Trial Outcomes & Findings for A Study to Determine the Effect of Methotrexate (MTX) Dose on Clinical Outcome and Ultrasonographic Signs in Subjects With Moderately to Severely Active Rheumatoid Arthritis (RA) Treated With Adalimumab (MUSICA) (NCT NCT01185288)

Last Updated: 2014-03-18

Results Overview

The DAS28(CRP) score includes 28 tender joint counts, 28 swollen joint counts, C-reactive protein, and participant's global assessment of disease activity. Scores on the DAS28(CRP) range from 0 to 10. A DAS28(CRP) score ≥ 5.1 indicates high disease activity, and a DAS28(CRP) score \< 2.6 indicates clinical remission. Least squares means and 95% CI were from 2-way ANCOVA model with effects for baseline DAS28(CRP) value, treatment group, and prior methotrexate dose group.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

309 participants

Primary outcome timeframe

Week 24

Results posted on

2014-03-18

Participant Flow

Participant milestones

Participant milestones
Measure	Adalimumab + Low Dose Methotrexate Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Overall Study STARTED	154	155
Overall Study COMPLETED	135	139
Overall Study NOT COMPLETED	19	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Adalimumab + Low Dose Methotrexate Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Overall Study Adverse Event	7	6
Overall Study Withdrawal by Subject	6	4
Overall Study Lost to Follow-up	2	5
Overall Study Lack of Efficacy	2	0
Overall Study Investigator discretion	1	0
Overall Study Did not meet inclusion criteria	1	0
Overall Study Noncompliance	0	1

Baseline Characteristics

A Study to Determine the Effect of Methotrexate (MTX) Dose on Clinical Outcome and Ultrasonographic Signs in Subjects With Moderately to Severely Active Rheumatoid Arthritis (RA) Treated With Adalimumab (MUSICA)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Adalimumab + Low Dose Methotrexate n=154 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).	Total n=309 Participants Total of all reporting groups
Age, Continuous	55.1 years STANDARD_DEVIATION 13.11 • n=5 Participants	54.5 years STANDARD_DEVIATION 11.09 • n=7 Participants	54.8 years STANDARD_DEVIATION 12.12 • n=5 Participants
Sex: Female, Male Female	120 Participants n=5 Participants	111 Participants n=7 Participants	231 Participants n=5 Participants
Sex: Female, Male Male	34 Participants n=5 Participants	44 Participants n=7 Participants	78 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 24

Population: All participants who were randomized and received at least one dose of study medication (intent to treat). Missing responses were imputed using last observation carried forward (LOCF).

Outcome measures

Outcome measures
Measure	Adalimumab + Low Dose Methotrexate n=154 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Disease Activity Score for 28 Joints Based on C-reactive Protein (DAS28[CRP]) at Week 24	4.11 scores on a scale Interval 3.88 to 4.34	3.75 scores on a scale Interval 3.52 to 3.97

SECONDARY outcome

Timeframe: Baseline, 24 weeks

Population: All participants who were randomized and received at least one dose of study medication (intent to treat). Missing responses were imputed by carrying forward the value at early termination visit (LOCF).

PD U/S assessed the severity of synovial inflammation in both hands (bilateral wrists, metacarpophalangeal joints 2, 3, 5, and metatarsophalangeal joint 5). Bilateral images based on dorsal midline imaging of the wrist, dorsal and volar imaging of metacarpophalangeal joints, and dorsal imaging alone of metatarsophalangeal joints are scored using a 4-grade scale: grade 0 or normal = normal joint (no Doppler signal); grade 1 or mild = mild synovitis (≤ 3 isolated signals); grade 2 or moderate = moderate synovitis (\> 3 isolated signals or a confluent signal in \< 50% of synovial area); grade 3 or marked = marked synovitis (signals in ≥ 50% of the synovial area). Each image is rated 0 to 3, for a total possible score ranging from 0 to 48 (16\*0, 16\*3) for 2 hands. Higher grade/score=more severe disease. Change = week 24 score - baseline score.

Outcome measures

Outcome measures
Measure	Adalimumab + Low Dose Methotrexate n=154 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Percentage of Participants With Power Doppler Ultrasound (PD U/S) Score for Synovial Vascularity Improvement by 30% at Week 24	45.45 percentage of participants	52.38 percentage of participants

SECONDARY outcome

Timeframe: Baseline, 24 weeks

Response, as defined by ACR50 criteria at week 24. A participant is a responder if the following 3 criteria for improvement from baseline are met: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: physician global assessment of disease activity, participant global assessment of disease activity, participant assessment of pain, disability index of the health assessment questionnaire, and acute phase reactant value (C-reactive protein).

Outcome measures

Outcome measures
Measure	Adalimumab + Low Dose Methotrexate n=154 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Percentage of Participants With American College of Rheumatology 50% (ACR50) Criteria Response at Week 24	29.80 percentage of participants	37.66 percentage of participants

SECONDARY outcome

Timeframe: Baseline, 24 weeks

Response, as defined by ACR70 criteria at week 24. A participant is a responder if the following 3 criteria for improvement from baseline are met: ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: physician global assessment of disease activity, participant global assessment of disease activity, participant assessment of pain, disability index of the health assessment questionnaire, and acute phase reactant value (C-reactive protein).

