clinical trials in lupus nephritis

8/13/2019 Clinical Trials in Lupus nephritis

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CLINICAL TRIALS IN LN02 January 2014

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NIH TRIAL: compared three regimens in 65 patients with a mean serum creatinine of approximately

1.6 to 2.0 mg/dl.

All received oral prednisolone beginning at a dose of 0.5 mg/kg per day and then tapering over aperiod of months to alternate-day maintenance therapy for control of extrarenal symptoms

(minimum dose 0.25 mg/kg every other day).

Parameters at 3

yrs

Regimen A :

IV CYC

Monthly x 6

20 pts

Regimen B:

A + 3 monthly

Iv CYC for

total 24

months

20 pts

Regimen C:

Iv methyl

prednisolone 1

g/mt sq monthly X 6

dose without CYC

25 pts

Doubling of sr

creatinine

Low

25 %

Low

25%

High

48%

relpase high Low

An extended course of pulse cyclophosphamide is more effective than 6 months of pulse

methylprednisolone in preserving renal function in patients with severe lupus nephritis. Addition of

a quarterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of

exacerbations.

patients with relatively mild disease (serum creatinine 1.3 mg/dL [115 micromol/L] and/or proteinexcretion 1.0 g/day) had a favorable prognosis.


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2nd NIH trial :

82 pts with mainly Diffuse proliferative lupus nephritis.

Mean baseline creatinine 1.1 mg/dl

All received oral prednisolone as above, and were randomised to 3 groupsPARAMETERS

STUDIED

Median FU 5 yrs

REGIMEN A

Monthly IV

MP 1 g/m sq

X 12 months

REGIMEN B

IV CYC .5-1 G/M sq X 6

mth--> 3 monthly IV

CYC = 24 mths

REGIMEN C

MP + IV CYC

REMISSION :

Non censored

censored

29%

26 %

62%

48%

85 %

61%

Relpase 36% 7 0

Adverse events

Osteonecrosis

Infection

Amenorrhea

osteoporosis

Ovarian failure

=

less

High

=

High 25%

High

High

High 52% High 52%

REMISSION defined as : rate of CR, cumulative remission and adverse effect.

2nd trial : 60 pts:

TAC+steroid vs MMF+ steroids vs high dose IV CYC + steroids.Similar CR and cumulative remission rate.

Rapid improvement in Sr albumin and proteinuria in above trial with TAC.

STUDIES MAINLY IN CHINESE. Efficacy in more diverse cohorts not known.

MULTITARGET THERAPY : TAC+ MMF

Bao H, Liu ZH, Xie HL, et al. Successful treatment of class V IV lupus nephritis with multitarget

therapy. J Am Soc Nephrol 2008; 19:20012010.

Cortes-Hernandez J, Torres-Salido MT, Medrano AS, et al. Long-term outcomesmycophenolate

mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol DialTransplant 2010; 25:39393948.


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Lanata CM, Mahmood T, Fine DM, et al. Combination therapy of mycophenolate mofetil and

tacrolimus in lupus nephritis. Lupus 2010; 19:935940.

EUROLUPUS NEOHRITIS TRIAL : ELNT 2002Houssiau FA, Vasconcelos C, D Cruz D , et al. Immunosuppressive therapy in lupusnephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002; 46:2121213190 pts enrolled. Multi centre prospective study == 19 european centres..Sept 1996 to sept 2000.

INCLUSION CRITERIA:

>14 yrs age. LN class 3, 4, 5c,5d : WHO Proteinuria > 500 mg/d

EXCLUSION CRITERIA :

Previous Rx with CYC or AZA 15 mg/ d prednisolone. 33% in the serum creatinine level

within a 1-month period.


