Diabetic Kidney Disease
Conditions
Brief summary
A Phase 2b Randomized, Double-blind, Placebo-controlled, Study to Evaluate the Efficacy and Safety of MEDI3506 in Subjects with Diabetic Kidney Disease
Detailed description
This is a Phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, PK, and immunogenicity of MEDI3506 on top of standard of care, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and dapagliflozin in adult subjects with diabetic kidney disease, defined as subjects with type 2 diabetes mellitus (T2DM) and an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2 with a UACR in the range of 100-3000 mg/g, who meet all eligibility criteria. Approximately 565 subjects, among multiple countries will be randomized to MEDI3506 dose 1, 2, 3 or dose 4, or placebo during a treatment period of 24 weeks. All subjects will receive Dapagliflozin daily, as administered orally from Day 85 to Day 168. The primary objective is to evaluate the effect of MEDI3506 on albuminuria in subjects with DKD. Secondary objectives include evaluating safety, PK and the incidence of ADA during the treatment period.
Interventions
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blinded study in which MEDI3506 and placebo. Neither the subject nor any of the investigator or sponsor staff who are involved in the treatment or clinical evaluation of the subjects will be aware of the treatment received.
Intervention model description
Eligible subjects will be randomized to receive MEDI3506 or placebo as follows: Group 1: MEDI3506 Dose 1. Group 2: MEDI3506 Dose 2. Group 3: MEDI3506 Dose 3 Group 4: MEDI3506 Dose 4 Group 5: Placebo (volume matched) All subjects will receive Dapa from Day 85 to Day 168.
Eligibility
Sex/Gender
ALL
Age
18 Years to 101 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria 1. Adult men or women ≥ 18 years of age. 2. Diabetic kidney disease DKD defined as: 1. diagnosis of T2DM 2. eGFR 25-75 mL/min/1.73 m2 3. UACR 100-3000 mg albumin/g creatinine 3. BP ≤ 150/100 mmHg 4. Stable dose of ACEi or ARB Key
Exclusion criteria
1\. Serum potassium \> 5.5 mmol/L 2. Significant hepatic disease 3. Hemoglobin A1c \> 10.5 % 4. B-type natriuretic peptide level \> 200 pg/mL 5. History of clinically significant heart disease 6. Anticipated dialysis or renal transplantation within 1 year 7. History of underlying condition that predisposes the subject to infections 8. Significant infection (viral, bacterial, or fungal) 9. Amputation due to peripheral artery disease 10. Subjects with a positive diagnostic nucleic acid test for SARS-CoV-2 11. Pregnancy, breastfeeding or intention to become pregnant during the course of the study, 12. Any other medical condition or clinically relevant abnormal findings in physical examination, laboratory results, or electrocardiogram (ECG) during screening that, in the opinion of the investigator, may compromise the safety of the subject in the study, reduce the subject's ability to participate in the study, or interfere with evaluation of the investigational product
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Day 169 (Week 24) in UACR - Per Protocol Population | From baseline to Day 169 | UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from baseline up to Day 169. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Day 85 (Week 12) to Day 169 (Week 24) in UACR - Per Protocol Population | From Day 85 to Day 169 | UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from Day 85 up to Day 169. |
| Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | Baseline and Day 169 | UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. Only participants with values at Baseline and Day 169 are included. |
| Percent Change From Baseline to Day 169 (Week 24) in UACR - Full Analysis Population | From baseline to Day 169 | UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from baseline up to Day 169. |
| Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Day 1 to Day 230 | For participants tested positive for COVID-19 during the intervention and follow-up periods, this analysis provides: * the number and proportion of subjects with any treatment-emergent adverse event * the number and proportion of subjects with any treatment-emergent serious adverse event |
| Percent Change From Baseline to Day 85 (Week 12) in UACR - Per Protocol Population | From baseline to Day 85 | UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from baseline up to Day 169. |
| Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | Baseline and Day 169 | UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. Only participants with values at Baseline and Day 169 are included. |
| Immunogenicity of MEDI3506 - PK Analysis Population | Day 1 to Day 230 | ADA prevalence: number of participants ADA positive (ADA+) at baseline and/or post-baseline. Treatment-induced ADA+: ADA not detected or missing at baseline and at least one post-baseline ADA+. Treatment-boosted ADA+: ADA+ at baseline and baseline titre is boosted by ≥ 4-fold increase at ≥ 1 post-baseline time point. Treatment-emergent ADA+ (TE-ADA + or ADA incidence): Treatment-induced ADA+ OR and Treatment-boosted ADA+. |
