Trial Outcomes & Findings for Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension - CATALYST (NCT NCT02657356)

NCT ID: NCT02657356

Last Updated: 2025-06-04

Results Overview

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

202 participants

Primary outcome timeframe

Baseline through 24 weeks after participant receives the first dose

Results posted on

2025-06-04

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Capsules Placebo capsules administered orally once a day for 24 weeks with sham titration.	Bardoxolone Methyl Capsules Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient was 5 mg and dose-escalated to 10 mg at Week 4, unless contraindicated clinically.
Overall Study STARTED	102	100
Overall Study COMPLETED	82	85
Overall Study NOT COMPLETED	20	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Capsules Placebo capsules administered orally once a day for 24 weeks with sham titration.	Bardoxolone Methyl Capsules Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient was 5 mg and dose-escalated to 10 mg at Week 4, unless contraindicated clinically.
Overall Study Death	1	0
Overall Study Withdrawal by Subject	5	6
Overall Study Terminated by Sponsor	8	5
Overall Study Rolled over to EAP study	6	4

Baseline Characteristics

Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension - CATALYST

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Capsules n=102 Participants Placebo capsules administered orally once a day for 24 weeks with sham titration.	Bardoxolone Methyl Capsules n=100 Participants Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient was 5 mg and dose-escalated to 10 mg at Week 4, unless contraindicated clinically.	Total n=202 Participants Total of all reporting groups
Age, Continuous	56.5 years STANDARD_DEVIATION 13.17 • n=99 Participants	55 years STANDARD_DEVIATION 13.57 • n=107 Participants	55.7 years STANDARD_DEVIATION 13.36 • n=206 Participants
Age, Customized Median Age	60 years n=99 Participants	57 years n=107 Participants	59 years n=206 Participants
Sex: Female, Male Female	91 Participants n=99 Participants	88 Participants n=107 Participants	179 Participants n=206 Participants
Sex: Female, Male Male	11 Participants n=99 Participants	12 Participants n=107 Participants	23 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	32 Participants n=99 Participants	27 Participants n=107 Participants	59 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	70 Participants n=99 Participants	73 Participants n=107 Participants	143 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	10 Participants n=99 Participants	16 Participants n=107 Participants	26 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	10 Participants n=99 Participants	6 Participants n=107 Participants	16 Participants n=206 Participants
Race (NIH/OMB) White	78 Participants n=99 Participants	76 Participants n=107 Participants	154 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=99 Participants	2 Participants n=107 Participants	6 Participants n=206 Participants
Region of Enrollment Argentina	14 participants n=99 Participants	12 participants n=107 Participants	26 participants n=206 Participants
Region of Enrollment Australia	8 participants n=99 Participants	7 participants n=107 Participants	15 participants n=206 Participants
Region of Enrollment Belgium	2 participants n=99 Participants	1 participants n=107 Participants	3 participants n=206 Participants
Region of Enrollment Brazil	5 participants n=99 Participants	4 participants n=107 Participants	9 participants n=206 Participants
Region of Enrollment Canada	5 participants n=99 Participants	5 participants n=107 Participants	10 participants n=206 Participants
Region of Enrollment Czechia	1 participants n=99 Participants	2 participants n=107 Participants	3 participants n=206 Participants
Region of Enrollment Germany	1 participants n=99 Participants	5 participants n=107 Participants	6 participants n=206 Participants
Region of Enrollment Spain	5 participants n=99 Participants	3 participants n=107 Participants	8 participants n=206 Participants
Region of Enrollment United Kingdom	1 participants n=99 Participants	2 participants n=107 Participants	3 participants n=206 Participants
Region of Enrollment Israel	2 participants n=99 Participants	2 participants n=107 Participants	4 participants n=206 Participants
Region of Enrollment Japan	7 participants n=99 Participants	9 participants n=107 Participants	16 participants n=206 Participants
Region of Enrollment Mexico	4 participants n=99 Participants	8 participants n=107 Participants	12 participants n=206 Participants
Region of Enrollment Netherlands	1 participants n=99 Participants	1 participants n=107 Participants	2 participants n=206 Participants
Region of Enrollment Philippines	1 participants n=99 Participants	4 participants n=107 Participants	5 participants n=206 Participants
Region of Enrollment United States	45 participants n=99 Participants	35 participants n=107 Participants	80 participants n=206 Participants
Six Minute Walk Distance (6MWD)	380.4 meters STANDARD_DEVIATION 91.19 • n=99 Participants	389.1 meters STANDARD_DEVIATION 107.78 • n=107 Participants	384.7 meters STANDARD_DEVIATION 99.6 • n=206 Participants

