An Open-Label Pilot Study of ACTH in the Treatment of IgA Nephropathy at High Risk of Progression
Phase: PHASE3
Conditions: Progressive IgA Nephropathy, Proteinuria
Sponsor: Mayo Clinic

 
 
An Open-Label Pilot Study of 
ACTH in the Treatment of IgA 
Nephropathy at high risk of 
progression 
 
NCT# 02282930 
 
March 11, 2015 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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STUDY TITLE: 
An Open-Label Pilot Study of ACTH in the Treatment of IgA Nephropathy at high risk of 
progression 
 
 
 
Study Drug 
ACTH (Acthar gel®) 
 
Study Phase 
Phase III 
 
 
Support Provided By 
Mallinckrodt Pharmaceuticals Inc. 
 
 
 
Sponsor Investigator/Institution 
Fernando C. Fervenza, MD, PhD 
Mayo Clinic, Rochester, MN 
 
 
 
Research Coordinator 
Julie Allen  
Tel: 507-266-1047 
 
 
 
 
Protocol Version Date: 03/11/15 
 
 
 
 
Mallinckrodt – Version 3.0 
 
 
  
 
 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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Signature Page 
STUDY TITLE: An Open-Label Pilot Study of ACTH in the Treatment of IgA Nephropathy at high 
risk of progression 
We, the undersigned, have read this protocol and agree that it contains all necessary 
information required to conduct the study. 
 
The Principle Investigator at 
local site: 
 
_____________________ 
Print name 
 
 
 
 
_____________________ 
Signature  
 
 
 
__ __ / __ __/ __ __ __ __ 
Date 
Primary Principle Investigator: 
Dr. Fernando Fervenza, M.D., 
Ph.D 
 
_____________________ 
Print name 
 
 
 
 
 
_____________________ 
Signature 
 
 
 
 
__ __ / __ __/ __ __ __ __ 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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Table of Contents 
 
1.0 Introduction 
 
 
 
 
 
 
 
 
 
2 
1.1 IgA Nephropathy Background 
1.2 ACTH Background 
          
1.2.1 Safety Profile  
1.3 Hypothesis and Rational for Study Design 
 
2.0 OBJECTIVES 
2.1 Primary Efficacy Endpoints 
2.1.1 Complete Response: At 12 months 
2.1.2 Partial Response: At 12 months 
2.1.3 No Response: At 12 months 
      2.2 Primary Safety Endpoints 
      2.3 Secondary Exploratory Efficacy Endpoints 
 
3.0 STUDY POPULATION 
     3.1 Inclusion Criteria  
3.1.1 Renal Histology-Entry Criteria  
     3.2 Exclusion Criteria  
 
4.0 STUDY DESIGN:  
    4.1 Treatment Plan 
    4.2 Treatment:  
    4.3 Test Schedule and Monitoring for ACTH Treatment (Clinical and Laboratory Evaluations) 
4.3.1 Screening Laboratory Data 
4.3.2 Baseline (Day 0) Laboratory Data 
4.3.3 Follow-Up Exam and Laboratory Assessment-month 1, 3, 6, 9, 12 
4.3.4 Study Discontinuation and Early Termination 
    4.4 Identification Number 
    4.5 Optional Research Lab (Biomarkers and DNA) 
 
 4.5.1 Collection and Banking of Blood and urine for future testing at Mayo:  
4.5.1.1. Shipping  
4.5.2 Optional DNA Testing 
4.5.2.1 Quantitative gene expression analysis 
   4.6 Optional Biopsy Review 
4.6.1 Histopathology 
4.6.1.1. Shipping  
 
5.0 Study Medication 
   5.1 ACTH dosage and administration 
 
5.1.1 Preparation for Administration 
   5.2 Compliance Control 
 
6.0 Investigational Product 

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   6.1 Clinical Study Materials 
   6.2 Pharmaceutical Formulation 
   6.3 ACTH storage includes Labeling and Packaging 
6.4 Dispensing Procedures 
 
7.0 Safety Assessments 
   7.1Specification of Variables and Procedures 
   7.2Reporting of Adverse Events 
 
7.2.1 Adverse Events and Serious Adverse Events: definitions, and guidance for reporting 
 
 7.2.1.1 Causality Assessment 
 
 7.2.1.2 Reporting SAE 
   7.3 Data Safety Monitoring Board 
7.3.1. DSMB-Committee Members 
 
8.0 STATISTICAL CONSIDERATIONS 
 
9.0 Data Management and Record Keeping 
   9.1 Data Management 
9.1.1 Hard Copy CRFs  
9.1.2 Computer Systems 
   9.2 record Keeping 
   9.3 Direct Access to source data/documents 
 
10.0 Quality control and Quality Assurance 
 
11.0 Ethics and Good Clinical Practice Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 INTRODUCTION 
This document is a protocol for a human research study.  This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  This study will be coordinated at up to four additional sites in addition 
to Mayo Clinic Rochester.  
 
