Clinical trial NCT03408639
Conditions: Anemia in End-Stage Renal Disease
Keywords: End-Stage Renal Disease, Anemia, Erythropoietin, Hemoglobin
Sponsor: Cinnagen
Start date: 2016-06-22; Completion date: 2017-07-19
Enrollment: 156 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase III, randomized, two-armed, parallel, double-blind, active-controlled clinical trial is designed to compare efficacy and safety of CinnaPoietin® (Beta erythropoietin) and Eprex® (epoetin alpha) on the treatment of anemia in 156 End-Stage Renal Disease hemodialysis patients. 156 patients have been planned to randomize and assign to receive CinnaPoietin® or Eprex® for a 26-week period. Administration dose for patients who are treated with erythropoietin is the similar dose of the previously administered amount (IV or SC without any change). After then, dose adjustment will be made based on patients' response. The primary objective of this study is to compare the efficacy of CinnaPoietin® with Eprex®. The secondary objectives of this study are further comparison and evaluation of efficacy along with safety between CinnaPoietin® and Eprex®.

Detailed description:
This study is a phase III, randomized, two-armed, parallel, double-blind (patient and assessor blinded), active-controlled noninferiority clinical trial to determine the non-inferior therapeutic efficacy and safety between CinnaPoietin® (Beta erythropoietin) and Eprex® (epoetin alpha) on the treatment of anemia in ESRD patient under hemodialysis. After signing the written informed consents, 156 patients have been planned to randomize and assign to receive CinnaPoietin® or Eprex® for a 26-weeks period. Administration dose for patients who are treated with erythropoietin is the similar dose of the previously administered amount (IV or SC without any change). After then, dose adjustment will be made based on patients' response. In addition to main intervention, Nephrovit tablet/day and B12 100 mcg/month were prescribed for patients. The primary objective of this study is to compare the efficacy of CinnaPoietin® with Eprex®. The secondary objectives of this study are further comparison and evaluation of efficacy and safety.

The clinical trial will be conducted according to the GCP considerations. A comprehensive validation check program is used to verify the data, and discrepancy reports are generated accordingly for resolution by the investigator.

In order to ensure the use of standard and unified procedure of each test, monitoring of each site and laboratory site are going to be applied by sponsor monitoring team and CRO as external monitoring team.

The same prefilled syringe is used for CinnaPoietin® to be sure that there is no difference between CinnaPoietin® and Eprex® as brand drug. The drugs will be relabeled, and the same label is used for both prefilled syringe. So neither investigators nor subjects are able to notice any differences between them and are blind to the assignment.

Determination of sample size 156 patients will be equally (1:1) divided into intervention arms (78 in each group considering drop out) for achieving 80% power in order to determine non-inferiority using a one-sided, independent sample t-test. The margin of non-inferiority is -1.00.

The true difference between the means is assumed to be -0.500. The significance level (alpha) of the test is 0.05. The data are drawn from populations with standard deviations of 1.200 and 1.200.

Arms: arm 1: The starting dose of Erythropoietin is 60 (50-100) IU/kg body weight/week for naïve patients. Administration dose for patients who are treated with erythropoietin is similar dose of previously administered amount (IV or SC without any change). After then, dose adjustment will be done based on patients' response.

In addition to main intervention, Nephrovit tablet/day and vitamine B12 100 mcg/month will be prescribed for patients. arm 2: The starting dose of Erythropoietin is 60 (50-100) IU/kg body weight/week for naïve patients. Administration dose for patients who are treated with erythropoietin is similar dose of previously administered amount (IV or SC without any change). After then, dose adjustment will be done based on patients' response. In addition to main intervention, Nephrovit tablet/day and vitamine B12 100 mcg/month will be prescribed for patients.
Interventions: intervention 1: CinnaPoietin® intervention 2: Eprex® intervention 3: Nephrovit intervention 4: Vitamin B12 Injection
Intervention descriptions: intervention 1: The starting dose of Erythropoietin is 60 (50-100) IU/kg body weight/week for naïve patients. Administration dose for patients who are treated with erythropoietin is similar dose of previously administered amount (IV or SC without any change). After then, dose adjustment will be done based on patients' response. intervention 2: The starting dose of Erythropoietin is 60 (50-100) IU/kg body weight/week for naïve patients. Administration dose for patients who are treated with erythropoietin is similar dose of previously administered amount (IV or SC without any change). After then, dose adjustment will be done based on patients' response. intervention 3: Nephrovit tablet is daily administered to all the patients. intervention 4: Vitamin B12 is monthly injected to all the patients.

