Clinical Trials Register

Summary
EudraCT Number:	2011-005058-70
Sponsor's Protocol Code Number:	APO-EPO-03
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-03-04
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2011-005058-70

A.3

Full title of the trial

A phase III, randomized, open-label, active-controlled, multicenter, correction phase study of the efficacy, safety, pharmacokinetics, and pharmacodynamics of APO-EPO (epoetin alfa) as compared to Epogen®/Procrit® when given subcutaneously to patients with anemia and chronic kidney disease not yet on hemodialysis

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study of safety, efficacy, pharmacokinetics and pharmacodynamics of APO-EPO versus Epogen®/Procrit® in patients with anemia and chronic kidney disease not yet on hemodialysis

A.4.1

Sponsor's protocol code number

APO-EPO-03

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	APOTEX Inc.
B.1.3.4	Country	Canada
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	APOTEX Inc.
B.4.2	Country	Canada
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Accelsiors CRO and Consultancy Services
B.5.2	Functional name of contact point	Clinical Trials Info
B.5.3	Address:
B.5.3.1	Street Address	50 Miskolci Ut
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1147
B.5.3.4	Country	Hungary
B.5.4	Telephone number	+3612990091
B.5.5	Fax number	+3612990096
B.5.6	E-mail	clinicaltrials@accelsiors.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	APO-EPO
D.3.2	Product code	n/a
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EPOETIN ALFA
D.3.9.1	CAS number	113427-24-0
D.3.9.2	Current sponsor code	n/a
D.3.9.3	Other descriptive name	Erythropoietin alfa
D.3.9.4	EV Substance Code	SUB06575MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Procrit®
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	n/a
D.3.2	Product code	n/a
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EPOETIN ALFA
D.3.9.1	CAS number	113427-24-0
D.3.9.2	Current sponsor code	n/a
D.3.9.3	Other descriptive name	Erythropoietin alfa
D.3.9.4	EV Substance Code	SUB06575MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of anemia due to chronic kidney disease in patients not yet on hemodialysis

E.1.1.1

Medical condition in easily understood language

treatment of low hemoglobin levels in patients with chronic kidney failure not yet on dialysis

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.1
E.1.2	Level	LLT
E.1.2	Classification code	10064848
E.1.2	Term	Chronic kidney disease
E.1.2	System Organ Class	100000004857

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety and efficacy of APO-EPO as compared to the reference product, Epogen®/Procrit® for correction of hemoglobin (Hb) concentrations in patients with anemia and chronic kidney disease (CKD) not yet on dialysis.

E.2.2

Secondary objectives of the trial

 To assess the long-term safety and efficacy of APO-EPO in the 6-month safety extension period (maintenance phase) of the study.
 To evaluate the bioequivalence of APO-EPO and Epogen®/Procrit® in a pharmacokinetic (PK)/pharmacodynamic (PD) substudy.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

pharmacokinetic (PK) /pharmacodynamic (PD) substudy
Objective: To test the bioequivalence of APO-EPO and Epogen®/Procrit®

E.3

Principal inclusion criteria

1. Written informed consent of the patient;
2. Hb level <10 g/dl;
3. Age: ≥ 18 years, male or female patients;
4. Patients suffering from chronic renal failure (CRF) not yet undergoing dialysis, with glomerular filtration rate (GFR) below 30 ml/min calculated from the plasma creatinine using the Cockroft-Gault formula;
5. Epoetin-naïve patients;
6. CRF patients with estimated time to progression to ESRF (end stage renal failure) of 8-12 months as estimated by the “Reciprocal creatinine vs time plot” method;
7. Serum ferritin level ≥ 100 ng/ml and transferrin saturation ≥ 20% prior to entry into the correction phase of the study;
8. Ability to comply with study medication use, study visits, and study procedures as judged by the investigator;
9. Females of childbearing potential agree to practice an acceptable method of birth control (e.g. abstinence, hormonal or barrier methods, partner sterilization, or IUD) for the duration of the study.