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An increase in proteinuriawas defined as the recurrence or appearance of nephrotic syndrome

(albuminemia


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The 3 secondary end pointswere as follows:

1)the kinetics of the response to therapy in the first year, based on serial measurements of serum

creatinine, serum albumin, 24-hour urinary protein, and serum C3 levels, as well as the ECLAM score;

2) the rate of renal remission, defined as


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Remission 30 (71%) 22 ( 54%)

RENAL FLARE 12 (27%)

11 during AZA Rx

13 (29%)

7 during IV CYC Rx

Adverse events

Infections ( SEVERE)

=

5 pts ( 7 episodes)

=

but numerically

higher infections

10 pts ( 17 episodes)

Death 2

A : 14 yr wih SKI + nephrotic proteinuria + CHF. 28

th day of Rx : MOF

B: 51 yr dropped o study @ 121 st week : Breast

cancer--> sudden death week 194 : cause ??

0

ESRD 1 (wk 208) 2 (wk : 104 & 193)

Doubling of serum

creatinine :

Gonadal toxicity = =

LONG TERM =10 yr FU of EUROLUPUS

Houssiau FA, Vasconcelos C, D'Cruz D, et al. The 10-year followup data of the Euro-Lupus Nephritis

Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010; 69:

6164

Limitations of the ELNT study:

Mainly done in Caucasian population,

Majority ( = 78% ) of patients had preserved renal function (creatinine


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1 yr cumulative

remission rate

83% highest 60% 27 % lowest

Quickest

remission

Few relapse

3rd : 2010Zavada J, Pesickova S, Rysava R, et al.Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: theCyclofa-Lune study. Lupus 2010; 19:12811289.

Jan 2002 - Dec 2006. Czech R + Slovakia40 pts with proliferative GN: steroids + one of

CYC IV 10 mg/kg

8 boluses in 9 months

Followed by oral CYC 10 mg/d 6 -

8 weeks interval

Csa induction 9 months

4-5 mg/kg/d in divided dose

Maintainence: gradual taper to 3.75-

1.25 mg.kg.d 9 month

CR in proteinuria 38% More 69%

Stable / improved

creatinine

More 86% 47%

Increase BP, decrase GFr

RITUXIMAB IN LN:

Off label use.

Bhat P, Radhakrishnan J. B lymphocytes and lupus nephritis: new insights into pathogenesis and

targeted therapies. Kidney Int 2008; 73:261268.==> role of B lymphocytes in LN.

STUDY OF RITUXIMAB + IV CYC + prednisolone in refractory LN == rituximab + steroid.

LUNAR. The Lupus Nephritis Assessment With Rituximab Study Trial==> largest . 144 pts.

OBJECTIVE : To evaluate the efficacy and safety of rituximab in a randomized, double-blind, placebo

controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate

mofetil (MMF) and corticosteroids.

MMF+steroid + Rituximab or placebo.

Primary end point : renal response at 52 weeks.

Rituximab given at dose of 1 g on day 1, 15, 168 and 182

MMF : 500 mg TDS --> by 4 week 3 g/d.--> continued for 52 weeks.

MP IV 1000 mg D1 7 D3

Oral prednisolone : 0.75 mg/kg max 60 mg for 16 days, tapered to < 10 mg/d by 16 week.

Any pt requiring rescue therapy --> labelled as non responder and withdrawn.

Overall response 57 vs 46%.


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The primary end point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required

cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and antidouble-

stranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median

reduction was associated with reduced proteinuria.Adverse events were equal, but

RTX associated with more neutropenia, leucopenia and hypotension.

LIMITAION:

Not included refractory cases.

Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis

: NDT 2012

A systematic review of use of Rituximab in refractory LN.


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Maintenance therapy trials:

First RCT on MMF:

Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J

Med 2004; 350:971980.

59 pts.

Induction with high dose IV CYC+ Prednisolone

Maintainance with : either MMF or AZA or Quarterly IV CYC.Primary endpoint was death / CRF.


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RESULT: MMF & AZA > to CYC

MMF with few relapse.

Lower infection with MMF & AZA.

SO IV CYC mainatinence was discarded

TRIALS comparing MMF with AZA:

MAINTAIN NEPHRITIS TRIAL:Houssiau FA, D'Cruz D, Sangle S, et al.Azathioprine versus mycophenolate mofetil for long-termimmunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010;69:20832089.

EUROPEAN POPULATION, july 2002 - march 2006, 105 ptsINDUCTION WAS ELNT.

