HER2-positive Carcinoma of Breast
Conditions
Brief summary
This study will determine whether CT-P6 and Herceptin are equivalent in patients with early-stage breast cancer undergoing neoadjuvant chemotherapy. Our hypothesis is that the pathologic complete response rate will be equivalent in patients treated with neoadjuvant CT-P6 or Herceptin. Patients will receive 8 cycles of neoadjuvant systemic therapy and up to 10 cycles of therapy in the adjuvant setting.
Interventions
DRUGTrastuzumab
Trastuzumab 6mg/kg is ongoing to be administered for both arms after 8mg/kg loading dose.
Sponsors
Nippon Kayaku Co., Ltd.
Celltrion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient who has histologically confirmed and newly diagnosed breast cancer * Patient who has clinical stage I, II, or IIIa operable breast cancer according to AJCC (American Joint Committee on Cancer) Breast Cancer Staging 7th edition * Patient who has HER2-positive status confirmed locally, defined as 3+ score by IHC (immuno-histochemistry).
Exclusion criteria
* Patient who has bilateral breast cancer * Patient who has received prior treatment for breast cancer, including chemotherapy, biologic therapy, hormone therapy, immunotherapy, radiation or surgery, including any prior therapy with anthracyclines.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients Achieving Pathological Complete Response Defined as the Absence of Invasion Tumor Cells in the Breast and in Axillary Lymph Nodes, Regardless of Ductal Carcinoma in Situ (DCIS) | After Neo-adjuvant therapy and Surgery (up to 30 weeks) | Subject who went through Neoadjuvant period completely (24 weeks), will receive surgery within 3-6 weeks after last treatment of neoadjuvant period. The primary endpoint, Pathological complete response, will be assessed using resected bio-specimens collected in breast and axilla during a surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients Achieving Pathological Complete Response of the Breast and Axillary Nodes With Absence of DCIS | After Neo-adjuvant therapy and Surgery (up to 30 weeks) | Subject who went through Neoadjuvant period completely (24 weeks), will receive surgery within 3-6 weeks after last treatment of neoadjuvant period. The secondary endpoint, other than pCR of breast and axillary nodes ragardless of DCIS which was primary endpoint, will be assessed using resected bio-specimens collected in breast and axilla during a surgery. |
| Overall Response Rate (ORR) From Local Review | After Neo-adjuvant therapy (up to 24 weeks) | The ORR was defined as the proportion of patients with a BOR of CR or PR as assessed by RECIST guideline Version 1.1 during the Nedadjuvant Period. |
| Disease-free Survival | Up to 3 years from the day of last patient enrollment (during whole study period) | Patients who underwent breast surgery were included in the DFS analysis. Disease-free survival was defined as the interval between the date of breast surgery and disease progression, recurrence, or death from any cause, whichever occurred first. Only a recurrence or progression of disease that occurred before beginning another anticancer therapy was regarded as an event. |
| Progression-Free Survival | Up to 3 years from the day of last patient enrollment (during whole study period) | Progression-free survival was defined as the interval between randomization and disease progression, recurrence, or death from any cause, whichever occurred first. Only a recurrence or progression of disease that occurred before beginning another anticancer therapy was regarded as an event. |
| The Percentage of Patients Achieving Pathological Complete Response (pCR) of the Breast Regardless of DCIS With Positive or Unknown Nodal Status | After Neo-adjuvant therapy and Surgery (up to 30 weeks) | Subject who went through Neoadjuvant period completely (24 weeks), will receive surgery within 3-6 weeks after last treatment of neoadjuvant period. The secondary endpoint, other than pCR of breast and axillary nodes ragardless of DCIS which was primary endpoint, will be assessed using resected bio-specimens collected in breast and axilla during a surgery. |
