz, Khoozestan, Iran.
Telephone: 00986133743281
·
Javad-al-aeme Hospital
Principal Investigator: Dr. Vahid Moazed, Kerman University of Medical Sciences.
Contact Address: aboozar 25, Kerman, Kerman Province
Telephone: 00983432510025
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Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Park Clinic
Principal Investigator: Dr. Behjat Kalantari, Kerman University of Medical Sciences.
Contact Address: Sadi St, Kerman, Kerman Province
Telephone: 00989162477801
·
Toos Hospital
Principal Investigator:
- Dr. Saeed Salimi, Iran University of Medical Sciences, Iran University of Medical Sciences.
- Dr. Mohsen Razavi, Iran University of Medical Sciences, Iran University of Medical Sciences.
Contact Address: Sanaie St., Motaharri St., Tehran, Iran.
Telephone: 00982188714891
·
Aliebne Abitaleb Hospital
Principal Investigator: Dr. Seyed Mehdi Hashemi, Zahedan University of Medical Sciences.
Contact Address: Salamat Blvd., Dr. Hesabi square, Zahedan, Iran.
Telephone: 00985433295570
·
Tohid Hospital
Principal Investigator: Dr. Bayazid Ghaderi, Sanandaj University of Medical Sciences.
Contact Address: Geryashan St., Sanandaj, Kordestan, Iran.
Telephone:00988733286112
·
Baqiyatallah Hospital
Principal Investigator: Dr.Mojtaba Qadyani, Shahid Beheshti University of Medical Sciences.
Contact Address: Molla Sadra St, Tehran Province, Tehran
Telephone:00982188050435
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Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Booali Hospital
Principal Investigator:
- Dr. Arash Jenabian, Azad University of Medical Sciences.
- Dr. Somaye khamsi, Azad University of Medical Sciences.
Contact Address: Imam Hossein Square, Beginning Damavand Avenue, Tehran, Iran
Telephone: 00982133286112
·
Sheikh Mofid Clinic
Principal Investigator: Dr. Ali Hajigholami, Isfahan University of Medical Sciences.
Contact Address: Sheikh mofid St, Sheikh Mofid clinic, Isfahan, Iran
Telephone: 00983136631677
statistics advisers
Name: Ramin Shahpari
Contact address: Orchid Pharmed company, No 2, Khorasani deadend, Derakhti St., Dadman blvd.,
Shahrak Gharb, Tehran, Iran.
Telephone: 00982143473000
Extension: 208
Name: Dr. Ali Akhlaghi
Contact address: Number 1547, Tehran University of Medical Sciences research center, Keshavarz
Blvd., North Kargar street, Tehran, Iran.
Telephone: 00982188963546
Role: Monitor data entry into the database, analyzes the results.
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Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Scientific steering committee
Name: Dr. Reza Safaeinodehi, Oncologist, Tehran University of Medical Sciences.
Contact address: Oncology and hematology center, Emam Khomeini hospital, Keshavarz BLVD.,
Tehran University of Medical Sciences, Tehran, Iran.
Telephone: 00982166581593
Name: Dr. Farhad Shahi, Oncologist, Tehran University of Medical Sciences.
Contact address: Oncology and hematology center, Emam Khomeini hospital, Keshavarz BLVD.,
Tehran University of Medical Sciences, Tehran, Iran.
Telephone: 00982166581593
Name: Dr. Safa Najar Najafi, Oncologist, Tehran University of Medical Sciences.
Contact address: Jahad Daneshgahi center, No.45, west Shahid Nazari St., Aboureyhan St.,
Enghelab Se., Tehran University of Medical Sciences, Tehran, Iran.
Telephone: 00982166404050
Name: Dr. Hamed Hosseini, Tehran University of Medical Sciences.
Contact address: Tehran University of Medical Sciences research center, Keshavarz Blvd., North
Kargar street, Tehran, Iran
Telephone: 00982188963546
Representatives of the sponsor to attend the meeting (at least one of the following will attend
each meeting):
Name: Dr. Somayeh Amini, Pharmacist, Medical Department Manager
Address: Orchid Pharmed company, No 2, Khorasani deadend, Derakhti St., Dadman blvd., Shahrak
Gharb, Tehran, Iran.
Telephone: 00982143473000
Extension: 211
Signature:
15


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Name: Dr. Nasim Anjidani, Pharmacist, Clinical Trial Department Manager
Address: Orchid Pharmed company, 5th floor, No 74, Hafezi St., Farahzadi blvd., Shahrak Gharb,
Tehran, Iran.
Telephone: 00982143473000
Extension: 510
Signature:
Name: Dr. Sahar Pedram, Pharmacist, Clinical Research Associate
Address: Orchid Pharmed company, 5th floor, No 74, Hafezi St., Farahzadi blvd., Shahrak Gharb,
Tehran, Iran.
Telephone: 00982143473000
Extension: 510
Signature:
Roles:
1- Establishing coordination among researchers in study centers.
2- Monitor and review the reports provided by the sponsor and CRO.
3- Signing of the protocol and protocol amendments and reports submitted to the Food and Drug
Administration of Iran and ethics committees on behalf of other professors.
4- Adopting a proper decision to address the conditions in which the profit-risk balance for
participants in the study, either individually or in general, conflicts. With regard to safety
information, these decisions may include the identification of the relationship between the
drug and the unwanted event observed, the adoption of appropriate strategies for the
continuation of study and the departure of the person who is no longer eligible for the study.
5- Make the right decision to decode the drug.
6- Establishment of meetings every two to three months (Due to the low rate of patient
recruitment, the frequency of the sessions will be every two to three months, and in case of
any serious complications, especially suspected complications, these sessions will be held as
soon as possible.).
16


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Introduction
Background
Breast cancer is a disease in which certain cells in the breast become abnormal and multiply
uncontrollably to form a tumor. Breast cancer is the second most commonly diagnosed cancer in
women. About one in eight women in the United States will develop invasive breast cancer in her
lifetime. Researchers estimate that more than 230,000 new cases of invasive breast cancer will be
diagnosed in U.S. women in 2015[1].
Some genes and the proteins they make can influence how a breast cancer behaves and how it might
respond to a specific treatment. Human epidermal growth factor receptor 2 (HER2) is one of such
genes that can play a role in the development of breast cancer [2]. The HER2 gene expresses HER2
protein receptors which help to control how a healthy breast cell grows, divides, and repairs itself.
This gene is over expressed in 25% to 30% of breast cancers, suggesting a role for overexpression in
tumorigenesis. This overexpression is most commonly the result of gene amplification that happens
when the HER2 gene doesn't work correctly and makes too many copies of itself. These extra HER2
genes tell breast cells to make too many HER2 receptors (HER2 protein overexpression). All these
process make breast cells grow and divide in an uncontrolled way [3].
Breast cancers with HER2 gene amplification or HER2 protein overexpression are called HER2-
positive in the pathology report. HER2-positive breast cancers tend to grow faster and are more likely
to spread and relapse compared to HER2-negative breast cancers. Several lines of evidence support
the role of HER2 overexpression in the pathogenesis and poor clinical outcome of human tumors. A
number of these studies have shown that breast cancers that overexpress HER2 have a more
aggressive course and higher relapse and mortality rates. HER2 overexpression in retrospective
analyses of adjuvant studies was also associated with resistance to cyclophosphamide, methotrexate,
and fluorouracil chemotherapy [4]. HER2 can be determined by any of several methods. The most
commonly used methods are the Fluorescence in situ hybridization (FISH), which detects gene
amplification by measuring the number of copies of the HER2 gene in the nuclei of tumor cells and
Immunohistochemistry (IHC), which measures the number of HER2 receptors on the cell surface and
therefore detects receptor overexpression [5]
Treatment
Several murine monoclonal antibodies against the extracellular domain of the HER2 protein were
found to inhibit the proliferation of human cancer cells that overexpressed HER2, both in vitro and
in vivo [6]. In the 1980s, a monoclonal antibody against HER-2 was developed. This antibody that
17


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
inhibited tumor growth, was called trastuzumab. In 1998, trastuzumab (Herceptin; Genentech Inc.
South San Francisco, CA) as a humanized monoclonal antibody directed against the extracellular
domain of HER2 was approved for the treatment of metastatic breast cancer [7]. In 2005, the results
of five adjuvant trials evaluating trastuzumab, involving >10,000 women, were presented. Despite
differences in study design and short follow-ups of only 1 to 2 years, these studies showed the same
remarkable results, adjuvant trastuzumab therapy halves the recurrence rate and reduces mortality by
30% [8]. This monoclonal antibody as a single agent has modest antitumor activity [9] but it had
synergistic effects when used in combination with cisplatin, carboplatin, docetaxel and ionizing
radiation and had additive effects when used with doxorubicin, cyclophosphamide, and paclitaxel [7].
In phase III randomized trials, trastuzumab in combination with standard chemotherapy (paclitaxel,
docetaxel or doxorubicin, and cyclophosphamide combinations) demonstrated improvement in time
to progression, overall response, duration of response and a favorable impact on survival compared
with the same chemotherapy alone as therapy for metastatic breast cancer overexpressing HER2 [10].
Women with breast cancers that overexpress HER2 are at greater risk for disease progression and
death than women whose tumors do not overexpress HER2. Herceptin® (Genentech/Roche), is a
proprietary name of trastuzumab which blocks downstream signaling of HER2 and substantially
improves the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive
breast cancers. Although Cardiac dysfunction was observed in 27% of patients treated with
trastuzumab and anthracycline-based combination therapy benefits seem to outweigh risks and the
ensuing congestive heart failure is generally reversible [11]. For women with newly diagnosed breast
cancer, a practical benefit of preoperative therapy is that it will downstage the primary tumor in most
patients, allowing a higher rate of breast conservation. It also provides an in vivo assessment of tumor
response to the particular drug regimen and, hence, an opportunity to optimize therapy. Furthermore,
by using pathologic Complete Response (pCR) assessment, after preoperative therapy, an appropriate
surrogate of long-term disease-free survival is available. It is hypothesized that a regimen that
produces higher rates of pCR in the neoadjuvant treatment setting will also result in higher rates of
long-term outcomes [4].
Trastuzumab common adverse events
-
Flu- like symptoms like mild fever, chills, headache, limb pain, weakness and lethargy
-
Skin rush
-
Nausea, vomiting, diarrhea
-
Decreased left ventricular ejection fraction (LVEF)
-
Dyspnea, cough
18


