The Use of Acthar (ACTH) in Patients With Focal Segmental Glomerulosclerosis (FSGS) Who Have Developed Chronic Kidney Disease Stage V (CKD) or End Stage Renal Disease (ESRD) and Are Undergoing a Renal Transplant
Phase: PHASE3
Conditions: FSGS
Sponsor: University of Colorado, Denver

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
1 
The Use of Acthar (ACTH) in Patients with Focal Segmental 
Glomerulosclerosis (FSGS) Who Have Developed Chronic Kidney Disease 
Stage V (CKD) or End Stage Renal Disease (ESRD) and Are Undergoing a 
Renal Transplant 
 
Principal Investigator: Monica Grafals, M.D., MPH 
Ph. 857-492-2513 
Email: monica.grafals@ucdenver.edu 
 
COMIRB 17-2336 
 
Version Date: July 11, 2018 
 
I.Hypotheses and Specific Aims 
 
This is an open-label pilot study where all subjects will be treated with the drug, 
Acthar.  The specific aim is to determine the rate of recurrent FSGS through 
evaluation of kidney biopsies performed post renal transplantation. FSGS is a 
type of nephrotic syndrome that can recur aggressively after renal 
transplantation. When FSGS recurs after transplant it increases patient morbidity 
and increases graft loss.  
 
It is believed that ACTH, besides steroid dependent properties, has steroid 
independent properties (see figure 1 on page 10). With the steroid independent 
properties it may stimulate the MCIR receptor which affects not only the 
podocytes, but also the T-cells, B-cells, NKR-cells and APC-cells.  
  
The primary end-point is to measure proteinuria prior (if patient still makes urine) 
and after renal transplantation and determine the change in proteinuria and the 
recurrence of FSGS as seen in kidney transplant biopsy. Kidney transplant 
biopsies will be performed at time O (at implantation), 3 months and 12 months 
post transplantation. Our hypothesis is that the use of Acthar, on patients with 
history of FSGS as cause of chronic kidney disease, at the time of renal 
transplantation and for a 6-month period of time following transplant, decreases 
the probabilities of patients developing recurrent disease after renal 
transplantation.  
 
Our secondary end point is to evaluate renal function after transplantation as 
measured by eGFR. We hypothesize that patients will maintain a stable eGFR 
and creatinine while on Acthar and after it is stopped.  
 
II. Background and Significance 
 
Wait time for kidney transplantation is on average at least 5 years and 
unfortunately many patients die while waiting for kidney transplantation. 
Recurrent disease affects 23-30% of renal transplant recipients with FSGS. No 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
2 
known genetic mutations have been identified among those with recurrence. 
Plasmapheresis has resulted in complete or partial remission in 75% of those 
with recurrence after transplant but this treatment is very aggressive as it 
increases bleeding risk and involves the placement of a catheter. Furthermore, it 
is performed usually three times a week for months in order to achieve remission. 
Modern immunosuppression does not reduce the rate of recurrent FSGS (1). 
Moreover, recurrence after transplantation, where the patient is already 
immunosuppressed, is a poor prognostic factor and it brings a high risk of graft 
failure.  
 
Typically, recurrence of primary FSGS occurs early in the post transplantation 
period with heavy proteinuria and progressive renal insufficiency and graft failure. 
Current animal and human data suggest that primary FSGS is likely to be 
initiated by podocyte injury; however, Savin et al. (2) described a circulating 
plasma factor and its association with many cases of primary and recurrent 
FSGS. The rapid nature of recurrent FSGS after transplantation is consistent with 
the theory that one or more circulating factors may be playing a major role in the 
pathogenesis of recurrence (3).  
 
Acthar is FDA approved for the treatment of nephrotic syndrome. The FDA 
package insert of Acthar: “To induce a diuresis or a remission of proteinuria in 
the nephrotic syndrome without uremia of the idiopathic type or that due to lupus 
erythematous.” (3). It still has not been studied in renal transplant patients, but 
clinical data in our center has been very encouraging and it has been used safely 
and effectively in renal transplant recipients with FSGS.  
 