MAINTAINANCE with MMF OR AZA :

The primary end point of the trial was time to renal fl are

RESULT--> no difference in renal flare over 4 yr period in both group.

Result MMF AZA

Renal flare

Nephrotic

Increase creat

Increase proteinuria

10 of 53

19%

8

2

13 of 52

25%

6

4

3

ADVERSE EVENTS

Cr X2

DEATH

3

2 (Infection; disease activity)

4 PTS

--

Cytopenia more in AZA group.

==> MMF == AZA, non superior

Limitation:

Caucasian Small sample size Non Blind Maintainence Rx started prior to achievement of significant renql response.

ALMS MAINTAINENCE TRIAL:

227 pts. Induction X 6 mths : IV CYC or MMF. Those who had attained renal response were ncluded.

116 : MMf 2 g/d mainatainence

111 AZA 2 mg/kg/d maintainence.

The primary efficacy end pointwas the time to treatment failure, which was defined as death, end-

stage renal disease, doubling of the serum creatinine level, renal flare, or rescue therapy for lupusnephritis.


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Secondary assessmentsincluded the time to the individual components of treatment failure and

adverse events.

3 yr follow up

Mmf : less treatment failure, and longer time to relapse.Adverse events similar in both

Serious adverse events more in AZA group.

Withdrawal due to SE more in AZA group.

==> favor MMF as mainatinance RX of choice irrespective of induction Rx, race, sex, geography.

Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy

for lupus nephritis. N Engl J Med 2011; 365:18861895. ** The ALMS maintenance trial is the largest

RCT conducted in the maintenance treatment of lupus nephritis, and the results favored MMF use

over AZA.

RECOMMENDATION IN LUPUS NEPHRITIS :1. Bertsias GK, Tektonidou M, Amoura Z, et al.Joint European League Against Rheumatism and

European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA)recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71:17711782.

2. Hahn BH, McMahon MA, Wilkinson A, et al.American College of Rheumatology guidelines forscreening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012; 64:797808.

CNIs In maintain therapy:Cyclosporine has been explored in two RCTs as maintenance therapy. The first trial compared

cyclosporine plus steroids to AZA plus steroids after 3 months of induction therapy with oral

cyclophosphamide and steroids.[43]

The SLE relapse rates were the same in both groups, there was

no difference in renal function, and more patients in the cyclosporine group achieved continued

undetectable proteinuria at 4 years of follow-up. The second study prescribed 9 months of induction

therapy with cyclosporine or intravenous cyclophosphamide (see above), then maintenance therapy

with cyclosporine or oral cyclophosphamide.[20]

At 9 months of maintenance therapy (18 months

total therapy), remission rates were similar, but more patients in the cyclosporine group had

complete remission in proteinuria.Tacrolimus has been studied as maintenance therapy in one pilot study in Japanese patients[44] andone recent RCT in Chinese patients.[45] The RCT was an extension of the tacrolimus induction

therapy RCT described above[25] and randomized patients who achieved complete or partial

remission to maintenance therapy with low-dose steroids plus either tacrolimus or AZA. At 6

months, relapses occurred in 0 of 33 patients in the tacrolimus group and 2 of 30 (7%) patients in the

AZA group, and leucopenia was more common in the AZA group.

Familiarity with the long-term use of the CNIs in transplant patients makes their use as maintenance

therapy in lupus nephritis an attractive option. However, the limited data and concern for

nephrotoxicity with prolonged use prevent their designation as the first-line maintenance therapies

in lupus nephritis

MMF as induction :

How & why was it used?


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Safety and efficacy in renal Tx pts. Animal studies1. Corna D, Morigi M, Facchinetti D, et al.Mycophenolate mofetil limits renal damage and

prolongs life in murine lupus autoimmune disease. Kidney Int 1997; 51:15831589.