| Asymptomatic Participants Tested Positive for COVID-19 During the Study - Safety Analysis Population | Day 1 to Day 230 | Participants were tested for COVID-19 during the course of the study. Descriptive analysis of asymptomatic participants tested positive for COVID-19 during the study. |
| Percent Change From Baseline to Day 85 (Week 12) in UACR - Full Analysis Population | From baseline to Day 85 | UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from baseline up to Day 169. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration of MEDI3506 - PK Analysis Population | Day 1, Day 29, Day 85 and Day 169 | MEDI3506/Tozorakimab serum concentrations were measured using a validated assay method. |
Countries
Argentina, Canada, Chile, Japan, Peru, South Korea, United States
Participant flow
Pre-assignment details
The following data were excluded from this analysis: * Data from patients enrolled in Phase 2a of the study: This phase was discontinued due to the COVID-19 pandemic. * Data from patients enrolled at a site that was discovered to not follow Good Clinical Practice (GCP) guidelines. * Data from patients not treated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive Placebo | 133 |
| MEDI3506 30 mg Participants were randomized to receive tozorakimab 30 mg | 95 |
| MEDI3506 60 mg Participants were randomized to receive tozorakimab 60 mg | 89 |
| MEDI3506 120 mg Participants were randomized to receive tozorakimab 120 mg | 93 |
| MEDI3506 300 mg Participants were randomized to receive tozorakimab 300 mg | 148 |
| Total | 558 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | (CRF) | 16 | 15 | 12 | 17 | 17 |
| Overall Study | Death | 1 | 1 | 1 | 1 | 1 |
| Overall Study | Due to COVID-19 Pandemic | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Enrolled in Site with GCP Breach | 6 | 1 | 2 | 2 | 4 |
| Overall Study | Lost to Follow-up | 3 | 3 | 0 | 3 | 1 |
| Overall Study | Not able to transition to phase 2b | 8 | 0 | 10 | 0 | 6 |
| Overall Study | Not Treated | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 13 | 6 | 5 | 4 | 9 |
Baseline characteristics
| Characteristic | Placebo | Total | MEDI3506 300 mg | MEDI3506 120 mg | MEDI3506 60 mg | MEDI3506 30 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 66.7 years STANDARD_DEVIATION 9.7 | 66.6 years STANDARD_DEVIATION 9.9 | 65.9 years STANDARD_DEVIATION 10.1 | 66.6 years STANDARD_DEVIATION 9.7 | 67.2 years STANDARD_DEVIATION 10.1 | 67.1 years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 61 Participants | 288 Participants | 81 Participants | 53 Participants | 31 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 72 Participants | 270 Participants | 67 Participants | 40 Participants | 58 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race American Indian or Alaska Native | 2 Participants | 12 Participants | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Race Asian | 29 Participants | 114 Participants | 29 Participants | 17 Participants | 24 Participants | 15 Participants |
| Race (NIH/OMB) Race Black or African American | 16 Participants | 48 Participants | 13 Participants | 4 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) Race More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race Native Hawaiian or Other Pacific Islander | 1 Participants | 8 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Race Unknown or Not Reported | 3 Participants | 11 Participants | 4 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race White | 81 Participants | 364 Participants | 96 Participants | 66 Participants | 53 Participants | 68 Participants |
| Region of Enrollment Argentina | 20 Participants | 113 Participants | 25 Participants | 28 Participants | 12 Participants | 28 Participants |
| Region of Enrollment Canada | 4 Participants | 21 Participants | 6 Participants | 2 Participants | 7 Participants | 2 Participants |
| Region of Enrollment Chile | 13 Participants | 53 Participants | 17 Participants | 9 Participants | 2 Participants | 12 Participants |
| Region of Enrollment Japan | 20 Participants | 75 Participants | 18 Participants | 11 Participants | 15 Participants | 11 Participants |
| Region of Enrollment Korea, Republic of; South Korea | 4 Participants | 15 Participants | 3 Participants | 3 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Peru | 0 Participants | 7 Participants | 4 Participants | 0 Participants | 0 Participants | 3 Participants |
| Region of Enrollment United States | 72 Participants | 274 Participants | 75 Participants | 40 Participants | 51 Participants | 36 Participants |
| Sex: Female, Male Sex Female | 46 Participants | 169 Participants | 43 Participants | 24 Participants | 23 Participants | 33 Participants |
| Sex: Female, Male Sex Male | 87 Participants | 389 Participants | 105 Participants | 69 Participants | 66 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 133 | 1 / 95 | 1 / 89 | 1 / 93 | 1 / 148 |
| other Total, other adverse events | 62 / 133 | 55 / 95 | 39 / 89 | 48 / 93 | 74 / 148 |
| serious Total, serious adverse events | 15 / 133 | 14 / 95 | 5 / 89 | 12 / 93 | 11 / 148 |
Outcome results
Primary
Percent Change From Baseline to Day 169 (Week 24) in UACR - Per Protocol Population
UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from baseline up to Day 169.