This medication has been studied in nephrotic syndrome in native kidney 
disease. Most studies have used a dose of 80 units twice a week (one cc of the 
medication contains 80 units). There is no data on the renal transplant 
population, but is interesting to note that with the steroid independent properties, 
Acthar may target several cell linages that are relevant in transplantation and 
maybe a reason of why this medication can work to decrease recurrence after 
transplantation.  
 
Recent data has shown an etiologic role of perturbations of the CD40 antigen in 
recurrent FSGS (4). It is unknown if Acthar would change CD40 in patients with 
FSGS. As part of our research investigation, we propose to investigate CD40 in 
kidney biopsies, by immunohistochemistry, and serum of patients, by ELISA.  
Patients will have one pre-transplant serum sample which will be measured for 
CD40 by utilizing the CD40 antibody through ELISA. A 2nd blood sample will be 
obtained at 3 months post transplant, at 6 months post transplant and at 1 year 
post transplant. This blood will be drawn with standard of care labs, so it would 
not impose additional blood draws to the patient.  
 
We expect from 7-10 patients a year to meet inclusion criteria.  
 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
3 
 
 
 
III. Research Methods and Design 
 
A. Study Type/Design:  
 
Prospective open-label study enrolling renal transplant recipients with the 
primary native kidney disease of FSGS. This protocol already has an IND 
exemption as this medication is FDA approved for the treatment of 
nephrotic syndrome. All subjects will receive Acthar. 
 
B. Endpoints 
 
The primary endpoint is rate of recurrence of FSGS as seen in renal 
transplant biopsies and in rate of proteinuria. 
 
The secondary endpoints are duration of remission after Acthar treatment 
(Time Frame: 1 year and 2 years of study follow-up after treatment 
completion ), changes in kidney fibrosis after Acthar treatment  and  safety 
and efficacy of Acthar in the post renal transplant population.  
 
C. Patient Recruitment 
 
Preliminary data was previously submitted in the American Transplant 
Congress 2017. Post renal transplant recipients that developed FSGS 
were treated with Acthar at the discretion of the investigator. Half of the 
patients experienced reductions in proteinuria. Prior to the introduction of 
this medication, developing recurrent FSGS in the renal transplant meant 
that the renal transplant would likely be lost within a year.  
 
This is a single center pilot study where the target subject number is 20 
patients and the target population is primary FSGS patients. By the 
current data, FSGS should recur in 23-30% of patients. Therefore, it would 
be expected that at least 4 patients will develop recurrent FSGS after 
renal transplantation.  
 
After we obtained data from this pilot study we would expect to request 
funding for a large multicenter study. 
 
Inclusion Criteria: 
1. Adult renal transplant recipients with primary FSGS 
2. Ability to consent 
 
Exclusion Criteria: 
1. Renal transplant recipients whose primary disease is not FSGS 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
4 
2. Patients who are receiving dual organ transplants  
3. Patients who have been on Acthar prior to transplantation.  
4. Intractable CHF (congestive heart failure) 
5. Uncontrolled hypertension definied as BP >180/100 
6. Uncontrolled diabetes defined as a HgbA1c>10% 
7. An acute infection 
8. Allergies to pig-derived proteins 
9. Have received a live vaccine three months prior to transplant 
10. Cushing’s syndrome 
11. Addison’s disease 
12. Previous intolerance to native ACTH or proteins of porcine origin 
13. History of scleroderma, osteoporosis, systemic fungal infections, ocular 
herpes simplex, recent surgery, history of or the presence of peptic 
ulcer, primary adrenocortical insufficiency or adrenocortical 
hyperfunction. 
14. Recent cardiovascular event within 3 months of screening including: 
Myocardial Infarction, CVA, TIA, New York Heart Association 
Functional Class III or IV failure, Obstructive valvular heart disease, or 
hypertrophic cardiomyopathy, second or third degree atrioventricular 
block not successfully treated with a pacemaker. 
15. History of HIV 
16. New diagnosis of cancer or recurrent cancer within 2 years of 
screening 
17. History of alcohol or drug abuse within 12 months of study entry. 
18. Receipt of any investigational drug within 30 days of enrollment. 
19. Psychiatric disorder that interferes with the patient's ability to comply 
with the protocol. 
20. Poorly controlled diabetes with an HbA1C > 10% 
21. Type 1 diabetes mellitus 
22. Pregnancy 
 
