scholarly journals Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome

2021 ◽  
pp. 1-10
Author(s):  
Glenn M. Chertow ◽  
Gerald B. Appel ◽  
Sharon Andreoli ◽  
Sripal Bangalore ◽  
Geoffrey A. Block ◽  
...  
Keyword(s):  
Kidney Function ◽  
Alport Syndrome ◽  
Genetic Disorder ◽  
Geometric Mean ◽  
Genetic Diagnosis ◽  
Significant Loss ◽  
The European Union ◽  
Phase 3 ◽  
Double Blind ◽  
Histologic Diagnosis

<b><i>Introduction:</i></b> Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (&#x3c;5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. <b><i>Methods:</i></b> The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m<sup>2</sup>, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values &#x3e;200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. <b><i>Results:</i></b> A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (<i>n</i> = 77) or placebo (<i>n</i> = 80). The average age at screening was 39.2 years, and 23 (15%) were &#x3c;18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m<sup>2</sup>, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m<sup>2</sup> despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. <b><i>Discussion/Conclusion:</i></b> CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

FC 023SAFETY OF BARDOXOLONE METHYL IN PEDIATRIC PATIENTS WITH ALPORT SYNDROME IN CARDINAL PHASE 3 TRIAL

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Bradley Warady ◽  
Vimal Chadha ◽  
Melanie Chin ◽  
Rasheed A Gbadagesin ◽  
Keisha Gibson ◽  
...  
Keyword(s):  
Body Weight ◽  
Kidney Disease ◽  
Alport Syndrome ◽  
Pediatric Patients ◽  
Adult Population ◽  
Geometric Mean ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Treatment Groups

Abstract Background and Aims Alport syndrome is a genetic disease accounting for an estimated 3% of children with end-stage kidney disease (ESKD) in the US (USRDS, 2014). Current management recommendations include the use of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with proteinuria, but no specific therapies have been approved for this disease. A Phase 3 study (CARDINAL; NCT03019185) assessed the safety and efficacy of bardoxolone methyl (Bard) in adult and adolescent patients with Alport syndrome. Method CARDINAL was an international, multicenter, double-blind, placebo-controlled, randomized trial. Eligible participants were 12 to 70 years old, had confirmed diagnosis of Alport syndrome, baseline eGFR 30-90 mL/min/1.73 m2 and urinary albumin to creatinine ratio (UACR) ≤ 3500 mg/g. For pediatric patients (12 to &lt; 18 years of age), eGFR was calculated using the Bedside Schwartz equation. Patients were randomized 1:1 to Bard or placebo and were to be followed for up to 104 weeks (2 treatment periods of 48 weeks and 4 weeks off treatment between Weeks 48 and 52). The primary efficacy endpoints were changes from baseline in eGFR in patients randomized to Bard compared to placebo at Week 48 and Week 100. The key secondary endpoints were the off-treatment changes from baseline in eGFR in patients randomized to Bard compared to placebo at Week 52 and Week 104, 4 weeks after withdrawal. Results A total of 23 (15%) pediatric patients were randomized to Bard (n=11) or placebo (n=12). The average age was 15.3 years, mean (± SD) baseline eGFR was 69.9 ± 15.4 mL/min/1.73 m2 and geometric mean (± SE) baseline UACR was 230.9 ± 95.8 mg/g. A total of 19 of 23 (83%) pediatric patients were male, and 14 (61%) patients had X-linked Alport syndrome, while 6 (26%) patients had autosomal disease. Mean (± SD) baseline body weight was 65.5 ± 10.2 kg and 57.8 ± 16.0 kg and baseline height was 171.7 ± 5.9 cm and 166.3 ± 14.9 cm for Bard and placebo patients, respectively. Seventeen (74%) pediatric patients were on RAASi treatment. Treatment of pediatric patients with Bard resulted in a significantly higher mean change from baseline in on-treatment eGFR relative to placebo at Week 100 (13.8 mL/min/1.73 m2; p = 0.017) and higher mean off-treatment eGFR relative to placebo at Week 104 (14.6 mL/min/1.73 m2; p = 0.0035). In pediatric patients treated with Bard, UACR remained generally unchanged relative to baseline at Week 100 (geometric mean ± SE to baseline ratio: 0.7 ± 0.3), while placebo patients had an increase in UACR (geometric mean ± SE to baseline ratio: 2.1 ± 0.9). Pediatric patients generally continued along their baseline growth curves for height and weight in both treatment groups. At Week 100, mean ± SD changes from baseline in body weight were 0.5 ± 3.9 kg and 3.2 ± 3.5 kg and those for height were 1.6 ± 1.4 cm and 4.3 ± 5.1 cm for Bard and placebo patients, respectively. Changes in blood pressure (BP) were similar across treatment groups. As seen in the adult population, treatment with Bard resulted in transient increases in mean aminotransferase levels in pediatric patients that remained below 3 x ULN for a majority (8/11 [73%]) of patients and returned to baseline at Week 104, 4 weeks after drug withdrawal (mean ± SD change from baseline in ALT: 0.4 ± 3.7 U/L; AST: -0.9 ± 5.6 U/L). Increases in ALT did not coincide with increases in total bilirubin and no Hy’s law cases were reported. No serious adverse events (AEs) were reported in pediatric patients treated with Bard and reported AEs were consistent with those observed in previous studies. One placebo-treated pediatric patient and no Bard patients developed ESKD during the trial. Conclusion In CARDINAL, the addition of Bard to RAASi in pediatric patients with chronic kidney disease due to Alport syndrome appeared to preserve kidney function and very importantly from a safety standpoint, was safe and well-tolerated.