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
-
Infusion reactions
Rationale for the study
The enhanced antitumor activity of trastuzumab has been shown in several studies. Given the high
prices of this antibody as a medicine in Iran, AryoGen Pharmed (Pharmaceutical Company in Tehran,
Iran) decided to produce this drug in the country. We designed this study in which patients with
HER2-positive locally advanced or inflammatory breast cancer will be randomly assigned to either
Herceptin® (Genentech/Roche trastuzumab) or AryoTrust (AryoGen Pharmed trastuzumab). Both
groups will receive 4 doses of Adriamycin, cyclophosphamide (AC) every 14 days, proceeded by 4
cycles of Docetaxel + trastuzumab every 21 days. The main goal of this study is to demonstrate that
the AryoTrust (AryoGen Pharmed trastuzumab) is not inferior to Herceptin® (Genentech/Roche
trastuzumab) in term of pCR rate. In addition, the efficacy characteristics, other than pCR, and safety
outcomes of AryoTrust vs. Herceptin® after 4 cycles of infusion in breast cancer volunteers will be
assessed.
19


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Objectives
Main objective
·
To verify the non-inferiority of AryoTrust (AryoGen Pharmed trastuzumab) vs. Herceptin®
(Genentech/Roche trastuzumab), both given concomitantly with docetaxel after Adriamycin plus
cyclophosphamide in the neoadjuvant setting according to pathological clinical response and
immunogenicity assay in patients with Human Epidermal Growth Factor Receptor 2–Positive
breast cancer.
Primary objective
·
The primary objective of this study is to verify the non-inferiority of AryoTrust vs. Herceptin®,
given concomitantly with docetaxel after Adriamycin plus cyclophosphamide in the neoadjuvant
setting according to pathological complete response (pCR) rate in patients with Human Epidermal
Growth Factor Receptor 2–Positive breast cancer.
Secondary objectives
·
To evaluate non-significance between AryoTrust and Herceptin®, given concomitantly with
docetaxel after Adriamycin plus cyclophosphamide in the neoadjuvant setting according to
clinical objective response (cOR), clinical complete response (cCR), clinical partial response
(cPR), clinically no change (cNC), clinical progressive disease (cPD), breast conservation rate.
·
To evaluate the safety of AryoTrust vs. Herceptin®, given concomitantly with docetaxel after
Adriamycin plus cyclophosphamide in the neoadjuvant setting in patients with Human Epidermal
Growth Factor Receptor 2–Positive breast cancer.
·
To assess the immunogenicity of AryoTrust vs. Herceptin®, given concomitantly with docetaxel
after Adriamycin plus cyclophosphamide in the neoadjuvant setting in patients with Human
Epidermal Growth Factor Receptor 2–Positive breast cancer.
Methods
Trial Design
This is a Phase III, randomized, two-armed, patient-outcome assessor-data analyzer blinded, parallel
active controlled non-Inferiority clinical trial study with a 1:1 allocation.
20


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Study setting
This trial will be initiated from July 2016 and 108 patients with breast cancer recruited from the
following centers. All centers implement same protocol and procedures by using same SOPs which
will be accompanied by training of personnel at the beginning, throughout and at the end of the trial.
Regular and strict monitoring visits are provided to ensure all processes will be carried out in
accordance with GCP. Probable variation of eligibility criteria and evaluation criteria will be resolved
through investigator meetings.
Eligibility criteria
Inclusion criteria:
o 18-70 years old female patients
o Patients with newly diagnosed stage III (locally advanced) or inoperable stage II (due
to sizes larger than 5 cm or high tumor to breast ratio) tumors are candidates for
participation. (Appendix 2)
o Willing and able to sign an informed consent
o Pathological diagnosis of adenocarcinoma of the breast
o ECOG status of 0-1
o With any ER/PR status
o HER2 positive (Immunohistochemical (IHC) 3+ intensity, amplification of the HER2
gene on fluorescence in situ hybridization (FISH+) or HER2 positive results of
Chromogenic in situ hybridization (CISH)).
NOTE: ductal carcinoma in situ (DCIS) components should not be considered in the
determination of degree of IHC staining or FISH amplification.
Exclusion Criteria
·
Clinical or radiologic evidence of metastatic disease
·
History of any other malignancy including previous breast cancer, second non-breast
malignant disease
·
History of previous chemotherapy
·
Left ventricular ejection fraction [LVEF] <55% confirmed by echocardiogram within
3 months before registration, Any prior myocardial infarction, History of documented
congestive heart failure (CHF),Any prior history of arrhythmia or cardiac valvular
21


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
disease requiring medications or clinically significant, Current use of medications for
treatment of angina pectoris, Current uncontrolled hypertension (diastolic>100 mmHg
or systolic>200 mmHg), A severe conduction abnormality (having pacemaker or
diagnosed by the ECG) and any other significant cardiovascular disease.
·
Hematologic abnormalities including baseline Absolute Neutrophil Count (ANC) of
≤1,500/µL or platelet count ≤ 100,000/µL
·
Liver dysfunction including: (baseline)
o Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) ≥ 3
Upper Limit Normal (ULN)
o Alkaline phosphatase (ALP) ≥3 ULN
o serum total bilirubin > 1.5 ULN
·
Renal dysfunction, defined as serum creatinine ≥2.5 mg/dL
·
Pregnant, lactating women or women of childbearing potential who are not willing to
use adequate contraception
Intervention
Intervention group:
All patients are scheduled to receive AC-Docetaxel+Trastuzumab regimen as detailed bellow:
Doxorubicin + Cyclophosphamide phase:
Cycle
length:
14
days.
Total cycles: 4 cycles
Drug
Dose and route
Administration
Given on days
Dilute with normal saline
(NS)        to        a        final
Doxorubicin
60 mg/m2 IV
concentration of 2 mg/mL
and administered as an IV
Day 1
bolus over three to five
minutes.
Dilute with 250 to 500 mL
Cyclophosphamide 600 mg/m2 IV
NS or D5W and administer
Day 1
over 30 to 60 minutes.
22


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
If there is a change in body weight of at least 10 percent, dose should be recalculated for all
drugs.
Pre-treatment considerations
·
Hydration:
Patients receiving cyclophosphamide should maintain adequate oral hydration (2 to 3 L/day
during administration and for one to two days thereafter) and void frequently to reduce the
risk of haemorrhagic cystitis.
·
Emesis risk:
HIGH (>90 percent frequency of emesis).
Aprepitant 125 mg PO pre-chemotherapy on Day 1 and 80 mg PO post-chemotherapy once
daily on Days 2 and 3
Granisetron 1 mg or 0.01 mg/kg IV
Dexamethasone 12 mg IV 8 mg oral or IV daily; days 2-3
·
Vesicant/irritant properties:
Doxorubicin is a vesicant and can cause significant tissue damage if an extravasation occurs.
For peripheral infusions, the IV line should be recently placed into a large, intact vein, with
good blood return established immediately prior to starting the infusion.
The IV or catheter site should be continuously monitored throughout drug administration
infusion. If extravasation occurs, apply ice to the site.
·
Cardiac issues:
A baseline assessment of LVEF is recommended, with periodic reassessment of during
therapy. The risk of doxorubicin-associated cardiac dysfunction is related to cumulative dose.
Monitoring parameters
·
CBC with differential and platelet count every two weeks prior to each treatment cycle.
·
Serum electrolytes and liver and renal function tests every two weeks prior to each treatment
cycle.
23


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
During treatment with AC and Docetaxel, assess line site periodically during infusion of
chemotherapy for signs and symptoms of extravasation.
·
Myelotoxicity:
Subsequent cycles should be delayed until the absolute neutrophil count is greater than
1000/microL and platelet count greater than 100,000/microL.
ANC (×109/L)
≥ 1.5
And
1.0-1.49
or
< 1
or
Platelets (×109/L)
≥ 90
70-90
< 70
Dose (both drugs)
100%
75%
delay
If there is more than a three-week delay in treatment, a dose reduction of 25 percent is
recommended.
Dose adjustment for hepatic or renal dysfunction
Doxorubicin
Renal Impairment
CrCl <50 mL/minute: No dosage adjustment necessary.
Hemodialysis: Supplemental dose is not necessary.
Hepatic Impairment
The manufacturers' labeling recommends the following adjustments:
Serum bilirubin 1.2 to 3 mg/dL: Administer 50% of dose.
Serum bilirubin 3.1 to 5 mg/dL: Administer 25% of dose.
Severe hepatic impairment (Child-Pugh class C or bilirubin >5 mg/dL): Use is contraindicated.
ALT/AST
2-3 × ULN
>3 × ULN
-
-
Or
Bilirubin (micromole/L)
-
20-50
51-85
> 85
Dose
75%
50%
25%
Do not administer
24


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Cyclophosphamide
Renal Impairment
Clcr ≥10 mL/minute: No dosage adjustment required.
Clcr <10 mL/minute: Administer 75% of normal dose.
Creatinine clearance (ml/min)
≥ 10
< 10
Cyclophosphamide dose
100%
75%
Hepatic Impairment
Serum bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75%
of dose.
Serum bilirubin >5 mg/dL: Avoid use.
25


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Docetaxel + AryoTrust phase:
Cycle
length:
21
days.
Total cycles: 4 cycles
Drug
Dose and route
Administration
Dilute in 250-500* mL NS
or D5W
Administer I.V. infusion
Docetaxel
100 mg/m2 IV
over
1-hour
through
nonsorbing
polyethylene
lined (non-DEHP) tubing
IV infusion in 250ml NS
over 90 minutes for first
dose (observe for 1 hour
after infusion)
IV infusion in 250 mL NS
over 1 hour on the second
8 mg/kg IV loading dose.
Observe
for
30
AryoTrust
dose (at cycle 1),
followed by 6 mg/kg
minutes post infusion
• IV infusion in 250 mL NS
at subsequent cycles      over     30     min     on     all
subsequent doses if no
adverse reactions. Observe
for 30 min post infusion
DO NOT mix with D5W,
and DO NOT infuse as an
IV push or bolus.
* use 250 mL for doses 74-185 mg, use 500 mL for doses greater than 185 mg
-
If there is a change in body weight of at least 10 percent, dose should be recalculated for all
drugs.
26


