Clinical Trials Register

Summary
EudraCT Number:	2015-000266-64
Sponsor's Protocol Code Number:	PEGF/USV/P3/003
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-09-28
Trial results	View 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

Bulgarian Drug Agency

A.2

EudraCT number

2015-000266-64

A.3

Full title of the trial

A Randomised, Multi-Centre, Assessor-Blinded, Active-Controlled, Parallel Group, Equivalence Phase III Study Comparing the Safety and Efficacy of USV Pegfilgrastim and Neulasta® in Breast Cancer Patients Undergoing Myelosuppressive Chemotherapy

A.3.1

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

Study of safety and efficacy of USV Pegfilgrastim and Neulasta® licensed/authorized in EU in patients with breast cancer

A.4.1

Sponsor's protocol code number

PEGF/USV/P3/003

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	USV Private Limited
B.1.3.4	Country	India
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	USV Private Limited
B.4.2	Country	India
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 Ltd
B.5.2	Functional name of contact point	Clinical Trials Info
B.5.3	Address:
B.5.3.1	Street Address	50 Miskolci Str
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	+361299 00 91
B.5.5	Fax number	+361299 00 96
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	USV Pegfilgrastim
D.3.2	Product code	USV Pegfilgrastim
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
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	PEGFILGRASTIM
D.3.9.1	CAS number	208265-92-3
D.3.9.2	Current sponsor code	USV Pegfilgrastim
D.3.9.4	EV Substance Code	SUB16451MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	Neulasta
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe BV
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
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	PEGFILGRASTIM
D.3.9.1	CAS number	208265-92-3
D.3.9.4	EV Substance Code	SUB16451MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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

Duration of Sever Neutropenia and incidence of febrile neutropenia

E.1.1.1

Medical condition in easily understood language

Low white blood cell counts in breast cancer patients undergoing chemotherapy

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10029354
E.1.2	Term	Neutropenia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10016288
E.1.2	Term	Febrile neutropenia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

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 efficacy of USV Pegfilgrastim compared to Neulasta® with respect to the mean duration of severe neutropenia (DSN) defined as the mean number of days with Grade 4 neutropenia [absolute neutrophil count (ANC) less than 0.5 × 109/L], during Cycle 1 of the chemotherapy treatment.

E.2.2

Secondary objectives of the trial

To further compare USV Pegfilgrastim and Neulasta® with respect to the efficacy, safety, and immunogenicity of both products.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written and informed consent before any study procedure is started;
2. Women ≥ 18 years of age;
3. Body weight within 40 and 120 kg;
4. Chemotherapy-naïve subjects with histologically proven breast cancer (Stage IIA, IIB, or IIIA) eligible for six chemotherapy cycles with TAC regimen as an adjuvant treatment;
5. Subjects within 60 days of complete surgical resection of the primary breast tumour: either lumpectomy or mastectomy with sentinel lymph node biopsy or axillary dissection, with clear margins for both invasive and ductal carcinoma in situ (DCIS);
6. Baseline bilateral mammography or other scan to exclude cancer on the contralateral breast;
7. Estimated life expectancy of more than six months;
8. Eastern cooperative oncology group (ECOG) performance status ≤ 2;
9. Normal cardiac function evidenced by a left ventricle ejection fraction (LVEF) >=50% on echocardiogram performed within 60 days from surgery;
10. Adequate bone marrow function prior to chemotherapy administration as indicated by:
a. Leukocyte count < 50 × 109/L,
b. ANC ≥ 1.5 × 109/L,
c. Platelet count ≥ 100 × 109/L, and
d. Haemoglobin (Hb) ≥ 10 g/dL.
11. Appropriate liver and renal functions:
a. Serum bilirubin =< ULN, AST =< 1.5X ULN and, ALT =< 1.5 X ULN concomitant with alkaline phosphatase =< 2.5 X ULN
b. Serum creatinine =< 1.5 ULN
12. All women of childbearing potential, should have a negative serum pregnancy test within one week prior to randomisation and should be using or willing to use a highly effective method of birth control diaphragm, condom (by the partner), copper intrauterine device (or hormonal), sponge, or spermicide, and hormonal contraceptives. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, s.c., intrauterine, or intramuscular agents). Reliable contraception should be maintained from four weeks prior to first dose and throughout the whole study.
13. Willing and able to undergo procedures required by this protocol.

