Cyclophosphamide Versus Mycophenolate Mofetil in Lupus Nephritis
Condition: To Compare the Effects of Mycophenolate Mofetil With Cyclophosphamide in Neplaese Lupus Nephritis Patients
MeSH terms: Nephritis; Lupus Nephritis
Study type: Interventional
Phase: Phase 2

Summary: 
      This was a prospective open label randomized control trial, which was conducted for a period
      of one and half year from January 2014 to June 2015. Out of 52 patients screened, 49 patients
      meeting the international society of nephrology/ renal pathology society (ISN/RPS) criteria
      were enrolled in the study comprising of 25 and 24 patients in the cyclophosphamide (CYC) and
      mycophenolate mofetil (MMF) groups respectively. Forty two patients (21 in each group) could
      complete the study till the end of 6 months and were included in final analysis. Baseline
      clinical evaluation and investigations were done and recorded. CYC was given intravenously as
      a monthly pulse in the dose of 0.5 to 1 gram per m2 body surface area. MMF was administered
      in the tablet form with the starting dose of 500 mg twice daily, which was increased to 750
      mg twice daily after a month. Patients were assessed and monitored monthly and the details
      were recorded. Efficacy of treatment was measured as primary end point for those who achieved
      partial remission (reduction of 24 hour urinary protein to < 3.5gms/day if baseline
      proteinuria >3.5 gms/day or decrease by 50% if baseline proteinuria <3.5 gms/day) and
      secondary end point for those who achieved complete remission (normalization of serum
      creatinine and < 500 mg of 24 hour urinary protein). Adverse events experienced by the
      patients were also recorded during monthly visit.
    

Detailed description: 
      Systemic lupus erythematosus (SLE) is an autoimmune disease associated with multiple organ
      involvement, among which kidney involvement, also known as lupus nephritis (LN), is quite
      common in SLE. LN is associated with a more than four-fold increase in mortality in patients
      with SLE. The management of SLE and LN comprises timely and coordinated management consisting
      of initial or induction phase of aggressive immunosuppression to bring the active disease
      under control followed by maintenance phase. The initial phase usually lasting for six months
      consists of treatment with steroid and cyclophosphamide or mycophenolate mofetil. So far
      there is no study published regarding the efficacy and adverse events of such treatments in
      Nepal. So, this study aimed to evaluate and compare the effectiveness and safety profile of
      mycophenolate mofetil and intravenous pulse cyclophosphamide in induction therapy of LN in
      Nepalese population.

      A total of 52 patients with international society of Nephrology/ renal pathology society
      (ISN/RPS) class III to V lupus nephritis were screened, 3 of which did not meet entry
      criteria and 49 patients were enrolled in the study comprising of 25 and 24 patients in the
      MMF and CYC group respectively. Twenty one patients in each groups could complete the study
      till the end of 6 months and were included for analysis.

      Patients in the CYC group received intravenous cyclophosphamide (CYC) in the dose of 0.5 to 1
      gram per m2 of body surface area. The medicine, which is available in the strength of 1 gram
      in powder form, was first dissolved in 20 ml of normal saline. Only15 ml of this preparation
      was mixed in 100 ml of normal saline and was infused over a period of one hour. CYC was not
      given to those patients who had total leukocyte counts (TLC) less than 2500/mm3. Those
      patients were re-evaluated after one week and intravenous pulse CYC was reinstituted if the
      total leucocyte count (TLC) exceeds 2500/mm3. Pulse CYC was administered every month for a
      total of six infusions.Patients were monitored monthly and the details were recorded. During
      follow ups, any adverse events in between were noted and detailed physical evaluation was
      done and all baseline investigations (except USG abdomen, chest X-ray, serum anti nuclear
      antibody (ANA) and anti double strain deoxy-ribonuccleic acid (anti dsDNA), complement factor
      3 (C3) and complement facotr 4 (C4) level) was repeated. Fasting lipid profile was repeated
      at the end of third and sixth month of treatment.

      During the course of treatment, if a patient had interruption of medication for less than a
      10 days' period due to any reason, s/he was considered as a regularly included subject. If
      the interruption extended beyond 10 days, the patient was withdrawn from the study.

      Patients in the MMF group were administered tablet mycophenolate mofetil at a starting dose
      of 500 mg twice daily if the weight of the patient was less than 50 kilograms and 750 mg
      twice daily if the weight was more than 50 kilograms. After one month, the dose of MMF was
      increased to 750 mg twice daily. The clinical response was monitored in terms of reduction in
      serum creatinine and proteinuria. MMF dose was decreased or interrupted in patients
      experiencing an absolute neutrophil count <1300/mm3 at any study visit; MMF treatment was
      discontinued if a patient experienced an absolute neutrophil count <1000/mm3.

      All patients, irrespective of randomized group, received concomitant corticosteroid therapy
      with oral prednisolone and hydroxychloroquine. Angiotensin receptor inhibitors (ACEi)/
      angiotensin receptor blocker (ARBs) were given to all patients if the blood pressure remained
      above or equal to 120 mmHg of systolic blood pressure and 80 mmHg of diastolic blood
      pressure. If the blood pressure remained persistently high despite the use of ACEi/ARBs,
      other antihypertensives were added as required to achieve target blood pressure <130/80 mmHg.
      Oral prednisolone was given at an initial dose of 1 mg/kg with a maximum dose of 60 mg/day.
      The starting dose of prednisolone was continued for initial one month. Then, the dose of oral
      prednisolone was tapered at the rate of 10 mg/day every 2 weeks and was maintained at the
      baseline dose of 5 to 7.5 mg per day then after. Additional intravenous methylprednisolone
      was given at the beginning of treatment for patients who presented as rapidly progressive
      glomerulonephritis (RPGN) and who had activity index of more than 8 out of 24 on kidney
      biopsy irrespective of the randomized group (MMF or CYC) of the patient. The dose of
      methylprednisolone was 1 gram, which was given after mixing with 100 ml of normal saline and
      was infused intravenously over 1 hour for 3 days.
    

Intervention name(s): Cyclophosphamide; Mycophenolate Mofetil
Intervention type(s): Drug; Drug
Intervention description(s): Cyclophosphamide injection was administered in the dose of 0.5 to 1 gram per m2 of body surface area. The medicine, which is available in the strength of 1 gram in powder form, was first dissolved in 20 ml of normal saline. Only15 ml of this preparation was mixed in 100 ml of normal saline and was infused over a period of one hour. CYC was not given to those patients who had total leukocyte counts (TLC) less than 2500/mm3. Those patients were re-evaluated after one week and intravenous pulse CYC was reinstituted if the TLC exceeds 2500/mm3. Pulse CYC was administered every month for a total of six infusions.; Participants in the MMF group were administered tablet mycophenolate mofetil at a starting dose of 500 mg twice daily if the weight of the patient was less than 50 kilograms and 750 mg twice daily if the weight was more than 50 kilograms. After one month, the dose of MMF was increased to 750 mg twice daily. The clinical response was monitored in terms of reduction in serum creatinine and proteinuria. MMF dose was decreased or interrupted in patients experiencing an absolute neutrophil count <1300/mm3 at any study visit; MMF treatment was discontinued if a patient experienced an absolute neutrophil count <1000/mm3.
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lupus Nephritis, cyclophosphamide, Mycophenolate mofetil