Trial Outcomes & Findings for Phase 2b Study of Cetuximab With Platinum-Based Chemo as First Line Treatment of Recurrent or Advanced NSCLC (NCT NCT00828841)

NCT ID: NCT00828841

Last Updated: 2013-11-06

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

601 participants

Primary outcome timeframe

Survival was measured from the date of randomization to date of death due to any cause, assessed up to 36 months. Subjects who were alive at the date of last contact were censored at the date of last contact.

Results posted on

2013-11-06

Participant Flow

The study was open to enrollment at 118 oncology clinics from November 2008 to May 2011.

Consent was obtained from all subjects. Subjects were stratified by histology (non-squamous vs. squamous), followed by disease stage (IIIb vs. IV). Subjects in the non-squamous stratum were randomized to 1 of 3 treatment arms (Arm A, B, or C); subjects in the squamous stratum were randomized to only 1 of 2 of these treatment arms (Arm A or B).

Participant milestones

Participant milestones
Measure	Paclitaxel, Carboplatin, Cetuximab (Arm A) Patients with squamous or non-squamous histologies will receive carboplatin and paclitaxel for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. Paclitaxel : Paclitaxel 200 mg/m2 Day 1 every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Gemcitabine, Cetuximab (Arm B) Patients with squamous or non-squamous histologies will receive gemcitabine with either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Gemcitabine : Gemcitabine 1,000 mg/m2 Days 1 and 8 every 21 days Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Pemetrexed, Cetuximab (Arm C) Patients with squamous histology will receive pemetrexed and either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Patients with non-squamous histology are not eligible for this arm. Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.
Overall Study STARTED	235	236	130
Overall Study COMPLETED	231	232	126
Overall Study NOT COMPLETED	4	4	4

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Phase 2b Study of Cetuximab With Platinum-Based Chemo as First Line Treatment of Recurrent or Advanced NSCLC

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Paclitaxel, Carboplatin, Cetuximab (Arm A) n=235 Participants Patients with squamous or non-squamous histologies will receive carboplatin and paclitaxel for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. Paclitaxel : Paclitaxel 200 mg/m2 Day 1 every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Gemcitabine, Cetuximab (Arm B) n=236 Participants Patients with squamous or non-squamous histologies will receive gemcitabine with either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Gemcitabine : Gemcitabine 1,000 mg/m2 Days 1 and 8 every 21 days Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Pemetrexed, Cetuximab (Arm C) n=130 Participants Patients with squamous histology will receive pemetrexed and either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Patients with non-squamous histology are not eligible for this arm. Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Total n=601 Participants Total of all reporting groups
Age Continuous	65.3 years STANDARD_DEVIATION 8.9 • n=93 Participants	64.9 years STANDARD_DEVIATION 9.5 • n=4 Participants	65.6 years STANDARD_DEVIATION 9.4 • n=27 Participants	65.2 years STANDARD_DEVIATION 9.2 • n=483 Participants
Sex: Female, Male Female	97 Participants n=93 Participants	90 Participants n=4 Participants	64 Participants n=27 Participants	251 Participants n=483 Participants
Sex: Female, Male Male	138 Participants n=93 Participants	146 Participants n=4 Participants	66 Participants n=27 Participants	350 Participants n=483 Participants
Region of Enrollment United States	235 participants n=93 Participants	236 participants n=4 Participants	130 participants n=27 Participants	601 participants n=483 Participants

PRIMARY outcome

Timeframe: Survival was measured from the date of randomization to date of death due to any cause, assessed up to 36 months. Subjects who were alive at the date of last contact were censored at the date of last contact.

Population: Two subjects in Arm A were censored due to negative event intervals.