| The Number of Patients Who Had Progressive Disease or Recurrence | Up to 3 years from the day of last patient enrollment (during whole study period) | If recurrence or progression of disease occurred at any time during the study, the progressed tumor site was recorded in the recurrence or progression of disease eCRF page as local, regional, or distant, with diagnostic method and whether positive cytology or histology or not. The resulting recurrence or progression of disease information was summarized as secondary endpoint. |
| Maximum Serum Concentration After Administration (Cmax) in Each Cycle | End of each treatment cycles, up to 24 weeks (during neoadjuvant period) | Pharmacokinetic samples were collected before study drug (CT-P6 or US-licensed Herceptin) administration (within 15 minutes prior to the beginning of the study drug infusion) and within 15 minutes after the end of the study drug infusion for each cycle during the Neoadjuvant Period. After the completion of treatment, an additional PK sample was collected at the EOT1. |
| Trough Serum Concentration (Ctrough) in Each Cycle | Pre-infusion of cycles 1 to 8 during neoadjuvant period | Pharmacokinetic samples were collected before study drug (CT-P6 or US-licensed Herceptin) administration (within 15 minutes prior to the beginning of the study drug infusion) and within 15 minutes after the end of the study drug infusion for each cycle during the Neoadjuvant Period. After the completion of treatment, an additional PK sample was collected at the EOT1. |
| Overall Survival | Up to 3 years from the day of last patient enrollment (during whole study period) | Overall survival was defined as the interval between randomization and death from any cause. |
Countries
Argentina, Belarus, Bosnia and Herzegovina, Chile, France, Georgia, Hungary, India, Italy, Japan, Latvia, Mexico, Peru, Philippines, Poland, Portugal, Romania, Russia, South Africa, Spain, Taiwan, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CT-P6 Patient received CT-P6 at an initial dose of 8 mg/kg administered by a single IV infusion on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of Cycles 2 through 8 (3-week cycles). Patients also received docetaxel 75 mg/m\^2 during cycles 1 through 4 and FEC (fluorouracil 500mg/m\^2, epirubicin 75mg/m\^2, and cyclophosphamide 500mg/m\^2) during Cycles 5 through 8. After a total of 8 treatment cycles of the neoadjuvant treatment, surgery was performed within 3 to 6 weeks from the last dose of study in the neoadjuvant period. Three to 6 weeks after surgery, patients entered the adjuvant period and received additional CT-P6 6 mg/kg (3-week cycles) for up to 1 year from the first day of study drug administration in the Neoadjuvant Period, excluding surgery (or up to 10 cycles after surgery). | 278 |
| Herceptin Patient received Herceptin at an initial dose of 8 mg/kg administered by a single IV infusion on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of Cycles 2 through 8 (3-week cycles). Patients also received docetaxel 75 mg/m\^2 during cycles 1 through 4 and FEC (fluorouracil 500mg/m\^2, epirubicin 75mg/m\^2, and cyclophosphamide 500mg/m\^2) during Cycles 5 through 8. After a total of 8 treatment cycles of the neoadjuvant treatment, surgery was performed within 3 to 6 weeks from the last dose of study in the neoadjuvant period. Three to 6 weeks after surgery, patients entered the adjuvant period and received additional Herceptin 6 mg/kg (3-week cycles) for up to 1 year from the first day of study drug administration in the Neoadjuvant Period, excluding surgery (or up to 10 cycles after surgery). | 284 |
| Total | 562 |
Baseline characteristics
| Characteristic | CT-P6 | Herceptin | Total |
|---|---|---|---|
| Age, Continuous | 53.0 years | 52.5 years | 53.0 years |
| Sex: Female, Male Female | 278 Participants | 284 Participants | 562 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 263 / 271 | 264 / 278 |
| serious Total, serious adverse events | 22 / 271 | 36 / 278 |
Outcome results
Primary
The Percentage of Patients Achieving Pathological Complete Response Defined as the Absence of Invasion Tumor Cells in the Breast and in Axillary Lymph Nodes, Regardless of Ductal Carcinoma in Situ (DCIS)
Subject who went through Neoadjuvant period completely (24 weeks), will receive surgery within 3-6 weeks after last treatment of neoadjuvant period. The primary endpoint, Pathological complete response, will be assessed using resected bio-specimens collected in breast and axilla during a surgery.
