Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome

Our hypotheses are the following:

Hypothesis 1: ACTH gel is superior to no treatment in maintaining remission in children with
frequently relapsing or steroid dependent nephrotic syndrome (NS).

Hypothesis 2: Relapses in children with frequently relapsing or steroid dependent nephrotic
syndrome receiving ACTH gel will increase when the dose of ACTH gel is reduced by 50%.

Hypothesis 3: ACTH gel will increase the percentage of children with frequently relapsing or
steroid dependent nephrotic syndrome that remain relapse free off medication.

Primary end-points:

The primary end-point related to Hypothesis 1 is the proportion of patients in each arm with
a relapse during the initial 6 months of treatment.

The primary end-point related to Hypothesis 2 is the proportion of relapse-free patients
during the first 6 months and second 6 months of treatment with ACTH. This will include
patients initially randomized to ACTH and patients who receive ACTH as rescue therapy
following their initial relapse in patients randomized to no treatment.

The primary end-point related to Hypothesis 3 is the proportion of patients who have relapses
in the 6 months following completion of one year of ACTH. This will be compared to the
proportion of patients with relapses during the initial 6 months in the patients randomized
to no treatment.

Secondary end-points:

Our secondary end-points are the following:

1. The total prednisone exposure over the initial 12 months in the two groups.

2. The number of relapses over the initial 6 months in the two groups.

3. The change in body mass index (BMI), height standard deviation score (SDS), and
cholesterol over the study period for both groups Study Design and Methods The
experimental design is a multi-center, prospective, controlled open label, randomized
trial comparing ACTH gel and no treatment in preventing relapses in pediatric patients
with frequently relapsing or steroid dependent nephrotic syndrome.

Patients will be randomized in a 1:1 ratio to either no treatment or treatment with ACTH gel.
The primary outcome will be the presence of a relapse within 6 months of starting ACTH gel or
no treatment.

After initial recruitment, enrollment will begin with a screening visit to determine
eligibility and obtain informed consent and assent. Randomization and weaning of all other
medications for the treatment of NS will begin after remission has been achieved for those
with active relapse. There will be a 2 week overlap of ACTH and current immunosuppressive
medications:

1. ACTH will be initiated 2 weeks prior to the completion of the prednisone taper for
patients who are receiving prednisone at the time of consent.

2. ACTH will be initiated 2 weeks prior to stopping preventive medications such as
tacrolimus, cyclosporin, and mycophenolate.

Patients randomized to no treatment will be followed for up to 6 months or until disease
relapse, whichever occurs first. Patients who relapse within 6 months will be given the
option of reassignment to the ACTH treatment group after remission has been achieved using
conventional corticosteroid therapy.

Patients randomized to ACTH treatment will be given ACTH for 12 months. During the second 6
months, the ACTH dose will be reduced to 50% of the starting dose. The outcome of interest is
the presence of relapses after dose reduction. Follow-up will occur throughout the 12 months
of therapy, and also for 6 months following the completion of ACTH therapy. The outcome of
interest is the percentage of patients with relapses in the 6 months after completing a 12
month course of ACTH treatment.

The primary end-point of the study and on which the statistical power is based is the
proportion of patients who have a relapse in the 6 months following randomization to either
ACTH or no ACTH.

We hypothesize that the 6 month relapse rate for patients receiving no treatment is 70%. In
order to detect a 6 month relapse rate of 30% for patients receiving the ACTH gel, we will
randomize 30 patients in each arm using a two sided z test with alpha=.05. Our statistical
power to detect such a difference is 91% which assumes two interim analyses at 50% and 100%
of accumulated information. That is, once 30 patients have 6 month relapse data, we will
conduct the first interim analysis. The last one will be completed once we have relapse data
on all 60 patients. The table below gives the operating characteristics for such a design:

Number of Patients with 6 Months Data Boundary p-value 30 0.006 60 0.045

Using the method of Lan-DeMets, we list the boundary p-value for this sequential design.
Thus, after our first interim look, we will reject the null hypothesis of equal 6 month
relapse rates between ACTH gel and no treatment if our test statistic renders a p-value <
.006. According to the intent to treat principle, patients will be analyzed according to the
treatment they have been assigned to during the randomization procedure. The odds ratio of
ACTH versus no ACTH, plus the Wald 95% confidence interval, will be also be calculated.

