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Statistical Analysis Plan

Protocol Number: BCD-066-2

CONFIDENTIAL Version 1.0 dated 10-Oct-2016 of 24

STATISTICAL ANALYSIS PLAN

Protocol Title: A Multicenter, Double-Blind, Randomized,

Comparative, Parallel-Group Clinical Study of the

Efficacy and Safety of BCD-066 (JSC BIOCAD, Russia)

and Aranesp® (Amgen Europe B. V., the Netherlands)

in the Treatment of Anemia in Hemodialysis Patients

with Impaired Kidney Function

Protocol Number:: BCD-066-2

Protocol version 2.2

Version Date: October 10, 2016

SAP version 1.0

SAP version date October 10, 2016

Name and address of the

clinical study sponsor

JSC BIOCAD, Russia

Legal address: 34 A, Ulitsa Svyazi, Strelna,

Petrodvortsoviy District, Saint Petersburg, Russian

Federation, 198515

Postal Address: Petrovo Dalneye, Krasnogorskiy District,

Moscow Region, Russian Federation, 143422.

Tel.: +7 (495) 992-66-28 Fax: +7 (495) 992-82-98

Name and function of

person(s), authorized to sign

the protocol and its

amendments for the sponsor:

Roman Alexeevich Ivanov, Vice President, Research &

Development

Address: Petrovo Dalneye, Krasnogorskiy District,

Moscow Region,

Russian Federation, 143422

Email: [email protected]

Tel.: + 7 (495) 992-66-28 (ext. 154)

Name, position, address and

telephone number of the

Medical Expert assigned by

the Sponsor for this Study

Aleksandr Andreevich Isaev, Medical Advisor, Category II

JSC BIOCAD, 34 A, Ulitsa Svyazi, Strelna,

Petrodvortsoviy District, Saint Petersburg, Russian

Federation, 198515

Email: [email protected]

Tel.: +7 (812) 380 49 33 (ext. 946); +7 (981) 788-04-11

All information contained in this document is strictly confidential and intended for use by investigators, members of Ethics

Committees and Health Authority personnel. This information cannot be disclosed to any other persons or entity, submitted

for publication or used for any purpose other than contemplated herein without the Sponsor`s prior written authorization,

unless it is necessary to get patient's consent for the participation in the study.

The above requirements are effective upon the signing of this protocol.




TABLE OF CONTENTS

1. INTRODUCTION ................................................................................................................................................... 3

2. GOALS AND OBJECTIVES ................................................................................................................................. 3

2.1. PURPOSE ......................................................................................................................................................... 3

2.2. OBJECTIVES .................................................................................................................................................. 3

3. STUDY DESIGN ..................................................................................................................................................... 4

3.1. DESIGN ............................................................................................................................................................ 4

3.2. STUDY FLOW CHART/TIME AND EVENTS SCHEDULE ..................................................................... 4

3.3. SELECTION OF STUDY POPULATION .................................................................................................. 11

3.3.1. INCLUSION CRITERIA ........................................................................................................ 11

3.3.2. EXCLUSION CRITERIA ....................................................................................................... 11

4. EFFICACY ASSESSMENT ................................................................................................................................. 13

4.1 PRIMARY ENDPOINT ......................................................................................................................................... 13

5. THE PLANNED ANALYSIS ............................................................................................................................... 14

6. SAMPLE SIZE CALCULATION ....................................................................................................................... 15

7. STATISTICAL ANALYSIS OF POPULATION ............................................................................................... 20

8. ANALYSIS PLAN AND STATISTICAL METHODS ...................................................................................... 21

8.1. THE SOFTWARE ............................................................................................................................................... 21

8.2. DESCRIPTION OF THE STATISTICAL METHODS TO BE EMPLOYED................................................................ 21

8.3. ACCOUNTING FOR MISSING, UNAVAILABLE OR DOUBTFUL DATA, OUTLIERS ............................................... 23

8.6. MULTIVARIATE COMPARISON AND MULTIPLICITY ...................................................................................... 24

8.7. SUBGROUP ANALYSIS, INTERACTION AND RELATED VARIABLES ................................................................... 24

9. OTHER PLANNED ANALYSES ........................................................................................................................ 24

10. DEVIATIONS FROM ANALYSIS METHODS DESCRIBED IN STUDY PROTOCOL ........................... 24




1. INTRODUCTION

The Statistical Analysis Plan (SAP) provides a detailed analysis plan and steps of study

report preparation for the clinical trial BCD-066-2.