Time frame: After Neo-adjuvant therapy and Surgery (up to 30 weeks)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CT-P6 | The Percentage of Patients Achieving Pathological Complete Response Defined as the Absence of Invasion Tumor Cells in the Breast and in Axillary Lymph Nodes, Regardless of Ductal Carcinoma in Situ (DCIS) | 46.77 percentage of responders |
| Herceptin | The Percentage of Patients Achieving Pathological Complete Response Defined as the Absence of Invasion Tumor Cells in the Breast and in Axillary Lymph Nodes, Regardless of Ductal Carcinoma in Situ (DCIS) | 50.39 percentage of responders |
Secondary
Disease-free Survival
Patients who underwent breast surgery were included in the DFS analysis. Disease-free survival was defined as the interval between the date of breast surgery and disease progression, recurrence, or death from any cause, whichever occurred first. Only a recurrence or progression of disease that occurred before beginning another anticancer therapy was regarded as an event.
Time frame: Up to 3 years from the day of last patient enrollment (during whole study period)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P6 | Disease-free Survival | 1 year | 0.95 proportion of participants |
| CT-P6 | Disease-free Survival | 2 years | 0.87 proportion of participants |
| CT-P6 | Disease-free Survival | 3 years | 0.82 proportion of participants |
| Herceptin | Disease-free Survival | 1 year | 0.96 proportion of participants |
| Herceptin | Disease-free Survival | 2 years | 0.89 proportion of participants |
| Herceptin | Disease-free Survival | 3 years | 0.82 proportion of participants |
Secondary
Maximum Serum Concentration After Administration (Cmax) in Each Cycle
Pharmacokinetic samples were collected before study drug (CT-P6 or US-licensed Herceptin) administration (within 15 minutes prior to the beginning of the study drug infusion) and within 15 minutes after the end of the study drug infusion for each cycle during the Neoadjuvant Period. After the completion of treatment, an additional PK sample was collected at the EOT1.
Time frame: End of each treatment cycles, up to 24 weeks (during neoadjuvant period)
Population: Safety Analysis Set: All patients randomly assigned to study drug and who receive at least 1 dose (fully or partially) of study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CT-P6 | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 1 | 186.428 µg/mL | Standard Deviation 69.0828 |
| CT-P6 | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 2 | 145.078 µg/mL | Standard Deviation 47.7899 |
| CT-P6 | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 3 | 145.183 µg/mL | Standard Deviation 44.5392 |
| CT-P6 | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 4 | 148.541 µg/mL | Standard Deviation 54.2737 |
| CT-P6 | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 5 | 136.210 µg/mL | Standard Deviation 44.6078 |
| CT-P6 | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 6 | 143.569 µg/mL | Standard Deviation 42.451 |
| CT-P6 | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 7 | 146.726 µg/mL | Standard Deviation 48.0249 |
| CT-P6 | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 8 | 145.081 µg/mL | Standard Deviation 41.5382 |
| Herceptin | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 8 | 144.238 µg/mL | Standard Deviation 57.3618 |
| Herceptin | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 1 | 178.567 µg/mL | Standard Deviation 55.38 |
| Herceptin | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 5 | 135.307 µg/mL | Standard Deviation 47.195 |
| Herceptin | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 2 | 138.989 µg/mL | Standard Deviation 45.7103 |
| Herceptin | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 7 | 141.468 µg/mL | Standard Deviation 43.1823 |
| Herceptin | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 3 | 141.130 µg/mL | Standard Deviation 43.8189 |
| Herceptin | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 6 | 143.605 µg/mL | Standard Deviation 51.2868 |
| Herceptin | Maximum Serum Concentration After Administration (Cmax) in Each Cycle | Cycle 4 | 137.465 µg/mL | Standard Deviation 45.6914 |
Secondary
Overall Response Rate (ORR) From Local Review
The ORR was defined as the proportion of patients with a BOR of CR or PR as assessed by RECIST guideline Version 1.1 during the Nedadjuvant Period.