Protocol documents:
Prot_000.pdf: 
 
 
1 
 
 
 
 
 
 
 
 
Cinnapoietin® Clinical Trial Protocol 
 
 
A Phase III, randomized, two armed, multicenter, parallel, double blind (patient and assessor 
blinded), active controlled non inferiority clinical trial to determine the non-inferior therapeutic 
efficacy and safety between CinnaPoietin® (Beta erythropoietin) and Eprex® (epoetin alpha) on 
treatment of anemia in ESRD hemodialysis patients. 
 
 
 
 
Date: 23 August 2015 
 
NCT number: NCT03408639 
 
 
 
 
 


 
 
2 
 
Cinnapoietin® clinical trial synopsis 
Title 
 
A Phase III, randomized, two armed, multicenter, parallel, double blind 
(patient and assessor blinded), active controlled non inferiority clinical 
trial to determine the non-inferior therapeutic efficacy and safety 
between CinnaPoietin® (Beta erythropoietin) and Eprex® (epoetin 
alpha) on the treatment of anemia in ESRD hemodialysis patients 
 
Aim 
of 
Study 
(Primary objective) 
Determination of non-inferior efficacy of Beta erythropoietin 
(CinnaPoietin®) compared with Eprex® (epoetin alpha) in correction of 
hemoglobin levels of anemic patients with chronic kidney disease 
(CKD) under hemodialysis 
 
Secondary 
objectives 
The secondary outcomes of interest include assessment of efficacy and 
safety of Beta erythropoietin (CinnaPoietin®). 
 
Study Design 
The study is designed as phase III, randomized, two armed, multicenter, 
parallel, double blind (patient and assessor blinded), active controlled 
non inferiority clinical trial with primary outcome of hemoglobin level 
change in anemic patients with CKD under hemodialysis. 
 
Registration 
This study is planned to be registered in Iranian Registry of Clinical Trial 
(IRCT)  
Sponsor 
CinnaGen Co 
Contract Research 
Organization 
(CRO) 
CRO Trial, Tehran University of Medical Sciences, Tehran, Iran. 
Principal 
Investigator 
Investigator name: 
Dr. Mohammad Reza Abbasi 
Affiliation: 
Nephrology Research Center, Tehran University of Medical Sciences, 
Tehran, Iran 
Recruitment centers: Ghiasi Hospital 


 
 
3 
 
Co-investigators 
and 
recruitment 
centers 
1. Dr. Jalal Azmandian 
Affiliation: 
Department of Nephrology, Kerman University of Medical Sciences, Kerman, 
Iran. 
Recruitment centers: 1. SHAFA Hospital 2. Javad Ol Aemeh Hospital 
2. Dr Vahid Pourfarziani 
Affiliation: 
Nephrology and Urology Research Center, Baqyiatallah University of Medical 
Sciences, Tehran, Iran 
Recruitment centers: 1. Milad Hospital 
3. Dr Shahrzad Ossareh 
Affiliation: 
Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, 
Iran 
Recruitment centers: 1.Hashemi Nezhad Hospital 
4. Dr Hooshang Sanadgol 
Affiliation: 
Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, 
Iran Recruitment centers: 1. Hashemi Nezhad Hospital 
5. Dr. Amirahmad Nasiri 
Affiliation: 
Imam Hossein Hospital, Shahid Beheshti University of Medical 
Sciences, Tehran, Iran 
Recruitment centers: 1. Imam Hossein Hospital 2. Madar Hospital 
6. Dr Shahrokh Ezzat zadegan jahromi 
Affiliation: 
Nephro-Urology Research Center, Shiraz University of Medical Sciences, 
Shiraz, Iran 
Recruitment centers: 1. Haj Ebrahimi dialysis center 
 
Investigational 
Drug 
Erythropietin beta biosimilar (CinnaGen co, Iran) 
Comparator 
Eprex® (erythropoietin alfa) (the reference drug, produced by Janssen-
Cilag) 
Sample size  
156 patients will be equally (1:1) divided into intervention arms (78 in 
each considering drop out) for achieving 80% power in order to 
determine non-inferiority using a one-sided, independent sample t-test. 
The margin of non-inferiority is -1. 