2. GOALS AND OBJECTIVES

2.1. Purpose

To demonstrate the equivalent efficacy and safety of BCD-066 and Aranesp® in hemodialysis

patients with renal anemia.

2.2. Objectives

Purpose:

To demonstrate the equivalent efficacy and safety of BCD-066 and Aranesp® in hemodialysis

patients with renal anemia.

Study objectives:

1. To evaluate and compare the change in hemoglobin concentration (g/L) from baseline to

the evaluation period (weeks 21 to 24) in the treatment groups;

2. To evaluate and compare the proportion (%) of patients achieving the target hemoglobin

level (100–120 g/L) in the treatment groups at weeks 21 to 24;

3. To evaluate and compare the mean doses of the test drug and the reference drug (µg/kg)

at weeks 21 to 24;

4. To evaluate and compare the proportion of patients receiving blood transfusions

(weeks 1–24);

5. To evaluate and compare the mean hemoglobin levels in the treatment groups at

weeks 21 to 24;

6. To evaluate and compare the proportion (%) of patients in both treatment groups who

maintained hemoglobin at 90–100 g/L for at least the last four weeks of treatment

(weeks 21 to 24);

7. To evaluate and compare the mean hemoglobin levels in the treatment groups during the

main study period (weeks 1 to 24);

8. To evaluate and compare the mean doses of the test drug and the reference drug (µg/kg)

during the main study period (weeks 1 to 24);

9. To evaluate and compare the mean hematocrit levels in the treatment groups during the

main study period (weeks 1 to 24);

10. To evaluate and compare the proportion of patients who required dose titration at the

beginning of the study (weeks 1 to 20);

11. To evaluate and compare the AE/SAE rate and severity, the rate of discontinuation due to

an AE/SAE in both treatment groups at weeks 1 to 24 and 1 to 52;




12. To evaluate and compare the rate of arterial and venous thrombotic events (e.g., impaired

cerebral circulation, arteriovenous fistula thrombosis) in both treatment groups at

weeks 1 to 24 and 1 to 52;

13. To evaluate and compare the proportion (%) of patients who developed binding and

neutralizing antibodies to darbepoetin alfa (at weeks 1 to 24 and 1 to 52).

3. STUDY DESIGN

3.1. Design

This clinical study comparing the efficacy and safety of BCD-066 (JSC BIOCAD,

Russia) and Aranesp®

(Amgen Europe B.V., the Netherlands) in the treatment of anemia in

hemodialysis patients with impaired kidney function has been designed as a multicenter, double-

blind, parallel-group randomized study.

This study will include 196 adult patients with renal anemia due to late-stage CKD,

receiving hemodialysis (CKD 5D), and whose dialysis is effective. Eligible patients have

previously received ESA therapy and achieved target Hb levels. The study will not include

patients with non-renal anemia (e.g., anemia due to vitamin B12, folate, or iron deficiency). This

is a maintenance phase study. This means it will include patients previously treated with

erythropoietins. Eligible patients have received rHuEPO (epoetin alfa or epoetin beta

q1w/q2w/q3w, darbepoetin alfa q1w) for at least three months before randomization. During this

period, stable doses of rHuEPO have successfully maintained target Hb concentration (100–

120 g/L).