Time frame: After Neo-adjuvant therapy (up to 24 weeks)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CT-P6 | Overall Response Rate (ORR) From Local Review | 84.27 percentage of responders |
| Herceptin | Overall Response Rate (ORR) From Local Review | 83.98 percentage of responders |
Secondary
Overall Survival
Overall survival was defined as the interval between randomization and death from any cause.
Time frame: Up to 3 years from the day of last patient enrollment (during whole study period)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P6 | Overall Survival | 1 year | 1.00 proportion of participants |
| CT-P6 | Overall Survival | 2 years | 0.98 proportion of participants |
| CT-P6 | Overall Survival | 3 years | 0.95 proportion of participants |
| Herceptin | Overall Survival | 1 year | 1.00 proportion of participants |
| Herceptin | Overall Survival | 2 years | 0.98 proportion of participants |
| Herceptin | Overall Survival | 3 years | 0.94 proportion of participants |
Secondary
Progression-Free Survival
Progression-free survival was defined as the interval between randomization and disease progression, recurrence, or death from any cause, whichever occurred first. Only a recurrence or progression of disease that occurred before beginning another anticancer therapy was regarded as an event.
Time frame: Up to 3 years from the day of last patient enrollment (during whole study period)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P6 | Progression-Free Survival | 1 year | 0.99 proportion of participants |
| CT-P6 | Progression-Free Survival | 2 years | 0.90 proportion of participants |
| CT-P6 | Progression-Free Survival | 3 years | 0.82 proportion of participants |
| Herceptin | Progression-Free Survival | 1 year | 0.98 proportion of participants |
| Herceptin | Progression-Free Survival | 2 years | 0.93 proportion of participants |
| Herceptin | Progression-Free Survival | 3 years | 0.87 proportion of participants |
Secondary
The Number of Patients Who Had Progressive Disease or Recurrence
If recurrence or progression of disease occurred at any time during the study, the progressed tumor site was recorded in the recurrence or progression of disease eCRF page as local, regional, or distant, with diagnostic method and whether positive cytology or histology or not. The resulting recurrence or progression of disease information was summarized as secondary endpoint.
Time frame: Up to 3 years from the day of last patient enrollment (during whole study period)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CT-P6 | The Number of Patients Who Had Progressive Disease or Recurrence | Overall Period | 41 participants |
| CT-P6 | The Number of Patients Who Had Progressive Disease or Recurrence | Neoadjuvant Period | 1 participants |
| CT-P6 | The Number of Patients Who Had Progressive Disease or Recurrence | Adjuvant Period | 5 participants |
| CT-P6 | The Number of Patients Who Had Progressive Disease or Recurrence | Follow-up Period | 35 participants |
| Herceptin | The Number of Patients Who Had Progressive Disease or Recurrence | Follow-up Period | 30 participants |
| Herceptin | The Number of Patients Who Had Progressive Disease or Recurrence | Overall Period | 35 participants |
| Herceptin | The Number of Patients Who Had Progressive Disease or Recurrence | Adjuvant Period | 3 participants |
| Herceptin | The Number of Patients Who Had Progressive Disease or Recurrence | Neoadjuvant Period | 2 participants |
Secondary
The Percentage of Patients Achieving Pathological Complete Response of the Breast and Axillary Nodes With Absence of DCIS
Subject who went through Neoadjuvant period completely (24 weeks), will receive surgery within 3-6 weeks after last treatment of neoadjuvant period. The secondary endpoint, other than pCR of breast and axillary nodes ragardless of DCIS which was primary endpoint, will be assessed using resected bio-specimens collected in breast and axilla during a surgery.
Time frame: After Neo-adjuvant therapy and Surgery (up to 30 weeks)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CT-P6 | The Percentage of Patients Achieving Pathological Complete Response of the Breast and Axillary Nodes With Absence of DCIS | 39.92 percentage of responders |
| Herceptin | The Percentage of Patients Achieving Pathological Complete Response of the Breast and Axillary Nodes With Absence of DCIS | 41.41 percentage of responders |
Secondary
The Percentage of Patients Achieving Pathological Complete Response (pCR) of the Breast Regardless of DCIS With Positive or Unknown Nodal Status
Subject who went through Neoadjuvant period completely (24 weeks), will receive surgery within 3-6 weeks after last treatment of neoadjuvant period. The secondary endpoint, other than pCR of breast and axillary nodes ragardless of DCIS which was primary endpoint, will be assessed using resected bio-specimens collected in breast and axilla during a surgery.