1.1 IgA Nephropathy Background: 
Immunoglobulin A nephropathy (IgAN) is an immune-complex mediated glomerulonephritis 
characterized by deposition of polymeric IgA in the mesangium of the kidney.1 It is the most 
common form of primary glomerulonephritis worldwide and is prevalent amongst all ages and 
racial demographics.2  Its pathogenesis has been under investigation for the last several 
decades and one of the key players is the aberrant glycosylation pattern of IgA1. There is now 
convincing evidence that the hinge region of IgA1 heavy chain has defective glycosylation with a 
reduction in the galactose and or sialic acid residues.3 As a result the N-acetylgalactosamine in 
the IgA1 hinge region is exposed and recognized by IgG antibodies. This in turn leads to 
formation of IgG-IgA immune complexes and their deposition in the mesangium and renal 
injury that subsequently ensues.4-7  
   
The renal outcomes of IgAN vary significantly between individuals ranging from minimal 
proteinuria and stable renal function to development of endstage renal disease (ESRD) in up to 
50% of the cases.8 Markers of poor prognosis include impaired kidney function at presentation, 
hypertension and persistent proteinuria > 1 g/24h.9,10 In addition, the recent Oxford 
classification has identified MEST (mesangial hypercellularity, endocapillary hypercellularity, 
segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis) as an independent indicator 
of poor renal outcome.11 Despite the prevalence and severity of IgA nephropathy, there is little 
consensus as to the most effective therapy. To date, the most effective therapies for IgAN 
appear to be angiotensin converting enzyme inhibitors (ACE-I), corticosteroids, and omega-3 
fish oil supplements that contain a high concentration of Eicosapentaenoic acid (EPA) and 
docosahexanoic acid (DHA). Other therapies including tonsillectomy and cytotoxic medications 
have been used in patients with IgAN with variable success. 12-18 In some patients renal disease 
progresses despite treatment and thus a search for additional forms of therapy is ongoing.  
      
While glucocorticoids and alkylating agents can successfully treat IgAN and other forms of 
primary glomerulonephritis, prolonged treatment with these agents is associated with 
significant clinical toxicities. Glucocorticoids are associated with steroid-induced diabetes, 
avascular necrosis of the hips and shoulders, excessive weight gain, osteoporosis, and increased 
risk for infectious complications.19-21 Cyclophosphamide has been used in combination with 
corticosteroids in the treatment of patients with IgAN with high-risk features.15 While alkylating 
agents allows clinicians to reduce the amount and duration of steroid therapy, only 20-40% of 
patients achieve a complete or partial response. Moreover, repeated use of cyclophosphamide 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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and other alkylating agents is associated significant toxicity including premature ovarian failure 
and increased incidence of secondary malignancies.22-25      
 
1.2 ACTH Background: 
H.P. Acthar® Gel (ACTH) is obtained from processing of the porcine pituitary gland and is 
currently the only FDA approved therapy for the treatment of nephrotic syndrome. The active 
ingredients in H.P. Acthar® Gel are part of the family of structurally related peptides known as 
melanocortin peptides. Melanocortin peptides, which include adrenocorticotrophic hormone 
(ACTH) and the α-, β-, and γ-melanocyte stimulating hormones, are derived from the natural 
protein pro-opiomelanocortin (POMC) and bind to the cell surface G-protein coupled receptors 
known as melanocortin receptors (MCRs).26,27 To date, 5 forms of MCRs have been cloned, each 
with different tissue distributions, affinities, and physiological roles. Although the functional 
roles of all the peptides in H.P. Acthar® Gel have not been fully elucidated, ACTH is known to 
have activity at all 5 MCRs.  
 
H.P. Acthar Gel has steroidogenic mechanisms of action through endogenous production of 
cortisol and is reported to have immunomodulatory properties facilitated through interactions 
with melanocortin receptors found in immune effector cells and other tissues. MCRs are 
expressed in glomerular podocytes and receptor stimulation has been demonstrated to reduce 
oxidative stress and improve glomerular morphology by diminishing podocyte apoptosis, injury 
and loss in the remnant kidney animal model.28 Inhibition of nuclear factor-kB (NF-kB) signaling 
is a key anti-inflammatory mechanism of melanocortin peptides.29 NF-kB controls the 
expression of many genes, including pro-inflammatory cytokines, cytokine receptors, 
chemokines, growth factors, and adhesion molecules, and modulation of NF-kB is a main 
mechanism behind the widespread and powerful effects of melanocortins on inflammatory 
pathways.30 
 
Apart from its anti-inflammatory effects, humans data also supports an anti-proteinuric effect 
in addition to a pronounced lipid-lowering effect in healthy individuals,31 in steroid-treated 
patients with renal disease32 and in hemodialysis patients33, using a similar synthetic ACTH 
preparation that is not available in North America.  More recently, using H.P. Acthar® Gel 
(ACTH) we were able to demonstrate a significant benefit in patient with Membranous 
Nephropathy.34  Twenty patients received a subcutaneous dose of 40 or 80 IU twice weekly. 
Baseline characteristics included mean proteinuria (9.1±3.4 g/day), albumin (2.7±0.8 g/dL), 
estimated glomerular filtration rate (77±30 ml/min) along with elevated total and LDL 
cholesterol. By 12 months of follow-up, there was a significant improvement in proteinuria in 
the entire cohort, decreasing to 3.87±4.24 g/day (p<0.001) with significant improvements in 
serum albumin, total and LDL cholesterol. A > 50% decrease in proteinuria was noted in 65% of  
the patients with a trend towards better outcomes among patients who received greater 
cumulative doses. No significant adverse effects were documented.  

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Similarly, a recent pilot study showed benefit of Acthar® Gel (ACTH) in the treatment of 
Systemic Lupus Erythematosus (SLE).35 Ten females (mean age = 49 year, disease duration = 7 
years, with SLE were treated with ACTH Gel 80 U for 7-15 days and were assessed weekly for 28 
days. Outcome measures included Physician and Patient Global Assessments, SLEDAI-2 K, Lupus 
Quality of Life scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) 
scale, erythrocyte sedimentation rate, and C-reactive protein. Student's t-test compared data 
obtained at days 7, 14, and 28 with those from baseline. The primary endpoint of SLEDAI-2 K 
improvement was reached at all observation times (p < 0.05) and statistically significant 
improvements were observed for most other parameters. No treatment-related serious or 
unexpected adverse events were observed. 
 