3.2. Study Flow Chart/Time and Events Schedule




Figure 1. Study flow chart

Screening

(28 days)

Test

Group

98 patients

Reference

Group

98 patients

Week

1 Week

1

Week

24

Week

24

B

C

D

0

6

6 s.c.

q1w

А

R

A

N

Е

S

P s.c.

q1w

Final efficacy evaluation, main safety and

immunogenicity assessment

Randomization

1:1

B

C

D

0

6

6 s.c. q1w

maintenance dose

А

R

A

N

Е

S

P

s.c. q1w

maintenance dose

Week

52

Additional safety and immunogenicity assessment

Week

25

Week

25

Week

52




Table 1. Schedule of Study Visits and Assessments

Study period Screening Main study period Additional study

period

Visit Screening 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Week 0 1 2 3 4 8 12 16 20 21 22 23 24 32 40 52

Day -28 – 0 1 8 15 22 29 57 85 11

3

14

1

148 155 16

2

169 225 281 365

Informed consent +

Medical history and

complaints

+

Concomitant therapy +1 + + + + + + + + + + + + + + + +

Blood pressure, heart rate,

and body temperature

+ + + + + + + + + + + + + + + + +

Physical examination,

body weight and height

+ + + + + + + + +

CBC (full panel) + + + + + + + +

CBC (“red blood”)2 + + + + + + + + +

Blood chemistry panel + + + + +

Iron metabolism + +

Intact PTH +

Coagulation tests +

Markers for HIV, HCV,

HBV, syphilis3

+ + +

Blood sampling for

BAB/NAB

+ + + + + + +

ECG + + + +

Chest X-ray +




Study period Screening Main study period Additional study

period

Visit Screening 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Week 0 1 2 3 4 8 12 16 20 21 22 23 24 32 40 52

Day -28 – 0 1 8 15 22 29 57 85 11

3

14

1

148 155 16

2

169 225 281 365

Echocardiography +

Pregnancy test

+

Eligibility +

Enrollment (randomization

and stratification)

+

IP injection (at the end of

the hemodialysis session)

+ + + + + + + + + + + + + + + +

AE/SAE Recording + + + + + + + + + + + + + + + + + 1 At the screening, the investigator also collects information about the concomitant medications that the subject received within 3 months prior to the enrollment.

2Hb, RBCs, reticulocytes, Hct.

3Syphilis tests will be performed only at screening.




Table 2. Clinical and Laboratory Tests Planned for the Study

Examination/

Test Control parameters Number

Physical

examination

Height

Body weight

Skin and mucous membranes

(visual examination)

Lymph nodes (visual

examination, palpation)

Ear/nose/throat, respiratory

organs (examination, lung

auscultation)

Cardiovascular system (heart

auscultation, visual

examination of the area of

major vessels)

GI tract (examination,

abdominal palpation)

Liver span (palpation,

percussion)

Spleen size (palpation,

percussion)

Urogenital system (kidney

punch, palpation of the kidney

and bladder area)

Nervous system (meningeal

signs, focal neurological signs)

Mental health (signs of a

depressive disorder, suicidal

ideation, an acute psychotic

disorder)

×9: at screening, on

days 1, 29, 85, 141,

169, 225, 281, 365

Vital signs BP

HR

body temperature

×17: at screening

and each visit

CBC

Hb

Hct

RBCs

reticulocytes

platelets

WBCs


days 8, 15, 22, 29,

85, 169, 365




Examination/


neutrophils

lymphocytes

monocytes

eosinophils

basophils

ESR

(blood volume: 3 mL)

CBC (“red

blood”)

Hb

Hct

RBCs

reticulocytes



days 1, 57, 113, 141,

148, 155, 162, 225,

281

Blood chemistry

panel

total protein

glucose

ALT

AST

ferritin

TSAT

C-reactive protein

potassium



days 29, 85, 169,

365

Iron metabolism ferritin

TSAT

× 2: on days 57 and

113

Blood

coagulation

INR

APTT

fibrinogen

×1: at screening

Blood for intact

PTH

Intact PTH (blood volume:

4 mL)

×1: at screening

Serological tests

for viral

infections1

anti-HIV

anti-HCV

HBsAg



day 169, day 365

Serological tests

for syphilis1

anticardiolipin antibody

test/RW

(blood volume: 10 mL; at the

×1: at screening




Examination/


screening, blood is sampled to

be tested for all infections)