Outcome measures

Outcome measures
Measure	Adalimumab + Low Dose Methotrexate n=154 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Percentage of Participants With American College of Rheumatology 70% (ACR70) Criteria Response at Week 24	13.25 percentage of participants	20.13 percentage of participants

SECONDARY outcome

Timeframe: Baseline, 24 weeks

The HAQ-DI is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0), with some difficulty (1), with much difficulty (2), and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 (no disability) to 3 (very severe, high dependency disability). The minimal clinically important difference (MCID) defined for the HAQ-DI is a change from baseline of ≤ -0.22. Normal physical function is defined by HAQ-DI score of \< 0.5. Negative change from baseline in the overall score indicates improvement.

Outcome measures

Outcome measures
Measure	Adalimumab + Low Dose Methotrexate n=154 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Percentage of Participants With a Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) ≤ -0.22 at Week 24	63.58 percentage of participants	65.58 percentage of participants

SECONDARY outcome

Timeframe: Baseline, 24 weeks

The least squares mean percentage change in MOS Sleep Problem Index 9 from baseline to week 24. The MOS Sleep Problem Index 9 consists of 9 questions to assess sleep, including how long it takes the participant to fall asleep (1=0 to 15 minutes, to 5=more than 60 minutes); and aspects of related to quality of sleep, including how often the participant felt that the sleep was not quiet, felt rested upon waking, awakened short of breath or with a headache, felt drowsy during the day, had trouble falling sleep, how often were awaken, had trouble staying awake during the day, and got needed amount of sleep (1=all the time; 5=none of the time). Least squares means and 95% CI were from 2-way ANCOVA model with effects for baseline MOS Sleep Problem Index value, treatment group, and prior methotrexate dose group.

Outcome measures

Outcome measures
Measure	Adalimumab + Low Dose Methotrexate n=154 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Percent Change From Baseline in Medical Outcomes Study Version II (MOS) Sleep Problem Index 9 at Week 24	-15.42 percent change Interval -25.36 to -5.49	-17.27 percent change Interval -27.95 to -7.58

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: All participants with available pharmacokinetics at week 24: For Adalimumab + Low Dose Methotrexate, n = 134; for Adalimumab + High Dose Methotrexate, n = 140.

Serum trough concentrations of adalimumab assessed at week 24 (24 weeks after the 1st dose).

Outcome measures

Outcome measures
Measure	Adalimumab + Low Dose Methotrexate n=154 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 Participants Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Serum Adalimumab Trough Concentrations at Week 24	7.1 µg/mL Standard Deviation 6.2	8.6 µg/mL Standard Deviation 5.2

Adverse Events

Adalimumab + Low Dose Methotrexate

Serious events: 6 serious events

Other events: 57 other events

Deaths: 0 deaths

Adalimumab + High Dose Methotrexate

Serious events: 11 serious events

Other events: 48 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Adalimumab + Low Dose Methotrexate n=154 participants at risk Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 participants at risk Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Gastrointestinal disorders DIARRHOEA	5.8% 9/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	3.9% 6/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Gastrointestinal disorders NAUSEA	9.7% 15/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	10.3% 16/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
General disorders FATIGUE	9.1% 14/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	2.6% 4/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	9.1% 14/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	7.7% 12/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations URINARY TRACT INFECTION	5.2% 8/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	7.1% 11/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Musculoskeletal and connective tissue disorders RHEUMATOID ARTHRITIS	5.8% 9/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	3.2% 5/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Nervous system disorders DIZZINESS	6.5% 10/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	5.8% 9/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Nervous system disorders HEADACHE	6.5% 10/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	5.8% 9/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Skin and subcutaneous tissue disorders ALOPECIA	7.1% 11/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	2.6% 4/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).

Additional Information

Global Medical Services

AbbVie (prior sponsor, Abbott)

Phone: 800-633-9110

Results disclosure agreements

Principal investigator is a sponsor employee AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.
Publication restrictions are in place

Restriction type: OTHER

Measure	Adalimumab + Low Dose Methotrexate n=154 participants at risk Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, low dose methotrexate (7.5 mg orally once weekly).	Adalimumab + High Dose Methotrexate n=155 participants at risk Open-label adalimumab (40 mg subcutaneous every other week) plus blinded, high dose methotrexate (20 mg orally once weekly).
Blood and lymphatic system disorders ANAEMIA	0.65% 1/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.00% 0/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Cardiac disorders ACUTE MYOCARDIAL INFARCTION	0.65% 1/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.00% 0/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Gastrointestinal disorders COLITIS	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Gastrointestinal disorders COLITIS ISCHAEMIC	0.65% 1/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.00% 0/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
General disorders NON-CARDIAC CHEST PAIN	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations ABSCESS SOFT TISSUE	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations CELLULITIS	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations HERPES ZOSTER OPHTHALMIC	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations PNEUMONIA	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations PNEUMONIA LEGIONELLA	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations SEPTIC SHOCK	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Infections and infestations STAPHYLOCOCCAL INFECTION	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Musculoskeletal and connective tissue disorders INTERVERTEBRAL DISC DISORDER	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) BILE DUCT CANCER	0.65% 1/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.00% 0/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) UTERINE LEIOMYOMA	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Nervous system disorders TRANSIENT ISCHAEMIC ATTACK	0.65% 1/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.00% 0/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Vascular disorders DEEP VEIN THROMBOSIS	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Vascular disorders HYPOTENSION	0.00% 0/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.65% 1/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).
Vascular disorders RAYNAUD'S PHENOMENON	0.65% 1/154 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).	0.00% 0/155 • AEs that occurred from the time of study drug administration until 70 days after last dose (total 34 weeks). SAEs were to be collected from the time that informed consent was obtained until 70 days after last dose (total 41 weeks).