These results suggest that ACTH Gel may provide a novel anti-inflammatory and 
immunomodulatory treatment option with possible mechanisms of action beyond 
steroidogenesis. Considering that IgA nephropathy is an inflammatory glomerular disease, we 
hypothesized that adrenocorticotrophic hormone (ACTH) therapy in the form of HP Acthar ®gel 
may reduce glomerular inflammation, improve podocyte survival and may provide an effective 
therapy in patients with IgA nephropathy and proteinuria. 
 
1.2.1 Safety Profile  
The Acthar Prescribing Information recommends the use of 40 to 80 U administered 
intramuscularly or subcutaneously every 24 to 72 hours in adults and children over 2 years of 
age; with the specific dosage individualized according to medical condition. Recent published 
use of Acthar in subjects with non-diabetic nephrotic syndrome included regimens of 80U 2 
times per week and 40U 2 to 3 times per week for 6 to 14 months. Bomback et al demonstrated 
promising efficacy results with the 6 month regimen of 80U 2 times a week; the results were 
less impressive with a 6 month regimen of 40U 2 to 3 times per week.36 Tumlin and colleagues 
reported promising results in an Investigator-initiated clinical trial of Acthar in subjects with 
diabetic nephropathy, which included Acthar regimens of 16U and 32U per day for 6 months, 
the original design for this present protocol planned to assess two Acthar regimens (40U 5 
times per week for 24 weeks and 80U 2 times a week for 24 weeks) in treatment-resistant iMN 
patients.37 As discussed above, we have used Acthar Gel 40 to 80U SC twice a week for up to 9 
months with minimal side-effects. Thus, the Acthar 80U 2 times per week regimen for 6-months 
proposed in the present study is consistent with the indicated use of Acthar and is believed to 
have an acceptable risk/benefit ratio in this population.  
 
The Acthar regimen will be administered as the solely immunosuppressive therapy.  The dosing 
will begin and end with Acthar 80U 2 times per week and will continue through Week 24 (6 
months). The 24 week regimen with a 24-week follow up was selected based on additional 
controlled studies in which subjects with nephrotic syndrome treated with modified release 
synthetic fragment ACTH(1-24).34,36-38  Data from these studies show that a 6 month regimen 
demonstrated remission (partial or complete) after 6 months of dosing that was sustained after 
6 months of follow-up. 
 
 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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1.3 Hypothesis and Rational for Study Design 
Hypotheses: In patients with progressive IgA nephropathy, ACTH gel injection at a dose of 80 
units subcutaneously twice weekly for 6 months is effective in inducing improvement in 
proteinuria and renal function.  
 
2.0 OBJECTIVES 
 
2.1 Primary Efficacy Endpoints: 
 
Patients achieving complete or partial response as defined below: 
 
2.1.1 Complete Response: At 12 months 
• < 300 mg proteinuria/24 hours 
• No greater than a 10% reduction in GFR as determined by quantified 
creatinine clearance 
 
2.1.2 Partial Response: At 12 months 
• > 50% reduction in 24 hour proteinuria  
• No greater than a 25% reduction in baseline GFR as quantified creatinine 
clearance   
 
2.1.3 No Response: At 12 months 
• A ≤ 50% reduction, unchanged or increasing proteinuria over baseline levels 
will be considered no response 
• A greater than a 25% reduction in baseline GFR as quantified creatinine 
clearance 
 
2.2  Primary Safety Endpoints:  
• Incidence of Infections: Defined as the development of pneumonia, complicated 
UTI/Pyelonephritis 
• Glucose control – development of diabetes 
 
2.3 Secondary Exploratory Efficacy Endpoints:  
• Improvement in hematuria  
 
Categorical: <3 rbc/hpf; up to 20 rbc/hpf; 20 to 50; 50 to 100; >100 rbc/hpf 
 
3.0 STUDY POPULATION 
This study will be completed in IgA Nephropathy patients whom are at risk of progression. 
 
3.1 Inclusion Criteria:  
 

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3.1.1 Renal Histology-Entry Criteria:  
Note: All eligible patients will have undergone a renal biopsy compatible with a diagnosis of IgA 
nephropathy within 36 months of study entry. The diagnostic criteria for IgA nephropathy are 
as follows: 
• Diagnosis of IgA nephropathy on renal biopsy.  
 
 
Clinical Criteria:  
Age > 18 years old 
• Proteinuria > 1000 mg/24h despite documented ACEi/ARB therapy and adequate blood 
pressure control for > 3 months  
• Quantified 24h creatinine clearance > 30 ml/min/1.73m2 
• Blood pressure <130/80 mmHg at >75% of the readings.   
• Henoch Schoenlein Purpura (HSP): Patients with biopsy proven IgA nephropathy and 
clinical features consistent with Henoch Schonlein Purpura will be considered eligible for 
the study 
• Patient must be able to receive injections to be enrolled in the study 
• Patient must have a Kidney biopsy slide on file- that can be sent to the Mayo Clinic. 
 
