MO230A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF ATRASENTAN IN PATIENTS WITH IGA NEPHROPATHY (THE ALIGN STUDY)

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Hiddo Lambers Heerspink ◽  
Donald Kohan ◽  
Richard Lafayette ◽  
Adeera Levin ◽  
Hong Zhang ◽  
...  
Keyword(s):  
High Risk ◽  
Kidney Disease ◽  
Iga Nephropathy ◽  
Kidney Function ◽  
Receptor Activation ◽  
End Stage Kidney Disease ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
End Stage

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally and an important cause of chronic kidney disease (CKD). Up to 40% of IgAN patients are at risk of progressing to end-stage kidney disease (ESKD) and proteinuria is the strongest predictor of progression. There are no approved therapies for IgAN, leaving an important need for new strategies to lower proteinuria and preserve kidney function in high-risk patients. Endothelin A (ETA) receptor activation drives proteinuria, along with kidney inflammation and fibrosis. Atrasentan, a potent and selective ETA antagonist, has been studied extensively in >5,000 patients with type 2 diabetes and kidney disease (DKD), demonstrating clinically significant and sustained reductions in proteinuria when administered on top of a maximum tolerated dose of RAS inhibitor (RASi). In a global Phase 3 outcome study in DKD (SONAR), atrasentan demonstrated a 35% reduced risk of the primary composite outcome of doubling of serum creatinine or end stage kidney disease (95% CI: 0.49, 0.88; P = 0.005). The most common adverse event was fluid retention. Selective ETA blockade represents a promising approach to reduce proteinuria and preserve kidney function in high risk IgAN patients. This is a presentation of a global, phase 3, double-blind, placebo-controlled trial to determine the effect of atrasentan in IgAN patients at high risk of kidney function loss. Method Approximately 320 patients across North America, South America, Europe, and Asia-Pacific with biopsy-proven IgAN will be randomized to receive 0.75 mg atrasentan or placebo daily for 132 weeks. Patients will continue receiving a maximally tolerated and stable dose of a RAS inhibitor as standard of care. The study will also include patients that are unable to tolerate RAS inhibitor therapy. Additional eligibility criteria include urine protein creatinine ratio (UPCR) ≥1 g/g and eGFR ≥30 mL/min/1.73 m2. Participants will have study assessments over two and a half years with options for remote study visits using telemedicine and home health visits. The primary objective is to evaluate the effect of atrasentan versus placebo on proteinuria at Week 24. Secondary objectives include evaluating the change from baseline in eGFR, safety, and tolerability, and quality of life. Results N/A Conclusion N/A

MO148A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, PARALLEL GROUP, PHASE III STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LNP023 IN PRIMARY IGA NEPHROPATHY PATIENTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Vlado Perkovic ◽  
Brad Rovin ◽  
Hong Zhang ◽  
Naoki Kashihara ◽  
Bart Maes ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Supportive Care ◽  
Iga Nephropathy ◽  
Efficacy And Safety ◽  
Complement Pathway ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Parallel Group ◽  
Kidney Disease Progression

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is an autoimmune disease characterized by deposits of IgA1-containing immune complexes in the glomerular mesangium leading to local inflammation and subsequent decline in kidney function. Currently, there are no targeted therapies for IgAN. The KDIGO guidelines (2012) recommend optimized long-term supportive care including inhibition of the RAS (ACEi or ARB) as well as lifestyle modification for blood pressure control and proteinuria reduction. Patients who remain at high risk of progressive CKD despite maximal supportive care might be considered for high-dose corticosteroids or immunosuppressants. In recent years, mounting evidence has supported an important role for complement activation in disease onset and progression of IgAN. The alternative complement pathway (AP) and lectin complement pathway (LP) are found to be activated in 75-90% and 17-25% of IgAN patients, respectively (Floege et al 2014, Maillard et al 2015). Factor B (FB) is an essential component of C3- and C5-convertases. Iptacopan (LNP023) is an oral, first-in-class, highly potent selective inhibitor of FB and thereby blocks the activity of AP C3 and C5 convertases, inhibiting the AP as well as the amplification of the classic and lectin complement pathways. Currently, iptacopan is being evaluated in an ongoing adaptive seamless double-blind and placebo-controlled dose-ranging Phase 2 study (CLNP023X2203, Part 1 and Part 2) in patients with biopsy-confirmed IgAN and elevated proteinuria [urine protein to creatinine ratio (UPCR) ≥ 0.75 g/g]. An interim analysis (IA) at 90 days of treatment in the Part 1 study showed that iptacopan administered up to 200 mg b.i.d for 90 days was safe, well tolerated and may be effective in reducing proteinuria. A further IA combining participants in Part 1 and Part 2 will be completed in early 2021 and the pivotal phase 3 trial is to start in early 2021. Aim APPLAUSE-IgAN (NCT04578834; CLNP023A2301) is a multicenter, randomized, double-blind, placebo-controlled parallel-group Phase 3 study which aims to evaluate the efficacy and safety of iptacopan (LNP023) compared with placebo in addition to supportive therapy on proteinuria reduction and slowing kidney disease progression in primary IgAN patients. Method Adult patients diagnosed with primary IgAN (based on kidney biopsy and elevated proteinuria [UPCR ≥ 1 g/day]) will be recruited. A run-in period will ensure that patients have received ACEi/ARB at a maximally tolerated dose for at least 90 days and receive required vaccinations at least 2 weeks prior to first dosing. Patients will be randomized in a 1:1 ratio to either iptacopan 200 mg b.i.d or matching placebo for a 24-month treatment period. The trial will enroll approximately 450 participants, aiming for 430 with eGFR ≥30 mL /min/1.73m2 (main study population). About 20 participants with eGFR 20 to <30 mL/min/1.73m2 (severe renal impairment population) will also be enrolled to explore PK and safety of iptacopan in this group, but will not be included in the efficacy analyses. Primary objectives 1) At IA (when approximately 250 patients have completed the 9 months visit): To demonstrate superiority of iptacopan vs. placebo in the reduction of proteinuria. The IA results may be submitted to support accelerated/conditional approval. 2) At final analysis (when approximately 430 patients have completed 24 months of active treatment): to demonstrate superiority of iptacopan vs. placebo in slowing kidney disease progression measured by the annualized total slope of eGFR decline over 24 months. Results Recruitment will start in Q1 2021. Conclusion This trial will evaluate the efficacy of iptacopan, a promising new therapy for IgAN, in reducing proteinuria and slowing loss of kidney function over 2 years.

