Clinical Trials Register

Summary
EudraCT Number:	2022-002188-31
Sponsor's Protocol Code Number:	HLX14-002-PMOP301
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2022-09-30
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

2022-002188-31

A.3

Full title of the trial

A Randomized, Double-Blind, International Multicenter, Parallel-Controlled Phase III Clinical Study to Evaluate Recombinant Anti-RANKL Human Monoclonal Antibody Injection (HLX14) Versus Denosumab Injection (Prolia®) in Postmenopausal Women with Osteoporosis at High Risk of Fracture

A.3.1

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

A randomized, double-blind, international multicenter, parallel-controlled phase III clinical study to compare the efficacy, safety, tolerability and immunogenicity of HLX14 vs. Denosumab Injection (Prolia®) in postmenopausal women with osteoporosis at high risk of fracture

A.4.1

Sponsor's protocol code number

HLX14-002-PMOP301

A.5.4

Other Identifiers

Name:

China clinical trial registration

Number:

CTR20220391

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	Shanghai Henlius Biotech, Inc.
B.1.3.4	Country	China
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	Shanghai Henlius Biotech, Inc.
B.4.2	Country	China
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Shanghai Henlius Biotech, Inc.
B.5.2	Functional name of contact point	Jin Li
B.5.3	Address:
B.5.3.1	Street Address	Room 330, Complex Building 222 Kangnan Road China
B.5.3.2	Town/ city	(Shanghai) Pilot Free Trade Zone
B.5.3.3	Post code	200120
B.5.3.4	Country	China
B.5.6	E-mail	jin_li@henlius.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	Recombinant Anti-RANKL Human Monoclonal Antibody
D.3.2	Product code	HLX14
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	HLX14
D.3.9.1	CAS number	615258-40-7
D.3.9.3	Other descriptive name	Denosumab biosimilar
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 Europe B.V.
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.3.1	Product name	Prolia
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	Prolia
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	120
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

Osteoporosis at High Risk of Fracture

E.1.1.1

Medical condition in easily understood language

Osteoporosis at High Risk of Fracture

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

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	10031282
E.1.2	Term	Osteoporosis
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

To assess the equivalence of the primary clinical efficacy endpoint between HLX14 and comparator Prolia® in postmenopausal women with osteoporosis at high risk of fracture.

E.2.2

Secondary objectives of the trial

To assess the equivalence of secondary clinical efficacy endpoints between HLX14 and comparator Prolia® in postmenopausal women with osteoporosis at high risk of fracture.
To compare the safety of HLX14 and comparator Prolia® in postmenopausal women with osteoporosis at high risk of fracture.
To compare the pharmacokinetics of HLX14 and comparator Prolia® in postmenopausal women with osteoporosis at high risk of fracture.
To compare the immunogenicity of HLX14 and comparator Prolia® in postmenopausal women with osteoporosis at high risk of fracture.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects who meet all the following criteria are allowed to be enrolled:
1. Subjects voluntarily sign the informed consent form, understand the nature, objectives, and procedures of the study, and are willing to comply with the procedures during the study.
2. Ambulatory postmenopausal women with osteoporosis aged 60–90 years (both inclusive).
3. Postmenopausal, defined as > 2 years of menopause, i.e., > 2 years of spontaneous amenorrhea or > 2 years after bilateral oophorectomy. If a subject has unknown status of bilateral oophorectomy or has undergone hysterectomy but with the ovaries reserved, follicular stimulating hormone (FSH) level > 40 U/L can be used to confirm the post-operative menopausal status.
4. Bone mineral density (BMD) T-score between −2.5 and −4.0 at the lumbar spine or total hip, i.e., −4.0 < T-score ≤ −2.5, as assessed by the central imaging at the time of screening, based on dual-energy x-ray absorptiometry (DXA) scans
5. At least 2 vertebrae in the L1-L4 region of lumbar spine and at least one hip are evaluable by DXA, assessed by the central imaging.
6. Non-smokers (A history of never smoking > 5 cigarettes/day and not smoking at all for at least the last 2 years prior to screening process) or light smokers (Should be situational smokers, those who often smoke while consuming alcohol or in another type of situation, but who do not smoke daily. Light smokers should have not smoked more than 1 cigarette in the week before starting the medical screening process.