3.2 Exclusion Criteria:  
 
Patients with any of the following criteria will NOT be considered eligible for study 
participation 
 
• Clinical and histologic evidence of IgA predominant Lupus nephritis 
• Patients with greater than 50% glomerular senescence or cortical scarring on renal 
biopsy 
• Serum Cr > 3.0 mg/dl or creatinine clearance GFR < 30 ml/min at the time of screening 
• Patients with history of Crohn’s disease or Celiac Sprue 
• Clinical evidence of cirrhosis, chronic active liver disease  
• Known infection with hepatitis B, hepatitis C, or HIV (patients will be serologically 
screened prior to study entry- if the test has been completed in the last two years- the 
patient will not have to undergo additional testing. ) 
• Active systemic infection with bacterial, viral, fungal, or mycobacterial or atypical 
mycobacterial infections (excluding fungal infections of nail beds) 
• Any major episode of infection requiring hospitalization or treatment with IV antibiotics 
within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening 
• Positive pregnancy test or breast feeding at time of study entry (urine pregnancy test 
will be performed for all women of childbearing potential no later than 7 days prior to 
treatment) or patients unwilling to comply with contraceptive measures as outlined above 

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• Patients receiving therapy with oral prednisone or glucocorticoid equivalent in the past 
3 months  
• Patients who had received immunosuppressive therapy including cyclophosphamide, 
MMF, cyclosporine, tacrolimus or azathioprine in the last 6 months  
• Current or recent (within 30 days) exposure to any investigational drug 
• Patients having received a live vaccine within 28 days of study enrollment 
• Hemoglobin:  < 8.5 gm/dL 
• Platelets:  < 100,000/mm 
• AST or ALT >2.5 x Upper Limit of Normal  
• Patients with anaphylaxis and/or known allergic reactions to ACTH 
• Previous Treatment with ACTH  
• History of drug, alcohol, or chemical abuse within 6 months prior to screening 
• Concomitant or previous malignancies, with the exception of adequately treated basal 
or squamous cell carcinoma of the skin or carcinoma in situ of the cervix 
• History of psychiatric disorder that would interfere with normal participation in this 
protocol 
• Significant cardiac or pulmonary disease (including obstructive pulmonary disease) 
• Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complication 
• Inability to comply with study and follow-up procedures 
 
4.0 STUDY DESIGN:  
An Open-Label Phase III Study of ACTH in the Treatment of patients with IgA Nephropathy at 
high risk for progression. The study will be completed at the Mayo Clinic and a possible 
additional four sites.  A total of twenty-one patients will be enrolled in the study. Up to ten 
participants in total may be enrolled by the potential sites outside Mayo.  
 
4.1 Treatment Plan 
Patients meeting all entry criteria for the study will be eligible to enroll in this phase III, open-
label trial.  The participants will be given ACTH injections for 6 months with an additional 6 
months of follow up.  
  
4.2 Treatment:  
• HP Acthar ®gel will be given in a dose of 80 units subcutaneously (SC) twice weekly for 
total of 6 months. 
 
4.3 Test Schedule and Monitoring for ACTH Treatment (Clinical and Laboratory Evaluations) 

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Test Schedule 
1 
2 
3 
4 
5 
6 
7 
Visits (month) 
 
Day 0 
1 mo 
3 moA 
6 mo 
9 moA 
12 
mo/EOT 
Study Phase  
Screening 
Baseline 
Treatment 
Follow up 
Window (days) 
-14 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-14 
History/Exam 
x 
x 
x 
x 
x 
x 
x 
Vitals 
x 
x 
x 
x 
x 
x 
x 
Drug Administration 
 
xe,f 
x 
x 
x 
 
 
  
  
  
  
  
  
  
  
Venipuncture Chg 
x 
x 
x 
x 
x 
x 
x 
CBC w/diff. 
x 
x 
x 
x 
x 
x 
x 
Metabolic Panel 
x 
x 
x 
x 
x 
x 
x 
Albumin 
x 
x 
x 
x 
x 
x 
x 
Glucose 
x 
x 
x 
x 
x 
x 
x 
Hemoglobin A1c 
xg 
x 
x 
x 
x 
x 
x 
Lipid Panel 
x 
x 
  
x 
x 
  
x 
HIV/Hepatitis B/C 
x 
 
 
 
 
 
 
Pregnancy (urine) 
x 
x 
 
 
 
 
x D 
 
 
 
 
 
 
 
 
Optional Research 
labs: Biomarker 
study  
 
xB,C 
 
xB,C 
xB,C 
xB,C 
xB,C 
Optional DNA 
 
xB,C 
 
 
 
 
 
Optional Biopsy 
Review 
 
 
 
 
 
 
x 
  
  
  
  
  
  
  
  
24 hour protein  
x 
x B 
x 
x 
x B 
x 
x B 
Creatinine 
Clearance  
x 
x B 
x 
x 
x B 
x 
x B 
Volume 
Measurement  
x 
x B 
x 
x 
x B 
x 
x B 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
A. 
At month 3 and 9, should fall on ‘Standard of Care’ visits- which means they will be considered ‘expanded standard care visits’.  This 
also means that the primary site (Mayo Clinic) will only be paying for the optional studies (if the patient is enrolled) and the 24 hour 
urine sample, which will be shipped.   
B. 
Each visit the following will be shipped to the Mayo Clinic: 24hour Urines- Creatinine Clearance and Volume measurements, and 
optional research bloods for DNA and biomarker study.  All others including the Urinalysis and panels will be performed at local 
sites. 
C. 
Optional Research labs (including biomarkers in both urine and blood) will be from one10ml red top tube which the serum will be 
drawn and divided equally into five 1 mL cryovials to be frozen and stored.  50 mL of urine will be drawn from a random urinalysis  
collection and then will be processed and aliquoted to be frozen and stored.  Two 10 ml EDTA tubes will be used for DNA extraction, 
and will be processed into 2 aliquots of white blood cells (buffy coat) and stored for future DNA extraction.    
D. 
The urine pregnancy test will be completed at screening, and baseline.  If the subject leaves the study early- an additional pregnancy 
test will be requested as a safety assessment. 
E. 
The drug will be administrated by trained staff members as a training lesson for the patients.  The patients are allowed to have a 
significant other take part in the lesson if the patient is unwilling or unable to administer the injection themselves.  
F. 
Please note the patients will be requested to wait with the training staff for 30minutes after the drug is administered- i.e. a safety 
observation period. 
G. 
If the patient has had a HIV, Hep B & C test in the last two years- this will count towards the study.  
 