 
 
4 
 
The true difference between the means is assumed to be -0.5. The 
significance level (alpha) of the test is 0.05. The data are drawn from 
populations with standard deviations of 1.2 and 1.2. 
Eligibility criteria 
Inclusion Criteria: 
 Aged between 18 and 70 
 ESRD patients who are on hemodialysis for ≥3 months. 
 Hb level 8- 11.5 g/dl 
 Patients are on adequate hemodialysis: the minimally adequate 
dose of hemodialysis given 3 times per week should be a spKt/V 
(single-pool delivered Kt/V; clearance of urea x dialysis 
time/volume of distribution) of 1.2 per dialysis. For treatment 
periods of less than 5 hours, an alternative minimum dose is a 
urea reduction rate (URR) of 65%. All types of hemodialysis 
systems and hemodiafiltration, including high-flux membranes 
are allowed as long as there is no plan to change the patient’s 
regimen during the study. 
 Sufficient iron stores, defined as serum ferritin ≥ 200 ng/ml and 
transferrin saturation ≥20%. (Patients not meeting these criteria 
may receive iron supplementation therapy during the Screening 
and stabilization period to appropriately correct their iron store 
deficiency to meet the criterion required for randomization); 
 Ability to comply with study medication use, study visits, and 
study procedures as judged by the investigator; 
 Females of childbearing potential agree to use an acceptable 
method of birth control (e.g., abstinence, hormonal or barrier 
methods, partner sterilization, or IUD) for the duration of the 
study. 
 Qualified and willing to sign the informed consent form with the 
commitment of complying with all the scheduled visits, and study 
procedures as judged by the investigator; 
 In any circumstances that potential participants are not able to 
give consent, it may be given by responsible parents or guardian. 
Exclusion criteria 
 Uncontrolled hypertension (defined as pre-dialysis diastolic 
blood pressure ≥ 100 mmHg or systolic blood pressure ≥180 
mmHg); 
 Anemia secondary to other causes different to the CKD (e.g. 
multiple myeloma, aplastic anemia, leukemia….) 


 
 
5 
 
 Decompensated liver failure; 
 Clinical evidence of concurrent uncontrolled 
hyperparathyroidism (defined as serum parathyroid hormone 
(iPTH) > 800 pg/ml); 
 Heart failure [New York Heart Association (NYHA) class III 
and IV]; 
 Unstable angina pectoris, active cardiac disease, stroke and/or 
cardiac infarction within the last six months; 
 History of or active blood coagulation disorders including DVT, 
PTE, native access Thrombosis during last six months. 
 Thrombocytosis (platelet count > 500,000/μl); 
 Thrombocytopenia (platelet count < 100,000/μl); 
 White blood cell count < 3,000/μl); 
 White blood cell count >15,000/μl) 
 Recent Bleeding (acute or chronic bleeding within three months 
prior to screening); 
 Suspicion of or confirmed occult bleeding (increased 
reticulocyte count); 
 Clinical evidence of concurrent systemic infection, or 
inflammatory disease (e.g; diabetic foot, bed sore, access 
infection, CRP> 30 mg/l) 
 Currently receiving treatment for epilepsy; 
 Major surgery within 3 months prior to randomization and 
during the conduct of the trial (except vascular access surgery); 
 Concomitant immunosuppressive therapy; patients on a short 
course of steroids (up to 7 days), topical or intranasal steroids 
are allowed in the study; 
 History of any malignant disease within the last 5 years (except 
excised non-melanoma skin cancer); 
 Women who are pregnant or breastfeeding; 
 Known history of severe drug-related allergies; 
 Known history of drug related allergy to Erythropoietin or one 
of the ingredients of the test or the reference products or 
hypersensitivity to mammalian-derived products; 
 Transplant received within one year prior to the start of the 
study; 


 
 
