Clinical trial NCT02132195
Conditions: Nephrotic Syndrome
Sponsor: Emory University
Start date: 2014-05-01; Completion date: 2018-03-01
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: Patients will receive ACTH twice weekly subcutaneously The initial dosing will be based on body surface area (BSA): 80 IU/1.73 m2

The patients will receive the initial dose for 6 months. At 6 months, the dose will be reduced by 50%. Patients who have side effects may have the dose reduced by 50% during the initial 6 months. A second dose reduction would still occur at 6 months (25% of initial dose). arm 2: Patients in this treatment arm will receive no treatment to prevent relapses of nephrotic syndrome. A relapse, if it occurs, will be treated with prednisone and the patient will leave the no treatment arm of the study. arm 3: There is an option for the patient in no-treatment arm to elect to be placed in the active treatment arm of the trial (rescue therapy).
Interventions: intervention 1: ACTH
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
ACTH Protocol, version March 2014  
1 
 
 
ACTH for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome 
 
Principal Investigator  (IND Holder): Larry Greenbaum, MD, Ph. D. 
 
Unique Protocol ID: IRB00068101  
NCT02132195    
Date: March 5, 2014 
 


ACTH Protocol, version March 2014  
2 
 
ACTH for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome 
 
INVESTIGATORS: Chia-shi Wang, M.D., Larry Greenbaum, MD, Ph.D. 
Sponsor (IND Holder): Larry Greenbaum, MD, Ph. D. 
Study-Supporter: Questcor Pharmaceuticals, Inc.  
 
Abstract 
ACTH, given in the form of a long-acting, repository injection, has recently been shown to 
be effective in inducing disease remission in adult patients with nephrotic syndrome.  Side 
effects are decreased compared to corticosteroids and other immunosuppressive agents, making 
it an attractive therapeutic choice for patients with frequently relapsing and steroid dependent 
nephrotic syndrome (FRNS and SDNS).  No published data exist on the use of long-acting 
ACTH gel in the pediatric nephrotic population.  We propose a multi-center, prospective, 
controlled open label, randomized trial to evaluate the effects of ACTH on the symptoms and 
biochemical profile in children with FRNS and SDNS.   
Introduction 
Treatment of frequently relapsing and steroid dependent nephrotic syndrome (FRNS and 
SRNS) in children remains challenging.  Current treatment exposes patients to morbidity from 
prolonged, high-dose corticosteroids as well as various immunosuppressive agents that have a 
variety of serious side effects, including nephrotoxicity1.  Chronic corticosteroid exposure leads 
to growth retardation, obesity, decreased bone density, and other complications. Short-term use 
of corticosteroids is associated with behavioral changes.  Furthermore, relapses of nephrotic 
syndrome are associated with potential complications such as infection and thromboembolic 
disease2,3.  
During the 1950s, parenteral adrenocorticotropic hormone (ACTH) was an effective 
treatment for nephrotic syndrome.  ACTH was utilized in frequent, often four times daily, high 
dose injections for days to weeks, necessitating hospitalization for treatment and monitoring4-7.  
Oral prednisone ultimately replaced ACTH. 
In recent years, there is renewed interest in ACTH for the treatment of nephrotic syndrome, 
stemming from adult studies demonstrating its ability to induce remission and improve serum 
lipid profile in cases where other immunosuppressive regimens have failed8-10.  In the United 
States, ACTH is now administered in the form of ACTH gel (HP Acthar Gel®, Questcor 
Pharmaceuticals, NY, USA), a long-acting, repository injection isolated from porcine pituitary 
extracts containing ACTH1-39, as well as other pro-opiomelanocortin (POMC) peptides.  The 
most common adult dosing regimen is 80 units twice weekly11.  A randomized pilot trial by 
Ponticelli et al showed that treatment with twice weekly ACTH for 1 year is comparable to 6 
months treatment with methylprednisolone and chlorambucil or cyclophosphamide in achieving 
and sustaining remission, with mild and reversible side effects in the ACTH treatment arm12.  It 
has recently been proposed that ACTH produces antiproteinuric, lipid-lowering, and 
renoprotective effects via the melanocortin system, in addition to its effect on increasing 
endogenous steroidogenesis11.   
With its side effect profile, ACTH would be an attractive therapeutic alternative for the 
treatment of FRNS and SDNS in children, who are especially vulnerable to the long-term 
adverse effects of corticosteroids and immunosuppressive agents on growth, bone health, and 
weight gain.  To our knowledge, there has not been any published experience with long-acting 