2. Van Bruggen MC, Walgreen B, Rijke TP, et al.Attenuation of murine lupus nephritis by

mycophenolate mofetil. J Am Soc Nephrol 1998; 9:1407

1415)

Trials in china :3. Chan TM, Li FK, Tang CS, et al.Efficacy of mycophenolate mofetil in patients with diffuse

proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med2000; 343:11561162. 44 pts , non in ferior ity. infect ion s =

4. Chan TM, Tse KC, Tang CS, et al.Long-term study of mycophenolate mofetil as continuousinduction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol2005; 16:10761084

1st RCT comp aring MMF to CYC :

42 patients randomised to MMF or CYC: Both received steroids.

42 pts MMF CYC

DOSE 2g/d X 6 mths

1g/d X 6 mths

Oral 2.5 mg/kg/d X 6 mths

AZA 1.5 mg/kg/d X 6 mths

CR & PR = =

Relapse = =

Infections More,deaths seen only in this group

CKD/ESRD = =

RCTs COMPARING MMF TO IV CYC.

Ginzler EM, Dooley MA, Aranow C, et al.Mycophenolate mofetil or intravenouscyclophosphamide for lupus nephritis. N Engl J Med 2005; 353:22192228.

a multicenter, open-label, noninferiority trial. DEC 1999 - OCT 2003


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Exclusion criteriawere creatinine clearance of less than 30 ml per minute, serum creatinine on

repeated testing greater than 3.0 mg per deciliter (265.2 mol per liter), severe coexisting

conditions precluding immunosuppressive therapy or conditions

requiring intravenous antibiotic therapy, prior treatment with mycophenolate mofetil,

treatment with intravenous cyclophosphamide within the past 12 months, monoclonal

antibody therapy within the past 30 days, or pregnancy or lactation.

MMF :

Mycophenolate mofetil was initiated at a dose of 500 mg twice daily, and the dose was

increased to750 mg twice daily at week 2and advanced weekly to a maximum dose of 1000

mg three times daily unless the white-cell count fell below 3000 per cubic millimeter.

Iv cyc : NIH regimen, nadir TLC 2500 @ 10 days.

Patients receivedprednisone at a dose of 1 mg per kilogram of body weight per day, with

tapering by 10 to 20 percent at one-week or two-week intervals, on the basis of clinical

improvement.

Clinical deteriortion Rxed with increasing steroid.

140 pts included Oral MMF ( 3 g/d) vs IV CYC Black and hispanics represented ( race with severe disease) Primary endpoint CR @ 24 weeks .CR == definedas the return to within 10 percent

of normal values of serum creatinine levels, proteinuria, and urine sediment.

secondary endpoint PR. == definedas improvement of 50 percent in all abnormal renal

measurements, without worsening (within 10 percent) of any measurement.Additional secondary end pointsincluded changes in renal function, complement

components, antidouble-stranded DNA (dsDNA) antibody titers, and serum albumin levels.

EARLY RESPONSE:

defined as an improvement of 30 percent in at least two measures of renal function (serum

creatinine, proteinuria, or urine sediment) if all three measures were abnormal at entry into

the study, or an improvement of 30 percent in one measure if one or two others were

abnormal, provided no measures that were normal at baseline became abnormal.

RX FAILURE:

a condition requiring higher doses of corticosteroids for disease control, failure to eet the

criteria for an early response, or failure to reach complete or partial remission at

24 weeks.


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@ 6months MMF IV CYC

CR 22.5% 5.8%

PR 29.6% 24.6%

RELAPSE ON FU = =

INFECTIONS MORE

GI SE

Upper

Lower

=

More.

= but required admission in 7 pts

Death 0 2

a: cerebral bleed, only 1 doseiv cyc

b: sepsis+active LN, 2 dose iv cyc

==> MMF noninferior even safer.


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LIMITATIONS:

Not blinded.

IV CYC dose was adjusted based on GI SE, so less CR rate ??

Short duration

Not studied the flare rate with MMF induction, and appropriate mainatainance regimen.

ALMS INDUCTION TRIAL: Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus

cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20:1103

1112. JASN

Above studies were in CHINA & US. Hence the following study was done globally.

Also 2 phase trial : Induction and maintenance

Randomised 370 pts. 88 centre, 20 countries. 12-75 yr age.

July 2005 - oct 2006 enrollment period.