scholarly journals Topline Results of the CARE-PWS Phase 3 Study: Intranasal Carbetocin Improves Hyperphagia and Anxiety and Distress Symptoms in Prader-Willi Syndrome (PWS)

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A689-A689
Author(s):  
Davis Ryman ◽  
Cheri L Deal
Keyword(s):  
Genetic Disorder ◽  
Statistical Significance ◽  
Prader Willi Syndrome ◽  
Obsessive Compulsive ◽  
Primary Analysis ◽  
Phase 3 ◽  
Double Blind ◽  
Multiple Endpoints ◽  
Behavioral Issues ◽  
Secondary Endpoints

Abstract Prader-Willi syndrome (PWS) is a complex genetic disorder associated with multiple neuroendocrine abnormalities including significantly decreased hypothalamic oxytocin levels, resulting in symptoms of severe hyperphagia (an unrelenting false sense of starvation) and multiple severe neuropsychiatric and behavioral issues. CARE-PWS, a multi-center, randomized, double-blind, placebo-controlled phase 3 study, has evaluated the efficacy, safety, and tolerability of intranasal carbetocin, a selective oxytocin receptor agonist, in participants with PWS. Eligible participants aged 7 through 18 with genetically confirmed PWS were randomized in equal proportions to three treatment arms for the 8-week placebo-controlled period of the study: carbetocin 9.6 mg, carbetocin 3.2 mg, or a matching placebo, administered by nasal spray three times a day with meals. The primary endpoint assessed changes from baseline to week 8 in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) or Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores for the carbetocin 9.6 mg arm vs placebo, and the first secondary endpoint assessed changes from baseline to week 8 in HQ-CT or CY-BOCS scores for the carbetocin 3.2 mg arm vs placebo. Additional secondary endpoints included changes from baseline to week 8 in PWS Anxiety and Distress Questionnaire (PADQ) scores, and Clinical Global Impression of Change (CGI-C) scores evaluating the overall change in severity of PWS symptoms at week 8. Due to COVID-19, enrollment was closed early with 119 evaluable participants for the primary analysis. In the carbetocin 9.6 mg arm, trends toward numerically greater improvements in HQ-CT and CGI-C scores relative to placebo were observed but did not reach statistical significance; however, the carbetocin 3.2 mg arm demonstrated a significant improvement in HQ-CT scores (LS mean improvement vs placebo -3.14 points, p=0.016). In the 3.2 mg arm, additional consistent evidence of improvements versus placebo was seen in multiple secondary endpoints, including CGI-C (p=0.027) and PADQ (p=0.027). Numeric trends toward improvement in CY-BOCS scores were observed in each dose arm, but did not reach statistical significance versus placebo. During the subsequent long-term follow-up period of the study, both carbetocin arms have experienced continued numeric improvements from baseline across multiple endpoints. Intranasal carbetocin was generally well-tolerated; the most frequently reported adverse event was flushing, which was generally mild and transient. In conclusion, results of the CARE-PWS study support that intranasal carbetocin appears to be safe and well tolerated, and reduces hyperphagia and anxiety and distress behaviors in PWS.

