Clinical trial NCT01560052: Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study (TESTING Low Dose Study)
Official title: Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study Low Dose Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: IgA Glomerulonephritis
Keywords: end stage kidney disease
IgA nephropathy
Lead sponsor: The George Institute
Sponsor class: OTHER
Collaborators: name: Peking University First Hospital
First posted: 2012-03-21
Enrollment: 503
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progressive kidney failure
timeFrame: 1-6 years
measure: primary outcome for low dose cohort
timeFrame: 1 year
Secondary outcomes:
measure: The composite of ESKD, 30% decrease in eGFR and all cause death
timeFrame: 1-6 years
measure: The composite of ESKD 40% decrease in eGFR and all cause death
timeFrame: 1-6 years
measure: The composite of ESKD 50% decrease in eGFR and all cause death
timeFrame: 1-6 years
measure: Annual eGFR decline rate
timeFrame: 1-6 years
measure: Each ESKD , death due to kidney disease and all cause death
timeFrame: 1-6 years
measure: Time averaged proteinuria post-randomisation
timeFrame: 1-6 years
Other outcomes:
Locations:
city: Concord
country: Australia
facility: Concord Repatriation and General Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Calgary
country: Canada
facility: University of Calgary/Alberta Health Services
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospitals
state: Alberta
city: Vancouver
country: Canada
facility: St Pauls Hospital
state: British Columbia
city: Hamiliton
country: Canada
facility: St. Joseph's Healthcare
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital,
state: Ontario
city: Montreal
country: Canada
facility: Hôpital Maisonneuve-Rosemont
state: Quebec
city: Beijing
country: China
facility: Chinese PLA General Hospital (301 Hospital)
state: Beijing
city: Guangzhou
country: China
facility: The First Affiliated Hospital, Sun Yat-Sen University
state: Guangdong
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital, Guangzhou
state: Guangdong
city: Shenzhen
country: China
facility: Peking University Shenzhen Hospital
state: Guangdong
city: Shijiazhuang
country: China
facility: The Second Hospital of Hebei Medical University
state: Hebei
city: Shijiazhuang
country: China
facility: The Third Hospital of Hebei Medical University
state: Hebei
city: Luoyang
country: China
facility: The First Affiliated Hospital of Henan University of Science &Technology
state: Henan
city: Zhengzhou
country: China
facility: Henan Provincial People's Hospital
state: Henan
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Wuhan
country: China
facility: ongji Hospital, Tongji Medical College, Huazhong University of Science & Technology
state: Hubei
city: Wuhan
country: China
facility: Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Renmin Hospital, Wuhan University
state: Hubei
city: Baotou
country: China
facility: The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology,
state: Inner Mongolia
city: Hohhot
country: China
facility: Inner Mongolia People's Hospital
state: Inner Mongolia
city: Nanjing
country: China
facility: General Hospital of Eastern Theater Command
state: Jiangsu
city: Nanjing
country: China
facility: The First Affiliated Hospital with Nanjing Medical University
state: Jiangsu
city: Changchun
country: China
facility: Jilin Province FAW General Hospital [Jilin University Fourth Hospital]
state: Jilin
city: Dalian
country: China
facility: he First Affiliated Hospital of Dalian Medical University, Dalian
state: Liaoning
city: Shengyang
country: China
facility: Shengjing Hospital Of China Medical University
state: Liaoning
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shandong
city: Jinan
country: China
facility: The First Affiliated Hospital of Shangdong First Medical University,Shangdong Provincial Qianfoshin
state: Shandong
city: Jinan
country: China
facility: Shandong Provincial Hospital
state: Shandong
city: Jinan
country: China
facility: Jinan Military General Hospital
state: Shandong
city: Yantai
country: China
facility: Yantai Yuhuangding Hospital
state: Shandong
city: Taiyuan
country: China
facility: he Second Hospital of Shanxi Medical University, Taiyuan
state: Shanxi
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
state: Sichuan
city: Chengdu
country: China
facility: Sichuan Academy of Medical Science, Sichuan Provincial People's Hospital
state: Sichuan
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Hangzhou Hospital of Traditional Chinese Medicine,
state: Zhejiang
city: Ningbo
country: China
facility: Ningbo Urology & Nephrology Hospital
state: Zhejiang
city: Sangzhou
country: China
facility: Zhejiang Provincial People's Hospital
state: Zhejiang
city: Beijing
country: China
facility: Beijing Anzhen Hospital, Capital Medical University
city: Beijing
country: China
facility: Peking University First Hospital
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: Beijing Hospital
city: Beijing
country: China
facility: Peking University Third Hospital
city: Chongqing
country: China
facility: XinQiao Hospital, Third Military Medical University
city: Shanghai
country: China
facility: Renji Hospital, Shanghai Jiaotong University School of Medicine
city: Shanghai
country: China
facility: Ruijin Hospital, Shanghai Jiaotong University, School of Medicine
city: Shanghai
country: China
facility: Huashan Hospital, Medical Centre of Fudan University
city: Kowloon
country: Hong Kong
facility: Princess Margaret Hospital
city: Hyderabad
country: India
facility: Osmania General Hospital
state: Andhra Pradesh
city: Hyderabad
country: India
facility: Nizam's Institute of Medical Science
state: Andhra Pradesh
city: Kozhikode
country: India
facility: Calicut Medical College
state: Kerala
city: Chandigarh
country: India
facility: Post Graduate Institue of Medical Education and Reasearch
state: Punjab
city: Chen
country: India
facility: Madras Medical College
state: Tamil Nadu
city: Lucknow
country: India
facility: Sanjay Gandhi Post Graduate Institute of Medical Science
state: Uttar Pradesh
city: Johor Bahru
country: Malaysia
facility: Hospital Sultanah Aminah
state: Johor
city: Kuala Lumpur
country: Malaysia
facility: Hospital Kuala Lumpur
state: Kulala Lumpur
city: Seremban
country: Malaysia
facility: Hospital Tuanku Jaafar Seremban
state: Negri Seremban
city: Ipoh
country: Malaysia
facility: Hospital Raja Permaisuri Bainun
state: Perak
city: Kuching
country: Malaysia
facility: Hospital Umum Sarawak
state: Samarahan
city: Kuala Lumpur
country: Malaysia
facility: University Malaysia Medical Centre
Study officials:
affiliation: Peking University
name: Hong Zhang
role: PRINCIPAL_INVESTIGATOR
affiliation: The George Institute
name: Vlado Perkovic
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.