Time frame: From baseline to Day 169
Population: Per Protocol Population:~All randomized participants who received any study drug and did not violate any relevant important protocol deviations affecting the primary efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to Day 169 (Week 24) in UACR - Per Protocol Population | -14.82 Percentage change from baseline |
| MEDI3506 30 mg | Percent Change From Baseline to Day 169 (Week 24) in UACR - Per Protocol Population | -17.25 Percentage change from baseline |
| MEDI3506 60 mg | Percent Change From Baseline to Day 169 (Week 24) in UACR - Per Protocol Population | -31.45 Percentage change from baseline |
| MEDI3506 120 mg | Percent Change From Baseline to Day 169 (Week 24) in UACR - Per Protocol Population | -29.70 Percentage change from baseline |
| MEDI3506 300 mg | Percent Change From Baseline to Day 169 (Week 24) in UACR - Per Protocol Population | -20.96 Percentage change from baseline |
p-value: 0.833890% CI: [-22.61, 21.94]MMRM
p-value: 0.116990% CI: [-35.92, 1.07]MMRM
p-value: 0.177490% CI: [-34.71, 4.32]MMRM
p-value: 0.537990% CI: [-24.05, 13.35]MMRM
Secondary
Asymptomatic Participants Tested Positive for COVID-19 During the Study - Safety Analysis Population
Participants were tested for COVID-19 during the course of the study. Descriptive analysis of asymptomatic participants tested positive for COVID-19 during the study.
Time frame: Day 1 to Day 230
Population: Safety Analysis Population:~All randomized participants who received any study drug.~Subset of participants tested positive for COVID-19 during the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Asymptomatic Participants Tested Positive for COVID-19 During the Study - Safety Analysis Population | 79 Participants |
| MEDI3506 30 mg | Asymptomatic Participants Tested Positive for COVID-19 During the Study - Safety Analysis Population | 54 Participants |
| MEDI3506 60 mg | Asymptomatic Participants Tested Positive for COVID-19 During the Study - Safety Analysis Population | 50 Participants |
| MEDI3506 120 mg | Asymptomatic Participants Tested Positive for COVID-19 During the Study - Safety Analysis Population | 53 Participants |
| MEDI3506 300 mg | Asymptomatic Participants Tested Positive for COVID-19 During the Study - Safety Analysis Population | 70 Participants |
Secondary
Immunogenicity of MEDI3506 - PK Analysis Population
ADA prevalence: number of participants ADA positive (ADA+) at baseline and/or post-baseline. Treatment-induced ADA+: ADA not detected or missing at baseline and at least one post-baseline ADA+. Treatment-boosted ADA+: ADA+ at baseline and baseline titre is boosted by ≥ 4-fold increase at ≥ 1 post-baseline time point. Treatment-emergent ADA+ (TE-ADA + or ADA incidence): Treatment-induced ADA+ OR and Treatment-boosted ADA+.