ACTH Protocol, version March 2014  
3 
 
ACTH gel for children with nephrotic syndrome.  We propose a study to evaluate the efficacy of 
ACTH on the symptoms and biochemical profile in children with FRNS and SDNS.   
Definitions 
 
FRNS  
≥2 relapses within 6 months after initial therapy or ≥4 relapses in any 12- 
month period. 
 
NS 
 
Edema, Up/c >2,000mg/g, or ≥300mg/dl or 3+ protein on  
Albustix, hypoalbuminemia ≤2.5 mg/l 
Relapse 
After remission, an increase in the first morning Up/c ≥2 or Albustix  
reading of ≥2 for 3 of 5 consecutive days. 
 
Remission 
Up/c <0.2 or Albustix negative or trace for 3 days. 
 
SDNS  
Relapse during taper or within 2 weeks of discontinuation of steroid  
therapy. 
 
SRNS  
Inability to induce a remission with 4 weeks of daily steroid therapy. 
 
SSNS  
Attains remission within 4 weeks of daily steroid therapy. 
 
GFR 
 
Calculated by the new Schwartz formula:  
 
 
 
 
(0.413 × ℎ𝑒𝑖𝑔ℎ𝑡) ÷ 𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 
 
 
 
 
Height in cm, serum creatinine in mg/dL 
 
Hypotheses and End-points 
 
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. 
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 


ACTH Protocol, version March 2014  
4 
 
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 BMI, height 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. 
Visits 
Screening visit: The study will be explained to the patient and family. Inclusion and exclusion 
criteria will be reviewed to determine eligibility. Consent and assent will be obtained as 
appropriate. Medical history will be recorded. A physical exam will be performed. If indicated, a 


ACTH Protocol, version March 2014  
5 
 
plan for prednisone tapering will be explained to the family. The date of the baseline visit will 
either be determined at that visit or via telephone for patients who are currently in relapse. 
Baseline visit: The patient will be seen and have baseline labs (renal function panel, cholesterol, 
urinalysis, urine protein/creatinine ratio).  A urine pregnancy test will be performed in females of 
childbearing age (achieved menarche) who are randomized to ACTH treatment along with 
counseling in required birth control.  An interval medical history and quality of life (QOL) 
survey will be performed.  Patients will have a physical examination.  Patients will be 
randomized to either ACTH gel or no treatment.  Patients will be given Albustix and instructions 
for daily monitoring of the urine and recording the results.  Patients randomized to ACTH gel 
will receive their first injection in clinic and be taught how to perform injections at home.  A stop 
date for other immunosuppressive medications will be provided, if appropriate, 2 weeks after 
starting ACTH. 
ACTH TreatmentACTH will be dosed by body surface area (BSA), with an initial dose of 80U 
per 1.73m2.  After 6 months of treatment, the initial dose will be reduced by 50% (1st reduction), 
to complete the second 6 months of ACTH therapy.   
 
If patients develop significant side effects on the initial dose, they will have an early dose 
reduction by 50% at the discretion of each individual site PI (1st reduction).  They will complete 
a total 6 months of treatment with the initial and reduced dose.  After 6 months, ACTH will be 
reduced again by 50% (2nd reduction), to complete the second 6 months of ACTH therapy. 
 
Patients who do not tolerate ACTH therapy despite an early dose reduction will exit the study 
with reporting of adverse events as appropriate. 
 
Patients who relapse on a reduced dose of ACTH during the second 6 months of treatment will 
have their dose reverted to the previous dose and complete a total of 12 months of treatment with 
no further dose reductions.       
 
Patients with two relapses on the highest tolerated ACTH dose will exit the study.  
 