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4.3.1 Screening Laboratory Data 
 
If any of the exams, tests or procedures for the screening visit are completed as routine 
standard of care within 14 days of study enrollment, participants do not need to repeat them 
for the screening visit.  It will be up to the study’s Principal Investigator to review and consider 
if the previous findings are appropriate and adequate to use.  If it is determined that the 
findings are not adequate the necessary items will be repeated for the screening visit.  
Additionally, if the screening data meets study inclusion criteria, the results will be used for the 
baseline visit as well to reduce the amount of blood draws for the patient.   
 
Patients meeting the entry criteria and consenting to participate in the protocol will undergo a 
complete physical exam and undergo the following laboratory tests: 
• Physical Exam 
• Complete Metabolic Panel including glucose, BUN, creatinine, potassium, sodium, 
chloride, bicarbonate, total bilirubin, alkaline, phosphatase, total protein, albumin, SGOT 
(AST), and SGPT (ALT), calcium, phosphorus 
• Lipid Panel including Cholesterol (serum- total), direct measurement, high density 
cholesterol (HDL), and triglycerides 
• CBC with differential and platelets 
• Hemoglobin A1c 
• 24 hr urine collection for protein and creatinine clearance 
• Urinalysis with microscopy 
• HIV test (unless completed in the last two years) 
• Hepatitis B and Hepatitis C screening (unless completed in the last two years) 
• Urinary Pregnancy test if female 
• Vital signs (including heart rate and blood pressure) 
 
 
4.3.2 Baseline (Day 0) Laboratory Data 
 
Patients meeting the entry criteria and consenting to participate in the protocol will undergo a 
complete physical exam and undergo the following laboratory tests: 
• Baseline physical exam 
• Complete Metabolic Panel including glucose, BUN, creatinine, potassium, sodium, 
chloride, bicarbonate, total bilirubin, alkaline, phosphatase, total protein, albumin, SGOT 
(AST), and SGPT (ALT), calcium, phosphorus 
• Lipid Panel including Cholesterol (serum- total) , direct measurement, high density 
cholesterol (HDL), and triglycerides 
• CBC with differential and platelets 
• Hemoglobin A1c 
• 24 hr urine collection for protein and creatinine clearance 
• Urinalysis with microscopy 
• Pregnancy test if female 

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• Biomarker studies: Blood and urine will be processed appropriately and frozen for 
future biomarker analysis.  The specific biomarkers to be analyzed will be determined at a 
later time.  
• DNA (Storage) 
• Vital signs (including heart rate and blood pressure) 
• Given Study Drug Diaries to complete 
 
4.3.3 Follow Up Exam and Laboratory Assessment-month 1, 3, 6, 9, 12 
• Physical exam and dictated office note will occur after 1 month and then every 3 
months- Medical history and response to treatment with ACTH.  Please note month 3 
and 9 should be considered ‘standard of care visits’ because patients with IgA 
nephropathy at risk of progression need to be seen at least once every 6 months. 
• Complete Metabolic Panel including- glucose, BUN, creatinine, potassium, sodium, 
chloride, bicarbonate, total bilirubin, alkaline, phosphatase, total protein, albumin, 
SGOT (AST), and SGPT (ALT), calcium, phosphorus  
• Lipid Panel (included at month 3,6 and 12) including Cholesterol (serum- total), direct 
measurement, high density cholesterol (HDL), and triglycerides 
• Hemoglobin A1c 
• 24 hr urine collection for protein and creatinine clearance 
• Urinalysis with microscopy 
• Biomarker studies (except for month 1): Blood and urine will be processed appropriately 
and frozen for future biomarker analysis.  The specific biomarkers to be analyzed will be 
determined at a later time.  
• If agreed- the optional biopsy review will occur at the 12month visit 
• Vital signs (including heart rate and blood pressure) 
 
4.3.4 Study Discontinuation and Early Termination 
• Pregnancy test (urine) for women of childbearing potential 
• Physical exam and Medical history will be completed in response to treatment with 
ACTH 
• Complete Metabolic Panel including- glucose, BUN, creatinine, potassium, sodium, 
chloride, bicarbonate, total bilirubin, alkaline, phosphatase, total protein, albumin, SGOT 
(AST), and SGPT (ALT), calcium, phosphorus 
• Lipid panel including Cholesterol (serum- total), direct measurement, high density 
cholesterol (HDL), and triglycerides 
• Hemoglobin A1c 
• 24 hr urine collection for protein and creatinine clearance 
• Urinalysis with microscopy 
• Vital signs (including heart rate and blood pressure) 
• Biomarker studies: Blood and urine will be processed appropriately and frozen for 
future biomarker analysis. The specific biomarkers to be analyzed will be determined at a 
later time.  
• If agreed- the optional biopsy review will occur.  
 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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Detailed methods for specimen handling, collection, processing, shipping and storage will be 
provided in the Laboratory Manual provided by Mayo Clinic. All laboratory tests will be 
performed by the designated central laboratory. 
 
4.4 Identification Number 
The subject/identification number will consist of the patient’s initials (First Middle and Last) 
along with the medication kit number.  This number will be used to identify the subject 
throughout the study and will be entered on all study documents. 
 