scholarly journals POS-380 A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF ATRASENTAN IN PATIENTS WITH IGA NEPHROPATHY (THE ALIGN STUDY)

2021 ◽  
Vol 6 (4) ◽  
pp. S164-S165
Author(s):  
H. Lambers Heerspink ◽  
D. Kohan ◽  
R. Lafayette ◽  
A. Levin ◽  
H. Zhang ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Controlled Study ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo

scholarly journals Treatment effects of Chinese medicine (Yi-Qi-Qing-Jie herbal compound) combined with immunosuppression therapies in IgA nephropathy patients with high-risk of end-stage renal disease (TCM-WINE): study protocol for a randomized controlled trial

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Shen Li ◽  
Jin-pu Li
Keyword(s):  
High Risk ◽  
Renal Disease ◽  
Iga Nephropathy ◽  
End Stage Renal Disease ◽  
Controlled Trial ◽  
Eligible Patient ◽  
Study Phase ◽  
Double Blind ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background IgA nephropathy (IgAN) is the most common glomerular disease worldwide. It has a high incidence in Asians and is more likely to progress to end-stage renal disease (ESRD). For high-risk IgAN, which is clinically characterized by massive proteinuria and renal dysfunction, however, there has been no international consensus on treatment options. Compared with other developed countries, IgAN patients in China are often found to have severe kidney function loss at initial diagnosis. Yi-Qi-Qing-Jie formula (YQF; a compound recipe of Chinese medicinal herbs) has shown potential renal protection in our previous clinical studies. To further confirm the efficacy and safety of YQF in the treatment of high-risk IgAN, we have designed a prospective double-blind randomized placebo-controlled trial. Methods/design The TCM-WINE study is a single-center, prospective, double-blind randomized placebo-controlled trial. We plan to randomize 60 participants with biopsy-proven IgAN to a YQF combined group (YQF compound combined with prednisolone, and cyclophosphamide if necessary) or an immunosuppression group (placebo-YQF combined with prednisolone, and cyclophosphamide if necessary). The two groups will enter a 48-week in-trial treatment phase and receive post-trial follow-up until study completion (3 years). All patients will receive optimal supportive care. The primary composite outcome is defined as the first occurrence of a 40% decrease in estimated glomerular filtration rate (eGFR) from the baseline lasting for 3 months, initiating continuous renal replacement treatment, or death due to chronic kidney disease (CKD) during the 3-year study phase. The secondary endpoint events are defined as the mean annual eGFR decline rate (eGFR slope, ml/min per 1.73 m2 per year), which is calculated by the eGFR regression curve for each eligible patient, and proteinuria remission (prescribed as proteinuria < 0.5 g/day) at weeks 24, 36, and 48 during the in-trial phase. The remission rate of symptoms and inflammation status will be evaluated at week 48. Safety monitoring and assessment will be undertaken during the study. Discussion The TCM-WINE study will evaluate the effects and safety of YQF combined therapy compared with immunosuppression monotherapy on the basis of the optimal supportive treatment in high-risk IgAN. The evidence from this study will provide a novel, effective, and safe Chinese characteristic therapy for high-risk IgAN patients. Trial registration ClinicalTrials.gov, NCT03418779. Registered on 18 June 2018.

scholarly journals The burden of unrecognised chronic kidney disease in patients with type 2 diabetes at a county hospital clinic in Kenya: implications to care and need for screening.

