UMIN-CTR Clinical Trial

Basic information
Public title	Clinical trial of tocilizumab versus cyclophosphamide for microscopic polyangiitis and granulomatosis with polyangiitis
Acronym	AAVTCZ
Scientific Title	Clinical trial of tocilizumab versus cyclophosphamide for microscopic polyangiitis and granulomatosis with polyangiitis
Scientific Title:Acronym	AAVTCZ
Region	Japan

Condition
Condition	Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (GPA)
Classification by specialty	Pneumology Nephrology Neurology Clinical immunology Ophthalmology Dermatology Oto-rhino-laryngology
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	To compare efficacy and safety between the treatment with intravenous tocilizumab (TCZ) plus high dose glucocorticoids (GC) and the treatment with intravenous cyclophosphamide (IVCY) plus high dose GC, in active patients with MPA and GPA.
Basic objectives2	Pharmacokinetics
Basic objectives -Others
Trial characteristics_1	Exploratory
Trial characteristics_2	Others
Developmental phase	Phase II

Assessment
Primary outcomes	The percentage of participants in complete remission at week 24 after randomization. Complete remission is defined as BVAS v3 = 0 (at week 20 and 24) and daily prednisone at a dose of 7.5mg at week 24.
Key secondary outcomes	Percentage of participants maintaining complete remission (BVAS v3 = 0 and daily prednisolone at a dose of 7.5mg) during week 24 to 52 after randomization. Percentage of participants who achieved BVAS v3 = 0 at two consecutive visits during 52 weeks after randomization. Time from randomization to achieving BVAS v3 = 0 at two consecutive visits. Percentage of participants who were able to taper daily prednisolone to a dose of 7.5mg during 52 weeks after randomization. Time from randomization to tapering daily prednisolone to a dose of 7.5mg. Total dosage of prednisolone. Percentage of participants who had flare. Time from randomization to first flare. Changes of BVAS score by categories. VDI SF-36 EQ5D Safety Pharmacokinetics

Base
Study type	Interventional

Study design
Basic design	Parallel
Randomization	Randomized
Randomization unit	Cluster
Blinding	Open -but assessor(s) are blinded
Control	Active
Stratification	NO
Dynamic allocation	YES
Institution consideration	Institution is not considered as adjustment factor.
Blocking	NO
Concealment	Central registration

Intervention
No. of arms	2
Purpose of intervention	Treatment
Type of intervention	Medicine
Interventions/Control_1	TCZ group Week 0-16: TCZ (8mg/kg) will be administrated intravenously every 2 weeks. Week 20 and 24: TCZ (8mg/kg) will be administrated intravenously every 4 weeks. If a participant does not achieve BVAS v3=0 at week 16, he/she can receive TCZ every 2 weeks until week 24. Week 28-52: If a participant achieves complete remission at week 24, he/she will receive TCZ (8mg/kg) intravenously every 4 weeks until week 48. PSL PSL will be prescribed by the same schedule to both treatment groups. Week 0-24: Oral PSL will be given at a dose of 0.8 mg/kg/day during first 4 weeks. And then, PSL will be tapered according to the prefixed schedule. Week 25-52: Participants continue taking oral PSL at a dose of 7.5mg per day.
Interventions/Control_2	IVCY group Week 0-24: CY (15mg/kg, doses will be modified for renal dysfunction) will be administrated intravenously every 4 weeks (at least 3 times, up to 6 times). From 4 weeks after the last IVCY to week 52: If a participants achieves complete remission 4 weeks after the last IVCY, he/she will take azathioprine (AZA) orally every day and continue until week 52. PSL PSL will be prescribed by the same schedule to both treatment groups. Week 0-24: Oral PSL will be given at a dose of 0.8 mg/kg/day during first 4 weeks. And then, PSL will be tapered according to the prefixed schedule. Week 25-52: Participants continue taking oral PSL at a dose of 7.5mg per day.
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	85 years-old >
Gender	Male and Female
Key inclusion criteria	1 Those with ANCA positive active MPA or GPA according to the diagnostic criteria of Japanese MHLW, or those with ANCA positive pauci-immune glomerulonephritis without non-renal vasculitis. They must have newly diagnosed MPA or GPA, or have a disease flare that fulfills the inclusion criteria. 2 They must be 20 years of age or older and be under 80 years old. 3 They must weigh at least 40 kg. 4 They must have active disease with BVAS v3 more than 3 with one or more of the major BVAS items. Or they must have active disease severe enough to require treatment with CY (i.e., an organ threatening disease if not treated appropriately) according to the discretion of site investigators. 5 Serum C-reactive protein level must be grater than1.0 mg/dl. 6 They must be willing to practice medically acceptable contraception until 70 days after the last administration of TCZ and until 90 days after the last administration of IVCY or AZA. 7 For female participants, they must be willing to refrain from breastfeeding throughout the trial. 8 They must be willing to comply with study procedures, including completion of all visits and treatments 9 They must be willing and able to provide informed consent.
Key exclusion criteria	Exclusion Criteria Patients who meet any of these criteria will not be enrolled in this study: Eosinophilic granulomatosis with polyangiitis or anti-glomerular basement membrane antibody disease patients. Other collagen diseases or systemic autoimmune diseases patients. Severity: limited disease according to EUVAS criteria. Those having serious lung, renal or heart disease. Those having infarction or bleeding of gastrointestinal tract or having diverticulitis.. Those having a history of severe drug allergic reactions. Those having an active infection or a deep-seated infection within 6 months of randomization. Those having active hepatitis B or a history of infection with HBV. Those having positive anti-HBs antibody or anti-HBc antibody, and HBV-DNA. Those having active hepatitis C or a history of hepatitis C. Those having an ALT or AST level greater than 2.5 times of the upper limit of normal. Those having active tuberculosis or mycosis Those having CMV antigenemia They have or have a history of malignancy, leukemia, lymphoma or lymphoproliferative disease in the past 5 years. Those having uncontrolled other disease. Those having a white blood cell count less than 4,000/mm3 or a platelet count less than 120,000/mm3. Those who have received TCZ or other biological agents. Those who were intolerant to CYC or AZA. Those who started GC or increased a dosage of GC within 4 weeks prior to enrollment. Those who started GC at or increased a dosage of GC to a prednisone-equivalent dose greater than 25mg per day between 5 and 8weeks prior to enrollment. Those who started or increased a dosage of immunosuppressive agents except for GC within 8 weeks prior to enrollment. Those who were treated with plasma exchange or IVIG within 4 weeks prior to enrollment. Those who received a live vaccine within 4 weeks prior to enrollment. Those who were enrolled in another clinical trial and received an investigational agent within 12 weeks prior to enrollment.
Target sample size	48

