Glomerulosclerosis, Focal Clinical Trial
Official title:
Focal Segmental Glomerulosclerosis Clinical Trial
The FSGS Clinical Trial is a multi-center, prospective, controlled, open label randomized trial designed to determine if treatment with mycophenolate mofetil (MMF) in conjunction with pulse steroids is superior to treatment with Cyclosporine-A (CSA) in inducing remission from proteinuria over 12 months.
Background/Rationale. Primary FSGS is a leading cause of end stage renal disease in both
children and adults, with complete loss of kidney function in 50% of patients over 10 years.
Evidence-based treatment guidelines for FSGS have not been developed because of the lack of
controlled studies and the small number of patients included in most reports. Over the past
decade, a number of studies have reported therapeutic efficacy for treatment with
Cyclosporine-A (CSA) in patients with nephrotic syndrome including patients with steroid
resistant FSGS. There have been two controlled trials of treatment with CSA in steroid
resistant FSGS, one in children and one in adult patients. Consequently, CSA is the only
medication that has been documented to be efficacious in a controlled trial in both children
and adults with steroid resistant FSGS. The experience with mycophenolate mofetil (MMF) in
the treatment of patients with steroid resistant FSGS has been limited to uncontrolled
trials in adult patients and children.
Patient Population. The patient population consists of children and adults between the ages
of 2 and 40 years with steroid resistant FSGS.
Study Design. The experimental design is a multi-center, prospective, controlled, open label
randomized trial comparing two treatment regimens, CSA vs. MMF/Pulse Steroids. The treatment
regimens in both arms also include angiotensin converting enzyme inhibitor (ACEI) therapy
and alternate day low dose prednisone. The CSA and MMF/Pulse steroid treatment regimens will
be implemented over the first 26 weeks after randomization and continued to 52 weeks if a
response in proteinuria occurs. The ACE inhibitor component continues for an additional 26
weeks after withdrawal of initial therapies.
Logistical Structure. Participants are recruited at over 130 participating sites in North
America which are affiliated with one of five Core Coordinating Centers.
Primary Objectives. The primary objective of the trial is to determine if treatment with
MMF/Pulse steroids is superior to treatment with CSA in inducing remission from proteinuria
over 12 months. The main secondary objective is to determine if treatment with MMF/Pulse
steroids is superior to treatment with CSA in inducing remissions which persist for at least
6 months following withdrawal of immunosuppressive therapy but while maintaining ACEI or
angiotensin receptor blocker (ARB) therapy.
Biorepository Specimens. Collection of specimens for biological and DNA repositories will
serve as a national resource for ancillary studies investigating the pathogenesis of FSGS.
Duration of Therapeutic Regimens and Follow-up. The study treatment duration for a
randomized patient depends on the level of response to treatment as follows: 26 weeks if
neither a partial or complete remission occurs at the 26-week visit; 52 weeks if there is a
partial or complete remission at 26 weeks but not at 52 weeks, and 78 weeks if partial or
complete remissions are recorded at both the 26- and 52-week visits. For all patients low
intensity follow-up for long-term assessment of renal function is maintained after
termination of the therapeutic regimens until September, 2008.
Inclusion Criteria.
- Age 2-40 years at onset of signs or symptoms of FSGS,
- Age ≤ 40 years at randomization,
- Estimated glomerular filtration rate (GFR) ≥ 40 ml/min/1.73 m2,
- Urine protein/creatinine (Up/c) > 1.0 on first am void,
- Biopsy confirmed primary FSGS (including all subtypes),
- Steroid resistance established by failure to achieve a sustained Up/c < 1.0 following a
steroid treatment course of at least 4 weeks with a minimum cumulative dose of 56 mg/kg
or 1,680 mg of prednisone, and
- Willingness to follow the clinical trial protocol, including medications, and baseline
and follow-up visits and procedures.
Exclusion Criteria.
- Secondary FSGS,
- Prior therapy with sirolimus, CSA, tacrolimus, MMF, or azathioprin (Imuran), - -
Treated with cytoxan, chlorambucil, levamisole, methotrexate, or nitrogen mustard in
the last 30 days,
- Lactation, pregnancy, or refusal of birth control in women of child bearing potential,
- Participation in another therapeutic trial concurrently or 30 days prior to
randomization,
- Active/serious infection,
- Malignancy,
- Blood pressure > 140/95 or > 95th percentile for age/height,
- Use of 4 or more antihypertensive agents for the primary purpose of controlling blood
pressure,
- Previously diagnosed diabetes mellitus type I or II (DM I or II),
- Clinical evidence of cirrhosis or chronic active liver disease,
- Absolute neutrophil count (ANC) < 2000/mm3 or hematocrit (HCT) < 28%,
- History of significant gastrointestinal disorder,
- Organ transplantation,
- Obesity (based on estimated dry weight at onset of disease prior to steroid therapy)
defined as body mass index (BMI) > 97th percentile for ages 2-20 years, and BMI > 40
kg/m2 for age ≥21 years,
- Allergy to study medications, and 17) Inability to consent/assent.
Therapeutic Regimens.
CSA Arm:
CSA: The initial target dose for CSA is 5 - 6 mg/kg per day divided into two daily doses.
Dosage is subsequently adjusted to maintain a 12-hour trough CSA blood concentration of 100
- 250 ng/ml. CSA is maintained for 12 months following randomization.
MMF/Pulse Steroid Arm:
MMF: The target dose for MMF is 25-36 mg/kg per day with a maximum dose of 2 g/day divided
into two daily doses, maintained for 12 months following randomization.