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Pretreatment considerations
•
Prophylaxis for infusion reactions:
Dexamethasone 8 mg PO bid for 3 days, starting one day prior to each Docetaxel
administration. Patient must receive minimum of 3 doses pre-treatment. Additional antiemetic
not usually required.
Trastuzumab may also cause infusion reactions. These can be severe, though most are mild;
they typically occur during or within 24 hours of the first infusion. The most common
symptoms are fever, chills, nausea, headache, abdominal pain, and dyspnea; less often are
vomiting, dizziness, rash, rhinitis, or hypotension. Most clinicians do not routinely
premedicate prior to the first trastuzumab dose.
NOTE: Trastuzumab infusion should be discontinued for anaphylaxis (bronchospasm,
hypotension, angioedema).
•
Infection prophylaxis:
filgrastim (G-CSF) 5 mcg/kg/day Days 3 to 10 reduce filgrastim treatment duration if ANC
greater than 10*1010 or intolerable bone pain.
•
Dose adjustment for baseline liver or renal dysfunction:
The available data suggest that disposition of trastuzumab is not altered based on serum
creatinine (≤2 mg/dL).
•
Cardiac issues:
Trastuzumab is associated with cardiotoxicity, and reassessment of LVEF prior to therapy
(after completion of AC) is indicated.
•
Pulmonary issues:
Trastuzumab has been associated with serious pulmonary toxicity (including acute respiratory
distress syndrome [ARDS] and interstitial pneumonitis) and should be used with caution in
patients with preexisting pulmonary disease.
27


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Monitoring parameters
·
CBC with differential and platelet count weekly during treatment with Docetaxel.
·
Serum electrolytes and liver and renal function tests prior to each treatment cycle of
Docetaxel.
·
Assess changes in neurologic function prior to each treatment cycle of Docetaxel.
·
Assess cardiac function prior to AC and prior to initiation of trastuzumab.
·
Assess cardiac function prior to trastuzumab and after 4 cycles of trastuzumab.
·
During treatment with docetaxel, assess line site periodically during infusion of chemotherapy
for signs and symptoms of extravasation.
Suggested dose alterations for toxicity
·
Myelotoxicity:
Subsequent cycles should be delayed until the absolute neutrophil count is greater than
1000/microL and platelet count greater than 100,000/microL.
If there is more than a three-week delay in treatment, a dose reduction of 25 percent is
recommended.
ANC
(×
109/L)
≥ 1.5
1.0-1.49
< 1
Platelet
109/L)
and >90
Or
70-90
Or
<70
(× Dose
(Docetaxel)
100%
75%
delay
Dose after neutropenic sepsis on
Docetaxel
75%
Delay
Delay
• Dose adjustment for hepatic or renal dysfunction:
Docetaxel
Renal impairment
No dose modification is indicated
Hepatic impairment
28


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Alkaline phosphatase
< 2.5 ULN
2.5-5 ULN
> 5 ULN
AST +/or ALT dose
And ≤ 1.5 ULN
100%
And 1.6-6 ULN
75%
or
>5 ULN
delay
Trastuzumab
Renal Impairment
There are no dosage adjustments provided in the manufacturer’s labeling, although
data suggest that the disposition of trastuzumab is not altered based on serum
creatinine (up to 2 mg/dL)
Hepatic Impairment
There are no dosage adjustments provided in the manufacturer’s labeling.
• Cardiotoxicity:
Asymptomatic patients-Trastuzumab continuation based on serial LVEFs
Relationship of LVEF Absolute Decrease of Absolute Decrease of Absolute Decrease of
to LLN                             less than 10 points 10-15     points     from greater than or equal to
from baseline                   baseline                           16        points        from
Within normal limits
1-5 points below LLN
Greater than or equal
to 6 points below LLN
Continue
Continue
Continue*
Continue
Hold*
Hold*
baseline
Hold*
Hold*
Hold*
·
* repeat LVEF assessment after 3-4 weeks, consider cardiac assessment
·
If criteria for continuation are met-resume trastuzumab
·
If 2 consecutive holds or a total of 3 holds occur, discontinue trastuzumab
Symptomatic patients:
·
Symptomatic patients with evidence of cardiac dysfunction should have trastuzumab
discontinued.
29


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
• Pulmonary toxicity:
Discontinue trastuzumab if patients develop ARDS, interstitial pneumonitis, or pulmonary
fibrosis.
30


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Control Group:
All patients are scheduled to receive AC-Docetaxel+Trastuzumab regimen as detailed bellow:
Doxorubicin + Cyclophosphamide phase:
Cycle
length:
14
days.
Total cycles: 4 cycles
Drug
Dose and route
Administration
Given on days
Dilute with normal saline
(NS)
to
a
final
Doxorubicin
60 mg/m2 IV
concentration of 2 mg/mL
and administered as an IV
Day 1
bolus over three to five
minutes .
Dilute with 250 to 500 mL
Cyclophosphamide 600 mg/m2 IV
NS or D5W and administer Day 1
over 30 to 60 minutes.
·
If there is a change in body weight of at least 10 percent, dose should be recalculated for all
drugs.
Pre-treatment considerations
·
Hydration:
Patients receiving cyclophosphamide should maintain adequate oral hydration (2 to 3 L/day
during administration and for one to two days thereafter) and void frequently to reduce the
risk of haemorrhagic cystitis.
·
Emesis risk:
HIGH (>90 percent frequency of emesis).
aprepitant 125 mg PO pre-chemotherapy on Day 1 and 80 mg PO post-chemotherapy once
daily on Days 2 and 3
Granisetron 1 mg or 0.01 mg/kg IV
Dexamethasone 12 mg IV 8 mg oral or IV daily; days 2-3
31


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Vesicant/irritant properties:
Doxorubicin is a vesicant and can cause significant tissue damage if an extravasation occurs.
For peripheral infusions, the IV line should be recently placed into a large, intact vein, with
good blood return established immediately prior to starting the infusion.
The IV or catheter site should be continuously monitored throughout drug administration
infusion. If extravasation occurs, apply ice to the site.
·
Cardiac issues:
A baseline assessment of LVEF is recommended, with periodic reassessment of during
therapy. The risk of doxorubicin-associated cardiac dysfunction is related to cumulative dose.
Monitoring parameters
·
CBC with differential and platelet count every two weeks prior to each treatment cycle.
·
Serum electrolytes and liver and renal function tests every two weeks prior to each treatment
cycle.
·
During treatment with AC and Docetaxel, assess line site periodically during infusion of
chemotherapy for signs and symptoms of extravasation.
·
Myelotoxicity:
Subsequent cycles should be delayed until the absolute neutrophil count is greater than
1000/microL and platelet count greater than 100,000/microL.
ANC (×109/L)
≥ 1.5
And
1.0-1.49
or
< 1
or
Platelets (×109/L)
≥ 90
70-90
< 70
Dose (both drugs)
100%
75%
delay
If there is more than a three-week delay in treatment, a dose reduction of 25 percent is
recommended.
Dose adjustment for hepatic or renal dysfunction
Doxorubicin
Renal Impairment
32


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
CrCl <50 mL/minute: No dosage adjustment necessary.
Hemodialysis: Supplemental dose is not necessary.
Hepatic Impairment
The manufacturers' labeling recommends the following adjustments:
Serum bilirubin 1.2 to 3 mg/dL: Administer 50% of dose.
Serum bilirubin 3.1 to 5 mg/dL: Administer 25% of dose.
Severe hepatic impairment (Child-Pugh class C or bilirubin >5 mg/dL): Use is
contraindicated.
ALT/AST
2-3 × ULN
>3 × ULN
-
-
Or
Bilirubin (micromole/L)
-
20-50
51-85
> 85
Dose
75%
50%
25%
Do not administer
Cyclophosphamide
Renal Impairment
Clcr ≥10 mL/minute: No dosage adjustment required.
Clcr <10 mL/minute: Administer 75% of normal dose.
Creatinine clearance (ml/min)
≥ 10
< 10
Cyclophosphamide dose
100%
75%
Hepatic Impairment
Serum bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75%
of dose.
Serum bilirubin >5 mg/mL: Avoid use.
33


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Docetaxel + Herceptin® phase:
Cycle
length:
21
days.
Total cycles: 4 cycles
Drug
Dose and route
Administration
Dilute in 250-500* mL NS
or D5W
Administer I.V. infusion
Docetaxel
100 mg/m2 IV
over
1-hour
through
nonsorbing
polyethylene
lined (non-DEHP) tubing
IV infusion in 250ml NS
over 90 minutes for first
dose (observe for 1 hour
after infusion)
IV infusion in 250 mL NS
over 1 hour on the second
8 mg/kg IV loading dose.
Observe
for
30
Herceptin®
dose (at cycle 1),
followed by 6 mg/kg
minutes post infusion
• IV infusion in 250 mL NS
at subsequent cycles      over     30     min     on     all
subsequent doses if no
adverse reactions. Observe
for 30 min post infusion
DO NOT mix with D5W,
and DO NOT infuse as an
IV push or bolus.
* use 250 mL for doses 74-185 mg, use 500 mL for doses greater than 185 mg
-
If there is a change in body weight of at least 10 percent, dose should be recalculated for all
drugs.
34


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Pretreatment considerations
•
Prophylaxis for infusion reactions:
Dexamethasone 8 mg PO bid for 3 days, starting one day prior to each Docetaxel
administration. Patient must receive minimum of 3 doses pre-treatment. Additional antiemetic
not usually required.
Trastuzumab may also cause infusion reactions. These can be severe, though most are mild;
they typically occur during or within 24 hours of the first infusion. The most common
symptoms are fever, chills, nausea, headache, abdominal pain, and dyspnea; less often are
vomiting, dizziness, rash, rhinitis, or hypotension. Most clinicians do not routinely
premedicate prior to the first trastuzumab dose.
NOTE: Trastuzumab infusion should be discontinued for anaphylaxis (bronchospasm,
hypotension, angioedema).
•
Infection prophylaxis:
filgrastim (G-CSF) 5 mcg/kg/day Days 3 to 10 reduce filgrastim treatment duration if ANC
greater than 10 or intolerable bone pain
•
Dose adjustment for baseline liver or renal dysfunction:
The available data suggest that disposition of trastuzumab is not altered based on serum
creatinine (≤2 mg/dL).
•
Cardiac issues:
Trastuzumab is associated with cardiotoxicity, and reassessment of LVEF prior to therapy
(after completion of AC) is indicated.
•
Pulmonary issues:
Trastuzumab has been associated with serious pulmonary toxicity (including acute respiratory
distress syndrome [ARDS] and interstitial pneumonitis) and should be used with caution in
patients with preexisting pulmonary disease.
35