Time frame: After Neo-adjuvant therapy and Surgery (up to 30 weeks)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CT-P6 | The Percentage of Patients Achieving Pathological Complete Response (pCR) of the Breast Regardless of DCIS With Positive or Unknown Nodal Status | 4.84 percentage of responders |
| Herceptin | The Percentage of Patients Achieving Pathological Complete Response (pCR) of the Breast Regardless of DCIS With Positive or Unknown Nodal Status | 4.69 percentage of responders |
Secondary
Trough Serum Concentration (Ctrough) in Each Cycle
Pharmacokinetic samples were collected before study drug (CT-P6 or US-licensed Herceptin) administration (within 15 minutes prior to the beginning of the study drug infusion) and within 15 minutes after the end of the study drug infusion for each cycle during the Neoadjuvant Period. After the completion of treatment, an additional PK sample was collected at the EOT1.
Time frame: Pre-infusion of cycles 1 to 8 during neoadjuvant period
Population: Safety Analysis Set: All patients randomly assigned to study drug and who receive at least 1 dose (fully or partially) of study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CT-P6 | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 1 | 18.915 µg/mL | Standard Deviation 22.9964 |
| CT-P6 | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 2 | 17.346 µg/mL | Standard Deviation 17.9771 |
| CT-P6 | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 3 | 16.796 µg/mL | Standard Deviation 17.2409 |
| CT-P6 | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 4 | 17.851 µg/mL | Standard Deviation 20.1572 |
| CT-P6 | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 6 | 18.902 µg/mL | Standard Deviation 20.2198 |
| CT-P6 | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 7 | 18.540 µg/mL | Standard Deviation 14.3313 |
| CT-P6 | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 8 | 17.901 µg/mL | Standard Deviation 7.2203 |
| CT-P6 | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 5 | 18.403 µg/mL | Standard Deviation 19.9042 |
| Herceptin | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 5 | 17.962 µg/mL | Standard Deviation 17.9429 |
| Herceptin | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 1 | 18.905 µg/mL | Standard Deviation 21.2967 |
| Herceptin | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 7 | 18.718 µg/mL | Standard Deviation 18.5976 |
| Herceptin | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 2 | 16.773 µg/mL | Standard Deviation 16.8134 |
| Herceptin | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 6 | 18.256 µg/mL | Standard Deviation 17.6964 |
| Herceptin | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 3 | 17.816 µg/mL | Standard Deviation 23.3438 |
| Herceptin | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 8 | 17.129 µg/mL | Standard Deviation 10.0491 |
| Herceptin | Trough Serum Concentration (Ctrough) in Each Cycle | Cycle 4 | 15.904 µg/mL | Standard Deviation 15.8754 |
Post Hoc
The Percentage of Patients Achieving Pathological Complete Response of the Breast and Axillary Nodes Regardless of DCIS
Subject who went through Neoadjuvant period completely (24 weeks), will receive surgery within 3-6 weeks after last treatment of neoadjuvant period. The secondary endpoint, other than pCR of breast and axillary nodes ragardless of DCIS which was primary endpoint, will be assessed using resected bio-specimens collected in breast and axilla during a surgery.
Time frame: After Neo-adjuvant therapy and Surgery (up to 30 weeks)
Population: Per-Protocol Set: All patients randomly assigned to study drug, regardless of whether or not any study treatment dosing is completed, except for those patients excluded because of major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CT-P6 | The Percentage of Patients Achieving Pathological Complete Response of the Breast and Axillary Nodes Regardless of DCIS | 51.61 percentage of responders |
| Herceptin | The Percentage of Patients Achieving Pathological Complete Response of the Breast and Axillary Nodes Regardless of DCIS | 55.08 percentage of responders |