The study number will not be assigned to more than one individual.  If a subject was not given a 
medication number, due to being excluded before a number had been assigned, the patient 
would be considered excluded with no issues in regards to number assignment.  However if the 
subject was later deemed ineligible to receive the treatment or needed to discontinue from the 
study, the subject would have been assigned a medication number and therefore once they 
discontinue on the study- that number cannot be used by an additional individuals.   
 
4.5 Optional Research Lab (Biomarkers) 
4.5.1 Collection and Banking of Blood and urine for future testing at Mayo:  
There has been a common antibody found in patients with vasculitis (ANCA) and in some 
patients with the diagnosis of membranous nephropathy (anti-PLA2R), which are example of 
diseases affecting the kidney.  In the future similar antibodies may be found for in patients with 
IgA nephropathy.  We would like to have the opportunity to test for those antibodies and any 
other markers related to IgA nephropathy that could be found in the future.  Labels will be 
provided in advance by the Mayo Clinic. 
 
• Optional Blood Sample (Baseline, 3, 6, 9 and 12 months) 
o 10 ml of blood in a red top tube 
o Let clot for 15-30 minutes at room temperature.   
o Centrifuge 3000 RPMs at 4 degrees for 15 minutes 
o Aliquot equally into 5 – 1ml tubes provided in advance by Mayo Clinic 
o Freeze at -80 C 
 
 
• Optional Urine Sample (Baseline, 3, 6, 9 and 12 months): 50 mL of urine will be drawn 
from a random urinalysis  collection and will be processed and aliquoted to be frozen and 
stored. 
• Add 12 mL of the urine into 4 - 15 mL conical tubes 
• Add 15 µL of protease inhibitor to the half that will be treated with protease 
inhibitor and invert tube 5 times to mix. 
• Spin the tube (and its counterbalance) at 1000 g for 12 minutes. 
• Aliquot the treated and untreated supernatant equally into 4 - 5 ml aliquots each 
and store at –80 °C 
 
Send all samples to Mayo Clinic upon patient’s completion of Month 12’s visit on 10 pounds Dry 
Ice. 

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4.5.1.1. Shipping  
Shipping to be pre-paid by Fed Ex labels on Monday, Tuesday or Wednesday: 
 
Biospecimens Accessioning and Processing (BAP) Freezers 
Stabile SL-16 
150 Third Street SW 
Rochester, MN  55902 
 
4.5.2 Optional DNA Testing 
Recent data show that in a number of glomerular disease (e.g. membranous nephropathy) 
mutations in HLA alleles are associated with an increased risk for developing the disease.39 The 
same has been proposed for IgA nephropathy.40  Thus we would like to evaluate potential 
genetic mutations in this group of patients.  We will ask for the patients consent to further 
evaluate this linkage by collecting samples of blood to perform additional testing as part of 
their informed consent form (ICF).  The DNA sample would be taken at Baseline, but shipped 
with the additional biomarkers listed above. 
• Two 10 ml EDTA tubes will be used for DNA extraction, and will be processed into 2 
aliquots of white blood cells (buffy coat) and stored for future DNA extraction. 
 
4.5.2.1 Quantitative gene expression analysis 
Quantitative gene expression analysis using real-time PCR and Microarray technology in 
peripheral blood mononuclear cells:  There is little information on global gene expression 
changes that occur during active nephrotic syndrome secondary to IgA nephropathy 
subsequent to remission of this disease.  Furthermore, there is no information on how 
ACTH  affects gene expression of potentially pathogenic genes.  As part of this study, peripheral 
blood will be collected at Time 0, and 12 months after therapy.  Following treatment with 
ACTH, B-cell-specific genes will be assessed to track the extent of treatment in the B-cell pool 
gene expression.  Both quantitative TaqMan real-time polymerase chain reaction and gene 
microarray (Affymetrix U133 chips) will be used to evaluate gene expression profiles.  Real-time 
PCR will be used only to confirm the findings of the gene chip for genes with statistical 
significance. 
 
 4.6 Optional Biopsy Review 
4.6.1 Histopathology 
Due to the expertise of the pathologists at each of the clinical centers and to the characteristic 
findings on the renal biopsy in IgA nephropathy a review of the biopsy slides will not be 
required prior to enrollment at a Central Pathology Laboratory.  However, a report 
documenting the results of the histology review including, light microscopy, 
immunofluorescence and electron microscopy results, as well as percentage of global and 
segmental glomerular sclerosis, tubulo-interstitial index, and immunofluorescence findings will 
be submitted and reviewed by the study P.I prior to enrollment into the study.   
 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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At the end of the study, Renal pathology biopsy slides for the patients that consented to have 
their slides reviewed will be centrally reviewed by Dr. Sanjeev Sethi, from the Pathology 
Department at Mayo Clinic Rochester. 
 
4.6.1.1. Shipping  
Shipping to be pre-paid by Fed Ex labels on Monday, Tuesday or Wednesday: 
 
Julie Allen 
Department of Nephrology and Hypertension 
Mayo Clinic, MA19-01-W2 
200 First Street, SW 
Rochester, MN  55905 
 
5.0 Study Medication 
5.1 ACTH dosage and administration 
Approximately twenty-one (21) subjects will receive HP Acthar ®gel.  The appropriate quantities 
of vials will be dispensed to each subject at each visit by the study team.  Each dose will consist 
of 80 U/mg given as an injection at home by the patient or trained family member. The 
injection will be given twice a week for a total of six months (24weeks).   
 
 
• Each Patient: 1.0 mL Acthar SC titrated to 2 times per week- dosing as follows: 
• Week 1: 1 injection (Day 0) will be completed in clinic- where the injection 
training will occur. Inject 2 will be completed by the patient or trained family 
member at home 
• Week 2 to 24 (month 6): 2 injections per week (cannot be 2 consecutive days, 
but no more than 3 days apart).  
 