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Monitoring parameters
·
CBC with differential and platelet count weekly during treatment with Docetaxel.
·
Serum electrolytes and liver and renal function tests prior to each treatment cycle of
Docetaxel.
·
Assess changes in neurologic function prior to each treatment cycle of Docetaxel.
·
Assess cardiac function prior to AC and prior to initiation of trastuzumab.
·
Assess cardiac function prior to trastuzumab and after 4 cycles of trastuzumab.
·
During treatment with docetaxel, assess line site periodically during infusion of chemotherapy
for signs and symptoms of extravasation.
Suggested dose alterations for toxicity
·
Myelotoxicity:
Subsequent cycles should be delayed until the absolute neutrophil count is greater than
1000/microL and platelet count greater than 100,000/microL.
If there is more than a three-week delay in treatment, a dose reduction of 25 percent is
recommended.
ANC
(×
109/L)
≥ 1.5
1.0-1.49
< 1
Platelet
109/L)
and >90
Or
70-90
Or
<70
(× Dose
(Docetaxel)
100%
75%
delay
Dose after neutropenic sepsis on
Docetaxel
75%
Delay
delay
Dose adjustment for hepatic or renal dysfunction
Docetaxel
Renal impairment
No dose modification is indicated
Hepatic impairment
Alkaline phosphatase
< 2.5 ULN
2.5-5 ULN
AST +/or ALT dose
And ≤ 1.5 ULN
100%
And 1.6-6 ULN
75%
36


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
> 5 ULN
or
>5 ULN
delay
Trastuzumab
Renal Impairment
There are no dosage adjustments provided in the manufacturer’s labeling, although
data suggest that the disposition of trastuzumab is not altered based on serum
creatinine (up to 2 mg/dL)
Hepatic Impairment
There are no dosage adjustments provided in the manufacturer’s labeling.
• Cardiotoxicity:
Asymptomatic patients-Trastuzumab continuation based on serial LVEFs
Relationship of LVEF Absolute Decrease of Absolute Decrease of Absolute Decrease of
to LLN                             less than 10 points 10-15     points     from greater than or equal to
from baseline                   baseline                           16        points        from
Within normal limits
1-5 points below LLN
Greater than or equal
to 6 points below LLN
Continue
Continue
Continue*
Continue
Hold*
Hold*
baseline
Hold*
Hold*
Hold*
·
* repeat LVEF assessment after 3-4 weeks, consider cardiac assessment
·
If criteria for continuation are met-resume trastuzumab
·
If 2 consecutive holds or a total of 3 holds occur, discontinue trastuzumab
Symptomatic patients:
·
Symptomatic patients with evidence of cardiac dysfunction should have trastuzumab
discontinued.
• Pulmonary toxicity:
Discontinue trastuzumab if patients develop ARDS, interstitial pneumonitis, or pulmonary
fibrosis.
37


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Outcomes
Primary outcomes
·
Pathologic Complete Response (pCR) defined as “the absence of residual invasive cancer on
hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled
regional lymph nodes following completion of neoadjuvant systemic therapy”1.
Secondary outcomes
·
clinical Complete Response (cCR)2: Disappearance of all target lesions. Any pathological
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm
·
clinical Partial Response (cPR)3: At least a 30% decrease in the sum of diameters of target
lesions, taking as reference the baseline sum diameters
·
clinically Stable Disease (cSD)4: Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest diameters while on study.
·
clinical Progressive Disease (cPD)5: At least 20% increase in the sum of diameters of target
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is
the smallest on study). In addition to the relative increase of 20%, the sum must also
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new
lesions is also considered progression)
·
clinical Objective Response(cOR): (cOR= cCR+ cPR)
·
breast conservation rate
Safety Outcomes
All safety measures including Left Ventricular Ejection Fraction (LVEF), Anemia,
Thrombocytopenia,
Leucopenia,
Neutropenia,
Febrile
neutropenia,
Fever
without
neutropenia, Nausea, Vomiting, Diarrhea, Stomatitis, Mucositis, Dysphagia/esophagitis,
Conjunctivitis, Allergic reactions, Edema, Asthenia, Hot flushes, Alopecia, Hand-foot
syndrome, Nail changes, Sensory neuropathy and any unexpected serious adverse events
should be assessed, recorded and reported.
1FDA: Guidance for Industry, Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage
Breast Cancer: Use as an Endpoint to Support Accelerated Approval.
2 New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1) 3
New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1) 4
New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1) 5
New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1)
38


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Immunogenicity
Samples for immunogenicity assessment (antidrug antibody [ADA] and neutralizing antibody
[nAb]) will be collected at the beginning of the first trastuzumab administration (visit 6), (visit
7), (visit 9) and 3 weeks after the surgery visit (visit 12) All patients in each treatment arm
were considered evaluable for ADA response to trastuzumab. The evaluation of both arms
immunogenicity used tiered strategies to detect, confirm, and characterize ADA responses.
Each tiered strategy included the following elements:
·
A screening assay to detect anti-trastuzumab antibodies;
·
A confirmatory assay to assess the specificity of screen positive samples by competition with
excess trastuzumab;
·
A titration assay to determine anti trastuzumab antibody titers for confirmed positive samples.
Serial dilutions of all confirmed positives were performed in order to estimate the magnitude
of a positive response. The highest dilution that produced a signal above the screening assay
cut point multiplied by the assay minimum required dilution (1:10) was deemed the end-point
titer and was expressed as a dilution factor (reciprocal of the dilution). Any potential effects
of ADAs on the efficacy (pharmacokinetics and pathologic complete response [pCR]) and
safety (administration-related reactions [ARRs]) of trastuzumab were explored using
descriptive statistics.
Termination policy
This decision is the responsibility of the scientific steering committee and should be approved by
the Food and Drug Administration of Iran, the Ethics Committee of Tehran University of Medical
Sciences and the Ethics Committee of Isfahan University of Medical Sciences.
39


Activity No.
- 3 to 0
Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Participant timelines
Visit No
0
1
2
3
4
5
6
7
8
9
10 11 12
Activity list
Timeline (weeks)
1
3
5
7
9
10 13 16 19 21 23 26
Eligibility criteria
Medical History
1
Physical Examination
X
Laboratory tests
Imaging for cancer staging
2
Informed consent
X
3
Demographic and baseline characteristics
X
4
Sonography, MRI or mammography (within last week is acceptable) X
5
Echocardiography for determination of LVEF
X
6
Randomization
7
Adverse Events evaluation/recording/reporting
8
CBC, BUN, Cr, ALT, AST, ALK, Bilirubin
X
9          Doxorubicin + Cyclophosphamide
10
Immunogenicity sampling
11
Intervention (Docetaxel + Trastuzumab)
12
Surgery, specimen collection, pathological assessment
X
X
X
X
X
X X X X X X
X
X
X
X
X
X
X X X X X
X X
X
X
X X X X
X
X
X
X
X
X
X
X
X
40


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Sample size
Using a non-inferiority margin of 0.25 for the primary end point, a sample size of 48 in each group
achieves 82% power to detect a non-inferiority margin difference between the group proportions for
the case the reference group proportion was considered as 0.60. The treatment group proportion was
assumed to be 0.35 under the null hypothesis of inferiority. The test statistic used for sample size
calculation is the one-sided Z test (unpooled) and the significance level of the test is targeted at 0.05.
Considering 0.10 losses to follow up, final sample size is 54 in each group.
Recruitment
This study has two arms and 108 subjects will participate:
1.
Group I: subjects will receive AryoTrust (produced by AryoGen Pharmed) IV infusion from
6th to 9th visit.
2.
Group II: subjects will receive Herceptin®
(the reference drug, produced by
Genentech/Roche) IV infusion from 6th to 9th visit.
Randomization
The randomization is based on blocked randomization. Patient's allocation will be carried on 1:1
allocation ratio by 27 blocks (length of each block is 4). Randomization sequence will be generated
using the random generation command in Microsoft Excel (RANDBETWEEN). Once the
randomization has been made, a unique code will be assigned to each eligible patient, what she will
be identified throughout the study by. The assigned code will be made up of four letters
(corresponding to the first two letters of the patient’s first name and the first two letters of the patient’s
family name), three digits (site code), two first letters of the drug’s generic name which is followed
by the study phase (e.g. TR3 for Trastuzumab phase 3 study) and four digits (corresponding to the
randomization number).
A code will be allocated to each package of Trastuzumab. This code consists of two English letters
and a digit and is a unique code for each patient. As a result, when the randomization number is
unique, each patient will receive a unique package of the drug which will be determined through the
randomization process. Sequence generation is one of the “Trial” CRO’s responsibilities
41


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Allocation (concealment process)
Randomization process will not be exposed to those who are conducting the study and will be
provided via telephone call for each consecutive eligible patient after the identification characteristics
of each eligible patient have been recorded by the randomization center. Since the randomization
code is unique, the next sequence is not predictable for site personnel. The allocation of randomization
code will be performed in fifth visit and after all inclusion criteria and none of exclusion criteria were
met and signing the informed consent was done.
Blinding
Both trastuzumab products are indistinguishable for patients and health care providers. So it will be
possible to make patients blind about the treatment group which they have been allocated to. In
addition to this, the outcome evaluators and data managers (data analyzer) will not be aware of
patients’ allocations.
Treatment compliance
Patient education will be done to reduce the lack of adherence to treatment in each visit. Each patient
has a reminder call before the visit. In addition to this, The nurse will administere all investigational
product only to subjects included in the study following the procedures set out in the study protocol. Subjects do
not receive home-take doses. The date of dosing will be recorded. In every monitoring session of the trial, drug
accountability data and also information relating to patients’ injections at appropriate times will be checked
by the monitor. If an injection is delayed, the reason will be checked.
The sponsor’s monitor tracked vials received and used and retained all unused vials
Treatment discontinuation
The reasons for discontinuation of the drug should be clearly stated in the CRF. Study participants
may be excluded from the study for the following reasons:
·
Patient dissatisfaction
·
Failure to adhere to treatment includes refusing to study drug requirements, refusing to
perform the procedures listed in the study protocol or using drugs that are prohibited for the
patient.
42


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Patients who do not complete all four courses of AC and all four periods of the Trastuzumab
+ Docetaxel regimen according to the schedule (Standard dose modification less than 20% or
a delay of less than 1 week is acceptable).
·
Pregnancy or suspected pregnancy
·
The occurrence of any blood, hepatic or renal complications requiring treatment
discontinuation.
·
The onset of any side effect that the investigator considers necessary for the patient to leave
the study
·
After 4 AC courses, if the LVEF level does not exceed 15% of its baseline level or below
55%, patients will be able to continue treatment with Trastuzumab + Docetaxel regimen.
·
Failure to follow the patient
43