 
D. Treatment Overview  
 
Screening will be performed by the Principal Investigator during the kidney 
transplant evaluation clinics and during the wait list kidney transplant 
evaluation clinic. All patients with FSGS will have induction therapy with 
thymoglobulin and maintenance immunosuppression with tacrolimus and 
mycophenolate. This is the standard regimen that we utilize post 
transplant in all our recipients.  
 
E. Dosage and Administration of Acthar  
 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
5 
The dose of Acthar to be given to every enrolled patient will be 80 units 
twice a week for 6 months.  The first dose of Acthar is given at the time of 
transplantation and will be continued, twice a week, for 6 months. See 
Appendix A (page 9) for additional details. 
 
Safety: 
1. Acthar  should always be injected beneath the skin or into the muscle. 
2. Never inject Acthar directly into a vein. 
 
Risks: 
1. Development of high blood sugars (10%) 
2. Development of high blood pressure (11%) 
3. Edema (1%) 
4. Mood and behavior changes (7%) 
5. Weight and appetite changes (1%) 
 
We will be monitoring all patients at the stated time points for all the above 
risks and side effects. We will be monitoring side effects with our research 
transplant coordinator and the PI who will be seeing the patients. We will also 
have a safety officer, Dr.Jessica Kendrick, who will be reviewing the adverse 
events. At every clinic visit, as standard of care, patients get their vital signs 
taken as well as urinalysis and laboratories. We will be reviewing all the 
results carefully and assess every patient to see if there are any signs of 
infection.  Dr.Kendrick will also be part of the DSMB.  While Dr. Kendrick will 
review safety date and adverse events every three months, the DSMB, of 
which she will be a member, will meet every 12 months. 
 
F. Laboratory Testing and Study Schedule  
 
Patients will have one pre-transplant serum sample which will be 
measured for CD40 Ab. A 2nd blood sample will be obtained at 3 months 
post transplant, 6 months post transplant and at 1 year post transplant. 
This blood will be drawn with standard of care labs, so it would not impose 
additional blood draws to the patient.  
Standard of care labs include CBC, BMP, tacrolimus level, BK PCR 
plasma, CMV PCR plasma, DSA, Allosure testing and urine 
protein/creatinine. 
 
 The first month post transplant, patients will have labs and clinic 
visit biweekly. 
 The second month post transplant patients will have labs and clinic 
visit weekly. 
 The third month post transplant patient will have labs weekly and 
clinic visit every other week. 
 From the 4th till the 6th month post transplant patients will have labs 
every other week and clinic visit monthly. 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
6 
 From month 6 till month 12 patients will have labs monthly and 
clinic visit every other month.  
 
Dr.Joshua Thruman, a nephrologist and immunologist, will be helping in 
the testing of CD40 Ab. ELISA will be used in patient’s serum to test for 
CD40. In addition, human kidney biopsy tissues will be fixed in formalin or 
AFA (alcohol–formalin–acetic acid) solution and embedded in paraffin. For 
CD40, antigen retrieval was performed by proteinase K digestion and then 
hydrolysis by heating in a microwave oven with citrate buffer. The rabbit 
polyclonal primary anti-CD40 Ab (Anti-CD40 Ab 11E9, Abcam) will be 
diluted at 1:150 and incubated overnight at +4°C. A three-step technique 
will be used with biotinylated anti-rabbit secondary Ab, avidin-biotin-
peroxidase complex as the vector, and 3,3′-diaminobenzidine (DAB) as 
the substrate. 
 
