Glioblastoma
Conditions
Brief summary
This 2 arm study investigated the efficacy and safety of the addition of bevacizumab to the current standard of care (multimodality therapy of concurrent radiotherapy plus temozolomide followed by adjuvant temozolomide) as compared to the current standard of care alone. Participants were randomly assigned to either the bevacizumab (10 milligrams per kilogram (mg/kg) intravenously \[IV\] once every 2 week \[q2w\]) or the placebo arm, in combination with radiation therapy (total dose 60 Gray \[Gy\], administered as 2 Gy fractions, 5 days/week) plus temozolomide (75 milligrams per meter squared \[mg/m\^2\] oral administration \[po\] daily) for 6 weeks. After a 4 week treatment break, participants continued to receive bevacizumab (10 mg/kg IV q2w) or placebo, plus temozolomide (150-200 mg/m\^2 po daily on days 1-5 of each 4 week cycle) for 6 cycles of maintenance treatment or until disease progression or unacceptable toxicity, whichever occured first. Following the maintenance phase, bevacizumab (15 mg/kg iv every 3 weeks \[q3w\]) or placebo monotherapy continued. The time on study treatment was until disease progression.
Interventions
DRUGBevacizumab
10 mg/kg intravenously q2w in the Concurrent and Maintenance Phases. 15 mg/kg intravenously q3w in the Monotherapy Phase.
DRUGTemozolomide
75 mg/m\^2 once daily for 6 weeks, followed by 150-200 mg/m\^2 once daily on days 1-5 of six 4 week cycles.
RADIATIONRadiation therapy
30 fractions of 2 Gy delivered on days 1-5 per week for 6 weeks.
DRUGPlacebo
Intravenously q2w in the Concurrent and Maintenance Phases and q3w in the Monotherapy Phase.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * newly diagnosed glioblastoma * World Health Organization (WHO) performance status less than or equal to (\<=2) * stable or decreasing corticosteroid dose within 5 days prior to randomization Key
Exclusion criteria
* evidence of recent hemorrhage on postoperative magnetic resonance imaging (MRI) of brain * any prior chemotherapy or immunotherapy for glioblastomas and low grade astrocytomas * any prior radiotherapy to brain * clinically significant cardiovascular disease * history of greater than or equal to (\>=) grade 2 hemoptysis within 1 month prior to randomization * previous centralized screening for Methylguanine-DNA methyltransferase (MGMT) status for enrollment into a clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator | Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months) | PFS is defined as time from randomization to disease progression (PD) or death. PD was assessed using adapted Macdonald response criteria (modified World Health Organization \[WHO\] criteria) based on 3 components: radiological tumor assessments using Magnetic Resonance Imaging \[MRI\] scans,neurological assessment and changes in corticosteroid use. PD is assessed as greater than or equal to(\>=) 25% increase in sum of products of the longest diameters of all index lesions (enhancing,measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing,non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment. |
| Co-Primary: Overall Survival (OS) | Randomization until OS Event (Until data cutoff= 28 February 2013 [up to 42.2 months]) | Overall Survival was defined as the time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier (KM) Estimate of Two Year Overall Survival | Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months]) | KM estimate of two year overall survival was reported (probability to survive for at least 2 years). Corresponding 95% CI was calculated using Greenwood's formula. |
| PFS as Assessed by an Independent Review Facility | Randomization until PFS Event (Until data cutoff= 31 March 2012 [up to 29.5 months]) | An Independent Review Facility reviewed the MRI scans used by investigator to evaluate radiological tumor response. PFS is defined as time from randomization to PD or death. PD was assessed using adapted Macdonald response (modified WHO) criteria based on 3 components: radiological tumor assessments using MRI scans, neurological assessment and changes in corticosteroid use. PD is assessed as \>=25% increase in sum of products of the longest diameters of all index lesions (enhancing, measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing, non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment. |
| Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death | Randomization until study completion (Until data cutoff= 09 Sep 2015 [up to 64 months]) | An adverse event (AE) was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as AE.A serious adverse event (SAE) is any experience that suggests a significant hazard,contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Non-serious adverse events (Non-SAEs) included all AEs except SAEs (non-SAEs = all AEs - SAEs). Nine participants randomized to the Placebo+RT+Temozolomide arm incorrectly received at least 1 dose of bevacizumab and were added to the Bevacizumab+RT+Temozolomide arm for Safety. |
| PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months) | EORTC QLQ-C30: 30 items; 5 functional scales; 9 symptom scales; & global health status. Most questions used 4-point scale (1:Not at all, 4:Very much), 2 questions used 7-point scale (1:very poor, 7:Excellent). EORTC QLQ-BN20: 20 items rated on a 4 point scale (1:not at all, 4:very much). EORTC QLQ-C30 and BN20 scores were transformed to a 0-100 scale, higher score=better functioning/global health (C30) or more severe symptoms (BN20). Stable HRQoL: change from baseline (BL) within 10 points. Improved HRQoL: an increase from BL \>/=10 points for functioning/global health status, & decrease of \>/=10 points for symptoms. PFS is reported for participants with Stable/Improved global health; physical, social functioning (C30); motor dysfunction & communication deficit (BN20). PFS: randomization to PD or death. PD: \>=25% increase in sum of products of longest diameters of index lesions; or progression of existing non-index lesions; or appearance of new lesions; or neurological worsening. |