Time frame: Day 1 to Day 230
Population: PK Analysis Population:~All subjects who are randomized and receive any study drug who have at least one detectable MEDI3506 serum concentration measurement post-treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-induced ADA+ | 1 Participants |
| Placebo | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-emergent ADA+ (Treatment-induced ADA+ or Treatment-boosted ADA+) | 1 Participants |
| Placebo | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-boosted ADA+ | 0 Participants |
| MEDI3506 30 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-boosted ADA+ | 1 Participants |
| MEDI3506 30 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-induced ADA+ | 6 Participants |
| MEDI3506 30 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-emergent ADA+ (Treatment-induced ADA+ or Treatment-boosted ADA+) | 7 Participants |
| MEDI3506 60 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-boosted ADA+ | 0 Participants |
| MEDI3506 60 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-induced ADA+ | 10 Participants |
| MEDI3506 60 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-emergent ADA+ (Treatment-induced ADA+ or Treatment-boosted ADA+) | 10 Participants |
| MEDI3506 120 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-induced ADA+ | 12 Participants |
| MEDI3506 120 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-emergent ADA+ (Treatment-induced ADA+ or Treatment-boosted ADA+) | 12 Participants |
| MEDI3506 120 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-boosted ADA+ | 0 Participants |
| MEDI3506 300 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-boosted ADA+ | 2 Participants |
| MEDI3506 300 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-induced ADA+ | 12 Participants |
| MEDI3506 300 mg | Immunogenicity of MEDI3506 - PK Analysis Population | Treatment-emergent ADA+ (Treatment-induced ADA+ or Treatment-boosted ADA+) | 14 Participants |
Secondary
Percent Change From Baseline to Day 169 (Week 24) in UACR - Full Analysis Population
UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from baseline up to Day 169.
Time frame: From baseline to Day 169
Population: Full Analysis Population:~All randomized participants who received any study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to Day 169 (Week 24) in UACR - Full Analysis Population | -15.82 Percentage change from baseline |
| MEDI3506 30 mg | Percent Change From Baseline to Day 169 (Week 24) in UACR - Full Analysis Population | -13.77 Percentage change from baseline |
| MEDI3506 60 mg | Percent Change From Baseline to Day 169 (Week 24) in UACR - Full Analysis Population | -28.98 Percentage change from baseline |
| MEDI3506 120 mg | Percent Change From Baseline to Day 169 (Week 24) in UACR - Full Analysis Population | -30.94 Percentage change from baseline |
| MEDI3506 300 mg | Percent Change From Baseline to Day 169 (Week 24) in UACR - Full Analysis Population | -21.19 Percentage change from baseline |
p-value: 0.853790% CI: [-17.35, 26.95]MMRM
p-value: 0.198990% CI: [-32.14, 4.89]MMRM
p-value: 0.134690% CI: [-34.01, 1.99]MMRM
p-value: 0.568390% CI: [-22.59, 13.23]MMRM
Secondary
Percent Change From Baseline to Day 85 (Week 12) in UACR - Full Analysis Population
UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from baseline up to Day 169.
Time frame: From baseline to Day 85
Population: Full Analysis Population:~All randomized participants who received any study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to Day 85 (Week 12) in UACR - Full Analysis Population | 16.86 Percentage change from baseline |
| MEDI3506 30 mg | Percent Change From Baseline to Day 85 (Week 12) in UACR - Full Analysis Population | 7.59 Percentage change from baseline |
| MEDI3506 60 mg | Percent Change From Baseline to Day 85 (Week 12) in UACR - Full Analysis Population | -7.23 Percentage change from baseline |
| MEDI3506 120 mg | Percent Change From Baseline to Day 85 (Week 12) in UACR - Full Analysis Population | -5.03 Percentage change from baseline |
| MEDI3506 300 mg | Percent Change From Baseline to Day 85 (Week 12) in UACR - Full Analysis Population | 1.35 Percentage change from baseline |
p-value: 0.422690% CI: [-22.3, 9.1]MMRM
p-value: 0.028790% CI: [-33.25, -5.58]MMRM
p-value: 0.049890% CI: [-31.7, -3.3]MMRM
p-value: 0.123690% CI: [-25.51, 0.98]MMRM
Secondary
Percent Change From Baseline to Day 85 (Week 12) in UACR - Per Protocol Population
UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from baseline up to Day 169.