6 
 
 Simultaneous participation in another clinical study or having 
received an Investigational Medicinal Product within three 
months before randomization in this study. 
 Psychiatric, addictive (drugs or alcohol) or any other disorder 
that compromises the ability to give an informed consent; 
 Any red blood cell transfusion during the last 3 months 
(measured at the time of eligibility verification); 
 Primary hematological disorder (e.g. myelodysplastic syndrome, 
myeloma, sickle cell anemia, hematological malignancy, 
multiple myeloma hemolytic anemia); 
 known resistance to the rHuEPO defined by a requirement > 450 
IU/kg/week by IV or 300 IU/kg/week by SC, equivalent to 
approximately 20.000 IU/week SC and in absence of iron 
deficiency; 
 who have suffered an event of active bleeding in the 30 days 
prior to the beginning of the study; 
 Morbid obesity, defined by a Body Mass Index (BMI) > 37 kg/m2 
in women and > 40 kg/m2 in men. 
Pre Intervention 
Pre-intervention treatment with iron will be of interest to reach a 
transferrin saturation percentage (TSAT) ≥ 20% and a ferritin ≥ 200 
ng/ml. 
According to the KDIGO guidelines [41], if the TSAT is <20% and the 
serum ferritin <200 ng/ml (<200 μg/l) and an increase in Hb 
concentration without starting ESA treatment is desired, it is suggested 
to administer a trial of IV iron. 
IV iron may be provided as a single large dose or as repeated smaller 
doses depending on the specific IV iron preparation used (with the 
highest single dose varying by specific formulation). It is common 
practice to provide an initial course of IV iron amounting to 
approximately1000 mg; this may be repeated if an initial dose fails to 
increase Hb level and allow a decrease in ESA dose and if the TSAT 
remains <20% and serum ferritin remains <200 ng/ml (<200 mg/l) 
 
Randomization 
Cluster Randomization Method will be used to randomize patients in the 
study. The randomization monitor will create unblinding envelopes and 
packaged the drug with blinded labels. After the randomization, each 
patient will be given an identification code in order to be recognized 


 
 
7 
 
during the study and the treatment will be started based on allocated 
group of intervention. 
Blinding 
To prevent the influence of knowing intervention group on study 
conclusion, the Subjects and those who assess the study outcomes will 
be unaware of the state of the patient with regard to receiving the active 
drugs or standard remedy. 
For this purpose, Subjects and administrator of drug will be blinded by 
using a similar masked prefilled syringes. All drugs packages will be 
identified by unique numbers. 
Intervention 
The treatment proposed in this study was elaborated according to the 
KDIGO guidelines. Before the beginning of the protocol, for the patient 
to be able to enter the treatment, it shall be controlled that the iron (Fe) 
stores are adequate. In addition to main intervention, Nephrovit tablet 
/daily and B12 100 mcg (Amp)/monthly will be prescribed. 
Outcomes 
Efficacy outcomes 
Primary outcomes: 
 The mean Hb change level during the last 4 weeks of treatment 
 The mean weekly epoetin dosage per kg body weight during the 
last 4 weeks of treatment necessary to maintain the Hb level 
within 10-12 g/dl during the last 4 weeks of treatment will be 
considered as a second primary endpoint 
 
Secondary outcomes: 
 
 The proportion of patients with any permanent or transient dose 
change during main study phase, 
 The proportion of patients with any Hb measurement outside the 
target range, 
 Incidence of blood transfusions. 
 Proportion of patients with treatment success (Hb 
concentration≥11.0 g/dl AND two consecutive weeks without 
any blood transfusion within the preceding 3 months), 
 Proportion of patients with maintenance success (maintenance 
of mean Hb concentration of 11.0 ± 1.0 g/dL for at least 4 
consecutive weeks), 
 Percentage of Hb measurements>10.0 g/dL, 


 
 