PRIMARY outcome

Timeframe: Baseline through 24 weeks after participant receives the first dose

Population: ITT population (all randomized patients categorized by their assigned treatment group regardless of treatment exposure)

Outcome measures

Outcome measures
Measure	Placebo Capsules n=102 Participants Placebo capsules administered orally once a day for 24 weeks with sham titration.	Bardoxolone Methyl Capsules n=100 Participants Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient was 5 mg and dose-escalated to 10 mg at Week 4, unless contraindicated clinically.
Change From Baseline in Six-minute-walk Distance (6MWD) Relative to Placebo at Week 24	9.25 meters Standard Error 4.954	-3.61 meters Standard Error 4.952

SECONDARY outcome

Timeframe: Baseline through the end of the study

Population: ITT population (all randomized patients categorized by their assigned treatment group regardless of treatment exposure)

At least one of the following four criteria must have been met: 1. Improvement by at least one WHO functional class coupled with no more than a 15% decrease from baseline in 6MWT 2. Increase from baseline in 6MWT by at least 10% and stability or improvement in the WHO functional class 3. Decrease from baseline in creatine kinase (a surrogate biomarker for muscle injury and inflammation) by at least 10% and no worsening in WHO functional class and no more than a 15% decrease from baseline in 6MWT 4. Improvement in estimated glomerular filtration rate eGFR ≥10% of baseline The persistence of the change in WHO functional class, 6MWT, eGFR, or creatine kinase must be confirmed by a subsequent assessment at least 14 days after the initial assessment, or at the next scheduled assessment. If persistent improvement is confirmed, the date of the event was considered the initial assessment of improved WHO functional class, 6MWT, eGFR, or creatine kinase.

Outcome measures

Outcome measures
Measure	Placebo Capsules n=102 Participants Placebo capsules administered orally once a day for 24 weeks with sham titration.	Bardoxolone Methyl Capsules n=100 Participants Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient was 5 mg and dose-escalated to 10 mg at Week 4, unless contraindicated clinically.
Time to First Persistent Clinical Improvement Event	17.9 weeks Standard Error 1.263	6.62 weeks Standard Error 0.646

Adverse Events

Placebo Capsules

Serious events: 18 serious events

Other events: 79 other events

Deaths: 1 deaths

Bardoxolone Methyl Capsules

Serious events: 16 serious events

Other events: 85 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

US Biogen Clinical Trial Center

Biogen

Phone: 866-633-4636

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Placebo Capsules n=102 participants at risk Placebo capsules administered orally once a day for 24 weeks with sham titration.	Bardoxolone Methyl Capsules n=100 participants at risk Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient was 5 mg and dose-escalated to 10 mg at Week 4, unless contraindicated clinically.
Cardiac disorders Arteriospasm coronary	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Cardiac disorders Atrial flutter	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Cardiac disorders Cardiac failure acute	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Cardiac disorders Cardiac failure congestive	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Cardiac disorders Right ventricular failure	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Ear and labyrinth disorders Vertigo	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Food poisoning	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Gastritis	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Gastrointestinal hypomotility	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Haematochezia	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Large intestine perforation	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Proctitis ulcerative	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
General disorders Chest pain	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
General disorders Non-cardiac chest pain	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
General disorders Pyrexia	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Bronchitis	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Bursitis infective	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Cellulitis	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Gastroenteritis	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Herpes zoster	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Pharyngitis streptococcal	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Pneumonia	2.9% 3/102 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	2.0% 2/100 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Pneumonia viral	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Pulmonary tuberculosis	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Tooth abscess	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Upper respiratory tract infection	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Urinary tract infection	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	2.0% 2/102 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Nervous system disorders Migraine	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Nervous system disorders Syncope	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Renal and urinary disorders Nephritis	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Respiratory, thoracic and mediastinal disorders Pulmonary arterial hypertension	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	4.0% 4/100 • Number of events 4 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.

