Tacrolimus Monotherapy for Idiopathic Membranous Nephropathy (IMN)

Idiopathic Membranous Nephropathy Clinical Trial

Official title:

Random, Open, Control and Monocentric Clinical Research on Tacrolimus Monotherapy for Idiopathic Membranous Nephropathy (IMN)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03549663
• Other study ID #: XH-18-006
• Status: Recruiting
• Phase: N/A
• Start date: July 4, 2018
• Est. completion date: October 2021

Study information

• Verified date: April 2019
• Source: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
• Contact: Fujun Lin, MD,PhD
• Phone: +86-13917983703
• Email: linfujun[@]xinhuamed.com.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The trial is a random, open, control and monocentric trial. Mainly to assess the urine protein remission rate of tacrolimus (TAC) monotherapy for idiopathic membranous nephropathy (IMN). Assuming that the urine protein remission rate of 48-week TAC for monotherapy of IMN is not lower than that in treatment group of TAC combined with glucocorticoid, attempt on de-hormonal therapy in the future IMN therapy can be attempted on the basis of the trial results.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 108
• Est. completion date: October 2021
• Est. primary completion date: October 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Age: 18 - 80 years;

2. Those whose clinical manifestation and renal biopsy pathologic diagnosis are IMN (Stages I-IV) with secondary membranous nephropathy excluded;

3. Those who meet any of the following high-risk IMN standards:

• Urinary protein>8g/24h

• Serum albumin<25g/l

• Serum PLA2R levels are 5 times higher than normal

• eGFR decline rate after confirmed IMN within 6-12 months is =30%

• Patients with serious complications: pulmonary embolism, lower extremity static Vein thrombosis/embolism, acute renal injury, etc.

4. Those without reaching the above high-risk IMN standard, but their course of disease is >6 months without spontaneous remission,and still present nephrotic syndrome;

5. Patients who have signed the informed consent forms.

Exclusion Criteria:

1. Those whose kidney pathological manifestation of interstitial fibrosis is >30%;

2. Those who are positive in active Hepatitis B (including HBsAg, HBeAg and HBcAb or HBsAg, HBeAb and HBC) or serological indexes (HBsAg or/and HBeAg or/and HBcAb) or infected with Hepatitis C, tuberculosis, cytomegalovirus, severe fungal or HIV infection;

3. Those who suffer from untreated active digestive tract ulcer within 3 months before random grouping;

4. Those who suffer from uncured malignant tumor for less than 5 years

5. Those who received glucocorticoid (prednisone or prednisolone), mycophenolatemofetil, tacrolimus, cyclosporine A and other drugs for treatment within 3 months before screen with a course of treatment exceeding 4 weeks or those who received cyclophosphamide (accumulated dose>1.0g);

6. Those whose ALT, AST or total bilirubin content goes beyond 1.5 times above normal upper limit;

7. Those who suffer from combined critical complications such as serious infection or other severe organ disease or dysfunction;

8. Pregnant or lactating women;

9. Those who are known to be allergic to drugs under trial or relevant products;

10. Those who participated in other clinical trials within 3 months before inclusion;

11. The patients who cannot comply with the research proposal as determined by the supervising physician.

Exit criteria

1. Those with incomplete or partial relieved proteinuria for 6 months after treatment;

2. Patients or their legal guardians voluntarily requests to withdraw;

3. Those against the inclusion criteria and exclusion criteria;

4. Those who need to take medications prohibited by the trail;

5. Those with poor compliance or stopping the drug for over 2 weeks;

6. Those with uncontrollable infection;

7. Those whit elevated blood glucose during the treatment, which is still difficult to control after routine treatment by endocrinologists;

8. In the TAC group, the eGFR decreased by >30%, the TAC dose was halved. And the drug concentration and renal function were reviewed after 2 weeks. If the eGFR decreased by <30%, it will continue to be used; if the eGFR still decreased by >30%, the TAC dose continues to halve, or give a minimum dose of 0.5mg / d. And the drug concentration and renal function were reviewed after 2 weeks. If the eGFR decreased by <30%, TAC will continue to be used, otherwise stop the drug;

9. Those whose ALT, AST or bilirubin rises to more than 2 times the upper limit of normal value after treatment, and continues to increase for 2 weeks; those whose ALT, AST or bilirubin rises to more than 2 times the upper limit of normal value after 2 weeks of treatment with liver protection, the drug will be discontinued. If it cannot be recovered after 2 weeks, the patient will withdraw;

10. Those with other unexplained severe comorbidities;

11. Those with pregnancy during treatment;

12. For security reasons, the research sponsor proposed to stop the study;

Related Conditions & MeSH terms

• Glomerulonephritis, Membranous
• Idiopathic Membranous Nephropathy
• Kidney Diseases

Intervention

Drug:
• Tacrolimus
Tacrolimus capsules: 0.5mg/pill, 50 pills/box, AstellasPharma (China) Co., Ltd.; Tacrolimus capsules: 1mg/pill, 50 pills/box, Hangzhou ZhongmeiHuadong Pharmacy Co., Ltd. Start to administer on the randomized grouping day (D0) with an initial dose by weight: initial dose of 0.05-0.075mg/kg/d (bid) following a strict administration interval of 12 hours or fasting or 2 hours after meal. Adjust TAC dose according to 24-hour urine protein, plasma concentration and eGFR changes. It is recommended that plasma trough concentration should be remained at 5-8ng/ml and TAC dose during the whole therapy stage should not be lower than 0.5mg/d. Drugs should be stopped if the 6-month therapy is ineffective. After 6-month therapy, for those whose urine protein achieved complete remission (CR) or partial remission (PR), TAC dose should be reduced gradually with a total therapy duration of 48 weeks.
• Prednisone
Glucocorticoid (prednisone): 5mg/pill, 100 pills/bottle: Shanghai Sine Pharmaceutical Factory Co., Ltd. The initial dose of prednisone should be 0.5mg/kg/d orally (maximum dose of 40mg/d) and administration should be continued for 8-12 weeks; then reduced by the monthly decreased amount of 0.1mg/kg/d till to 0.2mg/kg/d (5-10mg) to maintain. Prednisone should be stopped after administration for the entire 48 weeks.

