Protocol summary
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Study aim
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To verify the non-inferior efficacy of Denosumab (AryoGen) compared with Xgeva® (produced by Amgen) by time to first on-study Skeletal Related Event (SRE) in breast cancer patients with bone metastasis
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Design
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A phase III, Active-controlled, Parallel, double-blind, randomized clinical trial with 272 patients.
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Settings and conduct
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A phase III, randomized, two armed, double-blinded, parallel, active-controlled and multicenter clinical trial in Iran
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Participants/Inclusion and exclusion criteria
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Inclusion: Female patients 18-75 years old, breast adenocarcinoma, Radiographic evidence of at least one bone metastasis, Eastern Cooperative Oncology Group (ECOG) ≤2, Adequate organ function. Exclusion: Planned radiation therapy or bone surgery, Life expectancy <6 months, brain and liver metastasis, Prior administration of Denosumab or IV bisphosphonates, Non-healed dental/oral problem or condition which requires oral surgery, osteonecrosis/osteomyelitis of the jaw, Disorders associated with abnormal bone metabolism, Prior malignancy (other than breast cancer, basal cell carcinoma, or in situ cervical cancer) within 3 years prior to randomization, HIV, HBV, HCV, Receiving any investigational product or device in other clinical trials 30 days prior to the study, Allergy to any of the products, Received calcitonin, Parathyroid hormone related peptides, mithramycin, strontium ranelate, or gallium nitrate within 8 weeks prior to randomization, Any psychiatric disorder, organ disfunction or systemic disease, Pregnancy or breast feeding.
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Intervention groups
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Control group: Denosumab (Xgeva® produced by Amgen Co),
Intervention group: Denosumab (َproduced by AryoGen pharmed)
(Subcutaneous, 120 mg once every 4 weeks for 80 weeks)
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Main outcome variables
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Assessing the time to first on-study SRE in breast cancer patients with bone metastasis.
General information
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Reason for update
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According to the comment of the respected referee, the sections related to the exclusion & inclusion criteria were edited.
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Acronym
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IRCT registration information
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IRCT registration number:
IRCT20150303021315N21
Registration date:
2021-01-06, 1399/10/17
Registration timing:
prospective
Last update:
2023-12-05, 1402/09/14
Update count:
1
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Registration date
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2021-01-06, 1399/10/17
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Registrant information
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Recruitment status
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Recruitment complete
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Funding source
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Expected recruitment start date
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2021-02-03, 1399/11/15
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Expected recruitment end date
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2023-01-13, 1401/10/23
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Actual recruitment start date
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empty
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Actual recruitment end date
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empty
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Trial completion date
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empty
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Scientific title
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A Phase III, randomized, two armed, double-blind, parallel, active controlled, non-inferiority clinical trial to compare efficacy and safety of Denosumab (produced by AryoGen Pharmed Co.) versus Denosumab (Xgeva®, produced by Amgen Company) in breast cancer patients with bone metastasis
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Public title
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Evaluation of efficacy and safety of Denosumab (produced by AryoGen Pharmed Co.) versus Denosumab (Xgeva®, produced by Amgen Co.)
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Purpose
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Treatment
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Inclusion/Exclusion criteria
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Inclusion criteria:
Female patients aged 18-75 years old at the time of signing informed consent form ICF
History or known case of breast adenocarcinoma
Radiographic evidence of at least one bone metastasis
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
Adequate organ function: Albumin-adjusted serum calcium ≥ 2.0 mmol/L [≥ 8.0 mg/dL] and ≤ 2.9 mmol/L [≤ 11.5 mg/dL], Serum aspartate aminotransferase (AST) ≤2.5 ULN, Serum alanine aminotransferase (ALT) ≤2.5 ULN, Serum total bilirubin ≤2 ULN, Creatinine clearance ≥30 mL/min (stage 1-3 CKD patients), Serum Creatinine ≤1.5 ULN, Leukocytes > 3,000/mcL (without growth factor), Platelets > 100,000/mcL, Hemoglobin ≥8 g/d
Exclusion criteria:
Planned radiation therapy or bone surgery
Life expectancy less than 6 months
Known brain and liver metastasis
Prior administration of Denosumab or IV bisphosphonates
Non-healed dental/oral surgery
History or current evidence of osteonecrosis/osteomyelitis of the jaw
Active dental or jaw condition which requires oral surgery
Planned invasive dental procedure in the course of the study
Disorders associated with abnormal bone metabolism including uncontrolled hyperthyroidism or hypothyroidism or Paget’s disease
Prior malignancy (other than breast cancer, basal cell carcinoma, or in situ cervical cancer) within 3 years prior to randomization
Known infection with human immunodeficiency virus (HIV)
Known infection with Hepatitis B or Hepatitis C virus (HBV or HCV)
Receiving any investigational product or device in other clinical trials 30 days prior to the study
Allergy to any of the products to be administered during the study (eg, Denosumab, mammalian cell line products, calcium or vitamin D)
Treatment with calcitonin, parathyroid hormone-related peptides, mithramycin, strontium ranelate, or gallium nitrate within 8 weeks prior to randomization
Any psychiatric disorder, organ disfunction or systemic disease that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results
Pregnancy or breast feeding
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Age
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From 18 years old to 75 years old
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Gender
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Female
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Phase
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3
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Groups that have been masked
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Sample size
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Target sample size:
272
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Randomization (investigator's opinion)
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Randomized
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Randomization description
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Eligible patients will be assigned to treatment with the use of stratification, permuted block (length of each block is 2), and R-CRAN software (version 3.2.3) that will be designed to achieve the overall balance between groups; randomization will be stratified according to prior Skeletal Related Event (SRE), prior oral bisphosphonate use, and current chemotherapy (chemotherapy treatment from 6 weeks prior randomization until the randomization date). After the randomization procedure, a code will be allocated to each patient that will be used as a patient identifier throughout the study. The assigned code will be denoted by 4 initials (corresponding to the 2 first letters of the first name, the 2 first letters of the first surname) and 3 numbers (center code). Moreover, the code is followed by study unique identification consisting of the first three letters of the generic name of the investigational product (which is DEN-) and 3 numbers (corresponding to the randomization number), e.g. ABCD001DEN-001. The randomization number will be assigned in a consecutive way. Each Denosumab drug packages (allocated to each patient’s injection) will have an exclusive code. Also, CRO (Contract Research Organization) will monitor the way of patient’s drug allocation in treatment groups.
