Table 2:
Dose adjustment for bardoxolone methyl and withdrawal criteria.
|
Dose increase
Daily dose of bardoxolone methyl will be increased at the scheduled visits when the patients meet all of the dose increase criteria. |
| 1. Decrease in eGFR at the last previous visit compared with the eGFR at baseline |
| 2. No ≥3.5% increase in body weight associated with volume overload compared with the last previous scheduled visit |
| 3. Eligible for initiation, addition or change of diuretic therapy |
| 4. No onset or worsening of symptoms/signs of uncontrollable peripheral oedema |
| 5. ≥4 weeks after the day of dose reduction, if the dose of bardoxolone methyl has been reduced |
| 6. ≥4 weeks after the day of treatment resumption, if study treatment has been resumed after interruption |
| 7. Judged by the investigator or subinvestigator that the dose of bardoxolone methyl can be increased |
| Note that the dose of bardoxolone methyl should be a maximum of 10 mg for patients receiving a potent CYP3A4 inhibitor. |
|
Dose reduction
The dose of bardoxolone methyl should be promptly reduced if patients on 10 or 15 mg meet any of the dose reduction criteria. |
| 1. A ≥3.5% increase in body weight associated with volume overload compared with the last previous scheduled visit |
| 2. An increase in the BNP level to ≥2 times the level at baseline with a value of >300 pg/ml If patients meet the above criterion while on bardoxolone methyl 5 mg, it will be interrupted according to the discretion of the investigator or subinvestigator. |
| 3. Onset or worsening of symptoms/signs of peripheral oedema as an early manifestation of acute volume overload noted during physical examination or telephone interview |
| 4. Judged by the investigator or subinvestigator that the dose of bardoxolone methyl should be reduced for reasons other than those stated above |
|
Dose interruption
The dose of bardoxolone methyl should be promptly interrupted if patients on 10 or 15 mg meet any of the dose interruption criteria. The duration of interruption should be 12 weeks at the maximum; if interruption of >12 weeks is required, bardoxolone methyl should be permanently discontinued. |
| 1. A ≥3.5% increase in body weight associated with volume overload compared with the last previous scheduled visit |
| 2. An increase in the BNP to ≥2.5 times the level at baseline with a value >400 pg/ml |
| 3. Onset or worsening of symptoms/signs of peripheral oedema as an early manifestation of acute volume overload noted during physical examination or telephone interview |
| 4. Inability to check the patient's condition after treatment for a certain period of time for patient's personal reasons, as judged by the investigator or subinvestigator |
| 5. An increase in a hepatobiliary parameter defined as any of the following parameters in the results measured at the central laboratory and the unavailability of an additional test for confirmation for these parameters within 7 days after the first test: AST or ALT >3 times the ULN or ALP >2 times the ULN |
| 6. Confirmed concrete actions to be taken for renal transplantation (such as hospitalization for renal transplantation and use of immunosuppressants) |
| 7. Judgment by the investigator or subinvestigator that the bardoxolone methyl treatment should be interrupted for reasons other than those stated above |
|
Treatment resumption
Study treatment will be resumed when any of the following criteria are met at a scheduled visit and when the investigator or subinvestigator considers it appropriate. Treatment should be resumed at the dose before interruption or at a lower dose. |
| 1. In the case of dose interruption 1, recovery to a <3.5% increase in body weight compared with the body weight measured on the last visit day before interruption with the use of medication (e.g. diuretics) |
| 2. In the case of dose interruption 2 or because of an increase in the BNP level to ≥2 times the level at baseline (with a value >300 pg/ml) while on 5 mg of bardoxolone methyl, a decrease in the BNP level to ≤300 pg/ml with the use of medication (e.g. diuretics) |
| 3. In the case of dose interruption 3, resolution or resolving of the symptoms/signs with the use of medication (e.g. diuretics) |
| 4. In the case of dose interruption 4, judgment by the investigator or subinvestigator that the safety can be checked |
| 5. In the case of dose interruption 5, a decrease in the hepatobiliary parameter to the normal range in an additional test conducted ≥8 days after the first test |
| 6. In the case of dose interruption 6, followed by the postponement of renal transplantation: for patients who have received immunosuppressants for renal transplantation, the study treatment should be resumed within 12 weeks after interruption, with a washout period of at least 8 weeks after the discontinuation of immunosuppressants. |
| 7. In other cases wherein the investigator or subinvestigator judges that study treatment can be resumed |
|
Treatment discontinuation
Treatment with bardoxolone methyl must be discontinued if patients meet any of the following criteria. When the data obtained at the central laboratory after examination at a study visit are found to meet any of criteria 6–10, instructions to discontinue bardoxolone methyl must be made immediately by telephone. |
| 1. The patient wishes to withdraw from the bardoxolone methyl |
| 2. The patient is found to not meet the eligibility criteria after the start of the study |
| 3. The patient cannot undergo necessary observations and examinations for personal reasons |
| 4. The patient becomes pregnant or intends to become pregnant |
| 5. The investigator or subinvestigator determines that the patient should be withdrawn from bardoxolone methyl because of an adverse event experienced by the patient. |
| 6. AST or ALT level >5 times the ULN |
| 7. AST or ALT level >4 times the ULN for two consecutive measurements |
| 8. AST or ALT level >3 times the ULN with total bilirubin >2 times the ULN |
| 9. AST or ALT level >3 times the ULN with pyrexia, rash or >5% increase in eosinophils |
| 10. ALP level >4 times the ULN with pyrexia, rash or >5% increase in eosinophils |
| 11. More than 12 consecutive weeks of interruption of bardoxolone methyl according to the above interruption criteria after initiation of bardoxolone methyl administration |
| 12. ESKD is judged to be present by the investigator or subinvestigator |
| 13. The investigator or subinvestigator determines that the patient should be newly prescribed SGLT2 inhibitors or GLP-1 receptor agonists |
| 14. Hospitalization for renal transplantation |
| 15. The investigator or subinvestigator determines that the patient should be withdrawn from bardoxolone methyl for a reason other than those stated above |
|
Withdrawal (early termination)
Patients who meet any of the following criteria must be withdrawn from the study. |
| 1. The patient wishes to withdraw censent from the study |
| 2. The patient does not meet the eligibility criteria after the start of the study |
| 3. The patient cannot undergo necessary observations and examinations for personal reasons |
| 4. The investigator or subinvestigator determines that the patient should be withdrawn from the study because of an adverse event experienced by the patient |
| 5. The patient becomes pregnant or intends to become pregnant |
| 6. The patient undergoes maintenance dialysis for 4 weeks |
| 7. The eGFR remains at ≤6 ml/min/1.73 m2 for 4 weeks |
| 8. The investigator or subinvestigator determines that the patient should be newly prescribed SGLT2 inhibitors or GLP-1 receptor agonists |
| 9. The patient undergoes renal transplantation |
| 10. The patient develops reduced muscle mass with severe physical inability |
| 11. The investigator or subinvestigator determines that the patient should be withdrawn from the study for a reason other than above |
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, B-type natriuretic peptide; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2; ULN, upper limit of normal.