E.4

Principal exclusion criteria

1. Patients on regular hemodialysis or peritoneal dialysis;
2. C-Reactive protein (CRP) > 10 mg/l, as measured with a standard method;
3. Uncontrolled hypertension (defined as diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥ 180 mmHg);
4. Primary hematological disorder (e.g. myelodysplastic syndrome, multiple myeloma, sickle cell anemia, hematological malignancy, hemolytic anemia);
5. Decompensated liver failure;
6. Clinical evidence of concurrent uncontrolled hyperparathyroidism defined as serum parathyroid hormone (PTH) > 1000 pg/ml;
7. Previous stroke or evident disturbances of brain blood flow, e.g. transient ischemic attack (TIA);
8. Hypothyroidism without adequate replacement therapy (adequate defined as stable dose with stable thyroid hormone levels for at least 3 months prior to Screening);
9. Any red blood cell transfusion during the last 3 months (measured at the time of eligibility verification);
10. Heart failure [New York Heart Association (NYHA) class III and IV]
11. Unstable angina pectoris, active cardiac disease, stroke and/or myocardial infarction within the last six months prior to screening;
12. History of or active blood coagulation disease;
13. Thrombocytosis (platelet count > 500,000/μl);
14. Thrombocytopenia (platelet count < 100,000/μl);
15. Leukopenia (white blood cell count < 2,000/μl);
16. History of phenylketonuria;
17. Deficiency in vitamin B12 (if not corrected during the 6-week-anemia-work-up period);
18. Deficiency in folic acid (if not corrected during the 6-week-anemia- work-up period);
19. Overt bleeding (acute or chronic bleeding within the last two months prior to screening);
20. Suspicion of or confirmed occult bleeding (increased reticulocyte count);
21. Clinical evidence of concurrent systemic infection or inflammatory disease;
22. Presence of neutralizing antibodies or suspicion of or known pure red cell aplasia (PRCA);
23. Currently receiving treatment for epilepsy;
24. Major surgery within the last six months prior to Screening and during the conduct of the trial;
25. Proven HIV, HBV or HCV infection (to be tested if no test was performed within four weeks prior to the screening);
26. Any androgen therapy within the last two months prior to screening and during the study;
27. Concomitant immunosuppressive therapy; patients on a short course of steroids (e.g. treatment of a gout attack), topical or intranasal steroids are allowed in the study;
28. History of malignant disease within the last 5 years prior to Screening;
29. Pregnant or breastfeeding women;
30. Known history of severe drug-related allergies;
31. Known allergy to one of the ingredients of the test or reference product (including the preservative used for the multi-dose IP) or Venofer or hypersensitivity to mammalian-derived products;
32. Transplant received within 48 weeks prior to study entry;
33. Simultaneous participation in another clinical study or participation in a study within 3 months before randomization;
34. Psychiatric, addictive (drugs or alcohol), or any other disorder that compromises the ability to give an informed consent;
35. Any other condition which at the investigator’s opinion may put the patient at risk or may confound the study results.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable will be the proportion of patients achieving a hemoglobin response during the 24-week correction phase, defined as an increase in hemoglobin of ≥1.0 g/dl from baseline and a hemoglobin concentration 10-11 g/dl.
The co-primary, pharmacodynamic endpoint for bioequivalence evaulation will be the area under the effect curve (AUEC) of Hb, at four weeks of treatment (multiple dose administration) in the correction phase.
The co-primary, pharmacokinetic endpoints for bioequivalence evaluation will be the area under the curve (AUC48, md) and the maximum concentration (Cmax) of epoetin at four weeks of treatment (multiple dose administration) in the correction phase and pharmacokinetic parameters after single dose administration on Day 1 of the correction phase: Cmax,sd and AUC of epoetin (AUC0–48, sd).

E.5.1.1

Timepoint(s) of evaluation of this end point

Every second week of the correction phase

E.5.2

Secondary end point(s)

Clinical endpoints:
 Proportion of patients with treatment success, i.e. Hb concentration 10-11 g/dl for 2 consecutive weeks without any blood transfusion within the preceding 3 months (correction phase)
- Number of transfusions and proportion of patients needing blood transfusions during the treatment period (correction and maintenance phase);
- Increase in Hb concentration during the treatment period (correction and maintenance phase);
- Change in Hb concentration after the initial 4 weeks of treatment;
- Proportion of patients with maintenance success (maintenance of mean Hb concentration of 10-11 g/dl for at least 4 consecutive weeks in the maintenance phase);
- Percentage of Hb values outside the target range (>11 g/dl) (correction and maintenance phase);
- Mean weekly dose of epoetin per kilogram of body weight;
- Mean Hb concentration during each 4-week interval;
- Percentage of hematocrit measurements > 30% (correction and maintenance phase).
PK/PD endpoints:
 Pharmacokinetic parameters after single dose administration on Day 1 of the correction phase: baseline corrected AUC0–48, sd; baseline corrected Cmax, sd; tmax, sd; t½, sd; PTF; and Cmin;
 Pharmacokinetic parameters at four weeks of treatment (multiple dose administration) in the correction phase: baseline corrected AUC0–48, md; baseline corrected Cmax, md; tmax, md; t½ md; PTF; and Cmin;
 Pharmacodynamic parameters at four weeks of treatment (multiple dose administration) in the correction phase: AUEC of Hb after single dose administration; Cmax of RBC; Cmax of Hb; HCT; and Ret%.
Safety endpoints:
 Occurrence of anti-erythropoietin antibodies;
 Proportion of patients with an increase in Hb concentration of > 1.0 g/dl for 4 weeks;
 Number of Hb increases ≥2 g/dl within any 4-week period - both the number of study subjects and the number of episodes of such an increase;
 Maximum Hb increase within any 4-week period;
 Ratings of tolerability and evaluation of AEs;
 Results of the physical examination;
 Vital signs;
 ECG;
 Safety laboratory blood parameters;
 Coagulation parameters.

E.5.2.1

Timepoint(s) of evaluation of this end point

Clinical endpoints: correction and maintenance phase
PK/PD endpoints: first four weeks of correction phase (W1-4)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Bosnia and Herzegovina

Bulgaria

Czech Republic

Poland

Romania

Russian Federation

Serbia

Slovakia

Ukraine

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

180

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

196

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After participation in the trial, subject will continue with their standard treatment.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-01-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-28

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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