5.1.1 Preparation for Administration: The patients will be given vials from the study 
coordinator who will pick them up from pharmacy.  The vials will then by take home for self- 
injection.  The 1.0 mL multi-dose vials will contain the 80 units per mL needed to complete one 
of the two doses per week.   
 
5.2 Compliance Control 
Subjects will be trained on the study medication dosing and must exhibit proper technique 
before leaving the injection 1 (on Day 0) teaching session.  The subjects will also complete a 
dosing booklet and will bring it with ALL their medication vials to each visit.  At each visit the 
subject’s dosing booklet will be reviewed with the subject to discuss compliance and 
medication administration. 
 
6.0 Investigational Product: 
 
6.1 Clinical Study Materials: 
The H.P. Acthar ® Get will be provided free of charge by the Mallinckrodt.  The lot numbers and 
expiration dates (if available) will be supplied on the medication vials and will be recorded in a 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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drug dosing accountability log along with the number of vials returned empty and full.  A record 
will also be maintained indicating the receipt and dispensation of all medication supplies.  At 
the conclusion of the study, all used and unused study medication will be destroyed by the 
designated destruction facility.  
 
6.2 Pharmaceutical Formulation 
Acthar is a highly purified sterile preparation of prolonged-release ACTH in 16% gelatin for 
intramuscular or SC injection. Acthar contains 0.5% phenol, not more than 0.1% cysteine 
(added), and sodium hydroxide and/or acetic acid to adjust pH and water for injection. Acthar is 
obtained from processing porcine pituitary using a Food and Drug Administration (FDA) 
approved process. 
 
6.3 ACTH storage includes Labeling and Packaging 
H.P. Acthar Gel (repository corticotropin injection) should be warmed to room temperature 
before using. Do not over pressurize the vial prior to withdrawing the product.  
 
Store H.P. Acthar Gel (repository corticotropin injection) under refrigeration between 2°-8°C 
(36°- 46°F). Product is stable for the period indicated on the label when stored under the 
conditions described. 
 
Acthar will be labeled according to all applicable federal regulations.  
 
6.4 Dispensing Procedures 
Acthar will be supplied to the subject in kits containing the appropriate amount of vials.  During 
the treatment phase the subjects will receive a new kit at each visit that will contain the 
appropriate number of vials to get the patient to the following visit.   
 
7.0 Safety Assessments 
7.1 Specification of Variables and Procedures 
Safety outcomes will be assessed by treatment-emergent adverse events; physical 
examinations; laboratory measurements including 24-hour urine collections, glycemic status 
(HbA1c), hematology, chemistry (includes serum glucose) and urinalysis, blood pressure 
(seated), and heart rate. 
The following will also be completed as per the Schedule of Procedures 
• A complete medical history; 
• A complete physical examination will be performed at certain visits and a limited 
physical examination will be performed at certain visits. The limited physical 
examination will consist of measurement of weight; evaluation of lungs, heart, 
abdomen, and extremities  
• Vital signs (including heart rate and blood pressure); serum chemistry, Creatinine 
clearance (from 24-hour urine), hematology, and urinalysis; 
• A urine pregnancy test will be completed at certain visits for women of childbearing 
potential; 
• Glycemic status (HbA1c) will be assessed; 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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•    Adverse events will be recorded and assessed.  
7.2 Reporting of Adverse Events 
7.2.1 Adverse Events and Serious Adverse Events: definitions, and guidance for reporting: 
• An adverse event (AE) is any untoward medical occurrence in a patient participating in an 
investigational trial or protocol regardless of causality assessment.  An adverse event can be 
an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
syndrome or disease associated with or occurring during the use of an investigational 
product whether or not considered related to the investigational product. 
7.2.1.1 Causality Assessment: 
The relationship of an AE to the administration of the study medication is to be assessed 
according to the following definitions: 
No: 
Not Related - Onset of the event as relative to administration of the product is not 
reasonable; or, another cause itself can explain the occurrence of the AE between the 
administration of study medication and the occurrence or worsening of the AE is 
consistent with a causal relationship and no other cause (concomitant medications, 
therapies, complications, etc.) can be identified of the event. 
Unlikely to be related - Onset of the event as relative to administration of the product 
is possible but another cause itself can explain the occurrence of the event or there 
are no reasonable grounds for suspecting that the product could have caused the 
event. 
Yes: 
Possibly related - Onset of the event as relative to administration of the product is 
reasonable; however the event could have been due to another equally likely cause 
Probably related - Onset of the event as relative to administration of the product is 
reasonable and is more likely explained by the drug than by any other cause. 
Definitely related - Onset of the event as relative to administration of the product is 
reasonable and there is no other cause to explain the event; or a rechallenge (if 
feasible) is positive. 
 
• Serious adverse events (SAE) are adverse events occurring at any dose which meet one or 
more of the following serious criteria: 
 Results in death (i.e. the AE caused or lead to death) 
 Is life-threatening (i.e. the AE placed the patient at immediate risk of death; it does 
not apply to an AE which hypothetically might have caused the death if it were more 
severe) 
 Requires or prolongs inpatient hospitalization (i.e. the AE required at least a 24-hour 
inpatient hospitalization or prolonged a hospitalization beyond the expected length 
of stay; hospitalizations for elective medical/surgical procedures, scheduled 
treatments, or routine check-ups are not SAEs by this criterion) 
 Is disabling (i.e. the AE resulted in a substantial disruption of the patient’s ability to 
carry out normal life functions) 
 Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of 
a patient exposed to the trial drug prior to conception or during pregnancy) 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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 It does not meet any of the above serious criteria but may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes 
listed above 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
 
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified.  This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B.  For example, under 
this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated 
hepatic enzymes or hepatitis. 
 