Pregnancy test2 serum HCG (blood volume:

3 mL)

×1: at screening

Instrumental

examinations

12-lead ECG ×4: at screening, on

day 85, day 169,

day 365

Echocardiography ×1: at screening

Chest X-ray3 ×1: at screening

Immunogenicity

assessment

BABs and NABs in the serum


×7: at screening,

then once every 2

months until

day 281, and on

day 365




3.3. Selection of Study Population

3.3.1. Inclusion criteria

1. Signed Informed Consent Form.

2. Age: 18 to 75 years old (inclusive).

3. Late-stage renal failure.

4. Eligible patients have needed hemodialysis for at least three months before the

enrollment (randomization) in the study.

5. Eligible patients should require in-hospital hemodialysis for at least 12 hours per week.

6. Regular treatment with rHuEPO (epoetin alfa, epoetin beta, or darbepoetin alfa) within

at least three months before the enrollment (randomization) in the study. Epoetins have

been used at a stable dose with the same frequency (q1w/q2w/q3w).

7. Eligible patients have had a target Hb level of 100 to 120 g/L within three months

before the enrollment (randomization) in the study.

8. Effective hemodialysis: dialysis dose (Kt/V) ≥1.21.

9. TSAT ≥20%, ferritin >100 ng/mL.

10. Eligible patients with reproductive potential have agreed to practice acceptable

methods of birth control throughout the entire study period, starting from the screening

and up to four weeks after the last dose of the IP. This requirement does not apply to

patients after surgical sterilization. A combination of at least two birth control methods,

including one barrier contraceptive (e.g., spermicide plus condoms or oral

contraceptives plus condoms), is considered effective.

11. Patient’s ability (in the investigator’s opinion) to follow the protocol procedures.

3.3.2. Exclusion criteria

1 Kt/V = -Ln (R - 0.008 × t) + (4 - 3.5 × R) × UF/W

Where Ln is natural logarithm, R is a ratio between predialysis BUN and postdialysis BUN (or urea), t is dialysis

duration (hrs), UF is ultrafiltration volume (L), W is patient’s weight after dialysis.




1. Non-renal anemia: e.g., anemia due to vitamin B12 or folate deficiency, chronic blood

loss, aluminum poisoning, or a chronic disease (C-reactive protein >20 mg/L); sickle-cell

anemia; refractory anemia with excess blasts.

2. Lupus nephritis, CKD due to systemic vasculitis.

3. Platelets <100×109/L.

4. Hemoglobin <100 g/L and >120 g/L.

5. Scheduled kidney transplantation within the study period.

6. The presence of neutralizing/binding antibodies to erythropoietin/darbepoetin in the

blood.

7. History of severe hypersensitivity reactions (anaphylaxis or multiple drug allergy).

8. Vaccination within 8 weeks before randomization.

9. Cirrhosis of the liver with portal hypertension and/or splenomegaly and/or ascites.

10. HIV, active HBV or HCV infection2.

11. ALT, AST > 3×ULN.

12. Documented myelofibrosis.

13. Decompensated heart disease (NYHA Class IV CHF).

14. Resistant hypertension3.

15. Unstable angina.

16. Documented hemoglobinopathy, myelodysplastic syndrome, hematological malignancy.

17. Pure red cell aplasia.

18. Severe secondary hyperparathyroidism (intact PTH >9×ULN).

19. Gastrointestinal hemorrhage within less than three months before randomization.

20. A thrombotic event (e.g., myocardial infarction, a stroke, a transient ischemic attack,

deep vein thrombosis, or pulmonary embolism) within less than six months before

enrollment in the active phase of the study.

2 For eligible patients who tested positive for HBV/HCV markers at the screening, an infectious disease specialist should report the absence of active infection. To confirm the diagnosis of viral hepatitis, additional tests can be performed (e.g., serological examination or qualitative PCR test for viral DNA/RNA) [for details, please refer to section 4.7.4.4.].