The primary end-point related to specific aim 2 is the proportion of relapse-free patients
during the first 6 months and second 6 months of treatment with ACTH. This will include
patients initially randomized to ACTH and patients who receive ACTH as rescue therapy
following their initial relapse. We will estimate 6 month and 12 month relapse-free rate
using the method of Kaplan-Meier and compare treatments using a log-rank test.

The primary end-point related to specific aim 3 is the proportion of patients who have
relapses in the 6 months following completion of one year of ACTH. This will be compared to
the proportion of patients with relapses during the initial 6 months in the patients
randomized to no treatment using a z test statistic. Odds ratios of ACTH vs no ACTH will also
be calculated.

We will also compare patients as randomized by secondary endpoints such as total prednisone
exposure in 12 months, number of relapses, cholesterol and change in BMI with two sample
t-tests. If normality assumptions do not hold, appropriate non-parametric methods will be
used.

Growth data collected during the study will be summarized descriptively for each treatment
group at each time point. Based on height data collected during the study and published
reference height information, the height standard deviation score (SDS, also called z-score)
will be computed for each patient at each time point as:

(Height - mean height for that age category) / SD of height for that age category.

Descriptive statistics of this endpoint will be presented by time point and the z-scores will
allow identification of potential outliers.

Treatment Assignment and Randomization Treatment assignments will be stratified according to
clinical center. The treatment assignments will be generated by the Data Coordinating Center
(DCC) with the use of a pseudo-random-number generator with randomly permutated blocks that
will be used to ensure balance between the number of subjects assigned to each treatment
(ACTH or no ACTH). Before the study starts, the institutional research coordinator at each
clinical center will be given a batch of 20 sealed, sequenced, opaque envelopes containing
the treatment assignment and will have a unique identification number consisting of the
clinical center stratum.

Patients will be assigned to one of the two treatment arms in a ratio of 1:1.

Inclusion Criteria:

1. Age >1 year at onset of nephrotic syndrome

2. Age 2-20 years at time of randomization

3. Estimated glomerular filtration rate (GFR) > 50 ml/min/1.73 m2 at most recent measure
prior to randomization (Schwartz formula)

4. Steroid responsive nephrotic syndrome throughout clinical course (never required a
second agent to attain remission of a relapse of nephrotic syndrome)

5. History of frequently relapsing or steroid dependent nephrotic syndrome (defined as 2
or more relapses within 6 months after initial therapy or 4 or more relapses in any 12
month period OR relapse during taper or within 2 weeks of discontinuing prednisone).

6. Patient is currently in relapse of nephrotic syndrome or had a relapse within the last
4 months (defined as an increase in the first morning urine protein to creatinine
ratio ≥2 or Albustix reading of ≥2 for 3 or 5 consecutive days).

Exclusion Criteria:

1. Prior treatment with ACTH.

2. Cyclophosphamide or rituximab within the last 4 months.

3. Lactation, pregnancy, or refusal of birth control in females with child-bearing
potential

4. Planned treatment with live or live-attenuated vaccines once enrolled in the study.

5. Participation in another therapeutic trial concurrently or 30 days prior to
randomization

6. Active/serious infection (including, but not limited to Hepatitis B or C, HIV)

7. Malignancy concurrently or within the last 2 years.

8. Blood pressure >95% for age/height while receiving maximal doses of 3 or more
medications.

9. Prior diagnosis of diabetes mellitus (Type I or II) or fasting glucose >200mg/dL

10. Organ transplantation

11. Contraindications to Acthar: scleroderma, osteoporosis, systemic fungal infections,
ocular herpes simplex, recent surgery, history of or the presence of peptic ulcer,
congestive heart failure, uncontrolled hypertension, primary adrenocortical
insufficiency, or adrenal cortical hyperfunction

12. Secondary cause of nephrotic syndrome (e.g., SLE)

13. Biopsy demonstrating a diagnosis other than minimal change, focal segmental
glomerulosclerosis (FSGS) or a variant (mesangial proliferation, Immunoglobulin M
nephropathy)

14. Inability to consent/assent -