Clinical Trials Register

Summary
EudraCT Number:	2020-006017-38
Sponsor's Protocol Code Number:	RGB-14-101
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-06-15
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2020-006017-38

A.3

Full title of the trial

A Randomised, Double-blind, Multicentre Phase III Study to Assess the Efficacy and Safety of RGB-14-P Compared to Prolia® in Women with Postmenopausal Osteoporosis

Randomizált, kettős-vak, több központban végzett, III. fázisú vizsgálat az RGB-14-P hatásosságának és biztonságosságának értékelésére a Prolia®-val összehasonlítva a változókort követő csontritkulásban szenvedő nők esetében

A.3.1

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

Comparative Efficacy and Safety Study of RGB-14-P and Prolia in Women with Postmenopausal Osteoporosis

Összehasonlító hatásossági és biztonságossági vizsgálat a RGB-14-P és Prolia között változáskort követő csontritkulásban szenvedő nők esetében

A.3.2

Name or abbreviated title of the trial where available

JUNO

A.4.1

Sponsor's protocol code number

RGB-14-101

A.5.4

Other Identifiers

Name:

IND

Number:

146025

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	Gedeon Richter Plc.
B.1.3.4	Country	Hungary
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	Gedeon Richter Plc.
B.4.2	Country	Hungary
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gedeon Richter Plc.
B.5.2	Functional name of contact point	Medical Information Service
B.5.3	Address:
B.5.3.1	Street Address	Gyömrői út 19-21
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1103
B.5.3.4	Country	Hungary
B.5.4	Telephone number	+3615057032
B.5.6	E-mail	medinfo@richter.hu

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	RGB-14-P, proposed denosumab biosimilar
D.3.2	Product code	RGB-14-P
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	Denosumab
D.3.9.1	CAS number	615258-40-7
D.3.9.2	Current sponsor code	RGB-14-P
D.3.9.3	Other descriptive name	DENOSUMAB
D.3.9.4	EV Substance Code	SUB29173
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	60
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	Prolia
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	US licensed Prolia®
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	Denosumab
D.3.9.1	CAS number	615258-40-7
D.3.9.3	Other descriptive name	DENOSUMAB
D.3.9.4	EV Substance Code	SUB29173
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	60
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

Postmenopausal osteoporosis

E.1.1.1

Medical condition in easily understood language

Osteoporosis in women after menopause

E.1.1.2

Therapeutic area

Body processes [G] - Bones and nerves physological processes [G11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10031285
E.1.2	Term	Osteoporosis postmenopausal
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue 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

Efficacy
To demonstrate similar efficacy and effect of RGB 14 P with US licensed Prolia® on BMD at the lumbar spine at Week 52 in female participants with postmenopausal osteoporosis

Pharmacodynamics
To demonstrate similar pharmacodynamics (AUEC of %CfB in sCTX) of RGB 14 P with US licensed Prolia® in female participants with postmenopausal osteoporosis (only required for EMA)

E.2.2

Secondary objectives of the trial

Efficacy
To provide additional comparative efficacy data of RGB 14 P with US licensed Prolia® in female participants with postmenopausal osteoporosis

Pharmacodynamics
To provide additional comparative pharmacodynamic data of RGB 14 P with US licensed Prolia® in female participants with postmenopausal osteoporosis

Safety
To compare the safety and tolerability of RGB 14 P with US licensed Prolia® in female participants with postmenopausal osteoporosis

Immunogenicity
To compare the immunogenicity of RGB 14 P with US licensed Prolia® in female participants with postmenopausal osteoporosis

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Participant is ≥ 60 to ≤ 90 years of age at the time of signing the informed consent.
2. Participant is an ambulatory postmenopausal woman, diagnosed with osteoporosis, able to walk and not bedridden. A woman is considered postmenopausal if she meets any of the following criteria:
a. Has 12 months of spontaneous amenorrhea without an alternative medical cause with serum follicle stimulating hormone (FSH) levels falling in the normal postmenopausal range at the central laboratory at the time of the Screening Period.
b. Female participant underwent bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior to the Screening Period.
3. Participant has an absolute BMD consistent with T score ≤ 2.5 and ≥ 4.0 at the lumbar spine as measured by dual energy X ray absorptiometry (DXA) during the Screening Period and at least 2 lumbar vertebrae (from L1 to L4) must be evaluable by DXA.
4. Participant has body weight ≥ 50 and ≤ 90 kg at the Screening Period.
5. Participant is willing and able to give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
6. Participant has provided informed consent prior to any study specific activities/procedures.

Participant must meet the following criteria to be enrolled in the Transition Period:
7. Have been enrolled, received both doses of IMP and completed the scheduled Main Period (up to Week 52) of the RGB-14-101 study.