8 
 
 
References: 
1. Astor, B.C., et al., Association of kidney function with anemia: the Third National Health and Nutrition 
Examination Survey (1988-1994). Archives of internal medicine, 2002. 162(12): p. 1401-1408. 
2. Brittin, G., et al., Stability of blood in commonly used anticoagulants. Use of refrigerated blood for quality control 
of the Coulter Counter Model S. American journal of clinical pathology, 1969. 52(6): p. 690-694. 
3. Locatelli, F., et al., Revised European best practice guidelines for the management of anaemia in patients with 
chronic renal failure. Nephrology, dialysis, transplantation: official publication of the European Dialysis and 
Transplant Association-European Renal Association, 2004. 19: p. ii1-47. 
4. Wintrobe, M.M. and J.P. Greer, Wintrobe's clinical hematology. Vol. 1. 2009: Lippincott Williams & Wilkins. 
5. Weiss, G. and L.T. Goodnough, Anemia of chronic disease. New England Journal of Medicine, 2005. 352(10): p. 
1011-1023. 
6. Fehr, T., et al., Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and 
anemia. Kidney international, 2004. 66(3): p. 1206-1211. 
7. Rambod, M., C.P. Kovesdy, and K. Kalantar-Zadeh, Combined high serum ferritin and low iron saturation in 
hemodialysis patients: the role of inflammation. Clinical Journal of the American Society of Nephrology, 2008. 
3(6): p. 1691-1701. 
8. Aljama, P., et al., Serum ferritin concentration: A reliable guide to iron overload in uremic and hemodialyzed 
patients. Clinical nephrology, 1978. 10(3): p. 101-104. 
9. Barany, P., et al., Serum ferritin and tissue iron in anemic dialysis patients. Mineral and electrolyte metabolism, 
1996. 23(3-6): p. 273-276. 
10. Blumberg, A.B., H.R.M. Marti, and C.G. Graber, Serum ferritin and bone marrow iron in patients undergoing 
continuous ambulatory peritoneal dialysis. JAMA, 1983. 250(24): p. 3317-3319. 
11. Mirahmadi, K.S., et al., Serum ferritin level: determinant of iron requirement in hemodialysis patients. Jama, 
1977. 238(7): p. 601-603. 
12. Silverberg, D., et al., The effect of iv iron alone or in combination with low-dose erythropoietin in the rapid 
correction of anemia of chronic renal failure in the predialysis period. Clinical nephrology, 2001. 55(3): p. 212-219. 
 Percentage of hematocrit measurements>30% 
Safety outcomes: 
 
 The incidence of Hb levels above 13 g/dL, 
 Proportion of patients with an increase in Hb concentration of > 
1.0 g/dL for 4 consecutive weeks, 
 Incidence rate of adverse events 


 
 
9 
 
13. Fishbane, S., G.L. Frei, and J. Maesaka, Reduction in recombinant human erythropoietin doses by the use of 
chronic intravenous iron supplementation. American Journal of Kidney Diseases, 1995. 26(1): p. 41-46. 
14. Sunder-Plassmann, G. and W. Hörl, Importance of iron supply for erythropoietin therapy. Nephrology Dialysis 
Transplantation, 1995. 10(11): p. 2070-2076. 
15. Macdougall, I.C., et al., A randomized controlled study of iron supplementation in patients treated with 
erythropoietin. Kidney international, 1996. 50(5): p. 1694-1699. 
16. Chang, C., C. Chang, and S. Chiang, Reduction in erythropoietin doses by the use of chronic intravenous iron 
supplementation in iron-replete hemodialysis patients. Clinical nephrology, 2002. 57(2): p. 136-141. 
17. DeVita, M., et al., Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin 
requirement in hemodialysis patients. Clinical nephrology, 2003. 60(5): p. 335-340. 
18. Navarro, J.F., et al., Effectiveness of intravenous administration of Fe-gluconate-Na complex to maintain 
adequate body iron stores in hemodialysis patients. American journal of nephrology, 1996. 16(4): p. 268-272. 
19. Tessitore, N., et al., The role of iron status markers in predicting response to intravenous iron in haemodialysis 
patients on maintenance erythropoietin. Nephrology Dialysis Transplantation, 2001. 16(7): p. 1416-1423. 
20. Rozen-Zvi, B., et al., Intravenous versus oral iron supplementation for the treatment of anemia in CKD: 
systematic review and meta-analysis. American Journal of Kidney Diseases, 2008. 52(5): p. 897-906. 
21. Allegra, V., G. Mengozzi, and A. Vasile, Iron deficiency in maintenance hemodialysis patients: assessment of 
diagnosis criteria and of three different iron treatments. Nephron, 1991. 57(2): p. 175-182. 
22. Palmer, S.C., et al., Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. 
Annals of internal medicine, 2010. 153(1): p. 23-33. 
23. Pfeffer, M.A., et al., A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. New England 
Journal of Medicine, 2009. 361(21): p. 2019-2032. 
24. Parfrey, P.S. and T. Wish, Quality of life in CKD patients treated with erythropoiesis-stimulating agents. 
American Journal of Kidney Diseases, 2010. 55(3): p. 423-425. 
25. Gandra, S.R., et al., Impact of erythropoiesis-stimulating agents on energy and physical function in nondialysis 
CKD patients with anemia: a systematic review. American Journal of Kidney Diseases, 2010. 55(3): p. 519-534. 
26. Johansen, K.L., et al., Systematic review and meta-analysis of exercise tolerance and physical functioning in 
dialysis patients treated with erythropoiesis-stimulating agents. American Journal of Kidney Diseases, 2010. 55(3): 
p. 535-548. 
27. Solomon, S.D., et al., Erythropoietic response and outcomes in kidney disease and type 2 diabetes. New England 
Journal of Medicine, 2010. 363(12): p. 1146-1155. 
28. АНЕМІЇ, К., KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney international, 
2012. 2: p. 279. 


