Primary IgA Nephropathy
Conditions
Brief summary
This is a Phase 3b, multicenter, open-label extension (OLE) study to evaluate the efficacy and safety of Nefecon treatment in patients with IgAN who have completed the Phase 3 Study Nef-301 and continue to be treated with a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs). Patients who previously received Nefecon in Study Nef-301 will receive retreatment, whereas patients who previously received placebo in Study Nef-301 will be treatment naïve to Nefecon.
Detailed description
This is a Phase 3b, multicenter, open-label extension (OLE) study to evaluate the efficacy and safety of Nefecon treatment in patients with IgAN who have completed the Phase 3 Study Nef 301 and continue to be treated with a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs). Patients who previously received Nefecon in Study Nef-301 will receive retreatment, whereas patients who previously received placebo in Study Nef-301 will be treatment naïve to Nefecon. During Study Nef-301 OLE, the patients and Investigators will remain blinded to treatment given in Study Nef-301. During Study Nef-301 OLE, patients will receive Nefecon for a 9-month period. The dose may be reduced if clinically relevant adverse events (AEs) develop during the 9-month Treatment Period that the Investigator considers related to the study drug and that mandate dose reduction. Patients will remain on a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) throughout the study. The patient will come for a follow-up visit at 12 months after first dose.
Interventions
DRUGNefecon 16mg daily
All study patients received Nefecon 16 mg daily for 9 months.
Sponsors
Calliditas Therapeutics AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open label, single-arm study with active treatment
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients that completed study Nef-301 2. On a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) at the maximum allowed dose or maximum tolerated dose according to the 2012 KDIGO guidelines 3. Willing and able to provide written informed consent. 4. UPCR equal to or more than 0.8 g/gram 5. eGFR equal to or more than 30 mL/min per 1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
Exclusion criteria
1. Systemic diseases that may cause mesangial IgA deposition. 2. Patients who have undergone a kidney transplant; 3. Patients with presence of other glomerulopathies and/or nephrotic syndrome 4. Patients with acute, chronic, or latent infectious disease including hepatitis, tuberculosis (TB), human immunodeficiency virus (HIV), and chronic urinary tract infections; 5. Patients with liver cirrhosis, as assessed by the Investigator; 6. Patients with a diagnosis of type 1 or type 2 diabetes mellitus which is poorly controlled 7. Patients with history of unstable angina, class III or IV congestive heart failure, and/or clinically significant arrhythmia, as judged by the Investigator; 8. Patients with unacceptable blood pressure control defined as a blood pressure consistently above national guidelines for proteinuric renal disease, as assessed by the Investigator. 9. Patients with diagnosed malignancy within the past 5 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio of Urine Protein to Creatine Ratio (UPCR) at 9 Months Compared to Baseline | 9 months | The outcome is measured as UPCR based on 24 hour urine collections at 9 months following the first dose of Nefecon compared to baseline Ratio being: UPCR at 9 months in g/gram divided with UPCR at Baseline in g/gram |
| Ratio of Estimated Glomerular Filtration Rate (eGFR) at 9 Months Compared to Baseline | 9 months | The outcome is measured as ratio of eGFR in mL/min/1.73 m2 (calculated using the CKD-EPI formula) at 9 months following the first dose of Nefecon compared to baseline. I.e. eGFR at 9 months divided by eGFR at Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Microhematuria at 9 Months Compared to Baseline | 9 months | — |
| Number of Patients Receiving Rescue Treatment | 12 months | Systemic immunosuppressive drugs (including glucocorticoids in some situations ), dialysis, and renal transplantation are considered as rescue medications in this study. |
| Ratio of Urine Albumin to Creatinine Ratio (UACR) at 9 Months Compared to Baseline | 9 months | Ratio of urine albumin to creatinine ratio (UACR) measured by 24h urine sampling at 9 months compared to baseline. I.e. UACR at 9 months divided by eGFR at Baseline. |
| Change From Baseline Cortisol Suppression at 9 Months | Baseline & 9 months | Cortisol suppression at 9 and 12 months, measured as urinary cortisol excretion over 24 hours compared to baseline. |
| Change From Baseline Cortisol Suppression at 12 Months | Baseline & 12 months | Cortisol suppression at 9 and 12 months, measured as urinary cortisol excretion over 24 hours compared to baseline. |
| Proportion of Patients on Dialysis, Undergoing Kidney Transplantation, or With eGFR <15 mL/Min Per 1.73 m2 | 12 months | Looking at number of patients with end stage kidney disease defined as being on dialysis, undergoing kidney transplantation, or having eGFR \<15 mL/min per 1.73 m2 |
| Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Baseline & 12 months | Short Form 36 (SF-36) quality of life assessment at 12 months compared to baseline, i.e. change from baseline. The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting and have been widely used. It consists of eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Higher scores indicate better health. Scores represent the percentage of total possible score achieved, i.e. 0 is the minimum and 100 is the maximum score. |