Other adverse events
Measure	Placebo Capsules n=102 participants at risk Placebo capsules administered orally once a day for 24 weeks with sham titration.	Bardoxolone Methyl Capsules n=100 participants at risk Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient was 5 mg and dose-escalated to 10 mg at Week 4, unless contraindicated clinically.
Blood and lymphatic system disorders Iron deficiency anaemia	2.0% 2/102 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	6.0% 6/100 • Number of events 6 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Cardiac disorders Palpitations	2.0% 2/102 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Eye disorders Dry eye	2.9% 3/102 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	1.0% 1/100 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Abdominal distension	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Abdominal pain	2.9% 3/102 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Abdominal pain upper	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Abdominal tenderness	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Constipation	5.9% 6/102 • Number of events 6 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	5.0% 5/100 • Number of events 5 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Diarrhoea	20.6% 21/102 • Number of events 25 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	13.0% 13/100 • Number of events 15 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Dry mouth	2.9% 3/102 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	0.00% 0/100 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Dyspepsia	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Gastritis	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Gastrooesophageal reflux disease	3.9% 4/102 • Number of events 4 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	9.0% 9/100 • Number of events 10 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Nausea	10.8% 11/102 • Number of events 13 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	12.0% 12/100 • Number of events 12 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Gastrointestinal disorders Vomiting	6.9% 7/102 • Number of events 8 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	8.0% 8/100 • Number of events 8 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
General disorders Fatigue	12.7% 13/102 • Number of events 13 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	9.0% 9/100 • Number of events 9 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
General disorders Non-cardiac chest pain	5.9% 6/102 • Number of events 7 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
General disorders Oedema peripheral	11.8% 12/102 • Number of events 14 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	9.0% 9/100 • Number of events 9 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
General disorders Pyrexia	2.9% 3/102 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Bronchitis	4.9% 5/102 • Number of events 5 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	7.0% 7/100 • Number of events 7 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Gastroenteritis	2.0% 2/102 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	4.0% 4/100 • Number of events 4 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Influenza	6.9% 7/102 • Number of events 7 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	2.0% 2/100 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Nasopharyngitis	4.9% 5/102 • Number of events 5 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	11.0% 11/100 • Number of events 13 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Pneumonia	2.9% 3/102 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Sinusitis	3.9% 4/102 • Number of events 4 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	4.0% 4/100 • Number of events 4 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Upper respiratory tract infection	10.8% 11/102 • Number of events 15 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	19.0% 19/100 • Number of events 27 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Infections and infestations Urinary tract infection	5.9% 6/102 • Number of events 11 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	8.0% 8/100 • Number of events 11 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Injury, poisoning and procedural complications Fall	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Investigations Alanine aminotransferase increased	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	6.0% 6/100 • Number of events 6 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Investigations Aspartate aminotransferase increased	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	6.0% 6/100 • Number of events 6 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Investigations Blood alkaline phosphatase increased	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	5.0% 5/100 • Number of events 5 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Investigations Brain natriuretic peptide increased	2.0% 2/102 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Investigations Gamma-glutamyltransferase increased	2.0% 2/102 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	8.0% 8/100 • Number of events 8 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Investigations N-terminal prohormone brain natriuretic peptide increased	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	5.0% 5/100 • Number of events 5 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Investigations Weight decreased	2.0% 2/102 • Number of events 2 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	7.0% 7/100 • Number of events 7 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Metabolism and nutrition disorders Decreased appetite	2.9% 3/102 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	9.0% 9/100 • Number of events 9 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Metabolism and nutrition disorders Fluid retention	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	4.0% 4/100 • Number of events 6 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Metabolism and nutrition disorders Gout	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	5.0% 5/100 • Number of events 7 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Metabolism and nutrition disorders Hypokalaemia	0.98% 1/102 • Number of events 1 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	4.0% 4/100 • Number of events 4 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/102 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.	3.0% 3/100 • Number of events 3 • 28 weeks All adverse events that are observed or reported by the patient during the study (from the time of administration of the first dose at Day 1 until the final visit) must be reported, regardless of their relationship to study drug or their clinical significance.