Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study (TESTING Low Dose Study) (TESTING)

Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study Low Dose Study

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.

Study Overview

• Status: Completed
• Conditions: IgA Glomerulonephritis
• Intervention / Treatment: Drug: methylprednisolone; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 503
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation and General Hospital
    • Kingswood, New South Wales, Australia, 2747
      • Nepean Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3052
      • Royal Melbourne Hospital
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2R 0X7
      • University of Calgary/Alberta Health Services
    • Edmonton, Alberta, Canada, T6G 2B7
      • University Of Alberta Hospitals
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St Pauls Hospital
  • Ontario
    • Hamiliton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital,
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Hopital Maisonneuve-Rosemont
• China
  • Beijing, China
    • Peking University Third Hospital
  • Beijing, China, 100730
    • Beijing Hospital
  • Beijing, China, 100029
    • Beijing Anzhen Hospital, Capital Medical University
  • Beijing, China, 100034
    • Peking University First Hospital
  • Beijing, China, 100035
    • Peking University People's Hospital
  • Chongqing, China, 400037
    • Xinqiao Hospital, Third Military Medical University
  • Shanghai, China, 200001
    • Renji Hospital, Shanghai Jiaotong University School of Medicine
  • Shanghai, China, 200025
    • Ruijin Hospital, Shanghai jiaotong University, School of Medicine
  • Shanghai, China, 200040
    • Huashan Hospital, Medical Centre of Fudan University
  • Beijing
    • Beijing, Beijing, China
      • Chinese PLA General Hospital (301 Hospital)
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • The First Affiliated Hospital, Sun Yat-sen University
    • Guangzhou, Guangdong, China
      • Guangdong Provincial People's Hospital, Guangzhou
    • Shenzhen, Guangdong, China, 518036
      • Peking University Shenzhen Hospital
  • Hebei
    • Shijiazhuang, Hebei, China, 050051
      • The Third Hospital of Hebei Medical University
    • Shijiazhuang, Hebei, China, 050005
      • The Second Hospital of HeBei Medical University
  • Henan
    • Luoyang, Henan, China, 471003
      • The First Affiliated Hospital of Henan University of Science &Technology
    • Zhengzhou, Henan, China, 450052
      • The First Affiliated Hospital of Zhengzhou University
    • Zhengzhou, Henan, China, 450003
      • Henan Provincial People's Hospital
  • Hubei
    • Wuhan, Hubei, China, 430022
      • ongji Hospital, Tongji Medical College, Huazhong University of Science & Technology
    • Wuhan, Hubei, China, 430022
      • Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology
    • Wuhan, Hubei, China, 430060
      • Renmin Hospital, Wuhan University
  • Inner Mongolia
    • Baotou, Inner Mongolia, China, 014010
      • The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology,
    • Hohhot, Inner Mongolia, China, 010017
      • Inner Mongolia People's Hospital
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • The First Affiliated Hospital with Nanjing Medical University
    • Nanjing, Jiangsu, China, 210002
      • General Hospital of Eastern Theater Command
  • Jilin
    • Changchun, Jilin, China, 130011
      • Jilin Province FAW General Hospital [Jilin University Fourth Hospital]
  • Liaoning
    • Dalian, Liaoning, China, 116011
      • he First Affiliated Hospital of Dalian Medical University, Dalian
    • Shengyang, Liaoning, China
      • Shengjing Hospital of China Medical University
  • Shandong
    • Jinan, Shandong, China, 250021
      • Shandong Provincial Hospital
    • Jinan, Shandong, China, 250012
      • Qilu Hospital of Shandong University
    • Jinan, Shandong, China, 250014
      • The First Affiliated Hospital of Shangdong First Medical University,Shangdong Provincial Qianfoshin
    • Jinan, Shandong, China
      • Jinan Military General Hospital
    • Yantai, Shandong, China, 264000
      • Yantai Yuhuangding Hospital
  • Shanxi
    • Taiyuan, Shanxi, China, 030001
      • he Second Hospital of Shanxi Medical University, Taiyuan
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital of Sichuan University
    • Chengdu, Sichuan, China, 610072
      • Sichuan Academy of Medical Science, Sichuan Provincial People's Hospital
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • The First Affiliated Hospital, Zhejiang University of Medicine
    • Hangzhou, Zhejiang, China
      • Hangzhou Hospital of Traditional Chinese Medicine,
    • Ningbo, Zhejiang, China
      • Ningbo Urology & Nephrology Hospital
    • Sangzhou, Zhejiang, China
      • Zhejiang Provincial People's Hospital
• Hong Kong
  • Kowloon, Hong Kong
    • Princess Margaret Hospital
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500012
      • Osmania General Hospital
    • Hyderabad, Andhra Pradesh, India, 500082,
      • Nizam's Institute of Medical Science
  • Kerala
    • Kozhikode, Kerala, India, 673008,
      • Calicut Medical College
  • Punjab
    • Chandigarh, Punjab, India, 160 012
      • Post Graduate Institue of Medical Education and Reasearch
  • Tamil Nadu
    • Chen, Tamil Nadu, India, 600037
      • Madras Medical College
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226014
      • Sanjay Gandhi Post Graduate Institute of Medical Science
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaysia Medical Centre
  • Johor
    • Johor Bahru, Johor, Malaysia, 80100
      • Hospital Sultanah Aminah
  • Kulala Lumpur
    • Kuala Lumpur, Kulala Lumpur, Malaysia, 50586
      • Hospital Kuala Lumpur
  • Negri Seremban
    • Seremban, Negri Seremban, Malaysia, 70300
      • Hospital Tuanku Jaafar Seremban
  • Perak
    • Ipoh, Perak, Malaysia, 30990
      • Hospital Raja Permaisuri Bainun
  • Samarahan
    • Kuching, Samarahan, Malaysia, 93586
      • Hospital Umum Sarawak

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. IgA nephropathy proven on renal biopsy.
2. 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.
3. eGFR: 30 to 120ml/min per 1.73m²(inclusive) while receiving maximum tolerated RAS blockade

Exclusion Criteria:

1. 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.