3 Resistant hypertension includes all cases of hypertension that are not controlled by the combination of three anti-hypertensive drugs after the patient has achieved his/her dry weight.




21. History of acute hemolysis.

22. Seizures, including epilepsy.

23. Major surgery within one month before randomization.

24. Blood transfusion within three months before randomization.

25. An acute or active chronic infection/inflammation, for example, a septic lesion or aseptic

inflammation (hematomas, except for asymptomatic bruising around the venipuncture

site).

26. Any psychiatric disorder, including a history of major depression and/or suicidal

ideation/attempts that can, in the investigator’s opinion, put the patient at risk or affect

patient’s ability to follow the study protocol (including limited capacity).

27. Malignancy, except for cured basal-cell carcinoma and/or cervical carcinoma in situ.

28. Alcohol or drug abuse.

29. Documented hypersensitivity to darbepoetin alfa or any component of the investigational

products.

30. Documented hypersensitivity to iron(III)-hydroxide sucrose complex.

31. Simultaneous participation in another clinical study, previous participation in other

clinical studies within three months prior to the enrollment in this study.

32. Pregnancy and breastfeeding.

4. EFFICACY ASSESSMENT

4.1 Primary endpoint

Change in hemoglobin concentration from baseline (the mean Hb concentration for

screening and visit 1) to the evaluation period (the mean of at least two Hb measurements

between weeks 21 and 24). Change in hemoglobin concentration is calculate as difference

between evaluaton period level and baseline.

4.2. Secondary endpoints

Key secondary endpoints:




Proportion (%) of patients achieving the target hemoglobin level (100–120 g/L) at

weeks 21 to 24;

Mean dose of the investigational product (µg/kg) during the last four weeks of treatment

(weeks 21 to 24);

Proportion (%) of patients receiving blood transfusions during the entire treatment period

(weeks 1–24);

Proportion of patients who required dose titration at the beginning of the study (weeks 1

to 20).

Additional secondary endpoints:

Mean hemoglobin during the last four weeks of treatment (weeks 21 to 24);

Proportion (%) of patients who maintained hemoglobin at 90–100 g/L for at least the last

four weeks of treatment (weeks 21 to 24);

Hemoglobin concentration over time during the entire study period (weeks 1 to 24);

Mean dose of the investigational product (µg/kg) during every four weeks of treatment

(weeks 21 to 24);

Mean hemoglobin during every four weeks of treatment (weeks 21 to 24);

Mean hematocrit during every four weeks of treatment (weeks 1 to 24);

Safety assessment:

AE/SAE rate;

Rate of grade 3 to 4 AEs and SAEs;

Rate of study discontinuation due to an AE/SAE;

Rate of arterial and venous thrombotic events (e.g., impaired cerebral circulation,

arteriovenous fistula thrombosis).

Immunogenicity Endpoint

Proportion of BAB-/NAB-positive patients.

5. THE PLANNED ANALYSIS

The statistical analysis will be performed in one step, which will include the final analysis

for the primary endpoint.




Final Report

The Final Report will include the analysis of data obtained for both study groups after 24

weeks of blinded treatment with darbepoetin alfa (BCD-066 or Aranesp®) administered at a dose

adjusted with respect to the Hb level (weeks 1 to 24).

Supplementary Report

The Supplementary Report will include the analysis of data obtained for both study

groups after 52 weeks of blinded treatment with darbepoetin alfa (BCD-066 or Aranesp®

)

administered at a dose adjusted with respect to the Hb level (weeks 1 to 52).

6. SAMPLE SIZE CALCULATION

The study aims at demonstrating the equivalent efficacy of the BCD-066 and the

reference drug, Aranesp®

.

Unlike the equality hypothesis testing, testing for the equivalence allows a difference in

the efficacy variable (ε) between the test drug and the reference drugs. This difference should not

exceed a pre-specified equivalence margin (δ) for the test and reference drugs.