Countries
Argentina, Australia, Belarus, Belgium, Canada, Czechia, Finland, France, Germany, Greece, Italy, Poland, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study Nef-301-OLE study is an extension study to the Nef-301 study. Study results are analyzed based on treatment in the previous Nef-301 study where patients were randomized to receive either Nefecon or Placebo. Thus, in this Nef-301-OLE study the patients are either retreated with Nefecon or receiving Nefecon for the first time. | 45 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study Nef-301-OLE study is an extension study to the Nef-301 study. Study results are analyzed based on treatment in the previous Nef-301 study where patients were randomized to receive either Nefecon or Placebo. Thus, in this Nef-301-OLE study the patients are either retreated with Nefecon or receiving Nefecon for the first time. | 74 |
| Total | 119 |
Baseline characteristics
| Characteristic | Retreatment - Previously Treated With Nefecon in Nef-301 Study | Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Total |
|---|---|---|---|
| Age, Continuous | 46 years | 47 years | 47 years |
| Baseline Estimated glomerular filtration rate (eGFR) | 51.0 ml/min/1.73 m2 | 49.9 ml/min/1.73 m2 | 50.3 ml/min/1.73 m2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 36 Participants | 64 Participants | 100 Participants |
| Region of Enrollment Argentina | 6 participants | 3 participants | 9 participants |
| Region of Enrollment Australia | 2 participants | 7 participants | 9 participants |
| Region of Enrollment Belarus | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Belgium | 4 participants | 3 participants | 7 participants |
| Region of Enrollment Canada | 7 participants | 7 participants | 14 participants |
| Region of Enrollment Czechia | 2 participants | 13 participants | 15 participants |
| Region of Enrollment Finland | 1 participants | 3 participants | 4 participants |
| Region of Enrollment France | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Germany | 3 participants | 8 participants | 11 participants |
| Region of Enrollment Greece | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Italy | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Poland | 0 participants | 3 participants | 3 participants |
| Region of Enrollment South Korea | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Spain | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Sweden | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Turkey | 0 participants | 2 participants | 2 participants |
| Region of Enrollment United Kingdom | 3 participants | 3 participants | 6 participants |
| Region of Enrollment United States | 6 participants | 5 participants | 11 participants |
| Sex: Female, Male Female | 6 Participants | 19 Participants | 25 Participants |
| Sex: Female, Male Male | 39 Participants | 55 Participants | 94 Participants |
| Urine Protein to Creatine Ratio (UPCR) | 1.253 g/gram | 1.339 g/gram | 1.306 g/gram |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 74 |
| other Total, other adverse events | 32 / 45 | 46 / 74 |
| serious Total, serious adverse events | 5 / 45 | 5 / 74 |
Outcome results
Primary
Ratio of Estimated Glomerular Filtration Rate (eGFR) at 9 Months Compared to Baseline
The outcome is measured as ratio of eGFR in mL/min/1.73 m2 (calculated using the CKD-EPI formula) at 9 months following the first dose of Nefecon compared to baseline. I.e. eGFR at 9 months divided by eGFR at Baseline.
Time frame: 9 months
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Ratio of Estimated Glomerular Filtration Rate (eGFR) at 9 Months Compared to Baseline | 0.97 ratio |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Ratio of Estimated Glomerular Filtration Rate (eGFR) at 9 Months Compared to Baseline | 0.97 ratio |
Primary
Ratio of Urine Protein to Creatine Ratio (UPCR) at 9 Months Compared to Baseline
The outcome is measured as UPCR based on 24 hour urine collections at 9 months following the first dose of Nefecon compared to baseline Ratio being: UPCR at 9 months in g/gram divided with UPCR at Baseline in g/gram
Time frame: 9 months
Population: Number of participants analyzed reflects number of patients with available data at baseline and 9 months .
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Ratio of Urine Protein to Creatine Ratio (UPCR) at 9 Months Compared to Baseline | 0.67 ratio |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Ratio of Urine Protein to Creatine Ratio (UPCR) at 9 Months Compared to Baseline | 0.69 ratio |
Secondary
Change From Baseline Cortisol Suppression at 12 Months
Cortisol suppression at 9 and 12 months, measured as urinary cortisol excretion over 24 hours compared to baseline.
Time frame: Baseline & 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Cortisol Suppression at 12 Months | -7.660 ug/day | Standard Deviation 27.4262 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Cortisol Suppression at 12 Months | -11.954 ug/day | Standard Deviation 25.8052 |
Secondary
Change From Baseline Cortisol Suppression at 9 Months
Cortisol suppression at 9 and 12 months, measured as urinary cortisol excretion over 24 hours compared to baseline.