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Data management
Data collection methods
Data collection will be electronic-based and the data will be recorded in eCRF. Adequate heed will
be given to collect accurate and valid data. Investigators are responsible for completing the eCRF in
study centers. The sites will be equipped with personal computers or tablets. Only the investigator
or the person assigned by the investigator will have access to the database for data entry. ”Trial
CRO” and sponsor is responsible to set up a regular monitoring scheme by qualified staff.
Data management
The chief investigator, principal investigators, and other personnel assigned by the investigators will
be responsible for eCRF data entry. Each investigator will be given a specific username and password.
The chief investigator and principal investigators must not disclose the data obtained from the study.
All of the Investigators are responsible for keeping the study data safe. Sending and receiving the
patients' information must be done considering safety and security procedures. “Trial” CRO and
sponsor is responsible for planning a monitoring which will be conducted by qualified personnel in
order to check the eCRF for discrepancies with the patient source documents. The monitors or
auditors are not able to change eCRF data. However, they can make queries for blatant mistakes in
data entry and the investigator is responsible for rectifying such mistakes or answering to the queries.
The history of modification in eCRF data will be recorded meticulously and can be observed by the
monitors or auditors.
44


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Data monitoring
The objectives of the data quality control are:
·
To ensure the existence of the patients and the respect of ethics (including signed patient
informed consent)
·
To detect the issues (including systematic errors) as early as possible for appropriate
measures to be taken
·
To ensure the validity of the data
To meet these objectives, quality control should be applied via the following activities:
The schedule of site quality control evaluation, performed by the monitoring team must be
explained to the investigators at the time of site initiation and agreed upon. QC will be performed in
study sites by the monitoring team who are in charge of planning for action plans to improve study
site quality.
QC of the study site will be carried out during two main monitoring visits (30% and 70% of study
completion) and several periodic monitoring visits throughout the study.
In every monitoring visit the following items will be evaluated according to a pre-prepared check
list and the quality control report will be completed.
·
eCRF forms will be assessed in terms of completeness, the quality of data entry and
accordance with source data.
·
Informed consent forms signed by the patient and the physician for all the patients who have
gone through the screening visit
·
Evaluation of key variables regarding the wrong and missing data
Statistical methods & Statistical Analyses
Analysis Populations
The primary population for evaluating efficacy will be based on the per-protocol analysis. On the
other hand, all safety analysis will be based on the safety population. Safety population is an approach
in which all patients will be analyzed according to the treatment which they actually received (as-
treated analysis).
Missing data
45


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
QC and QA criteria will be adopted to hold up missing data at minimum. Source documents will be
retained in study sites and their data will be retrieved at request. The listwise dropping will be used
if the rate of main outcome (pCR) was missed out of the final data.
Covariate Adjustment
The primary statistical analyses for outcome variables will be unadjusted.
Trial profile
All patients who provide informed consent will be accounted for in the final statistical report. A
CONSORT style flow diagram will illustrate patient progression through the trial from initial
screening for eligibility to completion of the final primary outcome assessment. Number (percentage)
by treatment group will be given for patients in the PPS population, reasons for study withdrawal,
and major protocol deviations and violations.
Patient characteristics and baseline comparisons
Data will be described informatively, according to study's objectives. Categorical variables will be
summarized by frequencies and percentages. Continuous variables will be summarized by mean and
standard deviation or quartiles.
Analysis of the primary outcome
Treatment differences in proportions will be calculated for these outcomes. A 95% two-sided
confidence interval will be constructed and the upper bound to determine non-inferiority with a 2.5%
significance level will be used.
Analysis of secondary outcomes
Frequency and proportions will be calculated for all secondary efficacy endpoints include clinical
complete response (cCR), clinical partial response (cPR), clinically stable disease (cSD), clinical
progressive disease (cPD), clinical objective response (cOR), breast conservation rate.
Safety analysis
All safety data will be analyzed descriptively by each treatment group. Adverse events will be
reported as incidence. Absolute and relative frequencies of AEs will be reported. Laboratory data for
hematology and clinical chemistry will be plotted by treatment groups during the study. The
46


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
frequency of changes with respect to normal ranges between baseline and endpoint will be tabulated.
Frequencies of clinically noteworthy values (defined in the statistical analysis plan) occurring during
the study will also be given. Shifts from normal to abnormal between baseline and endpoint will be
evaluated.
Moreover, the mean and SD of baseline vital signs will be reported. Shifts from normal to abnormal
between baseline and endpoint will be evaluated for the physical examination.
Monitoring
Site initiation visit
SIV will be performed to ensure that the facility and medications required for the trial are available
in the study site and the investigators and staff involved in the study are aware of study objectives
and GCP principles. In the initiation visit the role of the monitor, CRA, project manager, and the
auditor will be defined clearly. After the introduction of the roles and responsibilities, staff will be
taught the protocol details including timelines, sample size, eligibility criteria, protocol conformity,
deviation, and reporting. The training should be documented. The eCRF details, ICD process,
source documentation, randomization and serious adverse event reporting will be discussed and
documented as well.
Site monitoring visit
site monitoring visit will be performed to ensure the conduct of the study according to approved
protocol and GCP principles. Before the trial starts, monitoring visits will be planned for each study
site and will be confirmed by the respective PI through email or letter. The monitoring visits during
the study will be scheduled in order to visit when the planned recruitment of patients will be in its
30% and 70% progress. Sponsor is responsible for the 30% monitoring visit and “Trial” CRO is in
charge of the 70% visit. In each visit, study elements will be monitored including source data,
consent forms, trial medicinal products accountability, adverse events, protocol compliance, team
qualification, and training. The monitoring report will be prepared and reported to both PI and
sponsor preferably in an arranged meeting.
Study closeout
study closeout visit will be performed to ensure the proper documentation of the data and
return of the medicinal product and the equipments related to the trial. After the last visit of the
last participant, site close-out will be scheduled in a meeting and in the presence of the PI. The
47


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
site close-out visit will start with a brief meeting with the PI and a decision will be made
regarding the disposal of the remaining investigational medicinal product. The study
documents will be available at the trial site. A copy all safety reports will remain with the PI
and one copy will be rendered to the sponsor. There will be a brief closure meeting with the
investigator at the site and the site close-out report will be prepared after the visit.
Adverse events
Adverse Event will be considered any medical event presented by the subjects involved in the study,
which do not necessarily have a causal relation with the treatment in study. It will be reported as an
adverse effect any symptom, sign (including any abnormal laboratory determination) or temporary
disease associated to the use if the drug in study, whether they are or not etiologically related to it.
The medical conditions present before the beginning of the study will only be considered as adverse
events if they worsen during the study and cannot be attributable to the natural evolution of the
disease. It will be considered a Serious Adverse Event (SAE) if the event:
ü results in death;
ü implies a death risk;
ü requires hospitalization;
ü extends prior hospitalization;
ü results in persistent or significant incapacity;
ü produces a congenital anomaly or malformation, or
ü requires medical or surgical intervention to avoid a permanent damage.
AE classification based on its severity:
AE will be classified according to its severity in relation to the guidelines established in the
Common Terminology Criteria for Adverse Events (CTCAE, version 5.0, published on November
27, 2017). Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with
unique clinical descriptions of severity for each AE based on this general guideline:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate
instrumental ADL*.
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care ADL**.
48


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
* A Semi-colon indicates ‘or’ within the description of the grade.
* Activities of Daily Living (ADL)
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone,
managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking
medications, and not bedridden.
AE classification based on its relation with the treatment in study:
In order to establish the relation between the AE or the DAR and the treatment in study, the following
definitions will be considered:
ü Certain: a clinical event including alterations in the laboratory tests manifesting with a
reasonable temporal sequence related to the administration of the drug and cannot be
explained by the current disease, or by other drugs or substances. The response to the drug
suppression (released; dechallenge) should be clinically plausible. The event should be final
from a pharmacological point of view, using, if necessary, a conclusive re-exposure
procedure.
ü Probable/Likely: a clinical event, including alterations in the laboratory tests manifesting
with a reasonable temporal sequence related to the administration of the drug, which is
unlikely to be attributed to the current disease, or other drugs and substances, and which when
releasing the drug (dechallenge) a clinically reasonable response appears. No information on
re-exposure (rechallenge) is required to assign this definition.
ü Possible: a clinical event, including alteration in the laboratory tests manifesting with a
reasonable temporal sequence related to the administration of the drug, but can also be
explained by the concurrent disease, or by other drugs and substances. The information
regarding the release of the drug may be missing or unclear.
ü Unlikely: a clinical event, including alterations in the laboratory tests manifesting with an
improbable temporal sequence related to the administration of the drug, and can be explained
in a more plausible way by the concurrent disease, or by other drugs or substances.
ü Conditional/Unclassified: a clinical event, including alterations in the laboratory tests,
notified as an adverse reaction, of which it is essential to obtain more data in order to make a
proper evaluation, or the additional data are under examination.
49


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
ü Non evaluable/Unclassifiable: a notification that suggests an adverse reaction, but cannot be
judged because the information is insufficient or contradictory and cannot be verified or
completed in its data.
50


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
WHO-UMC Causality Categories
Causality term
Assessment criteria*
Certain
• Event or laboratory test abnormality, with plausible time
relationship to drug intake
• Cannot be explained by disease or other drugs
•
Response
to
withdrawal
plausible
(pharmacologically,
pathologically)
• Event definitive pharmacologically or phenomenological (i.e. an
objective and specific medical disorder or a recognized
pharmacological phenomenon)
• Rechallenge satisfactory, if necessary
Probable/ Likely
• Event or laboratory test abnormality, with reasonable time
relationship to drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required
Possible
• Event or laboratory test abnormality, with reasonable time
Unlikely
Conditional/ Unclassified
Unassessable/ Unclassifiable
relationship to drug intake
• Could also be explained by disease or other drugs
• Information on drug withdrawal may be lacking or unclear
• Event or laboratory test abnormality, with a time to drug intake
that makes a relationship improbable (but not impossible)
• Disease or other drugs provide plausible explanations
• Event or laboratory test abnormality
• More data for proper assessment needed, or
• Additional data under examination
• Report suggesting an adverse reaction
• Cannot be judged because information is insufficient or
contradictory
• Data cannot be supplemented or verified
*All points should be reasonably complied with
51