Outcome measures

Outcome measures
Measure	Paclitaxel, Carboplatin, Cetuximab (Arm A) n=233 Participants Patients with squamous or non-squamous histologies will receive carboplatin and paclitaxel for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. Paclitaxel : Paclitaxel 200 mg/m2 Day 1 every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Gemcitabine, Cetuximab (Arm B) n=236 Participants Patients with squamous or non-squamous histologies will receive gemcitabine with either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Gemcitabine : Gemcitabine 1,000 mg/m2 Days 1 and 8 every 21 days Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Pemetrexed, Cetuximab (Arm C) n=130 Participants Patients with squamous histology will receive pemetrexed and either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Patients with non-squamous histology are not eligible for this arm. Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.
Overall Survival by Treatment Arm	9.5 Months Interval 8.3 to 11.4	8.3 Months Interval 7.1 to 9.9	10.6 Months Interval 8.0 to 14.5

SECONDARY outcome

Outcome measures

Outcome measures
Measure	Paclitaxel, Carboplatin, Cetuximab (Arm A) n=233 Participants Patients with squamous or non-squamous histologies will receive carboplatin and paclitaxel for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. Paclitaxel : Paclitaxel 200 mg/m2 Day 1 every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Gemcitabine, Cetuximab (Arm B) n=236 Participants Patients with squamous or non-squamous histologies will receive gemcitabine with either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Gemcitabine : Gemcitabine 1,000 mg/m2 Days 1 and 8 every 21 days Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Pemetrexed, Cetuximab (Arm C) n=130 Participants Patients with squamous histology will receive pemetrexed and either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Patients with non-squamous histology are not eligible for this arm. Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.
1-year Survival by Treatment Arm	39.7 percentage of participants Interval 33.7 to 46.6	37.2 percentage of participants Interval 31.3 to 44.2	47.3 percentage of participants Interval 39.1 to 57.1

SECONDARY outcome

Population: Subjects were stratified by histology prior to randomization to a treatment arm.

Outcome measures

Outcome measures
Measure	Paclitaxel, Carboplatin, Cetuximab (Arm A) n=200 Participants Patients with squamous or non-squamous histologies will receive carboplatin and paclitaxel for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. Paclitaxel : Paclitaxel 200 mg/m2 Day 1 every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Gemcitabine, Cetuximab (Arm B) n=399 Participants Patients with squamous or non-squamous histologies will receive gemcitabine with either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Gemcitabine : Gemcitabine 1,000 mg/m2 Days 1 and 8 every 21 days Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Pemetrexed, Cetuximab (Arm C) Patients with squamous histology will receive pemetrexed and either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Patients with non-squamous histology are not eligible for this arm. Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.
Overall Survival by Histology	8.7 Months Interval 7.4 to 10.1	9.9 Months Interval 8.3 to 11.4	—

Adverse Events

Paclitaxel, Carboplatin, Cetuximab (Arm A)

Serious events: 109 serious events

Other events: 221 other events

Deaths: 0 deaths

Platinum, Gemcitabine, Cetuximab (Arm B)

Serious events: 128 serious events

Other events: 215 other events

Deaths: 0 deaths

Platinum, Pemetrexed, Cetuximab (Arm C)

Serious events: 68 serious events

Other events: 119 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Vice President of Scientific Affairs