 
 
10 
 
Participants timeline 
 
Study Period 
 
Screening/ 
Intervention 
Allocation 
Post Allocation 
Close- 
out 
Time point 
Visit0 
Visit 1 
Visit 2 
Visit3 
Visit4 
Visit5 
Visit6 
Visit7 
Visit8-1 
Visit8-2 
Visit9 
Day 
-28 to 0 
1 
14 
± 2 
28 
± 2 
42 
± 2 
56 
± 2 
84 
± 2 
140 
± 2 
156 
± 2 
168 
± 2 
182 
± 2 
Week 
-4 - 0 
0 
2 
4 
6 
8 
12 
20 
22 
24 
26 
Screening 
× 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
× 
 
 
 
 
 
 
 
 
 
 
Allocation 
× 
 
 
 
 
 
 
 
 
 
 
Clinical 
evaluation. 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Concomitant 
medication 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Intervention 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
Adverse Event 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Drug 
accountability 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 

SAP_001.pdf: 
Statistical Analysis Plan                                                                                                                           Page 1 of 7 
 
        
 
 
CinnaGen CO. 
 
Confidential and Proprietary 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
A Phase III, randomized, two armed, multicenter, parallel, double blind (patient and assessor 
blinded), active controlled non inferiority clinical trial to determine the non-inferior therapeutic 
efficacy and safety between CinnaPoietin® (Beta erythropoietin) and Eprex® (epoetin alpha) on 
treatment of anemia in ESRD hemodialysis patients. 
 
 
 
 
Date: 19 April 2017 
NCT number: NCT03408639 
 
 
 
 
 
 
 
 


Statistical Analysis Plan                                                                                                                           Page 2 of 7 
 
        
 
 
CinnaGen CO. 
 
Confidential and Proprietary 
 
 
 
1. 
Section 1: Administrative information .................................................................................................... 3 
1.1. 
Title and Trial registration ............................................................................................................... 3 
1.1.1. 
Descriptive title that matches the protocol, with ‘Statistical analysis plan’ either as a fore 
runner or sub title, and trial acronym ..................................................................................................... 3 
1.1.2. 
Trial registration number ......................................................................................................... 3 
1.2. 
Objectives (Description of specific objectives or hypotheses) ........................................................ 3 
2. 
Section 2: Trial Methods ........................................................................................................................... 3 
2.1. 
Trial design – description of trial design (Brief description of trial design including type of 
trial, allocation ratio and brief description of interventions) .................................................................... 3 
2.2. 
Randomization (Randomization details) ......................................................................................... 4 
2.3. 
Sample size (Full details of the sample size calculation or alternatively reference to sample size 
calculation in protocol (instead of replication in SAP) .............................................................................. 4 
3. 
Section 3: Statistical Principles ................................................................................................................ 4 
3.1. 
Confidence intervals and p-values (Level of statistical significance) ............................................ 4 
3.2. Analysis populations (Definition of Analysis populations e.g. intention-to-treat (ITT), per-
protocol, complete case, safety.) ................................................................................................................... 4 
3.3. 
Baseline patient characteristics ........................................................................................................ 4 
3.3.1. 
List of baseline characteristics to be summarized .................................................................. 4 
3.3.2. 
Details of how baseline characteristics will be descriptively summarized............................ 5 
4. 
Section 4: Analysis ..................................................................................................................................... 5 
4.1. 
Outcome definitions ........................................................................................................................... 5 
4.1.1. 
Specification of outcomes and timings ..................................................................................... 5 
4.2. 
Analysis methods ............................................................................................................................... 6 
4.2.1. 
What analysis method will be used, and how the treatment effects will be presented ........ 6 
4.2.2. 
List and describe each primary and secondary outcome including details of: methods 
used for assumptions to be checked for statistical methods .................................................................. 6 
4.3. 
Statistical Software (Details of statistical packages to be used to carry out analyses) ................ 7 
 
 
 
 
 


Statistical Analysis Plan                                                                                                                           Page 3 of 7 
 
        
 
 
CinnaGen CO. 
 