BSA 
Initial Dose 
1st Reduction 
(50%) 
2nd Reduction (25%) 
0.50-0.60 
24U = 0.3mL 
12U = 0.15mL 
8U = 0.1mL 
0.61-0.75 
32U = 0.4mL 
16U = 0.2mL 
8U = 0.1mL 
0.76-0.95 
40U = 0.5mL 
20U = 2.5mL 
12U = 0.15mL 
0.96-1.09 
48U = 0.6mL 
24U = 0.3mL 
12U = 0.15mL 
1.10-1.25 
56U = 0.7mL 
28U = 0.35mL 
16U = 0.2mL 
1.26-1.45 
64U = 0.8mL 
32U = 0.4mL 
16U = 0.2mL 
1.46-1.60 
72U = 0.9mL 
36U = 0.45mL 
20U = 0.25mL 
≥ 1.61 
80U = 1.0mL 
40U = 0.5mL 
20U = 0.25mL 


ACTH Protocol, version March 2014  
6 
 
*Note: there is rounding of the doses to the closest administrable amount by subcutaneous 
injection.  
 
Interval Visits 
Telephone contact will occur weekly for the first 3 weeks after randomization. This will include 
screening for adverse events, reviewing medications and timing of medication changes, review 
of Albustix testing, and reviewing dosing of ACTH if applicable.  Patients randomized to ACTH 
treatment will have two additional telephone contacts one month after ACTH dose reduction or 
discontinuation.  This is to screen for symptoms of adrenal insufficiency. 
Follow-up visits in patients randomized to ACTH will occur 1 month, 2 months, 4 months, 6 
months, 8 months, 10 months, 12 months, 15 months and 18 months after the baseline visit.  An 
interval medical history (including screening for adverse events) will be performed. Patients will 
have a physical examination. A renal function panel, cholesterol, urinalysis, urine 
protein/creatinine ratio, and QOL survey will be obtained at months 6 and 12. Urine pregnancy 
test, if applicable, will be obtained at months 4 and 8. 
The dose of ACTH will be reduced by 50% after 6 months of treatment Patients who have 
significant side effects attributed to ACTH will have an earlier dose reduction (i.e., before 6 
months) at the discretion of each individual site PI. The PI will be asked to review possible side 
effects with the patient at each visit and decide if a dose reduction is warranted.  A telephone 
contact will be made 1 month after dose reduction to screen for symptoms of adrenal 
insufficiency. 
Relapses will be treated with prednisone, at 2mg/kg/day or 60mg/m2/day (maximum dose 60 
mg) until remission is achieved, with a subsequent taper off therapy over 4 weeks.  For patients 
receiving a reduced dose of ACTH, the dose will be reverted back to the last effective dosage on 
which remission was sustained, and continue at that dose until the end of the study.  If >1 relapse 
occurs on the initial ACTH dose, ACTH therapy will be considered a failure and terminated.  
The total ACTH therapy duration will be 12 months, after which, the subjects will be seen at 
follow-up at 15 and 18 months.   
Patients who are randomized to no treatment will have follow-up visits up to the time of 
relapse, at 1 month, 2 months, 4 months, and 6 months. An interval medical history (including 
screening for adverse events) will be performed. Patients will have a physical examination.  A 
renal function panel, cholesterol, urinalysis, and urine protein/creatinine ratio, and QOL survey 
will be obtained at month 6.  They will be treated with prednisone for any relapses and have the 
option to be placed on ACTH during the last 2 weeks of the prednisone taper if the relapse 
occurred within 6 months of the baseline visit.  The subsequent visit schedule and procedures 
will be identical to the schedule for subjects initially randomized to ACTH (i.e., it will include a 
baseline visit, telephone contacts, and 18 months of follow-up). Alternatively, the patient may 
elect to be treated via standard of care in collaboration with the treating nephrologist, and the 
patient will then exit the study. 


ACTH Protocol, version March 2014  
7 
 
Flow Chart of Study Course 
 
Participant Selection 
Sixty subjects will be recruited from 10-12 large pediatric centers.  Subjects may also be 
identified via physician or self-referral from advertisements placed on NephCure.  Additionally, 
subjects may be recruited from registries of individuals interested in research participation.   