The mathematical statement for the null hypothesis (equivalence) is as follows:

𝐻0: |휀| ≥ 𝛿, (1)

which is equivalent to considering the following one-sided hypotheses:

𝐻01: 휀 ≥ 𝛿 and 𝐻02: 휀 ≤ (−𝛿) (2)

The mathematical statement for the alternative hypothesis is as follows:

𝐻1: |휀| < 𝛿, (3)

which is equivalent to considering the following one-sided hypotheses:

𝐻11: 휀 < 𝛿 and 𝐻12: 휀 > (−𝛿) (4)

The null hypothesis (1) is rejected with the significance level α if the following two

inequalities are true:

휀 − 𝛿

𝜎√1

𝑛𝑇+

1𝑛𝑅

< −𝑧𝛼 and 휀 + 𝛿

𝜎√1

𝑛𝑇+

1𝑛𝑅

> 𝑧𝛼,




where 𝑛𝑇 и 𝑛𝑅 is the sample size of the test/reference group, is standard deviation, α is type I

error, ε is the true difference between mean values of the efficacy variable in the groups, δ is the

equivalence margin between the test and reference drugs.

Change in hemoglobin concentration from baseline (the mean Hb concentration for

screening and visit 1) to the evaluation period (the mean of at least two Hb measurements

between weeks 21 and 24) has been chosen as the primary efficacy endpoint.

We analyzed published data on pivotal clinical trials with Aranesp®4

. In study

NESP980117, patients with anemia due to chronic renal failure were converted from rHuEPOs

with a short half-life to darbepoetin alfa therapy. The mean change in Hb levels calculated for

150 assessable patients, who had Hb measurements at baseline and during the evaluation period,

was -0.013±0.091 g/dL (mean±SE). In study NESP980200, conducted in the same patient

population, the mean change in Hb levels was 0.007±0.06 g/dL (mean±SE). It was calculated for

302 patients who had Hb measurements at baseline and during the evaluation period. Using these

data, pooled sample variance was calculated for the mean change in Hb levels in patients

receiving darbepoetin alfa and the difference in this efficacy variable between the two

randomized clinical trials. These clinical data were considered to establish what sample size

would be large enough for a reliable comparison of BCD-066 and Aranesp® in terms of the

primary efficacy endpoint.

Figure 2: Mean Change in Hemoglobin Levels in Study NESP980117

4 http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm086021.pdf




Figure 3: Mean Change in Hemoglobin Levels in Study NESP980117

A difference of ±0.5 g/dL in Hb level was considered a clinically insignificant difference

for the treatment response between the originator and the biosimilar darbepoetin alfa. The EMA

Guideline on non-clinical and clinical development of similar biological medicinal products

containing recombinant erythropoietins [EMEA/CHMP/BMWP/301636/2008, 18 March 2010]

recommends this equivalence margin (δ) for the chosen primary efficacy endpoint: “If change

from baseline in haemoglobin is used as the primary endpoint, an equivalence margin of

±0.5 g/dL is recommended”.

The sample size was calculated using the formula developed for parallel-group

equivalence studies with equal allocation (Chow S.C., 2008, p.91)5:

𝑛𝑇 =(1 +

1𝑘

) ∗ (𝑧𝛼 + 𝑧𝛽/2)2 ∗ 𝜎2

(𝛿 − |휀|)2=

2 ∗ 1.138506 ∗ (−1.64 − 1.28)2

0.52≈ 78 subjects/group

nC ≈ 78 subjects/group

nт = nc is the sample size of each of the active treatment groups,

zα, zβ/2 are quantiles of normal distribution N(0,1) (mean=0, SD=1). The following values are

used in these calculations: type I error α=0.05, study power should be at least 80%, i.e. type II

error β=0.2.

ε is the true difference in mean values of the efficacy variable (for the biosimilar, ε=0),

δ is the equivalence margin (δ=0.5),

5 Shein-Chung Chow et al. Sample Size in Clinical Research, p.91

Lehana Thabane Sample Size Determination in Clinical Trials, p.10




k is the ratio between sample sizes of the test and reference groups: 𝑘 =𝑛𝑇

𝑛𝐶= 1.