| Kaplan-Meier (KM) Estimate of One Year Overall Survival | Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months]) | KM estimate of one year overall survival (probability to survive for at least 1 year) was reported. Corresponding 95% confidence interval (CI) was calculated using Greenwood's formula. |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Netherlands, New Zealand, Poland, Portugal, Romania, Russia, South Korea, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
The primary completion date for co-primary outcome of Progression-Free Survival (PFS) was 31 Mar 2012, whereas, the primary completion date for co-primary outcome of Overall Survival (OS) was 28 Feb 2013. Data for PFS and OS are reported according to these cut-off dates.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + RT + Temozolomide In the Concurrent Phase participants received radiotherapy (RT) in daily fractions of 2 Gray (Gy) given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 milligrams per square meter (mg/m\^2) daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 milligrams per kilogram (mg/kg) intravenous (IV) every 2 weeks for 6 weeks. There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m\^2 daily in the first 5 days of each cycle. The participants then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity. Participants then entered the last period: After Primary Overall Survival Analysis, in which participants were followed up for safety. | 458 |
| Placebo + RT +Temozolomide In the Concurrent Phase participants received RT in daily fractions of 2 Gy given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m\^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m\^2 daily in the first 5 days of each cycle. The participants then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity. Participants then entered the last period: After Primary Overall Survival Analysis, in which participants were followed up for safety. | 463 |
| Total | 921 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| After Primary Overall Survival Analysis | Administrative reasons | 10 | 16 |
| After Primary Overall Survival Analysis | Adverse Event | 11 | 0 |
| After Primary Overall Survival Analysis | Progression of Disease | 2 | 4 |
| After Primary Overall Survival Analysis | Withdrew Consent | 4 | 0 |
| Concurrent Phase | Administrative reasons | 2 | 1 |
| Concurrent Phase | Adverse Event | 50 | 27 |
| Concurrent Phase | Protocol Violation | 1 | 0 |
| Concurrent Phase | Refused treatment/Did not cooperate | 5 | 7 |
| Concurrent Phase | Withdrew consent | 3 | 7 |
| Maintenance Phase | Administrative reasons | 4 | 1 |
| Maintenance Phase | Adverse Event | 31 | 30 |
| Maintenance Phase | Failure to return | 0 | 1 |
| Maintenance Phase | Refused treatment/Did not cooperate | 6 | 3 |
| Maintenance Phase | Withdrew consent | 2 | 4 |
| Monotherapy Phase | Administrative reasons | 11 | 5 |
| Monotherapy Phase | Adverse Event | 42 | 5 |
| Monotherapy Phase | Failure to return | 2 | 1 |
| Monotherapy Phase | Refused treatment/ Did not cooperate | 8 | 2 |
| Monotherapy Phase | Withdrew Consent | 2 | 3 |
Baseline characteristics
| Characteristic | Bevacizumab + RT + Temozolomide | Placebo + RT +Temozolomide | Total |
|---|---|---|---|
| Age, Continuous | 55.9 years | 55.9 years | 55.9 years |
| Sex: Female, Male Female | 176 Participants | 165 Participants | 341 Participants |
| Sex: Female, Male Male | 282 Participants | 298 Participants | 580 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 437 / 461 | 412 / 450 |
| serious Total, serious adverse events | 179 / 461 | 115 / 450 |
Outcome results
Primary
Co-Primary: Overall Survival (OS)
Overall Survival was defined as the time from randomization to death due to any cause.
Time frame: Randomization until OS Event (Until data cutoff= 28 February 2013 [up to 42.2 months])
Population: Intent to treat population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + RT + Temozolomide | Co-Primary: Overall Survival (OS) | 16.8 Months |
| Placebo + RT + Temozolomide | Co-Primary: Overall Survival (OS) | 16.7 Months |
p-value: 0.098795% CI: [0.76, 1.02]Log Rank
Primary
Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator
PFS is defined as time from randomization to disease progression (PD) or death. PD was assessed using adapted Macdonald response criteria (modified World Health Organization \[WHO\] criteria) based on 3 components: radiological tumor assessments using Magnetic Resonance Imaging \[MRI\] scans,neurological assessment and changes in corticosteroid use. PD is assessed as greater than or equal to(\>=) 25% increase in sum of products of the longest diameters of all index lesions (enhancing,measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing,non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment.
Time frame: Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months)
Population: Intent to treat population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + RT + Temozolomide | Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator | 10.6 Months |
| Placebo + RT + Temozolomide | Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator | 6.2 Months |
p-value: <0.000195% CI: [0.55, 0.74]Log Rank
Secondary
Kaplan-Meier (KM) Estimate of One Year Overall Survival
KM estimate of one year overall survival (probability to survive for at least 1 year) was reported. Corresponding 95% confidence interval (CI) was calculated using Greenwood's formula.