Dexamethasone: The target dose for dexamethasone is 0.9 mg/kg per dose, with a maximum dose
of 40 mg, given as a single dose on two consecutive days at the start of weeks 1, 2, 3, 4,
5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 30, 34, 38, 42, 46 and 50 for a total of 46
doses.
Both Treatment Arms:
ACEI: A maximally tolerated dose of the angiotensin converting enzyme inhibitor, lisinopril
will be attempted in three steps at two-week intervals. The target maintenance dose ranges
from 0.4 mg/kg to 0.6 mg/kg depending on the patient's weight. Patients who are unable to
tolerate treatment with ACEI or who have been previously intolerant of ACEI will receive the
angiotensin receptor blocker (ARB) losartan. The duration for the ACEI or ARB therapy is 18
months.
Prednisone: Target dose for prednisone is 0.3 mg/kg per dose to a maximum dose of 15 mg,
administered as single dose every other day for the first 6 months of the 12-month treatment
period after randomization.
Dose Adjustments for Toxicity:
Known toxicities associated with each of the therapeutic agents are delineated in the
protocol. A stepped dosage reduction protocol is implemented following confirmed toxicities
as follows:
- Step 1: Reduce dosage to 2/3 of full target dose;
- Step 2: If the toxicity persists following Step 1, reduce dose to 1/3 of full target
dose;
- Step 3: If the toxicity persists following Step 2, discontinue medication. In certain
cases, the protocol stipulates that the attempts should be made to reverse the dose
reductions (following the stepped sequence in reverse order) following remission of
toxicities.
Study Visits and Measurements. Main Outcome Assessment Visits: The main visits for
assessment of study outcomes are conducted at baseline and at weeks 26, 52, and 78 of
follow-up. These visits each include 2 first-morning Up/c, a full panel of serum and urine
biochemistry measurements, complete blood count, a quality of life assessment (SF-36 in
adults; PedsQL in children), a complete physical examination, recording of medications and
side effects, plus additional urine, serum, plasma specimens for storage in a repository.
Whole blood for DNA extraction will be collected at onset of therapy and placed in a
repository for consenting patients.
Other Visits: In addition to the main outcome assessment visits at baseline and weeks 26,
52, and 78, first morning urine samples for determination of Up/c, basic blood chemistries
(BUN, creatinine, serum electrolytes and glucose) and hematology in the MMF/Pulse Steroids
arm are also obtained immediately after randomization, and at follow-up weeks 2, 4, 6, 8,
14, 20, 32, 38, 44, and 65. CSA trough level, fasting lipids, serum albumin, and other blood
chemistries are obtained at designated subsets of these visits.
Adverse event monitoring. Adverse events, including all hospitalizations, and all
modifications to the dosages of the study medications are recorded throughout the follow-up
period.
Definition of Partial and Complete Remissions. At each protocol assessment of proteinuria, a
partial remission is defined as a 50% or greater decline in the first morning Up/c from the
mean of two baseline measurements to a level between 0.2 and 1.0. A complete remission is
defined as a decline in Up/c to a level no greater than 0.2.
Primary Outcome. The primary outcome is a 6-level ordinal classification based on the
achievement of remission during the first 52 weeks after randomization. The least favorable
outcome, designated as level 6, is assigned if no partial or complete remission is achieved
between weeks 2 through 26, inclusive. Level 5 is assigned if the participant achieves at
least one partial or complete remission between weeks 2 and 20, but does not achieve either
a partial or complete remission at week 26. By this definition, the primary outcome is not
affected by the Up/c after 26 weeks if a partial or complete remission is not achieved at 26
weeks, allowing those participants to switch to alternative therapies without affecting the
primary analysis.
For participants with a partial or complete remission at week 26, a score between 1 and 4 is
assigned depending on the remission status between week 26 and week 52. Level 4 is assigned
if the participant fails to achieve either a partial or complete remission at week 52 or has
a sustained relapse between weeks 26 and 52. Level 3 is assigned if the participant achieves
a partial remission at week 52. Level 2 is assigned if the participant achieves a complete
remission at week 52 but has had at least one Up/c > 0.2 after week 26 but before week 52.
Level 1 is assigned if the participant achieves a complete remission at week 52 and has had
Up/c < 0.2 since the week 26 visit.
Main Secondary Outcome. The main secondary outcome is a 5-level ordinal classification which
evaluates the extent to which remissions from proteinuria persist during the period from
week 52 to week 78 after immunosuppressive therapy is withdrawn but while remaining on ACEI
or ARB treatment
Other Outcomes. Other outcomes include the change in quality of life, the numbers of adverse
events and extra-renal complications, and preservation of renal function.
Sample Size. The target sample size is 500 patients.
Primary Analysis. The primary statistical analysis will compare the six-level primary
outcome variable between the randomized treatment groups. The six levels will be assigned
scores ranging from 1 (for the most favorable category) to 6 (for the least favorable
category), and the mean response score will be compared between the CSA and MMF/Pulse
steroid groups within each of the four randomization strata defined by baseline estimated
GFR and race. The analysis will be carried out by intent-to-treat. A 2-sided test will be
conducted at the 5% significance level.
Study Power. Depending on the remission rate in the control group (classified as levels 1,
2, or 3 for the primary outcome), the sample size of 500 randomized patients is sufficient
to obtain 80% power to detect an absolute increase in remission rate of between 10.8% and
11.5% between the MMF/Pulse Steroid and the CSA groups.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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