Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
Condition: Nephrotic Syndrome
MeSH terms: Nephrotic Syndrome; Nephrosis; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      In childhood nephrotic syndrome, the kidneys leak protein, causing body swelling and a
      variety of possible complications such as infection, blood clots, and kidney failure. The
      first-line treatment for nephrotic syndrome is corticosteroids. Many children respond to
      prednisone treatment, but the disease comes back (relapses) when the prednisone is stopped or
      the dose is reduced. Children with frequently relapsing or steroid dependent nephrotic
      syndrome are at risk for toxicity from frequent exposure to corticosteroids.

      Currently, the standard treatment for frequently relapsing and steroid dependent nephrotic
      syndrome involves a variety of medications that suppress the immune system, which can produce
      serious side effects. We propose a study to examine the effects of a different medication,
      ACTH, on nephrotic syndrome. ACTH is a hormone naturally found in the body. Recently, in
      adult studies, ACTH has been shown to be effective for the treatment of nephrotic syndrome.
      It has also been shown to have mild and reversible side effects. ACTH is potentially an
      attractive therapeutic alternative for the treatment of frequently relapsing and steroid
      dependent nephrotic syndrome in children. Our study will randomly assign patients with
      frequently relapsing or steroid dependent nephrotic syndrome to either ACTH treatment or no
      treatment. This will allow us to study the effects of ACTH on this disease and its side
      effects, by comparing how patients do on ACTH treatment versus no treatment. We hypothesize
      that ACTH gel is superior to no treatment in maintaining remission in children with
      frequently relapsing or steroid dependent nephrotic syndrome.
    

Detailed description: 
      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.
    

Intervention name(s): ACTH
Intervention type(s): Drug
Intervention description(s): Patients will receive ACTH twice weekly for 6 months, with a 50% dose reduction allowed for side effects. The dose will be reduce by 50% at 6 months and continued for an additional 6 months.
Other intervention name(s): Acthar; Adrenocorticotropic hormone
Intervention MeSH terms: Adrenocorticotropic Hormone; Melanocyte-Stimulating Hormones; beta-Endorphin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment