Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study (TESTING Low Dose Study)
- Conditions
- IgA Glomerulonephritis
- Interventions
- Drug: Placebo
- Registration Number
- NCT01560052
- Lead Sponsor
- The George Institute
- Brief Summary
This study will evaluate the long-term efficacy and safety of low dose oral methylprednisolone compared to matching placebo, on a background of routine RAS inhibitor therapy, in preventing kidney events in patients with IgA nephropathy and features suggesting a high risk of progression.
- Detailed Description
IgA glomerulonephritis is the most common primary glomerulonephritis, and immunosuppression with steroids has been suggested to be a potential protective therapy, although the benefits and risks have not been clearly established.
The TESTING study was established to compare the effects of oral methylprednisolone 0.8 mg/kg/day weaning over 6-8 months, to matching placebo on the risk of kidney failure events, using a double-blind, randomised, controlled design.
After the randomisation of 262 participants to the TESTING an imbalance in serious adverse events was noted between the methylprednisolone and placebo arms of the trial by the Data Monitoring Committee, mostly due to infection. As the data also suggested likely benefit on kidney outcomes, a further 240 participants will be randomised to methylprednisolone 0.4 mg/kg/day compared to matching placebo (The TESTING low-dose group). Oral sulfamethoxazole/trimethoprim will also be provided to reduce the risk of infection All participants will undergo long term follow-up until at least 160 primary outcome events are observed (expected to be an average of at least 4 years), and the effects of steroids on the risk of the composite kidney outcome will be assessed on the study population as a whole, stratified for treatment regimen so long as there is no evidence of significant heterogeneity in the efficacy at reducing the primary outcome.
Each of the original and the low-dose cohorts in TESTING will also have separate power to detect reductions in proteinuria and effects on average eGFR, along with effects on important safety outcomes with the steroid regimens used.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 503
- IgA nephropathy proven on renal biopsy.
- Proteinuria: >=1.0g/day while receiving maximum tolerated dose of RAS blockade following the recommended treatment guidelines of each country where the trial is conducted.
- eGFR: 30 to 120ml/min per 1.73m²(inclusive) while receiving maximum tolerated RAS blockade
-
Indication for immunosuppressive therapy with corticosteroids, such as:
- Minimal change renal disease with IgA deposits Crescents present in >50% of glomeruli on a renal biopsy within the last 12 months.
-
Contraindication to immunosuppressive therapy with corticosteroids, including:
- Active infection, including HBV infection or clinical evidence of latent or active tuberculosis (nodules, cavities, tuberculoma, etc)
- Malignancy within the last 5 years, excluding treated non-melanoma skin cancers (ie. squamous or basal cell carcinoma)
- Current or planned pregnancy or breastfeeding women of childbearing age who are not able or willing to use adequate contraception.
-
Systemic immunosuppressive therapy in the previous year.
-
Malignant /uncontrolled hypertension (>160mm systolic or 110mmHg diastolic)
-
Current unstable kidney function for other reasons, e.g. macrohaematuria induced acute kidney injury
-
Age <18 years old
-
Secondary IgA nephropathy: e.g. due to lupus, liver cirrhosis, Henoch- Schonlein purpura
-
Patients who are unlikely to comply with the study protocol in the view of the treating physician.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description placebo Placebo Original Cohort: Matching placebo; Optimal blood pressure control and full dose of ACE inhibitors or ARBs as recommended by guidelines; Low Dose Cohort; Matching placebo: Optimal blood pressure control and full dose of ACE inhibitors or ARBs as recommended by guidelines. All participants will also receive standard guideline based care, without steroid therapy. Prophylactic trimethoprim/sulfamethoxazole (a single strength tablet daily or half a double strength tablet daily) will be used during the first 3 months in the low-dose cohort, after randomisation, for the prevention of severe PJP infection, unless there is a documented sulfa allergy oral methylprednisolone methylprednisolone oral methylprednisolone Original Cohort: Methylprednisolone group; start at 0.8mg/kg/day with a maximal 48mg/kg/day x 2months, taper by 8mg/day every month with optimal blood pressure control and full dose of ACE inhibitors or ARBs as recommended by guidelines. Low Dose Cohort: Methylprednisolone group; start at 0.4mg /kg/day with a maximal dose of 32mg/day and a minimum dose of 24mg/day, reducing over 6-9months. All participants will also receive standard guideline based care, without steroid therapy. Prophylactic trimethoprim/sulfamethoxazole (a single strength tablet daily or half a double strength tablet daily) will be used during the first 3 months in the low-dose cohort, after randomisation, for the prevention of severe PJP infection, unless there is a documented sulfa allergy.
- Primary Outcome Measures
Name Time Method Progressive kidney failure 1-6 years Progressive kidney failure, which is a composite of a 40% decrease in eGFR, the development of end stage kidney disease defined as a need for maintenance dialysis or kidney transplantation, and death due to kidney disease.