2. 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.
3. Systemic immunosuppressive therapy in the previous year.
4. Malignant /uncontrolled hypertension (>160mm systolic or 110mmHg diastolic)
5. Current unstable kidney function for other reasons, e.g. macrohaematuria induced acute kidney injury
6. Age <18 years old
7. Secondary IgA nephropathy: e.g. due to lupus, liver cirrhosis, Henoch- Schonlein purpura
8. Patients who are unlikely to comply with the study protocol in the view of the treating physician.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: oral 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.	Drug: methylprednisolone; Original Cohort: Oral methylprednisolone or placebo 0.8mg/kg/day with a maximum of 48mg/day x 2months, taper by 8mg/day every month, patients will also receive optimal blood pressure control and full dose of ACE inhibitors or ARBs as recommended by guidelines Low Dose Cohort: Oral methylprednisolone or placebo 0.4mg/kg/day with a maximum 32mg/day and minimum of 24mg/day then reducing over 6-9months. All the patients will also receive optimal blood pressure control and full dose of ACE inhibitors or ARBs as recommended by guidelines throughout the trial. Prophylactic trimethoprim/sulfamethoxazole (a single strength tablet daily or half a double strength tablet daily) will be used during the first 3 months after randomisation in the low dose cohort, for the prevention of severe PJP infection, unless there is a documented sulfa allergy.; Other Names: Medrol
Placebo Comparator: 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	Drug: Placebo; Intervention: Drug: Placebo Original Cohort: Matching placebo tablets, all the patients will receive optimal blood pressure control and full dose of ACE inhibitors or ARBs as recommended by guidelines throughout the trial. Low Dose cohort: Matching placebo will be given reducing over 6-9months. All the patients will also receive optimal blood pressure control and full dose of ACE inhibitors or ARBs as recommended by guidelines throughout the trial. Prophylactic trimethoprim/sulfamethoxazole (a single strength tablet daily or half a double strength tablet daily) will be used during the first 3 months after randomisation in the low dose cohort, for the prevention of severe PJP infection, unless there is a documented sulfa allergy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progressive kidney failure	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.	1-6 years
primary outcome for low dose cohort	Change in proteinuria from baseline at 6 and 12 months Mean change in eGFR at 6 and 12 months	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
The composite of ESKD, 30% 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
The composite of ESKD 50% decrease in eGFR and all cause death	1-6 years
Annual eGFR decline rate	1-6 years
Each ESKD , death due to kidney disease and all cause death	1-6 years
Time averaged proteinuria post-randomisation	1-6 years

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: Peking University First Hospital
• Investigators: Principal Investigator: Hong Zhang, Peking University; Principal Investigator: Vlado Perkovic, The George Institute

Publications and helpful links

General Publications

• Lv J, Wong MG, Hladunewich MA, Jha V, Hooi LS, Monaghan H, Zhao M, Barbour S, Jardine MJ, Reich HN, Cattran D, Glassock R, Levin A, Wheeler DC, Woodward M, Billot L, Stepien S, Rogers K, Chan TM, Liu ZH, Johnson DW, Cass A, Feehally J, Floege J, Remuzzi G, Wu Y, Agarwal R, Zhang H, Perkovic V; TESTING Study Group. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2022 May 17;327(19):1888-1898. doi: 10.1001/jama.2022.5368.
• Lv J, Zhang H, Wong MG, Jardine MJ, Hladunewich M, Jha V, Monaghan H, Zhao M, Barbour S, Reich H, Cattran D, Glassock R, Levin A, Wheeler D, Woodward M, Billot L, Chan TM, Liu ZH, Johnson DW, Cass A, Feehally J, Floege J, Remuzzi G, Wu Y, Agarwal R, Wang HY, Perkovic V; TESTING Study Group. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017 Aug 1;318(5):432-442. doi: 10.1001/jama.2017.9362.
• Yeo SC, Liew A, Barratt J. Emerging therapies in immunoglobulin A nephropathy. Nephrology (Carlton). 2015 Nov;20(11):788-800. doi: 10.1111/nep.12527.

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2012
• Primary Completion (Actual): July 23, 2021
• Study Completion (Actual): July 23, 2021

Study Registration Dates

• First Submitted: March 15, 2012
• First Submitted That Met QC Criteria: March 20, 2012
• First Posted (Estimate): March 21, 2012

Study Record Updates

• Last Update Posted (Actual): September 23, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: IgA nephropathy; end stage kidney disease
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Nephritis; Kidney Diseases; Glomerulonephritis; Glomerulonephritis, IGA; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: GI-R-01-2011