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 &gt;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

Abstract 3699: Efficacy and Safety of Colesevelam HCl in Pediatric Patients with Heterozygous Familial Hypercholesterolemia

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Evan A Stein ◽  
David Marais ◽  
Tamas Szamosi ◽  
Frederick Raal ◽  
Daniel Schurr ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Lipid Lowering ◽  
Controlled Study ◽  
Lipid Lowering Therapy ◽  
Efficacy And Safety ◽  
Degree Relative ◽  
Double Blind ◽  
Heterozygous Familial Hypercholesterolemia

Heterozygous familial hypercholesterolemia (heFH) is a genetic disorder resulting in elevated LDL-C, which confers a high risk for a coronary event. Colesevelam HCl (COL), a non-absorbable bile acid sequestrant, is approved to lower LDL-C in adults with primary hypercholesterolemia. This is the first data demonstrating the efficacy and safety of COL in pediatric pts with heFH. This 32wk multicenter, randomized, double-blind (DB), placebo (PLA)-controlled study included: a 4wk PLA run-in (to measure compliance); an 8wk DB period (pts randomized 1:1:1 to PLA, 1.875 g/d COL, or 3.75 g/d COL); an 18wk open-label (OL) treatment to goal (LDL-C <110 mg/dL) wherein all pts received COL 3.75 g/d (and were eligible to receive a statin); and a 2wk follow-up. Males and females, aged 10 –17yrs, with either genetic diagnosis of heFH or history of untreated LDL-C >160 mg/dL combined with familial dyslipidemia in a first degree relative, who had a baseline LDL-C >160 mg/dL (if naíve to lipid-lowering therapy) or >130 mg/dL (if on a statin [≥6wks]) and following a NCEP step 1 diet were included. Additional inclusion criteria were TG <250 mg/dL, ≥Tanner stage 2, and compliance ≥75% during the PLA run-in. Primary efficacy parameter was % change in LDL-C from baseline/Day 1 to Wk 8. The ITT population (randomized pts with a baseline and ≥1 post-baseline measurement) was used to evaluate efficacy parameters. Of the 194 pts randomized, 95.9% and 89.2% completed the DB and OL periods, respectively. Approximately 25% were on a statin at entry into the DB period; a further 10% added a statin during the OL period. At wk 8, LDL-C, TC, and apoB significantly decreased while HDL-C and apoA-I significantly increased with COL 3.75 g/d ( P <0.01 vs PLA for all; Table ). Adverse events were as expected; no choking was recorded. No effects were noted on growth, sexual maturation, hormone levels, absorption of fat-soluble vitamins, or clotting parameters. In summary, COL lowered LDL-C and was well tolerated in pediatric pts.

scholarly journals LB002ILLUMINATE-A, A PHASE 3 STUDY OF LUMASIRAN, AN INVESTIGATIONAL RNAI THERAPEUTIC, IN CHILDREN AND ADULTS WITH PRIMARY HYPEROXALURIA TYPE 1 (PH1)

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Sander Garrelfs ◽  
Yaacov Frishberg ◽  
Sally Hulton ◽  
Michael Koren ◽  
William O'Riordan ◽  
...  
Keyword(s):  
Adverse Events ◽  
Primary Endpoint ◽  
Genetic Disorder ◽  
Primary Hyperoxaluria ◽  
Least Square ◽  
Glycolate Oxidase ◽  
Phase 3 ◽  
Double Blind ◽  
Percent Change ◽  
First Results