σ2 is pooled sample variance calculated as follows:

𝜎2 =𝑠𝑇

2 ∗ (𝑛𝑇 − 1) + 𝑠𝐶2 ∗ (𝑛𝐶 − 1)

𝑛𝑇 + 𝑛𝐶 − 2= 1.138506,

where sT is SD for the test drug calculated as follows:

SET =𝑠𝑇

√nT

, where the sample size 𝑛𝑇 = 150, standard error 𝑆𝐸𝑇 = 0.091

𝑠𝑇 = 𝑆𝐸𝑇 ∗ √𝑛𝑇 = 0.091 ∗ √150 = 1.114518

where sC is SD for the reference drug calculated as follows:

SEC =sC

√nC

, where the sample size 𝑛𝐶 = 302, standard error 𝑆𝐸𝐶 = 0.06

𝑠𝐶 = 𝑆𝐸𝐶 ∗ √𝑛𝐶 = 0.06 ∗ √302 = 1.042689

Figures 4 and 5 present results of sample size calculations in Statistica 10.




Figure 4: Sample Size Versus Type I Error Rate

0,00 0,05 0,10 0,15 0,20 0,25 0,30

Type I Error Rate (Alpha)

30

40

50

60

70

80

90

100

110

120

130

Required S

am

ple

Siz

e (

N)




Figure 5: Sample Size Versus Study Power

0,6 0,7 0,8 0,9 1,0

Power Goal

50

60

70

80

90

100

110

120

130

140

Re

qu

ire

d S

am

ple

Siz

e (

N)

A further adjustment was made to account for an estimated 25% rate of dropout, resulting

in total planned enrollment of 98 patients per group.

With two groups and a randomization ratio of 1:1, the study should involve 196 patients.

This sample size suffices to show statistically significant differences (or their absence).

7. STATISTICAL ANALYSIS OF POPULATION

Efficacy Analysis

The efficacy will be analyzed in the intent-to-treat (ITT) and per protocol (PP)

populations.

Modified Intent-to-Treat Population




The total efficacy population is defined as the ITT population and will include all

randomized patients who have received at least one dose of the test drug or the reference drug.

According to the ITT principle, the patients will be analyzed by treatment groups to which they

have been randomly allocated.

Per Protocol Population

The per protocol (PP) population will include those ITT patients who have completed the

study without major protocol deviations and are assessable for the efficacy at weeks 21 to 24 of

the main study period.

Subjects can be withdrawn from the PP population for the following reasons:

• The subject discontinued his/her participation in the study before day 169 visit;

• Study therapy differs from that assigned by randomization or there were

significant deviations in the treatment regimen (for example, the subject received the test drug

instead of the reference drug, or vice versa);

• There is evidence for subject non-compliance.

Safety Analysis

The safety assessment population will include all subjects who have received at least one

dose of the investigational product and who attended at least one safety assessment visit after the

baseline. The analysis will be performed according to the actually received treatment.

8. ANALYSIS PLAN AND STATISTICAL METHODS

8.1. The software

For statistical analysis and to construct the tables and diagrams would be used the

software STATISTICA 10 and statistical programming language R.

8.2. Description of the Statistical Methods to be Employed

Quantitative Data

The following quantitative data will be analyzed in the study:

Efficacy:

Hemoglobin concentration,




Dose of the investigational product,

Hematocrit level

Safety:

CBC results,

Blood chemistry results,

Vital signs

The statistical analysis will include two-tailed hypothesis testing; the chosen significance

level is 0.05.

Quantitative variables will be tested for normality using the Shapiro-Wilk test.

Normally distributed quantitative variables will be tested using the two-sample Student’s

t-test, Welch’s t-test, and ANOVA.

Non-normally distributed quantitative variables will be tested using the Mann-Whitney

U-test, the Wilcoxon test, the Kruskal-Wallis test, and the Friedman test.

