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

Not Applicable

Completed

• Conditions: IgA Glomerulonephritis
• Interventions: Drug: Placebo; Drug: methylprednisolone

• 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.

Study Timeline

• Study First Submitted: 2012-03-15
• Study First Submitted QC: 2012-03-20
• Study First Posted: 2012-03-21
• Study Start: 2012-05-05
• Primary Completion: 2021-07-23
• Study Completion: 2021-07-23
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-21
• Last Update Posted: 2021-09-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 503

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 & 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 Adelaide Hospital; 🇦🇺 Adelaide, South Australia, Australia

Royal Melbourne Hospital; 🇦🇺 Melbourne, Victoria, Australia

University of Calgary/Alberta Health Services; 🇨🇦 Calgary, Alberta, Canada

University of Alberta Hospitals; 🇨🇦 Edmonton, Alberta, Canada

St Pauls Hospital; 🇨🇦 Vancouver, British Columbia, Canada

St. Joseph's Healthcare; 🇨🇦 Hamiliton, Ontario, Canada

London Health Sciences Centre; 🇨🇦 London, Ontario, Canada

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