Abstract Background and Aims PH1 is a rare genetic disorder characterized by hepatic oxalate overproduction, leading to recurrent kidney stones, nephrocalcinosis, progressive kidney failure, and multiorgan damage from systemic oxalosis. There are no approved pharmacologic therapies for PH1. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic that targets glycolate oxidase to reduce hepatic oxalate production. We report the first results from the six-month, double-blind period of ILLUMINATE-A, a randomized, placebo-controlled Phase 3 study to evaluate lumasiran in patients with PH1. Method Key inclusion criteria: age≥6 years, 24hr urinary oxalate (UOx)≥0.70 mmol/24hr/1.73m2, confirmed PH1 diagnosis, eGFR≥30 mL/min/1.73m2. Randomization: 2:1; lumasiran (n=26), placebo (n=13). Dosing: 3 mg/kg monthly×3, then quarterly. Primary endpoint: percent change in 24hr UOx excretion from baseline to month (M) 6. Primary comparison: least square (LS) mean treatment difference in percent change from baseline (average of M3-6). Results Lumasiran led to a statistically significant percent reduction in 24hr UOx excretion compared to placebo: the LS mean change from baseline to M6 (average of M3-6) was −65.4% with lumasiran and −11.8% with placebo (LS mean difference: −53.5%; p=1.7 × 10−14). Subgroup analyses of the primary endpoint showed a consistent effect of lumasiran across age, baseline UOx, eGFR, and concomitant pyridoxine use. Lumasiran led to statistically significant improvements in all hierarchically tested secondary endpoints, including: proportion of lumasiran-treated patients that achieved normalization or near-normalization of 24hr UOx at M6 (84% vs 0% of placebo-treated patients, p=8.3 × 10−7), and percent change in plasma oxalate from baseline to M6 (average of months 3-6) (-39.5%, p=2.9 × 10−8). There were no serious or severe adverse events. The most common adverse events related to lumasiran were mild, transient injection site reactions. Conclusion Lumasiran resulted in clinically meaningful, rapid, sustained, and statistically significant reductions in urinary and plasma oxalate levels compared to placebo during the six-month double-blind period. Lumasiran has a favorable safety profile.

scholarly journals 3. Phase 3 Pivotal Evaluation of 20-valent Pneumococcal Conjugate Vaccine (PCV20) Safety, Tolerability, and Immunologic Noninferiority in Participants 18 Years and Older

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S2-S2
Author(s):  
Brandon Essink ◽  
Charu Sabharwal ◽  
Xia Xu ◽  
Vani Sundaraiyer ◽  
Yahong Peng ◽  
...  
Keyword(s):  
Conjugate Vaccine ◽  
Pneumococcal Conjugate Vaccine ◽  
Geometric Mean ◽  
Pneumococcal Vaccination ◽  
Independent Contractor ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Double Blind ◽  
Age Cohorts ◽  
Younger Age

Abstract Background PCV20 contains the 13-valent pneumococcal conjugate vaccine (PCV13) components, and 7 additional conjugates (for serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F), extending pneumococcal serotype coverage. Key data from the pivotal Phase 3 evaluation of PCV20 in adults are presented. Methods Adults naïve to pneumococcal vaccination were enrolled into 3 age cohorts (≥60, 50–59, and 18–49 years of age). Participants ≥60 years received either PCV20 and saline 1 month later, or PCV13 and 23-valent pneumococcal polysaccharide (PPSV23) 1 month later (1:1 randomization, double blind). Participants 50–59 and 18–49 years received either a dose of PCV20 or PCV13 (3:1 randomization, double blind). Tolerability, safety and immunogenicity (opsonophagocytic activity [OPA] responses) were assessed. Results 3889 participants received vaccine. 1507 and 1490 participants ≥60 years received PCV20 or control respectively. All 20 vaccine serotypes induced robust responses and OPA geometric mean titers (GMTs) to all 13 matched serotypes were noninferior to PCV13. In addition, the OPA GMTs to 6 of the 7 additional serotypes 1 month after PCV20 were noninferior compared to the same serotypes in PPSV23. The OPA GMT of serotype 8 missed noninferiority by a very narrow margin (2-sided 95% lower bound of GMT ratio [20vPnC/PPSV23] was 0.49, with noninferiority criterion of &gt;0.5); this is unlikely to be clinically significant given the high geometric mean fold rise of OPA titers after PCV20 (22-fold above baseline). GMTs after PCV20 in each of the younger age cohorts (18–49 years, 50–59 years) were noninferior to adults 60–64 years. The tolerability and safety profile of PCV20 was similar to PCV13. Conclusion Based on the robust immune responses and comparability to licensed pneumococcal vaccines, as well as bridging to the younger age group, these data support that PCV20 will be protective against pneumococcal disease due to the 20 serotypes in adults. Disclosures Charu Sabharwal, MD, MPH, Pfizer (Employee, Shareholder) Xia Xu, PhD, Pfizer (Employee, Shareholder) Vani Sundaraiyer, PhD, MS, Pfizer (Independent Contractor) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Lisa Moyer, BS, Pfizer (Employee, Shareholder) Michael W. Pride, PhD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)

IP 1184. ZX008 (Fenfluramine) in Dravet’s Syndrome: First Results of a Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

2018 ◽  
Author(s):  
Tilman Polster ◽  
Lieven Lagae ◽  
Joseph Sullivan ◽  
Ulrich Brandl ◽  
Arne Herting ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
First Results
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