Time frame: From baseline to Day 85
Population: Per Protocol Population:~All randomized participants who received any study drug and did not violate any relevant important protocol deviations affecting the primary efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline to Day 85 (Week 12) in UACR - Per Protocol Population | 21.60 Percentage change from baseline |
| MEDI3506 30 mg | Percent Change From Baseline to Day 85 (Week 12) in UACR - Per Protocol Population | 5.77 Percentage change from baseline |
| MEDI3506 60 mg | Percent Change From Baseline to Day 85 (Week 12) in UACR - Per Protocol Population | -9.66 Percentage change from baseline |
| MEDI3506 120 mg | Percent Change From Baseline to Day 85 (Week 12) in UACR - Per Protocol Population | -0.53 Percentage change from baseline |
| MEDI3506 300 mg | Percent Change From Baseline to Day 85 (Week 12) in UACR - Per Protocol Population | 2.69 Percentage change from baseline |
p-value: 0.192990% CI: [-27.08, 3.75]MMRM
p-value: 0.006290% CI: [-37.83, -11.22]MMRM
p-value: 0.070590% CI: [-31.86, -1.81]MMRM
p-value: 0.076490% CI: [-27.82, -1.21]MMRM
Secondary
Percent Change From Day 85 (Week 12) to Day 169 (Week 24) in UACR - Per Protocol Population
UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. For the intercurrent events, if a subject is lost to follow-up (EOT), discontinues treatment due to AE, or uses prohibited medication, the UACR data are treated as missing on or after the event and no imputation is performed. The LS means of percent change and difference in percent change, corresponding 90% confidence intervals are calculated based on a mixed model with repeated measures (MMRM) of log (UACR post-baseline/UACR baseline) as the response, adjusting for fixed effects of treatment, visit, and treatment-by-visit interaction, SGLT2i, region (Japan or ROW), baseline log UACR, and baseline log UACR-by-visit interaction. The MMRM includes UACR values at protocol specified visits from Day 85 up to Day 169.
Time frame: From Day 85 to Day 169
Population: Per Protocol Population:~All randomized participants who received any study drug and did not violate any relevant important protocol deviations affecting the primary efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Percent Change From Day 85 (Week 12) to Day 169 (Week 24) in UACR - Per Protocol Population | -23.26 Percentage change from baseline |
| MEDI3506 30 mg | Percent Change From Day 85 (Week 12) to Day 169 (Week 24) in UACR - Per Protocol Population | -17.69 Percentage change from baseline |
| MEDI3506 60 mg | Percent Change From Day 85 (Week 12) to Day 169 (Week 24) in UACR - Per Protocol Population | -20.87 Percentage change from baseline |
| MEDI3506 120 mg | Percent Change From Day 85 (Week 12) to Day 169 (Week 24) in UACR - Per Protocol Population | -25.87 Percentage change from baseline |
| MEDI3506 300 mg | Percent Change From Day 85 (Week 12) to Day 169 (Week 24) in UACR - Per Protocol Population | -19.21 Percentage change from baseline |
p-value: 0.547490% CI: [-11.45, 29.88]MMRM
p-value: 0.79290% CI: [-14.83, 24.82]MMRM
p-value: 0.771190% CI: [-20.59, 17.51]MMRM
p-value: 0.616390% CI: [-11.08, 24.62]MMRM
Secondary
Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population
UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. Only participants with values at Baseline and Day 169 are included.
Time frame: Baseline and Day 169
Population: Full Analysis Population:~All randomized participants who received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 50% | 26 Participants |
| Placebo | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 40% | 37 Participants |
| Placebo | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 30% | 49 Participants |
| MEDI3506 30 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 30% | 36 Participants |
| MEDI3506 30 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 40% | 25 Participants |
| MEDI3506 30 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 50% | 18 Participants |
| MEDI3506 60 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 40% | 23 Participants |
| MEDI3506 60 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 50% | 19 Participants |
| MEDI3506 60 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 30% | 28 Participants |
| MEDI3506 120 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 40% | 32 Participants |
| MEDI3506 120 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 30% | 41 Participants |
| MEDI3506 120 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 50% | 26 Participants |
| MEDI3506 300 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 40% | 48 Participants |
| MEDI3506 300 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 50% | 38 Participants |
| MEDI3506 300 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Full Analysis Population | UACR reduction > 30% | 62 Participants |
Secondary
Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population
UACR values are collected as triplicates at baseline and at each CSP planned visit. For each triplicate, the UACR are averaged with geometric mean. Baseline is defined as the geometric mean of UACR measurements prior to first dose of study treatment. Only participants with values at Baseline and Day 169 are included.