Confidential and Proprietary 
 
 
1. 
Section 1: Administrative information 
1.1. 
Title and Trial registration  
1.1.1. Descriptive title that matches the protocol, with ‘Statistical analysis plan’ either as a fore 
runner or sub title, and trial acronym 
Statistical analysis plan for the Phase III, randomized, two armed, multicenter, parallel, double blind (patient 
and assessor blinded), active controlled non inferiority clinical trial to determine the non-inferior therapeutic 
efficacy and safety between CinnaPoietin® (Beta erythropoietin) and Eprex® (epoetin alpha) on treatment of 
anemia in ESRD hemodialysis patients. 
1.1.2. Trial registration number  
IRCT201601156135N6 
1.2. 
Objectives (Description of specific objectives or hypotheses) 
Assessment of non-inferiority effect of CinnaPoietin® (Beta erythropoietin) compared with Eprex® (epoetin 
alpha) in correction of hemoglobin levels of anemic ESRD hemodialysis patients. 
Primary objective(s): 
Determination of non-inferior efficacy of Beta erythropoietin (CinnaPoietin®) compared with Eprex® (epoetin 
alpha) in correction of hemoglobin levels of anemic patients with chronic kidney disease (CKD) under 
hemodialysis 
Secondary objective(s): 
The secondary outcomes of interest include assessment of efficacy, safety and immunogenicity of Beta 
erythropoietin (CinnaPoietin®). 
2. 
Section 2: Trial Methods 
2.1. 
Trial design – description of trial design (Brief description of trial design including type 
of trial, allocation ratio and brief description of interventions) 
The study is designed as phase III, randomized, two armed, multicenter, parallel, double blind (patient and 
assessor blinded), active controlled non inferiority clinical trial with primary outcome of hemoglobin level 
change in anemic patients with CKD under hemodialysis. 


Statistical Analysis Plan                                                                                                                           Page 4 of 7 
 
        
 
 
CinnaGen CO. 
 
Confidential and Proprietary 
2.2. 
Randomization (Randomization details) 
Cluster Randomization Method will be used to randomize patients in the study. After randomization procedure, 
a code will be allocated to each patients that will be used as patients’ identifier throughout the study. 
2.3. 
Sample size (Full details of the sample size calculation or alternatively reference to sample 
size calculation in protocol (instead of replication in SAP)   
156 patients will be equally (1:1) divided into intervention arms (78 in each considering drop out) for achieving 
80% power in order to determine non-inferiority using a one-sided, independent sample t-test. The margin of 
non-inferiority is -1.The true difference between the means is assumed to be -0.5. The significance level (alpha) 
of the test is 0.05. The data are drawn from populations with standard deviations of 1.2 and 1.2.  
3. 
Section 3: Statistical Principles  
3.1. 
Confidence intervals and p-values (Level of statistical significance) 
The primary endpoints will be performed using a one-sided test with 5% significance level. All other applicable 
statistical tests will be 2-sided and will be performed using a 5% significance level. 
3.2. 
Analysis populations (Definition of Analysis populations e.g. intention-to-treat (ITT), per-
protocol, complete case, safety.) 
The primary analysis population for efficacy analyses will be the Per-Protocol (PP) population as defined below. 
The secondary variables will be analyzed using the ITT population. All safety analysis will be based on the 
safety population.  
1- 
Per-protocol population. All patients who were randomized treated with study medication and did not 
have a major protocol deviation (to be defined before the unblinding of the database).  
2- 
Modified intention-to-treat population. All patients who were randomized and received at least one dose 
of study medication. Patients will be analyzed according to the treatment to which they were randomized.  
3- 
Safety population. All patients who were randomized and received at least one dose of study medication. 
Patients will be analyzed according to the treatment which they received. 
3.3. 
Baseline patient characteristics 
3.3.1. List of baseline characteristics to be summarized 
Patients will be described with respect to age, gender, weight, height, BMI, history of high blood pressure, and 
history of diabetes type 1 & 2 at baseline separately for the two randomized groups. In fact, descriptive statistics 
will be presented to assess the distribution of the baseline variables across treatment groups. 