Multinational MMF : 0.5 g BD= 1 wk; --> 1 g BD wk 2; --> 1.5 g BD wk 3 onwards. Those with SE, dose

decreased to 2 g/d IV CYC : NIH protocol Both : Prednisolone oral 60 mg/d starting dose.

Induction phase : till 24 weeks.Patients were withdrawn at week 12 when their serum creatinine was30% above baseline on

two successive measurements separated by at least 4 wk or when they required other

immunosuppressive treatment. Patients could be withdrawn if the MMF dosage fell below 2

g/d for 14 d or was stopped for 7 d.

AIM : to see is MMF superior to IV CYC?

MMF IV CYC

Cumulative remission 56% 53%

Outcomes @ 6mths = =

Deaths 97 due to infection

None due to SLE

52 infection

2 SLE

Infections 68.5 61.7

GI SE 61.4 66.7

Withdrawal due to SE 13% 7.2%

CONCLUSION:MMF no superiority over IV CYC.

High risk population responded better with MMF. BLACK RACE, LATINS, hispanics: responded poorly to IV CYC. Complete remission rates were low for both treatments in comparison with other studies.


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Persistent urine protein is common after 6mo of treatment for severe LN, regardless of

treatment regimen, and usually decreases further with continued follow-upSo is Induction of 6 months enough??

IS MMF effective in:a: DPGN & MN:

Radhakrishnan J, Moutzouris DA, Ginzler EM, et al. Mycophenolate mofetil and intravenous

cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney Int 2010;

77:152160.

Karim MY, Pisoni CN, Ferro L, et al. Reduction of proteinuria with mycophenolate mofetil in

predominantly membranous lupus nephropathy. Rheumatology (Oxford) 2005; 44:13171321.

Spetie DN, Tang Y, Rovin BH, et al. Mycophenolate therapy of SLE membranous nephropathy. Kidney

Int 2004; 66:24112415.

b: crescentic LN :

Tang Z, Yang G, Yu C, et al.Effects of mycophenolate mofetil for patients with crescentic lupus

nephritis.

c: black & hispanics:

Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis

treatment: the ALMS study. Rheumatology (Oxford) 2010; 49:128140.

Mohan S, Radhakrishnan J. Geographical variation in the response of lupus nephritis to

mycophenolate mofetil induction therapy. Clin Nephrol 2011; 75:233241.

* This study analyzed the lupus nephritis outcomes for MMF vs. other induction therapies in thecontext of geographic factors, and found that MMF led to more complete remissions in patients

outside of Asia

ADJUNCTIVES IN LN Rx:

HCQS :

The Canadian Hydroxychloroquine Study Groupdemonstrated via a small randomized withdrawal

trial that stable SLE patients who continued HCQ experienced less disease flares over a 24-week

period compared with those who took placebo.[46]

At 3 years of follow-up, there was a nonsignificant

trend toward less renal flares (relative risk 0.26, 95% confidence interval 0.032.54, P= 0.25) with

continuing HCQ.6% pts retinopathy =--> therefore regular opthalmological examination must.

RAAS blockade :

The Lupus in Minorities: Nature vs. Nurture study demonstrated an association between ACEI use

and less development of lupus nephritis in those who did not have renal disease, and an

improvement in proteinuria and decreased risk of disease activity in those with established lupus

nephritis.

Special Clinical Considerations

Women with SLE are 58 times more likely to have coronary heart disease than those in the general

population.[58,59] Although optimum cholesterol levels in lupus nephritis patients have not been


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established, it is appropriate to use statins in lupus nephritis similarly to other causes of chronic

kidney disease. Osteopenia and osteoporosis are common in SLE, perhaps linked to excess

glucocorticoid use, and lead to a five-fold increased risk of symptomatic fracture in SLE patients

compared with the general population.[60] Management of bone disease with calcium and vitamin

D supplementation should be considered in all patients with lupus nephritis. Finally, approximately

30% of patients with SLE will also develop the antiphospholipid antibody syndrome (APLS) and are atrisk for thromboembolic events, renal thrombotic microangiography, and catastrophic APLS.

clinical trials in lupus nephritis

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