Cal Robinson, Rulan Parekh | The Hospital for Sick Children

Reduced-dose Steroid Protocol for childhood Nephrotic Syndrome (RESPONSE): a Multicentre Bayesian Adaptive Randomized Controlled Trial

Co-applicant(s): Allison Dart, Anna Heath, Bibi Areefa Alladin-Karan, Damien Noone, Guido Filler, Jodie Davey, Kuan Liu, Larry Greenbaum, Lillian Sung, Mallory L Downie, Michelle Denburg, Rahul Chanchlani, Robert Myette, Sangeeta Hingorani, Silviu Grisaru, Srinivas Murthy, Terry Klassen, William E Smoyer

Lay Abstract

Background: Nephrotic syndrome is a common childhood kidney disease that affects 3,000 Canadian children every year. In nephrotic syndrome, the kidneys leak protein into the urine, which causes the body to swell. This leads to breathing problems, infections, and blood clots. Most children respond to steroid treatment (prednisone) but have multiple disease relapses. Repeated treatment with high-dose steroids for each relapse leads to many serious side effects, like poor growth, weight gain, diabetes, high blood pressure, and worse quality of life. Some studies have found that lower steroid doses may be effective for treating nephrotic syndrome relapses and cause fewer side effects. However, these studies were small and low quality. We still do not know the best steroid dose to treat children with nephrotic syndrome relapses. A high-quality clinical trial is needed to answer this question. Yet, it is hard to run traditional large clinical trials in rare childhood diseases like nephrotic syndrome. Efficient new clinical trial designs can be used to overcome these barriers and study new treatments for children living with rare kidney diseases.

Purpose: Our aim is to see if low-dose steroids are as effective and safer than usual high-dose steroid treatment for childhood nephrotic syndrome relapses.

Method: We will do this through a large-scale adaptive clinical trial at multiple children’s hospitals in Canada and the United States. An adaptive trial design allows us to stop the study early, as soon as we have enough information about the effectiveness of low-dose steroids. We will randomize children aged 1-18 years that have a nephrotic syndrome relapse to be treated with either low-dose steroids (intervention) or usual high-dose steroids (control). We will then compare the number of children that respond completely to treatment within two weeks. We will also compare the side effects of treatment, further relapses, and quality of life within one year.

Anticipated outcomes: We expect to find that low-dose steroids are as effective as high-dose steroids for treating children with nephrotic syndrome relapses and that low-dose steroids cause fewer side effects. Based on initial data from one Canadian center, it will be possible to complete this clinical trial within two years.

Patient engagement: This study will answer a key research question identified as a top priority by Canadian children with nephrotic syndrome and their caregivers in focus groups. Children with nephrotic syndrome and their caregivers will be involved in all stages of the design, conduct, and analysis of this study. We have already built a network of Canadian patient partners for this clinical trial.

Relevance to Patients/Community: This research will find the right dose of steroids to treat children with nephrotic syndrome relapses. More than 80% of children with nephrotic syndrome have one or more relapses. Therefore, the findings of this study are highly relevant to most patients. If low-dose steroids are effective and safe, this would greatly reduce a child’s lifetime steroid burden and the risk of long-term side effects.

Conclusion: The treatment of childhood nephrotic syndrome relapses has not changed in over 60 years and is not based on evidence. Although high-dose steroids effectively treat relapses, they cause many serious short and long-term side effects. Our research will determine if a lower dose of steroids is as effective as the current dose. If this is true, our findings could change the treatment of childhood nephrotic syndrome relapses globally. Decreasing the dose of steroids that a child receives during each relapse would lower their risk of serious side effects and improve their quality of life.