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3.3.2. Details of how baseline characteristics will be descriptively summarized 
Categorical data will be summarized by numbers and percentages. Continuous data will be summarized by 
mean, SD. 
4. 
Section 4: Analysis 
4.1. 
Outcome definitions 
4.1.1. Specification of outcomes and timings 
Primary outcomes: 
The primary efficacy endpoints will be analyzed using per-protocol (PP) analysis.  
The mean Hb change level during the last four weeks of treatment is considered as the primary endpoint of the 
study.  
The mean weekly epoetin dosage per kg body weight during the last four weeks of treatment necessary to 
maintain the Hb level within 10-12 g/dl during the last four weeks of treatment is considered as the second 
primary endpoint. 
Secondary outcomes: 
 
The secondary variables will be analyzed using the ITT population. 
 
The proportion of patients with any permanent or transient dose change during main study phase is 
considered as the first secondary endpoint.  
 
The proportion of patients with any Hb measurement outside the target range is considered as the second 
secondary endpoint.  
 
The incidence of blood transfusions is considered as the third secondary endpoint.  
 
The proportion of patients with treatment success (Hb concentration≥11.0 g/dl and two consecutive 
weeks without any blood transfusion within the preceding three months) is considered as the fourth 
secondary endpoint.  
 
The proportion of patients with maintenance success (maintenance of mean Hb concentration of 11.0 ± 
1.0 g/dl for at least four consecutive weeks) is considered as the fifth secondary endpoint.  
 
Percentage of Hb measurements>10.0 g/dl is considered as the sixth secondary endpoint.  
 
Percentage of hematocrit measurements>30% is considered as the seventh secondary endpoint.  
Safety outcomes: 
The incidence of Hb levels above 13 g/dl is considered as the first safety endpoint. Patients with at least one Hb 
measurement above 13 g/dL from week 2nd to week 26th will be taken into account to calculate this proportion.  


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The proportion of patients with an increase in Hb concentration of > 1.0 g/dl for four weeks is considered as the 
second safety endpoint.  
Adverse events will be reported as incidence rate. 
4.2. 
Analysis methods  
4.2.1. What analysis method will be used, and how the treatment effects will be presented 
For the primary efficacy variable, the following null hypothesis will be tested:  
H0: CinnaPoietin® is not non-inferior to Eprex®    
Versus  
H1: CinnaPoietin® is non-inferior to Eprex®   
CinnaPoietin® (produced by CinnaGen Company) efficacy will be judged non-inferior to Eprex® (the reference 
drug, produced by Janssen-Cilag) if the lower limit (UL) of the one-sided 95% confidence interval (95% CI) of 
the mean Hb change, calculated by Two Sample T-test, was more than accepted non inferiority margin.  
Chi-Square test or Fisher exact test (if the expected frequencies are less than 5) will be performed for analyzing 
the secondary and safety outcomes. 
All safety data will be analyzed descriptively by treatment group. 
4.2.2. List and describe each primary and secondary outcome including details of: methods 
used for assumptions to be checked for statistical methods  
For analyzing the primary efficacy outcomes using independent t-tests, following assumptions should be 
considered:  
- 
The dependent variable should be measured on a continuous scale 
- 
The independent variable should consist of two categorical, independent groups. 
- 
Observations should be independent, which means that there is no relationship between the observations 
in each group or between the groups themselves. 
- 
There should be no significant outliers. 
- 
The dependent variable should be approximately normally distributed for each group of the independent 
variable. 
- 
There needs to be homogeneity of variances. 


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For analyzing the secondary efficacy and safety outcomes using Chi-square tests, following assumptions should 
be considered:  
- 
The data in the cells should be frequencies, or counts of cases rather than percentages or some other 
transformation of the data. 
- 
The levels (or categories) of the variables are mutually exclusive. That is, a particular subject fits into 
one and only one level of each of the variables. 
- 
Each subject may contribute data to one and only one cell in the χ2. 
- 
The study groups must be independent. 
- 
There are 2 variables, and both are measured as categories, usually at the nominal level.  
- 
The value of the cell expected should be 5 or more in at least 80% of the cells, and no cell should have 
an expected of less than one. 
4.3. 
Statistical Software (Details of statistical packages to be used to carry out analyses) 
The analysis will be carried out using Stata version 14. Some graph will be plotted by R statistical software.