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

IgA Glomerulonephritis Clinical Trial

— TESTING  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01560052
• Other study ID #: GI-R-01-2011
• Status: Completed
• Phase: N/A
• Start date: May 5, 2012
• Est. completion date: July 23, 2021

Study information

• Verified date: September 2021
• Source: The George Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 503
• Est. completion date: July 23, 2021
• Est. primary completion date: July 23, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Glomerulonephritis
• Glomerulonephritis, IGA
• IgA Glomerulonephritis
• Kidney Diseases

Intervention

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.
• 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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Concord Repatriation and General Hospital	Concord	New South Wales
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Canada	University of Calgary/Alberta Health Services	Calgary	Alberta
Canada	University of Alberta Hospitals	Edmonton	Alberta
Canada	St. Joseph's Healthcare	Hamiliton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Hôpital Maisonneuve-Rosemont	Montreal	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto General Hospital,	Toronto	Ontario
Canada	St Pauls Hospital	Vancouver	British Columbia
China	The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology,	Baotou	Inner Mongolia
China	Beijing Anzhen Hospital, Capital Medical University	Beijing
China	Beijing Hospital	Beijing
China	Chinese PLA General Hospital (301 Hospital)	Beijing	Beijing
China	Peking University First Hospital	Beijing
China	Peking University People's Hospital	Beijing
China	Peking University Third Hospital	Beijing
China	Jilin Province FAW General Hospital [Jilin University Fourth Hospital]	Changchun	Jilin
China	Sichuan Academy of Medical Science, Sichuan Provincial People's Hospital	Chengdu	Sichuan
China	West China Hospital of Sichuan University	Chengdu	Sichuan
China	XinQiao Hospital, Third Military Medical University	Chongqing
China	he First Affiliated Hospital of Dalian Medical University, Dalian	Dalian	Liaoning
China	Guangdong Provincial People's Hospital, Guangzhou	Guangzhou	Guangdong
China	The First Affiliated Hospital, Sun Yat-Sen University	Guangzhou	Guangdong
China	Hangzhou Hospital of Traditional Chinese Medicine,	Hangzhou	Zhejiang
China	The First Affiliated Hospital, Zhejiang University of Medicine	Hangzhou	Zhejiang
China	Inner Mongolia People's Hospital	Hohhot	Inner Mongolia
China	Jinan Military General Hospital	Jinan	Shandong
China	Qilu Hospital of Shandong University	Jinan	Shandong
China	Shandong Provincial Hospital	Jinan	Shandong
China	The First Affiliated Hospital of Shangdong First Medical University,Shangdong Provincial Qianfoshin	Jinan	Shandong
China	The First Affiliated Hospital of Henan University of Science &Technology	Luoyang	Henan
China	General Hospital of Eastern Theater Command	Nanjing	Jiangsu
China	The First Affiliated Hospital with Nanjing Medical University	Nanjing	Jiangsu
China	Ningbo Urology & Nephrology Hospital	Ningbo	Zhejiang
China	Zhejiang Provincial People's Hospital	Sangzhou	Zhejiang
China	Huashan Hospital, Medical Centre of Fudan University	Shanghai
China	Renji Hospital, Shanghai Jiaotong University School of Medicine	Shanghai
China	Ruijin Hospital, Shanghai Jiaotong University, School of Medicine	Shanghai
China	Shengjing Hospital Of China Medical University	Shengyang	Liaoning
China	Peking University Shenzhen Hospital	Shenzhen	Guangdong
China	The Second Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	The Third Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	he Second Hospital of Shanxi Medical University, Taiyuan	Taiyuan	Shanxi
China	ongji Hospital, Tongji Medical College, Huazhong University of Science & Technology	Wuhan	Hubei
China	Renmin Hospital, Wuhan University	Wuhan	Hubei
China	Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei
China	Yantai Yuhuangding Hospital	Yantai	Shandong
China	Henan Provincial People's Hospital	Zhengzhou	Henan
China	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan
Hong Kong	Princess Margaret Hospital	Kowloon
India	Post Graduate Institue of Medical Education and Reasearch	Chandigarh	Punjab
India	Madras Medical College	Chen	Tamil Nadu
India	Nizam's Institute of Medical Science	Hyderabad	Andhra Pradesh
India	Osmania General Hospital	Hyderabad	Andhra Pradesh
India	Calicut Medical College	Kozhikode	Kerala
India	Sanjay Gandhi Post Graduate Institute of Medical Science	Lucknow	Uttar Pradesh
Malaysia	Hospital Raja Permaisuri Bainun	Ipoh	Perak
Malaysia	Hospital Sultanah Aminah	Johor Bahru	Johor
Malaysia	Hospital Kuala Lumpur	Kuala Lumpur	Kulala Lumpur
Malaysia	University Malaysia Medical Centre	Kuala Lumpur
Malaysia	Hospital Umum Sarawak	Kuching	Samarahan
Malaysia	Hospital Tuanku Jaafar Seremban	Seremban	Negri Seremban

Sponsors (2)

Lead Sponsor	Collaborator
The George Institute	Peking University First Hospital

Countries where clinical trial is conducted

Australia,  Canada,  China,  Hong Kong,  India,  Malaysia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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	The composite of ESKD, 30% decrease in eGFR and all cause death		1-6 years
Secondary	The composite of ESKD 40% decrease in eGFR and all cause death		1-6 years
Secondary	The composite of ESKD 50% decrease in eGFR and all cause death		1-6 years
Secondary	Annual eGFR decline rate		1-6 years
Secondary	Each ESKD , death due to kidney disease and all cause death		1-6 years
Secondary	Time averaged proteinuria post-randomisation		1-6 years