 
G. Patient Monitoring and Evaluation  
 
Patients will have a kidney biopsy at time 0 (at the time of implantation), 3 
months and 12 months. If at any other time it is clinically necessary to 
perform another biopsy it will be performed. Any extra kidney transplant 
tissue will be used to stain for CD40 Ab. This would not impose an extra 
risk as it will be part of the standard of care kidney transplant biopsy.  
We will be collecting clinical data from the patient’s medical record 
including medications, CBC, CMP, urine protein/creatinine, BK, CMV, 
adverse events, infections and any hospital admissions.  
 
H. Potential Pitfalls and Contingencies  
 
We will ideally attempt to avoid plasmapheresis after renal transplantation, 
but if a patient develops severe proteinuria will start plasmapheresis and 
monitor proteinuria until it decreases. If there is no change in proteinuria 
after a month on plasmapheresis, we will stop plasmapheresis and 
continue only with Acthar.  
 
I. Specific participant and study stopping criteria: 
1. Development of severe hypertension definied as BP > 180/100 
2. Development of congestive heart failure 
3. Severe edema that is impeding ability to breath 
4. Withdrawal of consent 
5. Pregnancy 
6. Use of immunosuppressive drugs other than those specified by the 
protocol except those needed to treat FSGS and proteinuria 
7. Any other protocol deviation that results in significant risk to the 
patient’s safety. 
 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
7 
 
J. Data Processing and Analysis  
 
Sample size: A sample size of 20 data pairs (for example from 
immediately post-transplant to 12 months post-transplant) achieves 80% 
power to detect an effect size of change in proteinuria of 0.66 standard 
deviations with a significance level (alpha) of 0.05 using a two-sided 
paired t-test. A sample size of 20 produces an exact two-sided 95% 
confidence interval from 0.087 to 0.491 when the recurrent FSGS 
proportion is 0.25, i.e. 5/20 patients. If only 4/20 patients develop recurrent 
FSGS the 95% confidence interval would be 0.057 to 0.437 and if 3/20 
patients developed FSGS the 95% confidence interval would be 0.032 to 
0.379. This lack of precision in the estimate of the proportion of patients 
developing recurrent FSGS is due to the small sample size. However, this 
is a pilot study to determine whether Acthar helps decrease the rate of 
recurrent FSGS after renal transplantation. The observed rate of recurrent 
FSGS in patients treated with Acthar will be used to power larger, 
multicenter studies. We will seek expert opinion from the participating 
centers regarding expected rates when planning the trial.  The outcomes 
which will be used to plan for a future, larger, more definitive trial will 
include recurrent FSGS as observed in this pilot study as well as change 
in proteinuria over time. 
 
Data analysis: Data will be analyzed using two-sided paired t-tests for 
comparing two time points as well as mixed effects models for multiple 
time points, to assess changes in proteinuria over time. Other clinical, 
pathological and laboratory variables may be included in the models to 
determine whether the change over time is affected by these covariates. 
Similar methods will be used to model changes in eGFR over time. The 
observed proportion of patients developing recurrent FSGS will be 
reported as a proportion with an exact 95% confidence interval. Standard 
of care labs including CBC, BMP, tacrolimus level, BK PCR plasma, CMV 
PCR plasma, DSA, Allosure testing and urine protein/creatinine as well as 
biopsy findings will be reported as summary statistics (means ± SD, 
medians (with interquartile range) and proportions as appropriate) at each 
time point. 
 
All patient information will be de-identified for study purposes.  
 
We will monitor the data and safety measures periodically. We will monitor 
AEs on a weekly basis.  
 