Accelerated Community Oncology Research Network, Inc.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The study funder will be provided with a copy of any results communication at least 30 days prior to its submission to a scientific journal or presentation at a scientific meeting to allow review of the publication for confidential information. If confidential information is being disclosed, it may be required to be redacted. Upon request by the study funder, the PI may be asked to withhold disclosure for an additional 90 days to allow the study funder to seek patent protection.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	Paclitaxel, Carboplatin, Cetuximab (Arm A) n=235 participants at risk Patients with squamous or non-squamous histologies will receive carboplatin and paclitaxel for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. Paclitaxel : Paclitaxel 200 mg/m2 Day 1 every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Gemcitabine, Cetuximab (Arm B) n=236 participants at risk Patients with squamous or non-squamous histologies will receive gemcitabine with either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Gemcitabine : Gemcitabine 1,000 mg/m2 Days 1 and 8 every 21 days Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.	Platinum, Pemetrexed, Cetuximab (Arm C) n=130 participants at risk Patients with squamous histology will receive pemetrexed and either carboplatin or cisplatin for a minimum of four and a maximum of six 21-day cycles, plus cetuximab, and then enter a maintenance phase with single-agent cetuximab. Cetuximab will be given on Day 1, and weekly during chemotherapy, followed by biweekly administration during the maintenance period. The choice of delivering four, five or six cycles of chemotherapy is at the investigator's discretion. The choice of platinum-based chemotherapy is also at the investigator's discretion. Patients with non-squamous histology are not eligible for this arm. Cisplatin : Cisplatin 75 mg/m2 Day I every 21 days Carboplatin : Carboplatin AUC 6 Day 1 every 21 days Cetuximab : Cetuximab will be administered at a loading dose of 400 mg/m2 on Day 1, Cycle 1 and at a dose of 250 mg/m2 weekly during chemotherapy. During the maintenance period, cetuximab will be dosed at 500 mg/m2 every two weeks.
Nervous system disorders Central Nervous System Hemorrhage	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Nervous system disorders Muscle Contractions Involuntary	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Surgical and medical procedures Central Venous Catheterization	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Ear and labyrinth disorders Cerumen Impaction	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.85% 2/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Gastrointestinal disorders Cheilitis	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.85% 2/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Injury, poisoning and procedural complications Chemical Injury	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
General disorders Chest Discomfort	1.3% 3/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	1.3% 3/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
General disorders Chest Pain	5.5% 13/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	7.6% 18/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	7.7% 10/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Musculoskeletal and connective tissue disorders Chest Wall Cyst	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Musculoskeletal and connective tissue disorders Muscle Spasms	1.3% 3/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.85% 2/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	2.3% 3/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Injury, poisoning and procedural complications Muscle Strain	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Musculoskeletal and connective tissue disorders Muscle Twitching	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Musculoskeletal and connective tissue disorders Muscular Weakness	3.8% 9/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	5.1% 12/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	10.0% 13/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Musculoskeletal and connective tissue disorders Musculoskeletal Chest Pain	3.8% 9/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	4.7% 11/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	6.9% 9/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Musculoskeletal and connective tissue disorders Musculoskeletal Discomfort	0.85% 2/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Nervous system disorders 7th Nerve Paralysis	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Gastrointestinal disorders Abdominal Discomfort	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	1.3% 3/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	1.5% 2/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Gastrointestinal disorders Abdominal Distension	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	1.5% 2/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Gastrointestinal disorders Abdominal Pain	8.1% 19/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	7.6% 18/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	5.4% 7/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Gastrointestinal disorders Abdominal Pain Lower	0.85% 2/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	2.1% 5/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Gastrointestinal disorders Abdominal Pain Upper	3.0% 7/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	2.5% 6/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	3.1% 4/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Psychiatric disorders Abnormal Dreams	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Surgical and medical procedures Abscess Drainage	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Infections and infestations Abscess Neck	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Skin and subcutaneous tissue disorders Acne	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Investigations Activated Partial Thromboplastin Time Prolonged	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Endocrine disorders Adrenal Insufficiency	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Endocrine disorders Adrenal Mass	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
General disorders Adverse Drug Reaction	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Psychiatric disorders Agitation	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	1.3% 3/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	1.5% 2/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Investigations Alanine Aminotransferase	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	1.3% 3/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	2.3% 3/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Investigations Alanine Aminotransferase Decreased	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Investigations Alanine Aminotransferase Increased	4.3% 10/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	3.0% 7/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	5.4% 7/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Skin and subcutaneous tissue disorders Alopecia	22.6% 53/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	11.4% 27/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	4.6% 6/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Investigations Amylase Increased	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.77% 1/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Gastrointestinal disorders Anal Fissure	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Immune system disorders Anaphylactic Reaction	0.43% 1/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Blood and lymphatic system disorders Anemia	35.3% 83/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	44.5% 105/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	40.0% 52/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Cardiac disorders Angina Pectoris	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.
Skin and subcutaneous tissue disorders Anhidrosis	0.00% 0/235 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.42% 1/236 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.	0.00% 0/130 • Adverse events collection began at the time the patient signed the informed consent and continued throughout the study until 30 days after the last dose. Systematic Assessment - subjects were assessed for adverse events by a member of the research team every 1-2 weeks.