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
AEs Recording
All the undesirable and unexpected AE that follow the administration of the drug will be accurately
recorded in the medical record of the patient and in the corresponding section of the CRF. The event
description should be recorded, as well as the temporal sequence regarding to the administration of
the drug, its duration, the procedures performed for the diagnosis if appropriate, the results of the
repeated exposure and the qualification made by the Researcher as regards its severity and its relation
to the administered drug.
AE Reporting Responsibilities
Principle investigator responsibilities:
- The investigator must report any SAE/R, which results in death or is life-threatening, to the sponsor
and IEC within the maximum of 24 hours by fax, email or etc.
- The investigator must immediately and not later than seven calendar days report those SAE/Rs
which are not life-threatening or do not result in death but may put subjects in danger or require
intervention (medical or surgical) to prevent life-threatening outcomes. These SAE/R need to be
reported to the sponsor and IEC as soon as possible but not later than seven calendar days of having
taken notice of the SAE/R.
- The investigator should report to the sponsor and IEC all predictable adverse events of
investigational medicinal product including for example injection site reactions, in case of patient
withdrawal from study or adverse event with a greater frequency than expected.
Sponsor responsibilities:
- SUSARs which result in death, or are life-threatening; need to be reported by the sponsor as soon
as possible but not later than seven calendar days, to IEC and IFDA, using CIOMS form (Suspect
Adverse Reaction Report Form). A follow-up report is to be submitted within 15 calendar days.
- The sponsor must report SUSARs which are not life-threatening or do not result in death, but may
put subjects in danger or require intervention (medical or surgical) to prevent life-threatening
outcomes, as soon as possible but not later than 15 calendar days, to IEC and IFDA, using CIOMS
form (Suspect Adverse Reaction Report Form). The follow-up report considering the relation between
the investigational medicinal product and an adverse event is to be submitted as soon as possible.
52


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
- All the reports and follow-up results of SAE/R need to be reported to IFDA within maximum 15
calendar days after sponsor awareness of SAE/R.
- If the severity or frequency of predictable adverse events, for example, injection site reactions,
results in patient withdrawal from the study, or in case of higher incidence than expected, the sponsor
must report it to IFDA within maximum 15 calendar days.
- The sponsor must report all the information regarding the SAE and serious ADR that are reported
during the course of the study and recommendations of investigators related to increasing of study
risk for subjects to Food and Drug Administration of Iran within 15 calendar days.
- The sponsor must report to IFDA all recommendations from investigators about possible increased
risk of adverse events or participants, within maximum 15 calendar days.
Follow-up
·
The Investigator should take all appropriate measures to ensure the safety of the patients,
notably he/she should follow up the outcome of any Adverse Events (clinical signs,
laboratory values or other, etc.) until the return to normal or consolidation of the patient's
condition;
·
In case of any Serious Adverse Event, the patient must be followed up until clinical
recovery is complete and laboratory results have returned to normal, or until progression
has been stabilized. This may imply that follow-up will continue after the patient has left
the study and that additional investigations may be requested by the Monitoring Team
·
In case of any Serious Adverse Event brought to the attention of the Investigator at any
time after cessation of Investigational Product and considered by him/her to be caused by
the Investigational Product with a reasonable possibility, this should be reported to the
Monitoring Team.
Withdrawal of patients:
Participants may be withdrawn from the study for any of the following reasons:
·
Withdrawal of consent by the patient
53


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
Noncompliance, including refusal of study medical requirements, refusal of procedures as
stated in the study protocol, or use of prohibited medications
·
In the case of suspected pregnancy, a pregnancy test for Beta hCG will be requested, and if
the test is positive, the patient will be excluded from the study
·
The occurrence of an undesirable event that causes the investigator to consider the patient's
exclusion from the study
·
Not possible to follow the patient's condition (Loss to follow-up)
The reason(s) for withdrawal should be stated clearly in the eCRF.
Patient Admission Criteria
Since all injections during the study are performed under the supervision of the nurse/nurses who
have been trained, we will ensure that patients who are present at all injection days and whose
injections are approved in the CRF, has an admission to the treatment.
Auditing
Regular auditing will be carried out to ensure strict adherence to the study protocol. the auditor will
be determined and introduced to regulatory authorities by the sponsor.
The Audit reports will be prepared for the sponsor and the results will be reported to chief investigator
as well.
Auditors will be responsible for:
-
Regular visits to the study centers to inspect the sufficiency of existing structures and
processes
-
Identifying training needs of study site staff
-
Making necessary arrangements to set up training courses
-
Monitoring adherence to all procedures foreseen in the study protocol
-
Preparing written report from each visit
-
Certifying the quality and reliability of the monitoring visits during the study
-
Certifying the quality and reliability of the study conduction by investigators and staff
-
Certifying the quality and veracity of the data to be reported to legal bodies
Ethics and dissemination
Research ethics approval
·
Ethics committee approval is mandatory for start of this study
·
No patient will be recruited to this study without a signed informed consent.
·
Patients will be informed that they can leave the study anytime they desire with no need for
any explanation.
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Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
·
To ensure the confidentiality in case a form is lost, the name and surname of the patients will
not appear on any forms.
·
Adverse effect report forms will be evaluated after every visit. The research team is
responsible for dealing with the immediate aftermath of any adverse event regardless of the
event being directly related to the medication that is being studied.
·
Before initiation of the trial, it will be reviewed with IFDA. The protocol, CRF, information
for patients and informed consent form will be submitted to the ethics committee of Tehran
university of medical sciences and Isfahan University of medical sciences, for review and
approval according to international regulatory guidelines.
Consent
The investigator will thoroughly explain the purpose of the study to the patient. The patient will be
provided with an information sheet and will be given sufficient time and opportunity to inquire
about the details of the study and to decide whether or not to participate in the study, e.g. to give
permission to use their data for investigative purposes, knowing their information will remain
confidential. The informed consent form should be signed and dated by the patient and the person
with whom they discuss the information regarding the consent form. The investigator will explain
that the patient is completely free to refuse to give permission for his/her data to be used or to
withdraw from the trial at any time and for any reason. Similarly, the investigator and/or sponsor
will be free to withdraw the patient at any time for administrative reasons. Any other requirements
necessary for the protection of the human rights of the patient will also be explained, according to
GCP guidelines, declaration of Helsinki and local regulation for clinical trials.
Confidentiality
All study-related information will be stored securely at the study site. To ensure confidentiality,
randomization codes will be used on all the reports, gathered data, information regarding the study
progress and administrative forms. All records that contain names or other personal identifiers, such
as subject identification form and informed consent forms, will be stored separately from study
records. All local databases will be secured with password-protected access systems. Forms, lists,
logbooks, appointment books, and any other lists which link participant’s randomization code to
other identifying information will be stored in a separate, locked file in an area with limited access.
All laboratory and other test results will be kept strictly confidential. All counseling and blood
sampling will be conducted in private rooms, and study staff will be required to preserve the
confidentiality of all participants.
55


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Amendment
Any modifications to the protocol which may impact on the conduct of the study, the potential
benefit of the patient or may affect patient safety, including changes to study objectives, study
design, patient population, sample size, study procedures, or significant administrative aspects will
require a formal amendment to the protocol. Such amendment will be agreed upon by chief
Investigator and AryoGen Pharmed company and should be approved by IFDA and the Ethics
Committee prior to implementation. Administrative changes to the protocol are minor corrections
and/or clarifications that have no effect on the way the study is to be conducted. These
administrative changes will be agreed upon by chief Investigator and AryoGen Pharmed company
and will be documented in a memorandum.
Declaration of interests
The presence or absence of any kind of financial and or nonfinancial relationship between the
sponsor and chief investigator and principal investigators (with the exemption of this study
contract) should be officially declared to IFDA as a written conflict of interest letter.
Funding organization
All expenses of this study including patients’ treatment and medicines, study conduct and performing
and research related injuries compensation will be provided by AryoGen Pharmed co.
Access to data
Chief investigator, sponsor and CRO Trial will have access to full dataset. In addition, ethic
committee and regulatory organizations can access to data, if needed.
Ancillary and post-trial care
Ancillary care (related to trial) will be provided by principal investigator under sponsor support for
participants.
Dissemination policy
No other publication is allowed before the primary publication. Any subsequent presentation or
publication ((including the sub-studies) by a study team member must be approved by the steering
committee and chief Investigator and the primary publication should be cited. The final decision to
publish any manuscript/ abstract/ presentation will be made by chief Investigator and the sponsor
after prior notice to the “steering committee for their review and comments.
56


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Appendix 1: Informed consent materials
Informed Consent Form
Study title: A PHASE III, RANDOMIZED, TWO ARMED PATIENT-OUTCOME ASSESSOR-DATA
ANALYZER BLINDED, PARALLEL ACTIVE CONTROLLED NON-INFERIORITY CLINICAL TRIAL
STUDY OF ARYOTRUST (ARYOGEN PHARMED TRASTUZUMAB) EFFICACY AND SAFETY IN
HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2–POSITIVE BREAST CANCER IN
COMPARISON TO HERCEPTIN® (GENENTECH/ROCHE) CONTROL.
Mr./Mrs. ………………………………
We invite you to participate in the above-mentioned clinical study. Information about this research is provided
in this sheet, and you are free to join this research or not.
You do not have to make an immediate decision and you are given a deadline to announce your opinion after
consulting the research team and anyone you desire, about participation and your involvement in this research is
entirely voluntarily. Before signing this consent, make sure that you understand all the information in this form
and
all
of
your
questions
are
answered.
Researcher: Dr. Seyed Reza Safaie Nodehi
1- I know that purposes of this research are: the evaluation of the efficacy and safety of trastuzumab of
AryoGen Pharmed company in comparison with trastuzumab of Genentech/Roche company.
2- I know that my participation in this study is completely voluntary and I am not obligated to participate
in this research. I was assured that if I were not willing to participate in this research, I would not be
deprived of routine diagnostic and therapeutic care and my therapeutic relationship with the health
center and my physician will not get affected.
3- I know that even after agreeing to participate in the research, I can resign freely at any time after
informing the researcher, without giving any reason and my withdrawal from the research will not
deprive me of the usual treatment services.
4- This is how my participation is in this study:
After the diagnosis of doctors about the need for using trastuzumab to treat my illness, and after
agreeing to participate in the study, I will randomly be assigned to one of the two groups receiving
trastuzumab of an Iranian company AryoGen Pharmed or trastuzumab of Genentech/Roche company.
57