primary outcome for low dose cohort 1 year Change in proteinuria from baseline at 6 and 12 months Mean change in eGFR at 6 and 12 months
- Secondary Outcome Measures
Name Time Method The composite of ESKD, 30% decrease in eGFR and all cause death 1-6 years Time averaged proteinuria post-randomisation 1-6 years The composite of ESKD 50% decrease in eGFR and all cause death 1-6 years The composite of ESKD 40% decrease in eGFR and all cause death 1-6 years Each ESKD , death due to kidney disease and all cause death 1-6 years Annual eGFR decline rate 1-6 years
Trial Locations
- Locations (66)
Concord Repatriation and General Hospital
🇦🇺Concord, New South Wales, Australia
Nepean Hospital
🇦🇺Kingswood, New South Wales, Australia
Royal North Shore Hospital
🇦🇺St Leonards, New South Wales, Australia
Royal Melbourne Hospital
🇦🇺Melbourne, Victoria, Australia
University of Calgary/Alberta Health Services
🇨🇦Calgary, Alberta, Canada
London Health Sciences Centre
🇨🇦London, Ontario, Canada
The Second Hospital of Hebei Medical University
🇨🇳Shijiazhuang, Hebei, China
The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology,
🇨🇳Baotou, Inner Mongolia, China
Inner Mongolia People's Hospital
🇨🇳Hohhot, Inner Mongolia, China
General Hospital of Eastern Theater Command
🇨🇳Nanjing, Jiangsu, China
The First Affiliated Hospital with Nanjing Medical University
🇨🇳Nanjing, Jiangsu, China
Jilin Province FAW General Hospital [Jilin University Fourth Hospital]
🇨🇳Changchun, Jilin, China
he First Affiliated Hospital of Dalian Medical University, Dalian
🇨🇳Dalian, Liaoning, China
Shengjing Hospital Of China Medical University
🇨🇳Shengyang, Liaoning, China
Qilu Hospital of Shandong University
🇨🇳Jinan, Shandong, China
Yantai Yuhuangding Hospital
🇨🇳Yantai, Shandong, China
Sichuan Academy of Medical Science, Sichuan Provincial People's Hospital
🇨🇳Chengdu, Sichuan, China
Hangzhou Hospital of Traditional Chinese Medicine,
🇨🇳Hangzhou, Zhejiang, China
Zhejiang Provincial People's Hospital
🇨🇳Sangzhou, Zhejiang, China
Beijing Anzhen Hospital, Capital Medical University
🇨🇳Beijing, China
Peking University People's Hospital
🇨🇳Beijing, China
Peking University First Hospital
🇨🇳Beijing, China
XinQiao Hospital, Third Military Medical University
🇨🇳Chongqing, China
Ruijin Hospital, Shanghai Jiaotong University, School of Medicine
🇨🇳Shanghai, China
Huashan Hospital, Medical Centre of Fudan University
🇨🇳Shanghai, China
Calicut Medical College
🇮🇳Kozhikode, Kerala, India
Madras Medical College
🇮🇳Chen, Tamil Nadu, India
Hospital Raja Permaisuri Bainun
🇲🇾Ipoh, Perak, Malaysia
Hospital Kuala Lumpur
🇲🇾Kuala Lumpur, Kulala Lumpur, Malaysia
Hospital Umum Sarawak
🇲🇾Kuching, Samarahan, Malaysia
Hospital Sultanah Aminah
🇲🇾Johor Bahru, Johor, Malaysia
Sanjay Gandhi Post Graduate Institute of Medical Science
🇮🇳Lucknow, Uttar Pradesh, India
University Malaysia Medical Centre
🇲🇾Kuala Lumpur, Malaysia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
The First Affiliated Hospital of Zhengzhou University
🇨🇳Zhengzhou, Henan, China
Renji Hospital, Shanghai Jiaotong University School of Medicine
🇨🇳Shanghai, China
Osmania General Hospital
🇮🇳Hyderabad, Andhra Pradesh, India
The First Affiliated Hospital, Sun Yat-Sen University
🇨🇳Guangzhou, Guangdong, China
Toronto General Hospital,
🇨🇦Toronto, Ontario, Canada
Guangdong Provincial People's Hospital, Guangzhou
🇨🇳Guangzhou, Guangdong, China
Peking University Shenzhen Hospital
🇨🇳Shenzhen, Guangdong, China
The First Affiliated Hospital of Henan University of Science &Technology
🇨🇳Luoyang, Henan, China
St. Joseph's Healthcare
🇨🇦Hamiliton, Ontario, Canada
Hôpital Maisonneuve-Rosemont
🇨🇦Montreal, Quebec, Canada
he Second Hospital of Shanxi Medical University, Taiyuan
🇨🇳Taiyuan, Shanxi, China
West China Hospital of Sichuan University
🇨🇳Chengdu, Sichuan, China
University of Alberta Hospitals
🇨🇦Edmonton, Alberta, Canada
The First Affiliated Hospital of Shangdong First Medical University,Shangdong Provincial Qianfoshin
🇨🇳Jinan, Shandong, China
St Pauls Hospital
🇨🇦Vancouver, British Columbia, Canada
The Third Hospital of Hebei Medical University
🇨🇳Shijiazhuang, Hebei, China
Nizam's Institute of Medical Science
🇮🇳Hyderabad, Andhra Pradesh, India
Hospital Tuanku Jaafar Seremban
🇲🇾Seremban, Negri Seremban, Malaysia
Chinese PLA General Hospital (301 Hospital)
🇨🇳Beijing, Beijing, China
ongji Hospital, Tongji Medical College, Huazhong University of Science & Technology
🇨🇳Wuhan, Hubei, China
The First Affiliated Hospital, Zhejiang University of Medicine
🇨🇳Hangzhou, Zhejiang, China
Henan Provincial People's Hospital
🇨🇳Zhengzhou, Henan, China
Post Graduate Institue of Medical Education and Reasearch
🇮🇳Chandigarh, Punjab, India
Peking University Third Hospital
🇨🇳Beijing, China
Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology
🇨🇳Wuhan, Hubei, China
Shandong Provincial Hospital
🇨🇳Jinan, Shandong, China
Jinan Military General Hospital
🇨🇳Jinan, Shandong, China
Ningbo Urology & Nephrology Hospital
🇨🇳Ningbo, Zhejiang, China
Renmin Hospital, Wuhan University
🇨🇳Wuhan, Hubei, China
Beijing Hospital
🇨🇳Beijing, China
Princess Margaret Hospital
🇭🇰Kowloon, Hong Kong