Research contact person
Last name of lead principal investigator	1st name Masayoshi Middle name Last name Harigai
Organization	Tokyo women's medical university
Division name	Institute of Rheumatology
Zip code	1628666
Address	8-1 kawada-cho shinjyuku-ku Tokyo Japan
TEL	03-3353-8111
Email	harigai.masayoshi@twmu.ac.jp

Public contact
1st name of contact person	1st name Michi Middle name Last name Tsutsumino
Organization	Tokyo women's medical university
Division name	Institute of Rheumatology
Zip code	1628666
Address	8-1 kawada-cho shinjyuku-ku Tokyo Japan
TEL	03-3353-8111
Homepage URL
Email	tsutsumino.michi@twmu.ac.jp

Sponsor
Institute	Tokyo women's medical university Institute of rheumatology
Institute
Department

Funding Source
Organization	Japan Medical Association
Organization
Division
Category of Funding Organization	Other
Nationality of Funding Organization

Other related organizations
Co-sponsor	Hokkaido university hospital Saitama medical center Tokyo women's medical university hospital Keio university hospital Juntendo university hospital Kyorin university hospital St. Marianna university hospital Okayama university hospital Kagawa university hospital Hospital of the university of occupational and environmental health, Japan Tokyo Medical Center Touhoku University Hospital Kyusyu University Hospital Hiroshima University Hospital
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Tokyo women's medical university Hospital
Address	8-1 kawada-cho shinjyuku-ku Tokyo Japan
Tel	03-5269-7839
Email	ar.twmu-chiken-ar@smo-msr.co.jp

Secondary IDs
Secondary IDs	YES
Study ID_1	JMA-IIA00325
Org. issuing International ID_1	Japan Medical Association
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions	東京女子医科大学病院（東京都） 北海道大学病院（北海道） 埼玉医科大学総合医療センター（埼玉県） 慶應義塾大学病院（東京都） 順天堂大学医学部附属順天堂医院（東京都） 杏林大学医学部付属病院（東京都） 聖マリアンナ医科大学病院（神奈川県） 岡山大学病院（岡山県） 香川大学医学部附属病院（香川県） 産業医科大学病院（福岡県）

Other administrative information
Date of disclosure of the study information	2017 Year 05 Month 01 Day

Related information
URL releasing protocol
Publication of results	Unpublished

Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Open public recruiting
Date of protocol fixation	2016 Year 10 Month 30 Day
Date of IRB
Anticipated trial start date	2018 Year 07 Month 02 Day
Last follow-up date
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information

Management information
Registered date	2016 Year 10 Month 26 Day
Last modified on	2019 Year 05 Month 07 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028278