2019 ◽  
Author(s):  
Frederick C. F. Otieno ◽  
Elijah N Ogola ◽  
Mercy W Kimando ◽  
Ken K Mutai
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
High Risk ◽  
Kidney Disease ◽  
County Hospital ◽  
End Stage Kidney Disease ◽  
Long Duration ◽  
End Stage

Abstract Background: Chronic Kidney Disease (CKD) in patients with type 2 diabetes enhances the cardiovascular risk profiles and disease, and is a strong predictor of progression to end-stage kidney disease. Early diagnosis is encouraged for referral to specialist kidney care to initiate active management that would optimize outcomes including forestalling progression to end-stage kidney disease. This study was conducted in a regional referral public health facility in Central Kenya with a high prevalence of type 2 diabetes. It was aimed at finding out the burden of undiagnosed chronic kidney disease in their clinic of ambulatory patients with type 2 diabetes who dwell mainly in the rural area. Methods: A cross-sectional study was conducted at the out-patient of Nyeri County hospital. A total of 385 patients were enrolled over five months. Informed consent was obtained and clinical evaluation was done, a spot sample of urine obtained for albuminuria and venous blood drawn for HbA1c, Lipids and serum creatinine. Estimated GFR (eGFR) was calculated using the Cockroft-Gault equation. Chronic kidney disease (CKD) was classified on KDIGO scale. Albuminuria was reported as either positive or negative. Main outcomes measure: Estimated Glomerular filtration rate and albuminuria as markers of chronic kidney disease. Results: A total of 385 participants were included in the study, 252 (65.5%) were females. There were 39.0 % (95%CI 34.3-44.2) patients in CKD/KDIGO stages 3, 4 and 5 and 32.7% (95%CI, 27.8-37.4) had Albuminuria. The risk factors that were significantly associated with chronic kidney disease/KDIGO stages 3, 4 and 5 were: age >50years, long duration with diabetes >5years and hypertension. Employment and paradoxically, obesity reduced the odds of having CKD, probably as markers of better socio-economic status. Conclusion: Unrecognized CKD of KDIGO stages 3,4 and 5 occurred in over thirty percent of the study patients. The risk factors of hypertension, age above 50, long duration of diabetes should help identify those at high risk of developing CKD, for screening and linkage to care. They are at high risk of progression to end-stage kidney disease and cardiovascular events. The imperative of screening for chronic kidney disease is availing care in publicly-funded hospitals.

scholarly journals The burden of unrecognised chronic kidney disease in patients with type 2 diabetes at a county hospital clinic in Kenya: implications to care and need for screening

2020 ◽  
Author(s):  
Frederick C. F. Otieno ◽  
Elijah N Ogola ◽  
Mercy W Kimando ◽  
Ken K Mutai
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
High Risk ◽  
Kidney Disease ◽  
County Hospital ◽  
End Stage Kidney Disease ◽  
Long Duration ◽  
End Stage

Abstract Background : Chronic Kidney Disease (CKD) in patients with type 2 diabetes enhances their cardiovascular risk and diseases, and a strong predictor of progression to end-stage kidney disease. Early diagnosis is encouraged for referral to specialist kidney care to initiate active management that optimizes outcomes, including forestalling progression to end-stage kidney disease. This study was conducted in a regional referral public health facility in Central Kenya with a high prevalence of type 2 diabetes. It was aimed at finding out the burden of undiagnosed chronic kidney disease in their clinic of ambulatory patients with type 2 diabetes who dwell mainly in the rural area. Methods : A cross-sectional study was conducted at the out-patient of Nyeri County hospital where 385 patients were enrolled over five months. Informed consent was obtained and clinical evaluation was done. A spot sample of urine was obtained for albuminuria and venous blood drawn for HbA1c, Lipids and serum creatinine. Estimated GFR (eGFR) was calculated using the Cockroft-Gault equation. Chronic kidney disease (CKD) was classified on KDIGO scale. Albuminuria was reported as either positive or negative. Main outcomes measure: Estimated Glomerular filtration rate and albuminuria as markers of chronic kidney disease. Results : A total of 385 participants were included in the study, 252 (65.5%) were females. There were 39.0 % (95%CI 34.3-44.2) patients in CKD/KDIGO stages 3, 4 and 5 and 32.7% (95%CI, 27.8-37.4) had Albuminuria. The risk factors that were significantly associated with chronic kidney disease/KDIGO stages 3, 4 and 5 were: age >50years, long duration with diabetes >5years and hypertension. Employment and paradoxically, obesity reduced the odds of having CKD, probably as markers of better socio-economic status. Conclusion : Unrecognized CKD of KDIGO stages 3,4 and 5 occurred in over thirty percent of the study patients. The risk factors of hypertension, age above 50, long duration of diabetes should help identify those at high risk of developing CKD, for screening and linkage to care. They are at high risk of progression to end-stage kidney disease and cardiovascular events. The imperative of screening for chronic kidney disease is availing care in publicly-funded hospitals.

Estimated plasma osmolarity and risk of end-stage kidney disease in patients with IgA nephropathy

2020 ◽  
Vol 24 (10) ◽  
pp. 910-918
Author(s):  
Shigeru Tanaka ◽  
Toshiaki Nakano ◽  
Masanori Tokumoto ◽  
Kosuke Masutani ◽  
Akihiro Tsuchimoto ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Iga Nephropathy ◽  
Plasma Osmolarity ◽  
End Stage Kidney Disease ◽  
End Stage
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