E.4

Principal exclusion criteria

1. Subjects with distant metastasis;
2. Subjects with severe chronic neutropenia (congenital, cyclic, or idiopathic);
3. History of chronic myeloid leukaemia or myelodysplastic syndrome;
4. History of sickle cell disease;
5. Subjects with active infections (including positive serology for human immunodeficiency virus [HIV] and active hepatitis B and C infection). Subjects with infections bacterial or fungal not controlled by antibiotic therapy; or history of uncontrolled seizures, or diabetes, or central nervous system disorders should be excluded as per the clinical judgement of the investigator precluding informed consent;
6. Previous or concurrent malignancy except non-invasive skin cancer (excluding melanoma), in situ carcinoma of the cervix, or other solid tumour treated with curative intent with no recurrence within two years prior to study entry;
7. Hormonal therapy (e.g. tamoxifen or aromatase inhibitors), immunotherapy and monoclonal antibodies or biological therapy concurrent or within 30 days of screening;
8. Significant neurologic or psychiatric disorders that would prohibit the understanding and giving of the informed consent;
9. Previous therapy with any recombinant human granulocyte colony stimulating factor (rhG-CSF) product, Lipegfilgrastim, or Pegfilgrastim preparation;
10. Concurrent radiotherapy;
11. Clinically significant cardiac dysfunction at the time of screening, history of myocardial infarction, heart failure, uncontrolled hypertension, severe valvular heart disease, unstable angina pectoris, pericardial disease, electrocardiographic evidence of acute ischemic changes or unstable arrhythmia within six months preceding the first treatment cycle;
12. History of pulmonary infiltrates or pneumonia within two years of study entry;
13. Known hypersensitivity to any of the chemotherapy drugs used in TAC regime or Escherichia coli (E. coli) proteins or any of the excipients used in the IMP;
14. Major organ allograft or condition requiring chronic immunosuppression (i.e. kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases). Subjects who received corneal transplants or cadaver skin or bone transplants are eligible;
15. Peripheral neuropathy >Grade 1;
16. Ongoing drug abuse and/or alcohol addiction and/or chronic alcoholism;
17. Participation in any other clinical study using an IMP within three months prior to the screening visit;
18. Pregnancy or breast feeding;
19. Any condition that by consideration of the investigators might affect the safety of the subject or interfere with the efficacy assessments of this study.

E.5 End points

E.5.1

Primary end point(s)

Mean duration of severe neutropenia (Grade 4), defined as the number of days in which the subject has an ANC < 0.5 × 109/L during Cycle 1 of chemotherapy.

E.5.1.1

Timepoint(s) of evaluation of this end point

Cycle 1

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
•Mean duration of severe neutropenia (DSN) during cycles 2 to 6;
•Depth of ANC nadir, defined as the subject’s lowest ANC in Cycles 1 to 6;
•The number and proportion of subjects with febrile neutropenia episodes defined as single temperature: ≥38,3°C measured orally or ≥38,0°C for over 1 hour; neutropenia: ANC <0,5 X 109/L or <1 X 109/L and a predicted decline to ≤0,5 X 109/L over the next 48 hours (ANC and temperature measured on the same day) in all cycles;
•Time to neutrophil recovery, defined as the time in days from the chemotherapy administration until the subject’s ANC increases to > 2.0 × 109/L after the nadir in Cycle 1;
•The number and proportion of subjects hospitalised, duration of hospitalisations and time in intensive care unit (ICU) due to neutropenia complications by cycle;
•The number and proportion of subjects with clinically documented infections by cycle;
•Use of intravenous (i.v.) antibiotics during each cycle.
Safety Endpoints:
•Probability of occurrence, and severity of the most common adverse events (AEs) associated with Pegfilgrastim treatment;
•Bone pain;
•Probability of occurrence, and severity of other AEs including mortality during treatment for any cause;
•Assessment of local tolerability at the injection site(s);
•Systemic tolerance (physical examination, vital signs, and laboratory assessments of safety parameters);
•Immunogenicity assessments up to six months after the last dose of the IMP.

E.5.2.1

Timepoint(s) of evaluation of this end point

Cycles 1-6 and six months follow up period

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Assessor-blinded

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.8.4.1

Number of sites anticipated in Member State concerned

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

Bulgaria

Georgia

Hungary

Romania

Russian Federation

Serbia

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

Last patient last visit (of follow up period –after 6 month of active treatment)

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

E.8.9.2

In all countries concerned by the trial days

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:

220

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

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

F.4.2.2

In the whole clinical trial

255

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 the end of the study treatment, each patient would be treated according to standard clinical practice.

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

2016-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-02-21

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