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Blinding (investigator's opinion)
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Double blinded
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Blinding description
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The participants, physicians, nurse (for injection) and those who assess the study outcomes will be unaware of the state of the patient with regard to receiving Denosumab (AryoGen) or Denosumab (Xgeva®). The drug packaging type is vial, therefore the drug will be exclusively prepared in similar syringes for injection by the nurse who opens the drug packages (blinding nurse). Another nurse who injects the drug will remain blind throughout the study. Thus, the process by which the drug will be prepared, make it impossible to identify the brand of Denosumab 120 mg for the patients and investigators.
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Placebo
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Not used
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Assignment
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Parallel
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Other design features
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Ethics committees
1
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Ethics committee
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Approval date
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2020-06-22, 1399/04/02
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Ethics committee reference number
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IR.IUMS.REC.1399.320
2
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Ethics committee
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Approval date
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2020-12-03, 1399/09/13
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Ethics committee reference number
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IR.SBMU.CRC.REC.1399.025
Health conditions studied
1
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Description of health condition studied
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Breast cancer
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ICD-10 code
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C50.919
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ICD-10 code description
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Malignant neoplasm of unspecified site of unspecified female breast
Primary outcomes
1
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Description
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Time to first on-study Skeletal-Related Event (SRE)
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Timepoint
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During a 21 months period (with monthly physician visits and imaging every 3 months)
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Method of measurement
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The time from the date of randomization to first SRE including date of pathologic fracture, radiation or surgery to bone, or spinal cord compression
Secondary outcomes
1
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Description
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Time to first and subsequent (multiple) Skeletal Related Event (SRE)
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Timepoint
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During a 21-month period (with monthly physician visits and imaging every 3 months)
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Method of measurement
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The time from the date of randomization to first and subsequent SRE
2
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Description
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Safety Outcomes
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Timepoint
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During a 21-month period
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Method of measurement
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Safety will be assessed based on clinical examinations and laboratory test results.
3
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Description
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Immunogenicity
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Timepoint
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Weeks 0, 24, 52, 84
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Method of measurement
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Blood test and antidrug antibody (ADA) presence evaluation
Intervention groups
1
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Description
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Denosumab (produced by AryoGen Pharmed Co.), Subcutaneous, 120 mg once every 4 weeks for 80 weeks (21 doses)
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Category
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Treatment - Drugs
2
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Description
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Xgeva®(produced by Amgen Co.), Subcutaneous, 120 mg once every 4 weeks for 80 weeks (21 doses)
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Category
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Treatment - Drugs
1
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Sponsor
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Grant name
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Grant code / Reference number
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Is the source of funding the same sponsor organization/entity?
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Yes
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Title of funding source
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AryoGen Pharmed Co.
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Proportion provided by this source
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100
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Public or private sector
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Private
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Domestic or foreign origin
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Domestic
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Category of foreign source of funding
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empty
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Country of origin
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Type of organization providing the funding
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Other
Sharing plan
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Deidentified Individual Participant Data Set (IPD)
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Undecided - It is not yet known if there will be a plan to make this available
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Study Protocol
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Undecided - It is not yet known if there will be a plan to make this available
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Statistical Analysis Plan
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Undecided - It is not yet known if there will be a plan to make this available
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Informed Consent Form
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Undecided - It is not yet known if there will be a plan to make this available
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Clinical Study Report
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Undecided - It is not yet known if there will be a plan to make this available
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Analytic Code
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Undecided - It is not yet known if there will be a plan to make this available
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Data Dictionary
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Undecided - It is not yet known if there will be a plan to make this available