ACTH Protocol, version March 2014  
8 
 
Patients and their caregivers will be approached during a relapse of nephrotic syndrome or 
within 4 months of a relapse.  The following criteria will be reviewed during the screening visit 
to determine eligibility: 
Inclusion criteria 
1. Age >1 year at onset of nephrotic syndrome 
2. Age 2-20 years at time of randomization 
3. Estimated 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 (abstinence qualifies) 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. Systolic or diastolic 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, FSGS or a variant 
(mesangial proliferation, IgM nephropathy) 
14. Inability to consent/assent 
 
Statistical Analysis 
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. 


ACTH Protocol, version March 2014  
9 
 
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 


ACTH Protocol, version March 2014  
10 
 
20 sealed, sequenced, opaque envelopes containing the treatment assignment and will have a 
unique ID consisting of the clinical center stratum. 
Patients will be assigned to one of the two treatment arms in a ratio of 1:1. 
 
Data Collection and Management 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization, the Investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization. For 
subjects that have revoked authorization, attempts should be made to obtain permission to collect 
follow-up safety information (e.g. has the subject experienced any new or worsened AEs) at the 
end of their scheduled study period. 
 
Data collection 
Data collection and analysis will be facilitated by the Data Coordination Center (DCC), 
which will be led by Traci Leong, PhD.  They will interact with the PIs, local site investigators, 
and study coordinators to collect data, analyze the results, and provide reports to the DSMB in a 
timely manner. 
REDCap will be used for data collection and management.  The data collection system for 
this study uses built-in security features to encrypt all data for transmission in both directions, 
preventing unauthorized access to confidential participant information. Access to the system will 
be controlled by a sequence of individually assigned user identification codes and passwords, 
made available only to authorized personnel who have completed prerequisite training. 
Using the REDCap Electronic Data Capture (EDC), the designated investigational staff will 
enter the data required by the protocol into the Electronic Case Report Forms (eCRF). The 
eCRFs have been built using fully validated secure web-enabled software. 
Site staff will not be given access to the EDC system until they have been trained. Validation 
programs will check for data discrepancies in the eCRFs and, allow modification or verification 
of the entered data by the investigator staff.  The Principal Investigator is responsible for 
assuring that the data entered into eCRF is complete, accurate, and that entry and updates are 
performed in a timely manner.  There will be regular reports of enrollment by site. 
 
Database Management and Quality Control 
The Data Coordinating Center (DCC) will review the data entered by investigational staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via email. The Principal Investigator and site investigator will be copied on 
all correspondences.  Designated investigator site staff members are required to respond 
promptly to queries and to make any necessary changes to the data. 


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After these actions have been completed and the data have been verified to be complete and 
accurate, the database will be declared locked and made available for data analysis.  
 
Adverse Event Reporting 
Screening for adverse events will begin at each telephone contact via interview and screening 
questionnaire.  Formal evaluations of side effects from ACTH will be made at each monthly visit 
with direct interview, physical examination, questionnaire, and laboratory evaluation.  Subjects 
will be provided with home urinary dipsticks to monitor relapse of nephrotic syndrome.  All 
Serious Adverse Events will be reviewed within the applicable guidelines and submitted to the 
sponsor and appropriate IRB.  Acute exacerbations of the subject’s condition that is not in 
keeping with the natural history will also be reported. 
A serious adverse event is defined as: death; life-threatening event; requires or prolongs 
hospitalization; results in disability significant, persistent, or permanent; pregnancy with a 
resultant birth defect; causes cancer; or overdoses of a study medication. 
In addition to the completion of the appropriate forms, any serious adverse event or serious 
and unexpected suspected adverse reaction occurring during the study or in a post-study period 
of one month will be reported to the principal investigator, the Data Monitoring Committee 
(DMC), the local IRB, the sponsor, the study supporter, and participating sites within 2 business 
days. The IND sponsor will make an assessment of whether the event constitutes an 
unanticipated problem posing risks to subjects or others (UP). This assessment will be provided 
to the Emory University IRB, which, in turn will make a final determination.  If the Emory IRB 
determines an event is a UP it will notify the appropriate regulatory agencies and institutional 
officials. 
Adverse events that do not meet criteria for Serious Adverse Event will be reported using the 
Adverse Event Form during the follow up visit. Information regarding the diagnosis, date of 
occurrence, severity of the event, and therapy will be recorded. A determination of the 
relationship of the adverse event to the study participation will be made by the Participating Site 
investigator.  Should a relationship be found, results will be reported to the sponsor, the study-
supporter, and the DMC within 1 business week. 
 