Time frame: Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months])
Population: Intent to treat population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + RT + Temozolomide | Kaplan-Meier (KM) Estimate of One Year Overall Survival | 0.72 probability of being alive |
| Placebo + RT + Temozolomide | Kaplan-Meier (KM) Estimate of One Year Overall Survival | 0.66 probability of being alive |
Secondary
Kaplan-Meier (KM) Estimate of Two Year Overall Survival
KM estimate of two year overall survival was reported (probability to survive for at least 2 years). Corresponding 95% CI was calculated using Greenwood's formula.
Time frame: Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months])
Population: Intent to treat population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + RT + Temozolomide | Kaplan-Meier (KM) Estimate of Two Year Overall Survival | 0.34 probability of being alive |
| Placebo + RT + Temozolomide | Kaplan-Meier (KM) Estimate of Two Year Overall Survival | 0.30 probability of being alive |
Secondary
Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death
An adverse event (AE) was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as AE.A serious adverse event (SAE) is any experience that suggests a significant hazard,contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Non-serious adverse events (Non-SAEs) included all AEs except SAEs (non-SAEs = all AEs - SAEs). Nine participants randomized to the Placebo+RT+Temozolomide arm incorrectly received at least 1 dose of bevacizumab and were added to the Bevacizumab+RT+Temozolomide arm for Safety.
Time frame: Randomization until study completion (Until data cutoff= 09 Sep 2015 [up to 64 months])
Population: Safety Population included all randomized participants who received study treatment during the treatment period (10 participants did not receive at least one dose of study treatment and were therefore excluded, 4 in Placebo and 6 in Bevacizumab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab + RT + Temozolomide | Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death | Non-SAEs | 437 Participants |
| Bevacizumab + RT + Temozolomide | Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death | SAEs | 179 Participants |
| Bevacizumab + RT + Temozolomide | Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death | Death | 335 Participants |
| Placebo + RT + Temozolomide | Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death | Non-SAEs | 412 Participants |
| Placebo + RT + Temozolomide | Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death | SAEs | 115 Participants |
| Placebo + RT + Temozolomide | Number of Participants With Non-Serious Adverse Events, Serious Adverse Events and Death | Death | 337 Participants |
Secondary
PFS as Assessed by an Independent Review Facility
An Independent Review Facility reviewed the MRI scans used by investigator to evaluate radiological tumor response. PFS is defined as time from randomization to PD or death. PD was assessed using adapted Macdonald response (modified WHO) criteria based on 3 components: radiological tumor assessments using MRI scans, neurological assessment and changes in corticosteroid use. PD is assessed as \>=25% increase in sum of products of the longest diameters of all index lesions (enhancing, measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing, non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment.
Time frame: Randomization until PFS Event (Until data cutoff= 31 March 2012 [up to 29.5 months])
Population: Intent to treat population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + RT + Temozolomide | PFS as Assessed by an Independent Review Facility | 8.4 Months |
| Placebo + RT + Temozolomide | PFS as Assessed by an Independent Review Facility | 4.3 Months |
p-value: <0.000195% CI: [0.53, 0.71]Log Rank
Secondary
PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20)
EORTC QLQ-C30: 30 items; 5 functional scales; 9 symptom scales; & global health status. Most questions used 4-point scale (1:Not at all, 4:Very much), 2 questions used 7-point scale (1:very poor, 7:Excellent). EORTC QLQ-BN20: 20 items rated on a 4 point scale (1:not at all, 4:very much). EORTC QLQ-C30 and BN20 scores were transformed to a 0-100 scale, higher score=better functioning/global health (C30) or more severe symptoms (BN20). Stable HRQoL: change from baseline (BL) within 10 points. Improved HRQoL: an increase from BL \>/=10 points for functioning/global health status, & decrease of \>/=10 points for symptoms. PFS is reported for participants with Stable/Improved global health; physical, social functioning (C30); motor dysfunction & communication deficit (BN20). PFS: randomization to PD or death. PD: \>=25% increase in sum of products of longest diameters of index lesions; or progression of existing non-index lesions; or appearance of new lesions; or neurological worsening.
Time frame: Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months)
Population: Intent to treat population. Number of Participants Analyzed = overall participants evaluable for this outcome measure; n = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bevacizumab + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Physical functioning (n=353, 318) | 7 Months |
| Bevacizumab + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Motor dysfunction (n=361, 314) | 7 Months |
| Bevacizumab + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Social functioning (n=352, 327) | 8 Months |
| Bevacizumab + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Communication deficit (n=365, 329) | 8 Months |
| Bevacizumab + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Global health status (n=354, 309) | 8 Months |
| Placebo + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Communication deficit (n=365, 329) | 4 Months |
| Placebo + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Global health status (n=354, 309) | 4 Months |
| Placebo + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Physical functioning (n=353, 318) | 5 Months |
| Placebo + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Social functioning (n=352, 327) | 4 Months |
| Placebo + RT + Temozolomide | PFS in Participants With Stable/Improved Health Related Quality of Life (HRQoL) Based on European Organization for Research & Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30)(EORTC QLQ-C30) & EORTC QLQ Brain Neoplasm 20 (BN20) | Motor dysfunction (n=361, 314) | 4 Months |