Time frame: Baseline & 9 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Cortisol Suppression at 9 Months | -24.122 ug/day) | Standard Deviation 25.169 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Cortisol Suppression at 9 Months | -32.126 ug/day) | Standard Deviation 30.6978 |
Secondary
Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months
Short Form 36 (SF-36) quality of life assessment at 12 months compared to baseline, i.e. change from baseline. The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting and have been widely used. It consists of eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Higher scores indicate better health. Scores represent the percentage of total possible score achieved, i.e. 0 is the minimum and 100 is the maximum score.
Time frame: Baseline & 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Bodily Pain | -4.518 Change in percentage of total Score | Standard Deviation 10.0522 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | General Health | -4.290 Change in percentage of total Score | Standard Deviation 7.4076 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Mental Component Summary | -2.282 Change in percentage of total Score | Standard Deviation 7.127 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Mental Health | -1.725 Change in percentage of total Score | Standard Deviation 7.1576 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Physical Component Summary | -3.952 Change in percentage of total Score | Standard Deviation 6.6367 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Physical Functioning | -2.697 Change in percentage of total Score | Standard Deviation 7.467 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Role Emotional | -2.928 Change in percentage of total Score | Standard Deviation 7.239 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Role Physical | -3.421 Change in percentage of total Score | Standard Deviation 7.1914 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Social Function | -4.102 Change in percentage of total Score | Standard Deviation 8.4631 |
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Vitality | -2.633 Change in percentage of total Score | Standard Deviation 7.6406 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Role Physical | -2.793 Change in percentage of total Score | Standard Deviation 7.6901 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Bodily Pain | -3.756 Change in percentage of total Score | Standard Deviation 9.9213 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Physical Functioning | -1.996 Change in percentage of total Score | Standard Deviation 6.6726 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | General Health | -3.301 Change in percentage of total Score | Standard Deviation 5.8211 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Vitality | -2.376 Change in percentage of total Score | Standard Deviation 7.6968 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Mental Component Summary | -1.061 Change in percentage of total Score | Standard Deviation 6.6251 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Role Emotional | -0.747 Change in percentage of total Score | Standard Deviation 7.4962 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Mental Health | -1.570 Change in percentage of total Score | Standard Deviation 6.3522 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Social Function | -2.364 Change in percentage of total Score | Standard Deviation 6.3713 |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Change From Baseline Short Form 36 (SF-36) Quality of Life Assessment at 12 Months | Physical Component Summary | -3.403 Change in percentage of total Score | Standard Deviation 6.1115 |
Secondary
Number of Patients Receiving Rescue Treatment
Systemic immunosuppressive drugs (including glucocorticoids in some situations ), dialysis, and renal transplantation are considered as rescue medications in this study.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Number of Patients Receiving Rescue Treatment | 1 Participants |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Number of Patients Receiving Rescue Treatment | 0 Participants |
Secondary
Number of Patients With Microhematuria at 9 Months Compared to Baseline
Time frame: 9 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Number of Patients With Microhematuria at 9 Months Compared to Baseline | 10 Participants |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Number of Patients With Microhematuria at 9 Months Compared to Baseline | 17 Participants |
Secondary
Proportion of Patients on Dialysis, Undergoing Kidney Transplantation, or With eGFR <15 mL/Min Per 1.73 m2
Looking at number of patients with end stage kidney disease defined as being on dialysis, undergoing kidney transplantation, or having eGFR \<15 mL/min per 1.73 m2
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Proportion of Patients on Dialysis, Undergoing Kidney Transplantation, or With eGFR <15 mL/Min Per 1.73 m2 | 2 Participants |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Proportion of Patients on Dialysis, Undergoing Kidney Transplantation, or With eGFR <15 mL/Min Per 1.73 m2 | 0 Participants |
Secondary
Ratio of Urine Albumin to Creatinine Ratio (UACR) at 9 Months Compared to Baseline
Ratio of urine albumin to creatinine ratio (UACR) measured by 24h urine sampling at 9 months compared to baseline. I.e. UACR at 9 months divided by eGFR at Baseline.
Time frame: 9 months
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Retreatment - Previously Treated With Nefecon in Nef-301 Study | Ratio of Urine Albumin to Creatinine Ratio (UACR) at 9 Months Compared to Baseline | 0.60 ratio |
| Delayed Treatment - Previously Treated With Placebo in Nef-301 Study | Ratio of Urine Albumin to Creatinine Ratio (UACR) at 9 Months Compared to Baseline | 0.65 ratio |