E.4

Principal exclusion criteria

1. Participant has a history and/or presence of one severe or more than two moderate vertebral fractures as determined by central reading of lateral spine X ray during the Screening Period.
2. Participant has a history and/or presence of hip fracture.
3. Participant has a history and/or presence of atypical femur fracture.
4. Participant presents with an active healing fracture according to the assessment of the Investigator.
5. Participant has a bilateral hip replacement (unilateral is allowed if the other hip is evaluable with DXA).
6. Participant has a vitamin D deficiency, the assessment may be repeated once after vitamin D supplementation. Appropriate vitamin D dosing in addition to vitamin D supplementation is permitted at the discretion of the Investigator during the Screening Period.
7. Participant has hypocalcaemia or hypercalcaemia at the Screening Period, the assessment may be repeated once in the case of hypercalcaemia.
8. Participant has a history and/or presence of bone metastases, renal osteodystrophy, osteomyelitis, any metabolic, endocrine or traumatic bone disease (except postmenopausal osteoporosis) that may interfere with the interpretation of the results.
9. Participant has a current uncontrolled status of hypothyroidism or hyperthyroidism.
10. Participant has a history (within 5 years prior to Screening) and/or current hypoparathyroidism or hyperparathyroidism other than clinically not significant secondary hyperparathyroidism.
11. Participant has had major surgery within 8 weeks prior to the Screening Period or planned, anticipated major surgery during the study.
12. Participant has malignancy within 5 years before Screening (except completely cured in situ cervical carcinoma or non metastatic squamous or basal cell carcinoma of the skin).
13. Participant has a history and/or presence of significant cardiac disease or ECG abnormalities indicating significant risk for participating in the study as judged by the Investigator.
14. Participant has a known intolerance or malabsorption of calcium or vitamin D supplements.
15. Participant has a known hypersensitivity (including severe allergic reaction) to monoclonal antibodies or a history of systemic hypersensitivity to any components of the IMPs.
16. Participant shows contraindications to denosumab therapy (e.g., hypocalcaemia), or calcium or vitamin D supplementation before starting IMP administration.
17. Participant has a latex allergy.
18. Participant has a history and/or presence of ONJ or risk factors for ONJ.
19. Participant has history and/or presence of osteonecrosis of the external auditory canal.
20. Participant requiring ongoing use of any osteoporosis treatment (other than calcium and vitamin D supplements).
21. Participant has previously received denosumab or biosimilar denosumab.
22. Participant has previously received any of medicines listed in protocol.
23. Participant is receiving or has received any investigational drug (or is currently using an investigational device) within 3 months before receiving IMP, or at least 10 times the respective elimination half life (whichever period is longer).
24. Participant has weight or girth measurements which may preclude accurate DXA measurements in Investigator’s opinion.
25. Participant has inadequate renal and hepatic function at the Screening Period defined as patient on dialysis or estimated glomerular filtration rate (eGFR) < 30 mL/min (calculated using the modification of diet in renal disease [MDRD] formula) and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 ×upper limit of normal (ULN) or total bilirubin ≥ 1.5 ×ULN.
26. Participant presents with clinically significant leukopenia, neutropenia or anaemia as judged by the Investigator, the assessment may be repeated once if the condition is deemed to be temporary by the Investigator.
27. Participant has an active infection, including, but not limited to SARS CoV 2, hepatis B, hepatitis C and human immunodeficiency virus infections during the Screening Period.
28. Current or past alcohol or drug abuse.
29. Any other clinically significant disorder/condition/disease or laboratory abnormality that in the opinion of the Investigator would pose a risk to participant safety or interfere with the study evaluation, procedures or completion.

Participant meeting the following criteria must not be enrolled in the Transition Period:
30. Treatment continuation in the study is against the best interest of the participant as deemed by the Investigator.

E.5 End points

E.5.1

Primary end point(s)

Efficacy
%CfB in lumbar spine BMD

Pharmacodynamics
AUEC of %CfB sCTX0-m6

E.5.1.1

Timepoint(s) of evaluation of this end point

Efficacy
%CfB in lumbar spine BMD at Week 52

Pharmacodynamics
AUEC of %CfB sCTX0-m6 until Week 26

E.5.2

Secondary end point(s)

Efficacy
•%CfB in total hip BMD
•%CfB in lumbar spine BMD
•%CfB in femoral neck BMD
•Vertebral fragility fracture incidence
•Non vertebral fragility fracture incidence

Pharmacodynamics
•%CfB in serum P1NP
•%CfB in sCTX

Safety
•AE, SAE, clinical laboratory safety assessments (haematology, clinical chemistry and urinalysis), vital signs, physical examination, ECG and injection site reaction

Immunogenicity
•Incidence of binding ADAs and NAbs
•Titer determination of binding ADAs

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy
•%CfB in total hip BMD at Weeks 26, 52 and 78
•%CfB in lumbar spine BMD at Weeks 26 and 78
•%CfB in femoral neck BMD at Weeks 26, 52 and 78
•Vertebral fragility fracture incidence at Weeks 52 and 78
•Non vertebral fragility fracture incidence at Weeks 52 and 78

Pharmacodynamics
•%CfB in serum P1NP at Weeks 4, 26, 52 and 78
•%CfB in sCTX at Weeks 4, 26, 52 and 78

Safety
•AE, SAE, clinical laboratory safety assessments (haematology, clinical chemistry and urinalysis), vital signs, physical examination, ECG and injection site reaction up to Week 78

Immunogenicity
•Incidence of binding ADAs and NAbs at Weeks 0, 2, 4, 26, 28, 30, 52, 54, 56 and 78
•Titer determination of binding ADAs at Weeks 0, 2, 4, 26, 28, 30, 52, 54, 56 and 78

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

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

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

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

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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.8.4.1

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

Ukraine

United States

Bulgaria

Hungary

Italy

Poland

Spain

Czechia

E.8.7

Trial has a data monitoring committee

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

End of the study is defined as the date of the last scheduled procedure shown in the SoA for the last participant in the study.

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:

108

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

326

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

286

F.4.2.2

In the whole clinical trial

434

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)

The Investigator must ensure that appropriate follow-up osteoporosis treatment according to local guidelines is provided for all participants who completed the Main and Transition Periods of the study.

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

2021-07-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-11-15

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