Clinical trial NCT04146220: Efficacy of Lower Dose Prednisolone in the Induction of Remission of Lupus Nephritis
Official title: Efficacy of Lower Dose Prednisolone in the Induction of Remission of Lupus Nephritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Lupus Nephritis
Lead sponsor: Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Sponsor class: OTHER
First posted: 2019-10-31
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The LN is a common cause of mortality and morbidity in SLE. The use of high-dose glucocorticoids (GC) with an immunosuppressive agent is usual practice for treating this condition. Higher dose of GC use might cause adverse effects along with clinical improvement. Studies had reported comparable outcome of lower dose of GC with minimum side effects. The aim of this study was to determine the outcome of lower dose prednisolone in the induction of remission of proliferative LN.

This prospective, clinical trial was conducted in Rheumatology outpatient and inpatient department of BSMMU from July 2018 to September 2019. Thirty-two subjects were enrolled after having informed consent. The ACR (American College of Rheumatology) criteria was followed for diagnosis of SLE. The patients of both genders, age ≥18 years, who fulfilled the ACR criteria of LN and unable to afford MMF were enrolled.

The patient evaluation tool was SELENA-DAI and Bengali version of SF-12 questionnaire. The 24-hour urinary protein, urine R/M/E, serum creatinine, CBC, serum C3, C4 levels and anti-dsDNA were done at baseline and at final visit of the study.

All patients received pulse I/V methylprednisolone 500 mg/day daily for 3 doses. After then experimental group received oral prednisolone 0.5 mg/kg/day and control group received oral prednisolone 1 mg/kg/day for a period of 4 weeks. After then the prednisolone was tapered by 10 mg/day in every two weeks until 40 mg/day, then 5 mg/day in every two weeks until 10 mg/day is reached, after two weeks the dose was tapered by 2.5 mg/day to a maintenance dose of 7.5 mg/day. Both groups were treated in the background of hydroxychloroquine (HCQ), angiotensin receptor blocker (ARB) and pulse I/V cyclophosphamide (CYC) for 6 cycle.

The ethical clearance was obtained from Institutional Review Board (IRB) of BSMMU and technical clearance was taken from rheumatology technical board.

Detailed description: Rationale:

Lupus nephritis (LN) is a very common complication of systemic lupus erythematosus (SLE). Currently available all guidelines suggest an induction phase with glucocorticoids along with another immunosuppressive agent. However, the basis of using high dose of glucocorticoids are mostly empirical. There is no published data comparing low and high dose glucocorticoids in the treatment of LN. Use of high dose of glucocorticoids may increase morbidity like osteopenia, osteonecrosis of neck of femur, Cushing syndrome etc. Moreover, rate of infectious disease is very high in the investigator's country. Patient treated with high dose glucocorticoids may prone to develop serious infectious conditions. Researchers are currently trying to develop new regimen, which can replace the use of long-term glucocorticoids to treat LN. Unless the alternative regimen developed, well-controlled study is necessary to establish a lowest possible dose of glucocorticoid to treat this condition.

Research question:

Is lower dose prednisolone similar efficacious as the higher dose regimen in achieving complete remission of proliferative lupus nephritis?

Null hypothesis:

Lower dose prednisolone regimen is inferior to the higher dose regimen by more than - Δ in achieving the complete remission of proliferative lupus nephritis.

H0: P1-P2 ≤ - Δ P1 = Test drug (Prednisolone 0.5 mg/kg/day) P2 = Control drug (Prednisolone 1 mg/kg/day) Δ = Non-inferiority margin

Alternative hypothesis:

Lower dose prednisolone regimen is inferior to the higher dose regimen by less than - Δ in achieving the complete remission of proliferative lupus nephritis.

H1: P1-P2 \> - Δ

General objective:

To assess efficacy of prednisolone 0.5 mg/kg/day in achieving remission of proliferative LN compared to 1 mg/kg/day

Specific objectives:

To compare:

* Changes of UTP level from the baseline to 24 weeks
* Changes of active urinary sediments level from the baseline to 24 weeks
* Changes of serum creatinine level from the baseline to 24 weeks
* Changes of quality of life from the baseline to 24 weeks
* Adverse effects during study period

Primary endpoint: (Time frame: at the end of 24th week)

• Complete renal remission

Secondary endpoints: (Time frame: at the end of 24th week)

* Renal remission (complete/partial) at 24 weeks
* Changes of UTP level from the baseline at 24 weeks
* Proportion of subjects with active urinary sediment at 24 weeks
* Changes of serum creatinine level from the baseline at 24 weeks
* Changes of eGFR from the baseline at 24 weeks
* Changes of anti-dsDNA level from the baseline at 24 weeks
* Changes of complements (C3 and C4) level from the baseline at 24 weeks
* Changes of SELENA-SLEDAI score from the baseline at 24 weeks
* Changes of SF-12 score from the baseline at 24 weeks

Study procedure:

This open labeled randomized controlled clinical trial was conducted in the outpatient and the inpatient department of Rheumatology, BSMMU from July 2018 to September 2019. Patients of SLE were interviewed after taking verbal consent. They were screened with history, physical examination, urine RME, 24hours UTP reports. Patients fulfilling the inclusion and exclusion criteria were enrolled in the study after taking informed written consent. Total 32 patients of SLE with proliferative LN were enrolled in the study. After the enrollment study subjects were randomized into experimental group (low dose group) and control group (high dose group) by lottery. Baseline laboratory tests were urine R/M/E, 24 hours UTP, serum creatinine, anti-dsDNA, C3, C4, CBC with ESR, SGPT. Baseline quality of life was assessed by Bengali version SF-12 questionnaire.