Locations

Country	Name	City	State
China	Shanghai Xinhua Hospital affliated to Shanghai Jiao Tong University, School of Medicine	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Xinhua Hospital, Shanghai Jiao Tong University School of Medicine

Country where clinical trial is conducted

China, 

References & Publications (14)

Chen M, Li H, Li XY, Lu FM, Ni ZH, Xu FF, Li XW, Chen JH, Wang HY; Chinese Nephropathy Membranous Study Group. Tacrolimus combined with corticosteroids in treatment of nephrotic idiopathic membranous nephropathy: a multicenter randomized controlled trial. Am J Med Sci. 2010 Mar;339(3):233-8. doi: 10.1097/MAJ.0b013e3181ca3a7d. — View Citation

du Buf-Vereijken PW, Branten AJ, Wetzels JF. Idiopathic membranous nephropathy: outline and rationale of a treatment strategy. Am J Kidney Dis. 2005 Dec;46(6):1012-29. Review. — View Citation

Hofstra JM, Fervenza FC, Wetzels JF. Treatment of idiopathic membranous nephropathy. Nat Rev Nephrol. 2013 Aug;9(8):443-58. doi: 10.1038/nrneph.2013.125. Epub 2013 Jul 2. Review. — View Citation

Hoxha E, Thiele I, Zahner G, Panzer U, Harendza S, Stahl RA. Phospholipase A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy. J Am Soc Nephrol. 2014 Jun;25(6):1357-66. doi: 10.1681/ASN.2013040430. Epub 2014 Mar 7. — View Citation

KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int 2012, 2: 139-274.

Liang Q, Li H, Xie X, Qu F, Li X, Chen J. The efficacy and safety of tacrolimus monotherapy in adult-onset nephrotic syndrome caused by idiopathic membranous nephropathy. Ren Fail. 2017 Nov;39(1):512-518. doi: 10.1080/0886022X.2017.1325371. — View Citation

Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B, Melis P, Valzorio B, Sasdelli M, Pasquali S, Pozzi C, Piccoli G, Lupo A, Segagni S, Antonucci F, Dugo M, Minari M, Scalia A, Pedrini L, Pisano G, Grassi C, Farina M, Bellazzi R. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol. 1998 Mar;9(3):444-50. — View Citation

Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. 1995 Nov;48(5):1600-4. — View Citation

Praga M, Barrio V, Juárez GF, Luño J; Grupo Español de Estudio de la Nefropatía Membranosa. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int. 2007 May;71(9):924-30. Epub 2007 Mar 21. — View Citation

Ramachandran R, Hn HK, Kumar V, Nada R, Yadav AK, Goyal A, Kumar V, Rathi M, Jha V, Gupta KL, Sakhuja V, Kohli HS. Tacrolimus combined with corticosteroids versus Modified Ponticelli regimen in treatment of idiopathic membranous nephropathy: Randomized control trial. Nephrology (Carlton). 2016 Feb;21(2):139-46. doi: 10.1111/nep.12569. — View Citation

Xu J, Zhang W, Xu Y, Shen P, Ren H, Wang W, Li X, Pan X, Chen N. Tacrolimus combined with corticosteroids in idiopathic membranous nephropathy: a randomized, prospective, controlled trial. Contrib Nephrol. 2013;181:152-62. doi: 10.1159/000348475. Epub 2013 May 8. — View Citation

Xu X, Wang G, Chen N, Lu T, Nie S, Xu G, Zhang P, Luo Y, Wang Y, Wang X, Schwartz J, Geng J, Hou FF. Long-Term Exposure to Air Pollution and Increased Risk of Membranous Nephropathy in China. J Am Soc Nephrol. 2016 Dec;27(12):3739-3746. Epub 2016 Jun 30. — View Citation

Zhu LB, Liu LL, Yao L, Wang LN. Efficacy and Safety of Tacrolimus Versus Cyclophosphamide for Primary Membranous Nephropathy: A Meta-Analysis. Drugs. 2017 Feb;77(2):187-199. doi: 10.1007/s40265-016-0683-z. Review. — View Citation

Zhu P, Zhou FD, Wang SX, Zhao MH, Wang HY. Increasing frequency of idiopathic membranous nephropathy in primary glomerular disease: a 10-year renal biopsy study from a single Chinese nephrology centre. Nephrology (Carlton). 2015 Aug;20(8):560-6. doi: 10.1111/nep.12542. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete remission rate of 24-hour urine protein	The proportion of patients with complete remission of 24-hour urine protein in the total evaluated patients. Evaluation criteria of complete remission: post-therapy urine protein level is <0.3g/24h.	At week 48
Secondary	Partial remission remission rate of 24-hour urine protein	The proportion of patients with partial remission of 24-hour urine protein in the total evaluated patients. Evaluation criteria of partial remission: post-therapy urine protein decline is >50% compared with the peak value.	At week 48
Secondary	PLA2R antibody negative conversion rate	The proportion of patients with PLA2R antibody negative conversion in the total evaluated patients. Evaluation criteria of negative conversion: PLA2R antibody level is <20RU/ml.	At week 48
Secondary	Number of patients with adverse events	Number of patients with adverse events	up to 48 weeks