Time frame: Baseline and Day 169
Population: Per Protocol Population:~All randomized participants who received any study drug and did not violate any relevant important protocol deviations affecting the primary efficacy endpoint.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 30% | 43 Participants |
| Placebo | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 40% | 33 Participants |
| Placebo | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 50% | 22 Participants |
| MEDI3506 30 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 30% | 34 Participants |
| MEDI3506 30 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 50% | 17 Participants |
| MEDI3506 30 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 40% | 23 Participants |
| MEDI3506 60 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 30% | 28 Participants |
| MEDI3506 60 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 50% | 19 Participants |
| MEDI3506 60 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 40% | 23 Participants |
| MEDI3506 120 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 40% | 29 Participants |
| MEDI3506 120 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 30% | 38 Participants |
| MEDI3506 120 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 50% | 23 Participants |
| MEDI3506 300 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 50% | 35 Participants |
| MEDI3506 300 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 30% | 59 Participants |
| MEDI3506 300 mg | Proportion of Subjects With Reduction in UACR at Day 169 (Week 24) - Per Protocol Population | UACR reduction > 40% | 45 Participants |
Secondary
Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population
For participants tested positive for COVID-19 during the intervention and follow-up periods, this analysis provides: * the number and proportion of subjects with any treatment-emergent adverse event * the number and proportion of subjects with any treatment-emergent serious adverse event
Time frame: Day 1 to Day 230
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any serious adverse event | 11 Participants |
| Placebo | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any adverse event | 47 Participants |
| MEDI3506 30 mg | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any adverse event | 35 Participants |
| MEDI3506 30 mg | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any serious adverse event | 9 Participants |
| MEDI3506 60 mg | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any serious adverse event | 1 Participants |
| MEDI3506 60 mg | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any adverse event | 23 Participants |
| MEDI3506 120 mg | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any adverse event | 30 Participants |
| MEDI3506 120 mg | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any serious adverse event | 6 Participants |
| MEDI3506 300 mg | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any serious adverse event | 3 Participants |
| MEDI3506 300 mg | Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events Among COVID-19 Positive Participants - Safety Analysis Population | Any adverse event | 40 Participants |
Other Pre-specified
Plasma Concentration of MEDI3506 - PK Analysis Population
MEDI3506/Tozorakimab serum concentrations were measured using a validated assay method.
Time frame: Day 1, Day 29, Day 85 and Day 169
Population: PK Analysis Population:~All subjects who are randomized and receive any study drug who have at least one detectable MEDI3506 serum concentration measurement post-treatment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 29 | 0.01983 ng/mL | Geometric Coefficient of Variation 533.3 |
| Placebo | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 169 | 0.02435 ng/mL | Geometric Coefficient of Variation 919.4 |
| Placebo | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 1 | 0.01063 ng/mL | Geometric Coefficient of Variation 418.9 |
| Placebo | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 85 | 0.02898 ng/mL | Geometric Coefficient of Variation 711.3 |
| MEDI3506 30 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 1 | 0.005232 ng/mL | Geometric Coefficient of Variation 38.16 |
| MEDI3506 30 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 29 | 0.2185 ng/mL | Geometric Coefficient of Variation 110.3 |
| MEDI3506 30 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 169 | 0.2495 ng/mL | Geometric Coefficient of Variation 132.2 |
| MEDI3506 30 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 85 | 0.2754 ng/mL | Geometric Coefficient of Variation 155.6 |
| MEDI3506 60 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 29 | 0.4454 ng/mL | Geometric Coefficient of Variation 144.4 |
| MEDI3506 60 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 1 | 0.005261 ng/mL | Geometric Coefficient of Variation 33.33 |
| MEDI3506 60 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 169 | 0.4231 ng/mL | Geometric Coefficient of Variation 188.4 |
| MEDI3506 60 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 85 | 0.4701 ng/mL | Geometric Coefficient of Variation 140.1 |
| MEDI3506 120 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 29 | 0.7036 ng/mL | Geometric Coefficient of Variation 119.7 |
| MEDI3506 120 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 1 | 0.005111 ng/mL | Geometric Coefficient of Variation 12.3 |
| MEDI3506 120 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 169 | 0.7027 ng/mL | Geometric Coefficient of Variation 200.1 |
| MEDI3506 120 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 85 | 0.9547 ng/mL | Geometric Coefficient of Variation 103.2 |
| MEDI3506 300 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 29 | 1.884 ng/mL | Geometric Coefficient of Variation 64.34 |
| MEDI3506 300 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 1 | 0.005443 ng/mL | Geometric Coefficient of Variation 79.38 |
| MEDI3506 300 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 85 | 2.326 ng/mL | Geometric Coefficient of Variation 80.1 |
| MEDI3506 300 mg | Plasma Concentration of MEDI3506 - PK Analysis Population | Day 169 | 2.402 ng/mL | Geometric Coefficient of Variation 91.04 |