Normally distributed quantitative data will be described using the following descriptive

statistics: mean, SD, CV, min, and max. Non-normally distributed quantitative data will be

described using the following descriptive statistics: median, quartiles, CV, min, and max.

Categorical Data

The following categorical data will be analyzed in the study:

Efficacy:

Proportion of patients maintaining the target hemoglobin level,

Proportion of patients receiving blood transfusion,

Proportion of patients who required dose titration at the beginning of the study

(weeks 1 to 20).

Safety:

ECG findings,

Rate and severity grades of AEs/SAEs,

Rate of Grade 3-4 AEs,

The frequency of early withdrawals due to AEs/SAEs,




Rate of arterial and venous thrombotic events (e.g., impaired cerebral circulation,

arteriovenous fistula thrombosis).

Immunogenicity:

The percentage of BAB- and NAB-positive patients.

Categorical data will be processed using frequency tables, contingency tables, the

Fisher’s exact test, the test of equal frequencies, Pearson’s 𝜒2 test, and the Cochran-Mantel-

Haenszel test. Percentages or proportions will be used to describe categorical data.

The equivalence hypothesis in terms of the primary endpoint (change in Hb

concentration) will be tested by comparing 95% CIs calculated for the arithmetic means of

changes in the Hb concentration in the study groups with the pre-specified equivalence margin.

The change in the Hb concentration will be calculated for each patient in both study groups. It is

defined as the difference between the mean Hb during the last four weeks of treatment and the

mean Hb at baseline. The former variable is calculated as the arithmetic mean of all Hb values

(at least two) measured between weeks 21 and 24 of the mean study period. The latter one is

calculated as the arithmetic mean of the Hb values measured at the screening and visit 1.

The null hypothesis (𝐻0: |휀| ≥ 𝛿, where δ is the equivalence margin) will be rejected and

the drugs will be considered equivalent if the boundaries of the 95% CI for the difference in

mean change in the Hb level fall within the equivalence margin (δ = 0.5 g/dL).

The Benjamini-Yekutieli correction for multiple testing will be used.

Statistical methods will be chosen according to the type of initial data and their

distribution. Appropriate statistical tests will be established after the data collection has been

completed because the type of data distribution, sample homogeneity, etc. are unknown before

the study start. For appropriate data processing, the list of statistical methods used may expand

during the analysis.

8.3. Accounting for missing, unavailable or doubtful data, outliers

All information specified in the e-CRFs should be supported by relevant data in source

documents.

After entering all data into the electronic database, a database specialist checks it for

inconsistencies, errors, and missing data points. The Clinical Study Database Manager or




Medical Expert of JSC BIOCAD generates queries to correct error data or to request missing

data; the queries are site-specific and subject-specific (i.e., individual queries are generated for

each subject). The Clinical Study Monitor will send queries to the study site by fax or email. The

queries should be resolved by the investigator within five business days from the date they have

been submitted to the study site. Copies of responses to queries must be kept at the study site;

original responses must be stored at JSC BIOCAD.

When responses to queries are received from investigators, the database specialist checks

it for inconsistencies, errors, and missing data points. When all data at all study sites have been

collected and entered, the database is closed. Afterwards, statistical processing can be started.

Missing, unused, and spurious data will not be substituted.

Spurious and unevaluable data are revealed during the outlier analysis by examination of

Mahalanobis or Cook distance, visual analysis of scatter plots and box plots.

All actions taken to handle missing, unevaluable, spurious data and outliers before/during

the statistical analysis will be described in the Clinical Study Report.

8.6. Multivariate Comparison and Multiplicity

Refer to Section 8.2.

8.7. Subgroup analysis, interaction and related variables

Not available.

9. OTHER PLANNED ANALYSES

No additional analyses are planned in this study.

10. DEVIATIONS FROM ANALYSIS METHODS DESCRIBED IN STUDY PROTOCOL

This Statistical Analysis Plan has no deviations from methods described in Study

Protocol.

statistical analysis plan - clinicaltrials.gov · 1 at the screening, the investigator also...

Documents