Both groups received pulse I/V methylprednisolone 500 mg/day daily for 3 doses. Then, patients of the low dose group received oral prednisolone 0.5 mg/kg/day (maximum 30 mg/day) and high dose group received oral prednisolone 1 mg/kg/day (maximum 60 mg/day) for initial 4 weeks. In the low dose group, prednisolone was tapered by 5 mg/day in every two weeks until 10 mg/day was reached, then after two weeks the dose was tapered by 2.5 mg/day to a maintenance dose of 7.5 mg/day. In the high dose group, prednisolone was tapered by 10 mg/day in every two weeks until 40 mg, then 5 mg/day in every two weeks until 10 mg/day is reached, after two weeks it was tapered by 2.5 mg/day to a maintenance dose of 7.5 mg/day.

Patients of both groups were treated with monthly CYC infusion, first dose 750 mg/m2 body surface area, subsequent doses were adjusted based on leukocyte nadir (≥ 4000 cells/mm3, doses were increased by 25%, to a maximum of 1 gm/m2 body surface area, the dose were reduced by 25% for leukocyte counts \<4000 cells/mm3). Both groups of patients received hydroxychloroquine (HCQ), angiotensin receptor blocker (ARB) and other relevant medications. Patient education, vaccinations against influenza and pneumococcus were given to all the enrolled subjects. All patients were given Pneumocystis jirovecii prophylaxes.

Primary endpoint (complete remission) was assessed at the end of 24th week. Urine R/M/E, CBC with ESR, SGPT and serum creatinine were done in every 4 weeks. Twenty-four hours UTP were done at the end of 12 weeks and 24 weeks. Anti-dsDNA, C3 and C4 were done at the end of 24 weeks. Data were collected from a set of written questionnaires which was supplied to the patients and from physical examination and investigation findings. Quality of life was assessed by Bengali version of SF-12 questionnaire.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years of both sexes
2. Diagnosed case of systemic lupus erythematosus (SLE) as per ACR criteria
3. Patients consenting to participate in the study
4. Class III/IV lupus nephritis (LN) as evidenced by:

   * Confirmed proteinuria ≥ 500 mg/24 hours when assessed by 24-hour urine collection And
   * High titer anti-dsDNA (\>75 U/ml) and low C3 (\<0.9 g/l) and/or C4 (\<0.1 g/l) Or
   * Kidney biopsy: with a histologic diagnosis of class III or IV lupus nephritis (International Society of Nephrology/Renal Pathology Society 2003 classification of lupus nephritis)

Exclusion Criteria:

1. Subjects not giving written informed consent
2. Pregnant or lactating women
3. Patient willing to be treated with MMF rather than CYC
4. Had taken CYC within 4 weeks prior to screening
5. Had taken \>15 mg/day of prednisolone (or equivalent) for a period of \>10 days during the previous month
6. Renal thrombotic microangiopathy
7. Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation of ≤45 mL/min/1.73 m2 at screening
8. Dialysis dependent patients, currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to require dialysis during the study period
9. A previous kidney transplant or planned transplant within study treatment period
10. Altered liver function (alanine aminotransferase greater than 2.5 times the upper limit of normal) at screening and confirmed before randomization
11. Malignancy
12. Lymphoproliferative disease or previous total lymphoid irradiation
13. Active bleeding disorders
14. Active tuberculosis (TB)
15. Diabetes mellitus
16. Any known hypersensitivity or contraindication to CYC, corticosteroids or any components of these drug products
17. Any overlapping autoimmune condition for which the condition or the treatment of the condition may affect the study assessments or outcomes (e.g., scleroderma with significant pulmonary hypertension; any condition for which additional immunosuppression is indicated)

Primary outcomes:
measure: Number of participants achieving complete renal remission
timeFrame: At the end of 24th week
Secondary outcomes:
measure: Number of participants achieving partial renal remission
timeFrame: At the end of 24th week
Other outcomes:
measure: Rate of achievement of normal anti-dsDNA level
timeFrame: At the end of 24th week
measure: Rate of achievement of normal complements level
timeFrame: At the end of 24th week
measure: Rate of reduction of Safety of Estrogens in Systemic Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index score
timeFrame: At the end of 24th week
measure: Rate of improvement of Short Form-12 score
timeFrame: At the end of 24th week
Locations:
city: Dhaka
country: Bangladesh
facility: Bangabandhu Sheikh Mujib Medical University
Study officials:
affiliation: Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
name: Prof. Nazrul Islam, FCPS, MD
role: STUDY_CHAIR
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