7.2.1.2 Reporting SAE: 
If considered a UPIRSTO (a Serious Adverse Events that is possibly due to the study medication) 
should be reported to the reviewing Institutional Review Board (IRB) according to individual 
requirements. A copy of that report must be retained at the investigative site and filed in the 
Investigator Site File. 
 
The Investigator must continue to follow the subject until the SAE has subsided, or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies. Within 24 hours of receipt of new information, the investigator must update the 
SAE form and submit any supporting documentation, (e.g., laboratory test reports, patient 
discharge summary, or autopsy reports), to the Dr. Fernando Fervenza M.D, Ph.D via email or 
fax. 
 
Case follow-up with the site will be initiated by Dr. Fernando Fervenza M.D, Ph.D. All site 
queries will be transmitted by e-mail to an e-mail address containing Dr. Fernando Fervenza 
M.D, Ph.D or the investigative site's secure e-mail address, or if no secure e-mail address is 
available, the query will be transmitted by fax. 
 
If a subject is early terminated from the study for a reason other than an SAE, he/she will be 
followed for 30 days after discontinuation of the study drug. If a subject is terminated early 
from the study at any time due to an SAE, he/she will be followed until resolution of the SAE or 
end of study (if SAE is still ongoing). 
 
7.3 Data Safety Monitoring Board:  
A four person DSMB (clinical researchers) not affiliated with the study will be responsible for 
evaluating the progress of the study and will be provided unblinded data on a regular basis to 
monitor patient safety. This committee will communicate by meeting every 6 months.  They will 
be responsible for determining if and when the study must be discontinued as a result of 
excessive adverse events. Study data will be provided to the DSMB by the data coordinating 
center (including all adverse event reports and the GFR data).  Data will be reviewed by the 
DSMB in an unblinded fashion. Randomization codes for each enrolled patient will be provided 
by the research pharmacist at that specific site. The Committee will make its recommendations 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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by periodically monitoring progress, data, outcomes, toxicity, safety and other confidential 
data, and may recommend stopping the clinical trial if an excessive number of serious adverse 
events are observed. 
 
7.3.1. DSMB-Committee Members 
1) Nelson Leung MD, Nephrology and Hypertension, Mayo Clinic Rochester, MN 
2) Andrea Kattah MD, MSGME Foundation Dean, Mayo Clinic Rochester, MN 
3) Hatem Amer MD, Nephrology and Hypertension, Mayo Clinic Rochester, MN 
4) Ziad El-Zoghby MD, Nephrology and Hypertension, Mayo Clinic Rochester, MN  
 
8.0 STATISTICAL CONSIDERATIONS 
Sample size  
This is an open label phase III study involving 21 patients. The response rate to ACTH in IgAN is 
unknown. Thus it is impossible to perform a power calculation.  At this time a standard t-test 
will be performed for proteinuria and renal function at Baseline (Day 0), 6month and 12months.  
 
9.0 Data Management and Record Keeping 
 
9.1 Data Management 
The data will be housed in both hard copy case report forms (CRFs) and eCRFs through a system 
called redcap.  
 
9.1.1 Hard Copy CRFs  
The hard copy documents will be utilized by the primary site monitor.  Each subject will have 
their own binder which will house each visit CRFs. 
 
9.1.2 Computer Systems 
The data will be entered by the local coordinator using a validated computer system 
conforming to regulatory requirements- redcap.  The data should be entered within 5 days of 
the subject’s visit.  A; study site personnel must log into the system using their secure username 
and password in order to enter, review or correct study data. There procedures must comply 
with the Title 21 Code of Federal Regulations (21 CFR part 11) and other appropriate 
international regulations.  All passwords will be strictly confidential.   
 
9.2 Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study 
product, regulatory documents, and other correspondence pertaining to the study must be 
kept in the appropriate study files at the local site. Source data is defined as all information in 
original records and certified copies of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the evaluation and reconstruction of the clinical 
study. Source data are contained in source documents (original records or certified copies). 
These records will be retained in a secure file for the period as set forth in the Clinical Study 
Agreement. Prior to transfer or destruction of these records, the Mayo Clinic must be notified 
in writing and be given the opportunity to further store such records. 
 

ACTH in the Treatment of Progressive IgA Nephropathy 
 
 
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9.3 Direct Access to source data/documents 
Dr. Fernando Fervenza, M.D., Ph.D and the IRB/Independent Ethics Committee, and 
representatives from the regulatory agencies will have the right, both during and after the 
clinical study, to review and inspect pertinent medical records related to the clinical trial. 
 
10.0 Quality control and Quality Assurance 
The Mayo Clinic will perform quality control and quality assurance checks of all additional sites. 
Before the enrollment of any subject in this study, designated study personnel will review with 
the investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs.  Site visits will be performed by the Mayo Clinic study team. During these visits, 
information recorded on the eCRFs will be verified against source documents and requests for 
clarification or correction may be made. After the eCRF data is entered by the site, safety 
information will be reviewed for completeness, accuracy, and logical consistency. Computer 
programs that identify data inconsistencies may be used to help monitor the clinical study. If 
necessary, requests for clarification or correction will be sent to investigators. 
By signing the protocol, the Mayo Clinic agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written standard operating 
procedures to ensure that studies are conducted and data are generated, documented, and 
reported in compliance with the protocol and accepted standards of Good Clinical Practice. 
 
11.0 Ethics and Good Clinical Practice Compliance 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are 
protected; consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Tumlin JA, Galphin CM, Rovin BH. Advanced diabetic nephropathy with 
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