Our plan is to have an abstract submitted for a large meeting, such as the 
American Transplant Congress, the American Society of Nephrology 
Meeting or the World Transplant Congress.  
 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
8 
K. Designation of Independent Monitor: 
The PI will designate an Independent Monitor to perform an independent 
review of ongoing study progress and safety. The Independent Monitor 
should not be involved with the study or work with the PI, although he/she 
could work within the same institution. The Independent Monitor for this 
study is Dr. Jessica Kendrick. Dr. Kendrick is not associated with this 
research project and thus works independently of the PI, Dr. Monica 
Grafals. Dr. Kendrick is not a part of the key personnel involved in this 
grant, and is qualified to review the patient safety data generated by this 
study because of her unique expertise in the area of the nephrology. Dr. 
Kendrick’s CV is attached. Dr.Kendrick will be in the DSMB.  She will 
review safety date every 3 months and then meet formally as a DSMB 
every 12 months. 
 
 
 
 
 
IV. References 
 
1. Recurrent focal segmental glomerulosclerosis in the renal allograft: single 
center experience in the era of modern immunosuppression. Schachter ME1, 
Monahan M, Radhakrishnan J, Crew J, Pollak M, Ratner L, Valeri AM, Stokes 
MB, Appel GB. Clin Nephrol. 2010 Sep;74(3):173-81. 
2. Circulating factor associated with increased glomerular permeability to 
albumin in recurrent focal segmental glomerulosclerosis. Savin VJ, Sharma 
R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar 
S, Chonko AM, Artero M, Vincenti F. N Engl J Med334 :878–883,1996. 
 
3. Acthar Full Prescribing Information 
 
4. Recurrent glomerulonephritis after renal transplantation: an unsolved 
problem. Golgert WA, Appel GB, Hariharan S.Clin J Am Soc Nephrol. 2008 
May;3(3):800-7. Epub 2008 Feb 13. 
 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
9 
Appendix A – Acthar (ACTH) Study Visit Schedule 
 
*1 All laboratories (except CD40 Ab – see footnote *3) are part of SOC/Standard of Care.  
SOC labs include CBC, BMP, tacrolimus level, BK PCR plasma, CMV PCR plasma, DSA, 
Allosure and urine protein/creatinine.   
 
*2 Study medication (Acthar) will continue twice a week through month 6 post-transplant.  
 
*3 CD40 Ab which will be measured pre transplant, at 3, 6 and 12 months. This laboratory will 
be drawn at the same time as SOC labs so that patient does not have an additional blood 
drawn. Dr. Josh Thurman will assist with the testing of the CD40 Ab. 
 
 
 
 
 
 
 
 
 
 
SCR OR
 
Day 
 
Week Month   
 
 
 
 
 
 
 
 
 
-21- 0 0
 4 7 10 14 18 21 25 28 5 6 7 8 
3 
4 5 6 7 8 9 10 11 12 18 30 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Background 
information 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Transplant 
information 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Pregnancy test
 
 x 
  
      
  
  
  
  
 
        
 
  
 
 
 
 
 
 
 
 
 
Vital signs 
 x 
 x  x  x x  x  x   x  x x  x x  x  x  
x 
x x x  x  x 
 
x 
 
 
Physical exam 
 x 
 x x   x  x x  x  x  x  x  x  x  x x  
x 
x x x  x  x 
 
x 
 
 
Laboratory tests *1 
 x 
 x x  x  x   x  x  x  x x x  x  x   x 
x 
x x x x x x x x x 
 
 
Renal Biopsy
 
  
 x       
  
  
  
  
 
        
x 
  
 
 
 
 
 
 
x 
 
 
Study medication *2   
x  x   x x  x  x   x x  x x   x  x  x 
x 
x x x  
 
 
 
 
 
 
 
CD40 Ab *3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  X  
 
 
 
 
X 
 
 
Follow-up (for secondary data 
on remission: yes or no) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

COMIRB 17-2336 
P.I. Grafals, Monica 
Version 7-11-2018 
 
10 
Figure 1