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

Sponsor

The George Institute (Other)

Overall Status

Completed

CT.gov ID

NCT01560052

Collaborator

Peking University First Hospital (Other)

503

Enrollment

Locations

Arms

110.6

Actual Duration (Months)

7.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
IgA Glomerulonephritis	Drug: methylprednisolone Drug: Placebo	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

503 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 5, 2012

Actual Primary Completion Date :

Jul 23, 2021

Actual Study Completion Date :

Jul 23, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Concord Repatriation and General Hospital	Concord	New South Wales	Australia	2139
2	Nepean Hospital	Kingswood	New South Wales	Australia	2747
3	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2065
4	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
5	Royal Melbourne Hospital	Melbourne	Victoria	Australia	3052
6	University of Calgary/Alberta Health Services	Calgary	Alberta	Canada	T2R 0X7
7	University of Alberta Hospitals	Edmonton	Alberta	Canada	T6G 2B7
8	St Pauls Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
9	St. Joseph's Healthcare	Hamiliton	Ontario	Canada	L8N 4A6
10	London Health Sciences Centre	London	Ontario	Canada	N6A 5A5
11	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
12	Toronto General Hospital,	Toronto	Ontario	Canada	M5G 2N2
13	Hôpital Maisonneuve-Rosemont	Montreal	Quebec	Canada	H1T 2M4
14	Chinese PLA General Hospital (301 Hospital)	Beijing	Beijing	China
15	The First Affiliated Hospital, Sun Yat-Sen University	Guangzhou	Guangdong	China	510080
16	Guangdong Provincial People's Hospital, Guangzhou	Guangzhou	Guangdong	China
17	Peking University Shenzhen Hospital	Shenzhen	Guangdong	China	518036
18	The Second Hospital of Hebei Medical University	Shijiazhuang	Hebei	China	050005
19	The Third Hospital of Hebei Medical University	Shijiazhuang	Hebei	China	050051
20	The First Affiliated Hospital of Henan University of Science &Technology	Luoyang	Henan	China	471003
21	Henan Provincial People's Hospital	Zhengzhou	Henan	China	450003
22	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan	China	450052
23	ongji Hospital, Tongji Medical College, Huazhong University of Science & Technology	Wuhan	Hubei	China	430022
24	Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei	China	430022
25	Renmin Hospital, Wuhan University	Wuhan	Hubei	China	430060
26	The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology,	Baotou	Inner Mongolia	China	014010
27	Inner Mongolia People's Hospital	Hohhot	Inner Mongolia	China	010017
28	General Hospital of Eastern Theater Command	Nanjing	Jiangsu	China	210002
29	The First Affiliated Hospital with Nanjing Medical University	Nanjing	Jiangsu	China	210029
30	Jilin Province FAW General Hospital [Jilin University Fourth Hospital]	Changchun	Jilin	China	130011
31	he First Affiliated Hospital of Dalian Medical University, Dalian	Dalian	Liaoning	China	116011
32	Shengjing Hospital Of China Medical University	Shengyang	Liaoning	China
33	Qilu Hospital of Shandong University	Jinan	Shandong	China	250012
34	The First Affiliated Hospital of Shangdong First Medical University,Shangdong Provincial Qianfoshin	Jinan	Shandong	China	250014
35	Shandong Provincial Hospital	Jinan	Shandong	China	250021
36	Jinan Military General Hospital	Jinan	Shandong	China
37	Yantai Yuhuangding Hospital	Yantai	Shandong	China	264000
38	he Second Hospital of Shanxi Medical University, Taiyuan	Taiyuan	Shanxi	China	030001
39	West China Hospital of Sichuan University	Chengdu	Sichuan	China	610041
40	Sichuan Academy of Medical Science, Sichuan Provincial People's Hospital	Chengdu	Sichuan	China	610072
41	The First Affiliated Hospital, Zhejiang University of Medicine	Hangzhou	Zhejiang	China	310003
42	Hangzhou Hospital of Traditional Chinese Medicine,	Hangzhou	Zhejiang	China
43	Ningbo Urology & Nephrology Hospital	Ningbo	Zhejiang	China
44	Zhejiang Provincial People's Hospital	Sangzhou	Zhejiang	China
45	Beijing Anzhen Hospital, Capital Medical University	Beijing		China	100029
46	Peking University First Hospital	Beijing		China	100034
47	Peking University People's Hospital	Beijing		China	100035
48	Beijing Hospital	Beijing		China	100730
49	Peking University Third Hospital	Beijing		China
50	XinQiao Hospital, Third Military Medical University	Chongqing		China	400037
51	Renji Hospital, Shanghai Jiaotong University School of Medicine	Shanghai		China	200001
52	Ruijin Hospital, Shanghai Jiaotong University, School of Medicine	Shanghai		China	200025
53	Huashan Hospital, Medical Centre of Fudan University	Shanghai		China	200040
54	Princess Margaret Hospital	Kowloon		Hong Kong
55	Osmania General Hospital	Hyderabad	Andhra Pradesh	India	500012
56	Nizam's Institute of Medical Science	Hyderabad	Andhra Pradesh	India	500082,
57	Calicut Medical College	Kozhikode	Kerala	India	673008,
58	Post Graduate Institue of Medical Education and Reasearch	Chandigarh	Punjab	India	160 012
59	Madras Medical College	Chen	Tamil Nadu	India	600037
60	Sanjay Gandhi Post Graduate Institute of Medical Science	Lucknow	Uttar Pradesh	India	226014
61	Hospital Sultanah Aminah	Johor Bahru	Johor	Malaysia	80100
62	Hospital Kuala Lumpur	Kuala Lumpur	Kulala Lumpur	Malaysia	50586
63	Hospital Tuanku Jaafar Seremban	Seremban	Negri Seremban	Malaysia	70300
64	Hospital Raja Permaisuri Bainun	Ipoh	Perak	Malaysia	30990
65	Hospital Umum Sarawak	Kuching	Samarahan	Malaysia	93586
66	University Malaysia Medical Centre	Kuala Lumpur		Malaysia	59100