A Trial of Bardoxolone Methyl in Patients With CKD at Risk of Rapid Progression (MERLIN)
Condition: Chronic Kidney Diseases
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Intervention: Bardoxolone methyl oral capsule; Placebo oral capsule
Intervention description: Bardoxolone methyl capsules dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status; Capsule containing an inert placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 81.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Advanced CKD; Chronic Kidney Disease; Bardoxolone methyl; RTA 402; eGFR; Advanced Chronic Kidney Disease

Summary:

      This multi-center, randomized, double-blind, placebo-controlled, Phase 2 trial will study the
      safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with CKD due
      to multiple etiologies at risk of rapid disease progression. Approximately 70 patients will
      be enrolled and randomized 1:1 to either bardoxolone methyl or placebo. Patients with CKD
      secondary to varying etiologies will be enrolled from age 18-70 years with eGFR ≥ 20 to < 60
      mL/min/1.73 m2, and other risk factors for rapid progression of kidney disease.

      The maximum target dose will be determined by baseline proteinuria status. Patients with
      baseline urine albumin to creatinine ratio (UACR) ≤ 300 mg/g will be titrated to a maximum
      dose of 20 mg, and patients with baseline UACR > 300 mg/g will be titrated to a maximum dose
      of 30 mg. Qualified patients will be randomized 1:1 to receive either bardoxolone methyl or
      placebo once daily (preferably in the morning) throughout a 12-week dosing period.

      Patients in the study will follow the same visit and assessment schedule. Patients will be
      assessed during treatment at Day 1, Weeks 1, 2, 4, 6, 8, and 12 and by telephone contact on
      Days 3, 10, 21, 31, 35, and 45. Date of last dose and the end-of-treatment assessments mark
      the end of the treatment period. Patients will not receive study drug during a 5-week
      off-treatment period between Weeks 12 and 17. The off-treatment (OT) period includes 5 visits
      requiring various assessments to characterize eGFR from the time of study drug
      discontinuation through Day 35 off-treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of CKD with screening eGFR (average of Screen A and Screen B eGFR values) ≥
             20 to < 60 mL/min/1.73 m2

          -  Patient must meet at least one of the following criteria:

               1. UACR ≥ 300 mg/g; OR

               2. eGFR decline at a rate of ≥ 4 mL/min/1.73 m2 in prior year; OR

               3. Hematuria defined as > 5-10 red blood cells (RBCs) per high power field (HPF,
                  manual method), or documented history of positive urinary dipstick for blood in
                  prior year, or macroscopic hematuria in prior 3 years;

          -  Systolic blood pressure ≤ 150 mmHg and diastolic blood pressure ≤ 90 mmHg at Screen A
             visit after a period of rest (≥ 5 minutes);

          -  Treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or an angiotensin
             II receptor blocker (ARB) at the maximally tolerated labeled daily dose for at least 6
             weeks prior to the Screen A visit and with no anticipated changes to dose(s) during
             study participation.

          -  Able to swallow capsules -

        Exclusion Criteria:

          -  Prior exposure to bardoxolone methyl;

          -  CKD secondary to or associated with any of the following:

               1. History of rapidly progressive glomerulonephritis (RPGN)

               2. Glomerulonephritis requiring immunosuppression in the last 6 months prior to
                  Screen A;

          -  Concomitant use of tolvaptan.

          -  Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks
             prior to Day 1 or anticipated need for immunosuppression during the study;

          -  Patients currently taking a sodium/glucose cotransporter-2 inhibitor (SGLT2i),
             requiring dose adjustments within 12 weeks prior to Day 1 or if dose is anticipated to
             change during study participation;

          -  B-type natriuretic peptide (BNP) level > 200 pg/mL at Screen A visit;

          -  Uncontrolled diabetes (HbA1c > 11.0%) at Screen A visit;

          -  Serum albumin < 3 g/dL at Screen A visit;

          -  Kidney or any other solid organ transplant recipient or a planned transplant during
             the study;

          -  Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or
             during Screening;

          -  History of clinically significant cardiac disease;

          -  Systolic blood pressure < 90 mmHg at Screen A visit after a period of rest;

          -  Body mass index < 18.5 kg/m2 at the Screen A visit;

          -  History of malignancy within 5 years prior to Screen A visit, with the exception of
             localized skin or cervical carcinomas;

          -  Coronavirus disease 2019 (COVID-19) diagnosis within 3 months prior to Screen A or
             have ever required COVID-19 related hospitalization;

          -  Participation in other interventional clinical studies within 3 months (or if relevant
             5 half-lives of that study medication, whichever is the longer) prior to Screen B;

          -  Unwilling to practice acceptable methods of birth control;

          -  Women who are pregnant or breastfeeding.