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
I know that the other treatments and prescribed medications are similar between the two groups, and
the randomization between the two groups is completely accidental and no one predetermines it.
During the study, I must receive the prescribed medication and refer to the doctor's instructions for the
tests and related visits on a regular basis. I know that the procedures in each visit are as follows: At the
first session (visit 0), my health status is evaluated by the physician, and previous laboratory data and
imaging results are monitored and recorded. Next, a blood sample of me is taken to assess the physical
condition and health indicators. Then an echocardiographic test and a breast sonography will be done. If
I have done a sonography, MRI or mammography within the last week, there is no need to do it again.
If the results of the tests, imaging and evaluation of the physician were not inconsistent with my
presence in the study, I will be included in the study and will receive the first dose of cyclophosphamide
and adriamycin. My participation in the study includes two stages of treatment, in the first stage of 4
cycles (including visits one, two, three, and four), I go to the health center every two weeks and receive
cyclophosphamide and adriamycin as treatment, except for the first session (visit 1), which is in the
same time as I present the results of my previous laboratory test. In the next three sessions of this stage,
a blood sample will be taken from me every time to evaluate my health and my ability to continue the
study. At the end of these four sessions, an echocardiography and sonography will be done for me
again, these results and the result of blood tests will be presented to my doctor for review and record in
the next visit (visit 5). In visit 6, the second stage of treatment, which consists of 4 cycles, every 3
weeks, starts for me. In each session, I will receive docetaxel (100 mg per square meter of body surface
area) and one of the two AryoTrust or Herceptin® (the first course is 8 mg per kilogram, and in the next
3 courses, 6 mg per kilogram). I know that AryoTrust is the trastuzumab drug which is produced by
AryoGen Pharmed company in Iran, and the Herceptin® drug is the brand trastuzumab drug which is
produced by Genentech/Roche Company. I will receive AryoTrust, If I am in the first group, and I will
receive Herceptin® and if I am in the second group. I know that it's totally coincidental that I am
selected for which group and I will not be aware of my group until the end of the study. My doctor
explained to me that the process of choosing a therapeutic group unknowingly is completely scientific
and is because of evaluating the drugs properly. My doctor also assured me that regardless of in which
group of treatments I am, all the necessary procedures for appropriate treatment will be done for me,
and wherever participation in this study is considered to be dangerous for my health, I will be excluded
from the study and I will receive the appropriate treatment according to my health condition. I know
that all medications in the two treatment groups are similar and the difference between the two groups is
due to the difference in the company that makes the drug trastuzumab. At each of the treatment
sessions, my health status is evaluated by the medical staff of the study, and in order to fully control my
health conditions, in addition to the blood tests performed in each session (8 times total), in the first
visit, the 5th visit and before the surgery (9th visit), echocardiography of the heart (3 times total)
58


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
and sonography (3 times total) will be done for me. The total number of visits is 10 sessions and the
duration of the treatment is 21 or 23 weeks. In every visit, questions about my health conditions from
the previous visit until now, are asked. At the end of the course of drug therapy, regardless of the
treatment group, I will be referred for surgery. I know that after the end of the study (if I need to
continue treatment), given the fact that the trastuzumab of both types (Iranian and brand) is available in
the pharmaceutical market of the country, and given the insurance coverage of this drug, I can
provide this drug from reputable pharmacies. I know that according to the principles of conducting
clinical trials of AryoGen Pharmed company, the cost of trastuzumab will be paid up to the end of the
study, and after the completion of the study, it will be my responsibility, like other patients.
5- The possible benefits of my participation in this research are as follows:
I receive free treatment for 23 weeks. Also, in each of the study groups, during this study, I will be
examined and evaluated by the physicians with greater precision and sensitivity regarding my condition
and the side effects of drugs. Also, the effects of my treatment will be carefully evaluated. After
surgery, I will be informed of the outcome of my treatment, and the treatment outcomes will fully be
explained to me, and my questions about my health status and the continuation of treatment will
completely be answered. The contact number of the researcher or his authorized representative is
available to me so that if I had a question during the study or if a health problem occurred to me, I can
have immediate access to him.
6- The possible harms and adverse events of my participation in this research are as follows:
I have been informed that previous studies on AryoTrust have shown similar side effects as Herceptin®,
and there is no evidence that AryoTrust has more adverse effects than Herceptin®. I know that receiving
trastuzumab (AryoTrust or Herceptin®) in the first cycle may cause fever and chills and flu-like
symptoms and there is only a small chance that these symptoms are severe and associated with nausea
and skin rashes.
These complications will usually get milder in subsequent visits. Less likely, trastuzumab may cause
cardiomyopathy and reduce heart's ability to transfer blood to organs, although in most cases it is not
seen, or it is so insignificant that it does not cause a symptom, or only it causes symptoms such as
transient shortness of breath, but in some cases it may also lead to congestive heart failure or cerebral
stroke. During the study and after each session I receive medical treatment, health examinations and
diagnostic laboratory tests will be done for me, as well as three times echocardiography in the first,
fourth (the end of the first stage treatment) and the ninth visit (The end of the second stage of treatment
and before surgery) will be done for me, and if the continuation of the study is dangerous for my health,
I will be excluded from this treatment. In the case of mild flu-like syndromes, I will receive treatments
for reducing the symptoms. If these complications cause disability for me, with the doctor's diagnosis,
the interval between treatment cycles may get longer, or even the treatment can be discontinued for a
59


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
while. In the case of cardiac complications, temporary or permanent cessation of treatment, my heart
status will be consulted with the help of a cardiologist. In the case of any complication that occurs for
me in this study, the investigator will report them to the responsible authorities in accordance with the
relevant laws. Also, me or my family should inform my doctor of any adverse event occurrence during
the study (including events leading to hospitalization and death) as soon as possible. This undesirable
event may not be due to the drug being studied, but in any case, I should inform my doctor as soon as
possible. I know that if any complication occurs for me in this study, the investigator will report them
to the responsible authorities in accordance with the relevant laws, and I will regularly be monitored by
the treatment team for the incidence of these complications.
7- In the case of unwillingness to participate in the research, the usual services (therapeutic, diagnostic,
etc.) for me will be provided which the benefits and harms are as follows:
In case of unwillingness to participate in the research, the usual services (therapeutic, diagnostic, etc.),
for me will be provided which is the same treatment described in the second group of study (the
Herceptin® group, trastuzumab of Roche company). A routine visit will be performed by the doctor
and the usual care will be provided. My drugs will be prescribed to me by my physician diagnosis. The
cost of laboratory testing and drugs will be paid by myself according to my insurance coverage, and I
will be referred for surgery at the end of the treatment cycles. Also, because the treatment is routinely
similar to that used in the study, the complications and drug adverse events are similar to the research.
8- I know that the researchers of this study will keep all of my information confidential and are only
allowed to publish the overall and collective results of this research without mentioning my name and
my profile.
9- I know that the Ethics Committee in my study is allowed to have access to my information to monitor
my rights.
10- I know that I should not pay any of the costs below:
1-Trastuzumab drug cost (Iranian or brand), 2-Costs related to diminishing the complications related
to the study drug, 3-Costs of diagnostic procedures related to the company in the study and related to
the side effects of the drug studied, including laboratory tests, imaging, echocardiography and
pathology, 4-The cost of the patient's share of other medications (after deducting the share of insurance)
during the study in 26 weeks (about 6 months). In the case of no need for more diagnostic procedures,
the number of diagnostic procedures is as follows: Total blood tests 8 times, Echocardiography (total
3 times) and Sonography (total 3 times).
11- I know that if during and after the research any physical and mental problems arose because of my
participation in this research, it will be the responsibility of the researcher to treat the complications
and the related damages.
60


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
I know that if I become hospitalized due to participation in this study, or a disability or any other
unpleasant consequence occurs to me in this study, that if I did not attend this study, it would not have
happened for me, the relevant compensation is AryoGen Pharmed company responsibility and I am
insured by the AryoGen Pharmed company concerning the adverse events occurring for me because of
my participation in the study.
12- Mrs. Elham Farhang has been introduced to me for answering my questions, and I was told that during
the study any time a health problem occurred to me or if I had a question regarding participation in this
research, I can share with her and ask for guidance. Her following address and phone number were
given to me:
Address: Fifth floor, No 74, Near faculty of Nutrition, Hafezi Street, Shahrak Gharb, Tehran, Iran.
Telephone: 00982188078848
Cell phone: 00989129592162
13- I know that if I have a problem or objection to executors of the research or the research process, I can
contact the Ethics Committee of the Tehran University of Medical Sciences at the address of: Room
605, 6th Floor, Central headquarters of Tehran University of Medical Sciences, Qods Street, Keshavarz
Blvd., Tehran, Iran. Telephone: 009821-81633626 or Vice-Chancellor for Research in Isfahan
Province with the telephone number of 031-36682407, and present my problem either verbally or in
writing.
This form of information and informed consent is provided in two copies and will be signed by the researcher
and me. A signed copy will be given to me and a signed copy will be given to the researcher.
I have read and understood the explanations mentioned above, and based on that, I declare my
informed consent to participate in this research.
Participant signature:
I consider myself bound to comply with the obligations of the executor in the above provisions,
and I undertake to work on the rights and safety of people participating in this research.
Researcher signature:
61


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
Appendix 2: breast cancer staging
62


Clinical Trial Protocol
AryoTrust vs. Herceptin®: a non-inferiority study
References
1.
Ma, J. and A. Jemal, Breast cancer statistics, in Breast Cancer Metastasis and Drug Resistance. 2013,
Springer. p. 1-18.
2.
Bissell, M.J., et al., Tissue structure, nuclear organization, and gene expression in normal and
malignant breast. Cancer Research, 1999. 59(7 Supplement): p. 1757s-1764s.
3.
Rubin, I. and Y. Yarden, The basic biology of HER2. Annals of Oncology, 2001. 12(suppl 1): p. S3-
S8.
4.
Buzdar, A.U., et al., Significantly higher pathologic complete remission rate after neoadjuvant therapy
with trastuzumab , paclitaxel , and Adryamicin chemotherapy: results of a randomized trial in human
epidermal growth factor receptor 2–positive operable breast cancer. Journal of clinical oncology, 2005.
23(16): p. 3676-3685.
5.
Bilous, M., et al., Current perspectives on HER2 testing: a review of national testing guidelines.
Modern pathology, 2003. 16(2): p. 173-182.
6.
Shepard, H.M., et al., Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene
to the clinic. Journal of clinical immunology, 1991. 11(3): p. 117-127.
7.
Slamon, D.J., et al., Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic
breast cancer that overexpresses HER2. New England Journal of Medicine, 2001. 344(11): p. 783-
792.
8.
Chang, J.C., HER2 inhibition: from discovery to clinical practice. Clinical Cancer Research, 2007.
13(1): p. 1-3.
9.
Vogel, C.L., et al., Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-
overexpressing metastatic breast cancer. Journal of Clinical Oncology, 2002. 20(3): p. 719-726.
10.
Extra, J., et al. First-line trastuzumab (Herceptin (R) plus docetaxel versus docetaxel alone in women
with HER2-positive metastatic breast cancer (MBC): results from a randomised phase II trial
(M77001). in Breast Cancer Research and Treatment. 2003: KLUWER ACADEMIC PUBL VAN
GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS.
11.
Braga, S., et al., Use of trastuzumab for the treatment of early stage breast cancer. 2006.
12.
Chrubasik S, K.O.B.A.C.C.K.F. Potential economic impact of using a proprietary willow bark extract
in outpatient treatment of low back pain: an open non-randomized study.
2001 Jul//];
4:[241].Availablefrom:http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=cctr&NEW
S=N&AN=CN-00373602.
63