Data and Safety Monitoring Plan 
An external Data Monitoring Committee (DMC) will be constituted prior to the 
randomization of the first patient.  The DMC will consist of a minimum of three individuals 
outside the Division of Pediatric Nephrology.  The individuals shall be practicing clinicians with 
experience in clinical research.  At least one member will be a nephrologist, and two members 
will be pediatric subspecialists.  Details on the membership, responsibilities and working 
procedures of the DMC will be described in the DMC Charter. 
The DMC will perform the first safety review using a data cutoff 6 months after 
randomization of the first patient and every 6 months thereafter, unless otherwise requested by 
the Chairman of the DMC. The DMC will also receive reports on a regular basis on all SAEs 
reported for this trial. One interim analysis and one final analysis are planned. These analyses 
will coincide with the timing of the scheduled DMC meetings.  Recruitment will not be 
interrupted unless otherwise requested by the Chairman of the DMC.  Results of the DMC 
review will be shared with the PI and all participating sites within 1 business week.  
The study would be stopped if the DMC and the PI believe that there is a significant safety 
issue or that the interim analysis indicates that completing the study is not appropriate.  Should a 


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decision be made to stop the study, a report will be made to all participating sites within 2 
business days.   
 
Data Quality and Compliance Site Monitoring  
A separate data safety monitoring plan (DSMP) provides details on data quality and site 
monitoring. 
Pharmaceutical Information 
See attached ACTH gel (HP Acthar Gel, Questcor Pharmaceuticals, NY, USA) Package 
Insert. 
 
REFERENCES  
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Lombel RM, Gipson DS, Hodson EM, Kidney Disease: Improving Global O. Treatment 
of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatric 
Nephrology. Mar 2013;28(3):415-426. 
2. 
Lombel RM, Hodson EM, Gipson DS. Treatment of steroid-resistant nephrotic syndrome 
in children: new guidelines from KDIGO. Pediatric Nephrology. Mar 2013;28(3):409-
414. 
3. 
Eddy AA, Symons JM. Nephrotic syndrome in childhood. The Lancet. 
2003;362(9384):629-639. 
4. 
Riley CM. The effect of adrenocorticotrophic hormone on salt and water excretion in 
children with the nephrotic syndrome. Am J Dis Child. Sep 1950;80(3):520-521. 
5. 
Heymann W, Gilkey C, Salehar M. Effect of adrenocorticotropic hormone (ACTH) and 
cortisone on proteinuria and hematuria in the nephrotic syndrome. Pediatrics. Jan 
1955;15(1):49-53. 
6. 
Lange K, Slobody LB, Strang RH. Prolonged intermittent corticotropin (ACTH) and 
cortisone therapy in the nephrotic syndrome: immunologic basis and results. Am J Dis 
Child. Oct 1953;86(4):478-481. 
7. 
Metcoff J, Rance CP, Kelsey WM, Nakasone N, Janeway CA. Adrenocorticotrophic 
hormone (ACTH) therapy of the nephrotic syndrome in children. Pediatrics. Nov 
1952;10(5):543-566. 
8. 
Berg AL, Arnadottir M. ACTH-induced improvement in the nephrotic syndrome in 
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9. 
Berg AL, Nilsson-Ehle P, Arnadottir M. Beneficial effects of ACTH on the serum 
lipoprotein profile and glomerular function in patients with membranous nephropathy. 
Kidney International. Oct 1999;56(4):1534-1543. 
10. 
Bomback AS, Tumlin JA, Baranski J, et al. Treatment of nephrotic syndrome with 
adrenocorticotropic hormone (ACTH) gel. Drug Design, Development and Therapy. 
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11. 
Gong R. The renaissance of corticotropin therapy in proteinuric nephropathies. Nature 
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12. 
Ponticelli C, Passerini P, Salvadori M, et al. A randomized pilot trial comparing 
methylprednisolone plus a cytotoxic agent versus synthetic adrenocorticotropic hormone 
in idiopathic membranous nephropathy. American Journal of Kidney Diseases. Feb 
2006;47(2):233-240.