SAP_001.pdf: 
Statistical Analysis Plan 
Final Version 1.0 
Page 1 of 5 
23 Dec 2017 
AryoGen Pharmed 
Confidential and Proprietary 
 
 
 
 
  
 
STATISTICAL ANALYSIS PLAN 
 
A Phase III, randomized, two-armed, double blinded, parallel, active controlled, non-Inferiority clinical 
trial study of AryoTrust (AryoGen Pharmed Trastuzumab) efficacy and safety in Human Epidermal Growth 
Factor Receptor 2–Positive breast cancer in comparison to Herceptin® (Genentech/Roche) control.  
 
 
 
Name of Test Drug: 
AryoTrust 
Phase: 
III 
Methodology: 
Randomized, two-armed, double-blind (patient and assessor 
blinded), parallel, active controlled, non-inferiority clinical 
trial 
Sponsor: 
AryoGen Pharmed 
No.140. Corner of Tajbakhsh Street 
24th Kilometer of Tehran-Karaj Makhsous Road, Alborz, 
Iran. 
Sponsor Representatives: 
Dr. Araz Sabzevari 
Orchid Pharmed company CEO 
NCT Number: 
NCT03425656 
Statistical Analysis Plan Date: 
23 Dec 2017 
Statistical Analysis Plan Version: 
Version 1.0 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Final Version 1.0 
Page 2 of 5 
23 Dec 2017 
AryoGen Pharmed 
Confidential and Proprietary 
 
 
 
 
 
1. 
Section 1: Administrative information .........................................................................................................3 
1.1. 
Title and Trial registration ....................................................................................................................3 
1.1.1. 
Descriptive title that matches the protocol, with ‘Statistical analysis plan’ either as a fore 
runner or sub title, and trial acronym ............................................................................................................3 
1.1.2. 
Trial registration number ..............................................................................................................3 
1.2. 
SAP Version (SAP version number with dates) ...................................................................................3 
2. 
Section 2: Introduction .................................................................................................................................3 
2.1. 
Objectives .............................................................................................................................................3 
3. 
Section 3: Trial Methods ..............................................................................................................................3 
3.1. 
Trial design – description of trial design ..............................................................................................3 
3.2. 
Randomization ......................................................................................................................................4 
3.3. 
Sample size ...........................................................................................................................................4 
4. 
Section 4: Statistical Principles ....................................................................................................................4 
4.1. 
Protocol Deviations ..............................................................................................................................4 
4.1.1. 
Description of which protocol deviations will be summarized .....................................................4 
4.2. 
Analysis populations ............................................................................................................................4 
5. 
Section 5: Trial Population ...........................................................................................................................5 
5.1. 
Recruitment (Information to be included in the CONSORT flow diagram) ........................................5 
5.1.1. 
Details of how baseline characteristics will be descriptively summarized ...................................5 
6. 
Section 6: Analysis .......................................................................................................................................5 
6.1. 
Analysis methods ..................................................................................................................................5 
6.1.1. 
What analysis method will be used, and how the treatment effects will be presented .................5 
6.1.2. 
List and describe each primary and secondary outcome including details of: methods used for 
assumptions to be checked for statistical methods .......................................................................................5 
6.2. 
Statistical Software ...............................................................................................................................5 


Statistical Analysis Plan 
Final Version 1.0 
Page 3 of 5 
23 Dec 2017 
AryoGen Pharmed 
Confidential and Proprietary 
 
 
 
 
1. 
Section 1: Administrative information 
1.1. 
Title and Trial registration 
1.1.1. Descriptive title that matches the protocol, with ‘Statistical analysis plan’ either as a 
fore runner or sub title, and trial acronym 
Statistical analysis plan for AryoTrust study (Phase III): A Phase III, randomized, two-armed, double-blind 
(patient and assessor blinded), parallel, active controlled, non-inferiority clinical trial to evaluate the efficacy and 
safety of AryoTrust (AryoGen Pharmed Trastuzumab) in Human Epidermal Growth Factor Receptor 2–Positive 
breast cancer in comparison to Herceptin® (Genentech/Roche) control. 
1.1.2. Trial registration number 
    IRCT201606226135N7 
1.2. 
SAP Version (SAP version number with dates) 
Version: 1.0, Date: 23 Dec 2017 
 
2. 
Section 2: Introduction 
2.1. 
Objectives 
To verify the non-inferiority of AryoTrust (AryoGen Pharmed Trastuzumab) vs. Herceptin® (Genentech/Roche 
trastuzumab), both given concomitantly with docetaxel after Adriamycin plus cyclophosphamide in the 
neoadjuvant setting according to pathological clinical response and immunogenicity assay in patients with 
Human Epidermal Growth Factor Receptor 2–Positive breast cancer. 
Primary objective(s): 
 
The primary objective of this study is to verify the non-inferiority of AryoTrust vs. Herceptin®, given 
concomitantly with docetaxel after Adriamycin plus cyclophosphamide in the neoadjuvant setting according to 
pathological complete response (pCR) rate in patients with Human Epidermal Growth Factor Receptor 2–
Positive breast cancer. 
Secondary objective(s): 
 
The secondary purposes of this study are to establish the overall response rate (ORR), breast-conserving surgery 
(BCS) and assess safety of AryoTrust (AryoGen Pharmed Trastuzumab) group in comparison with Trastuzumab 
(Herceptin®) group. 
 
3. 
Section 3: Trial Methods 
3.1. 
Trial design – description of trial design 
This is a, Phase III, multi-center, randomized, two-armed, double blind (patient and assessor blinded), 
parallel, active controlled, non -  inferiority clinical trial with a 1:1 allocation. 


Statistical Analysis Plan 
Final Version 1.0 
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AryoGen Pharmed 
Confidential and Proprietary 
 
 
 
 
3.2. 
Randomization 
The randomization is based on blocked randomization. Patient's allocation will be carried on 1:1 allocation ratio 
by 27 blocks (length of each block is 4). Randomization sequence will be generated using the random generation 
command in Microsoft Excel (RANDBETWEEN). Once the randomization has been made, a unique code will 
be assigned to each eligible patient, what she will be identified throughout the study by. The assigned code will 
be made up of four letters (corresponding to the first two letters of the patient’s first name and the first two 
letters of the patient’s family name), three digits (site code), two first letters of the drug’s generic name which 
is followed by the study phase (e.g. TR3 for Trastuzumab phase 3 study) and four digits (corresponding to the 
randomization number). 
3.3. 
Sample size 
Using a non-inferiority margin of 0.25 for the primary end point, a sample size of 48 in each group achieves 
82% power to detect a non-inferiority margin difference between the group proportions for the case the reference 
group proportion was considered as 0.60. The treatment group proportion was assumed to be 0.35 under the null 
hypothesis of inferiority. The test statistic used for sample size calculation is the one-sided Z test (unpooled) 
and the significance level of the test is targeted at 0.05. Considering 0.10 losses to follow up, final sample size 
is 54 in each group.  
 
4. 
Section 4: Statistical Principles 
4.1. 
Protocol Deviations 
4.1.1. Description of which protocol deviations will be summarized 
The number (and percentage) of patients with major and minor protocol deviations will be summarized by 
treatment group with details of type of deviation provided. No formal statistical testing will be undertaken. 
4.2. 
Analysis populations 
All tests of the effect of treatment on the primary outcome will be conducted on a per-protocol basis. The intent-
to-treat (ITT) patient population includes all patients who signed the informed consent form and underwent 
random assignment. The per-protocol set (PPS) population will be defined as the ITT population excluding 
patients who violated protocols to a considerable extent, including major protocol inclusion/exclusion criteria 
or treatment protocols. Slight deviations may be acceptable. The primary outcome was first evaluated in the PP 
population and then in the ITT population (with and without imputation) as a sensitivity analysis. In the 
imputation for pCR, patients with no available data were considered as nonresponders. The safety will be 
assessed in the as-treated population, which includes all patients who received at least one dose of the assigned 
trial treatment. 
 
 
 


Statistical Analysis Plan 
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5. 
Section 5: Trial Population 
5.1. 
Recruitment (Information to be included in the CONSORT flow diagram) 
In the “CONSORT” diagram, the number of people screened, eligible, randomized and receiving their 
allocated treatment will be provided. 
5.1.1. Details of how baseline characteristics will be descriptively summarized 
Categorical data will be summarized by numbers and percentages. Continuous data will be summarized by mean 
and SD. Tests of statistical significance will not be reported for the baseline characteristics. 
 
6. 
Section 6: Analysis 
6.1. 
Analysis methods 
6.1.1. What analysis method will be used, and how the treatment effects will be presented 
For the primary endpoint, comparison of pathologic complete response (pCR) rate, treatment differences in 
proportions will be calculated and p-value will be reported based on proportion test. A 95% two-sided 
confidence interval will be constructed and the upper bound to determine non-inferiority with a 2.5% 
significance level will be used.  
For the secondary endpoints objective response rate (ORR) and breast conservation rate (BCS), frequency and 
proportions, and p-value will be reported based on proportion test. 
Adverse events will be reported as incidence rate. Safety will assess on the basis of reports of adverse events, 
laboratory test results, and vital sign measurements. Moreover, the causality assessment of ADR will be reported 
in two groups. 
6.1.2. List and describe each primary and secondary outcome including details of: methods 
used for assumptions to be checked for statistical methods 
   There is no assumption to check based on the proportion test. 
6.2. 
Statistical Software 
The analysis will be carried out using Stata version 14.