E.4

Principal exclusion criteria

1.Diseases affecting bone metabolism:osteomalacia or osteogenesis imperfecta; Paget's disease of bone; Cushing's syndrome; hyperprolactinemia; hypopituitarism; acromegaly; multiple myeloma; hyperparathyroidism; hypoparathyroidism.
2.Thyroid disorders: Hyper- or hypothyroidism; only subjects with hypothyroidism receiving stable thyroid hormone replacement therapy may be included, according to the following criteria:
1.If TSH level is below local normal range, subject is not eligible for the study.
2.If TSH level increases (> 5.5 μIU/mL but ≤ 10.0 μIU/mL), meanwhile serum FT4 is within the normal range, subject is eligible.
3.If TSH level is > 10.0 μIU/mL, subject is not eligible for the study.
3.Rheumatoid arthritis; ankylosing spondylitis.
4.Active malignancies (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical cancer or breast ductal carcinoma in situ) within the last 5 years prior to signing the ICF.
5.Malabsorption syndrome or various gastrointestinal disorders associated with malabsorption, e.g., Crohn's disease and chronic pancreatitis, malabsorption of calcium or vitamin D.
6.Severe renal impairment due to renal disease with a glomerular filtration rate < 30 mL/min.
7.Hepatic diseases
8.Serious primary diseases in the cardiovascular, cerebrovascular, or hematopoietic system judged by PI.
9.Positive for human immunodeficiency virus (HIV) antibody.
10.Vitamin D deficiency: 25-(OH) vitamin D level < 20 ng/mL. Re-testing allowed for 25-(OH) vitamin D level after vitamin D repletion.
11.Abnormal serum calcium: Current hypocalcemia or hypercalcemia, defined as that albumin-adjusted serum calcium level is not within the normal limit. Subjects must not receive calcium supplements within 24 h before blood drawing for serum calcium screening.
12.Oral and dental diseases: Prior or present evidence of osteomyelitis or osteonecrosis of the jaw; acute dental or jaw disease requiring oral surgery; planned invasive dental procedures; non-healed dental or oral surgery.
13.Active or uncontrolled infection requiring systemic therapy within 2 weeks prior to first dose.
14.Type 1 diabetic patients, or type 2 diabetic patients who have poor blood glucose control or are treated with insulin, glucagon-like peptide-1 (GLP-1), thiazolidinediones, SGLT2 inhibitors, etc.
15.Participating in clinical trials of other medical devices or drugs or reaching less than 30 days or 5 half-lives after the last visit in the clinical trials of other medical devices or drugs (non-bone metabolism related drugs) (whichever is longer). Bone metabolism related drugs should comply with the corresponding prohibition time limit, and anti-osteoporosis drugs should be excluded. Those who have failed in the screening period of other clinical trials but have not yet been treated with drugs/clinical devices can be included in the study.
16.Received Denosumab and its biosimilars, or Romosozumab and its biosimilars, or cathepsin K inhibitor therapy prior to randomization.
17.Received the following osteoporosis treatments, or medications that affect bone metabolism, or any herbal medications:
1.fluoride, strontium, or intravenous bisphosphonates within the last 5 years prior to randomization;
2.Cumulative use > 3 years or dosing within 12 months of oral bisphosphonates prior to randomization;
3.parathyroid hormone (PTH) or PTH analogues, such as teriparatide, within 12 months prior to randomization.
4.systemic hormone replacement therapy (HRT), selective estrogen receptor modulators, tibolone, anabolic hormones, testosterone, androgens, gonadotropin releasing hormone agonists, or adrenocorticotropic hormone, within 12 months prior to randomization.
5.any of the following within 3 months prior to randomization: calcitonin, calcitriol, heparin, warfarin, anticonvulsants (except benzodiazepines), systemic use of ketoconazole, cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, and oral or parenteral glucocorticoids (≥ 5 mg/day prednisone daily or equivalent for > 10 days).
6.any herbal medications within 2 weeks.
18.History of more than two vertebral fractures.
19.Presence of active healing fracture in the opinion of the investigator.
20.Subjects at very high risk of fracture who must be treated immediately with an active drug in the opinion of the investigator.
21.Known allergic to the drugs listed in the study protocol, including a history of allergy to denosumab, any recombinant protein drugs, or any ingredients used in HLX14 or Prolia®.
22.History of drug or alcohol abuse, and evidence of alcohol or drug abuse within 12 months.
23.Various physical or psychiatric disorders or laboratory abnormalities which will prevent the subject from following the study procedures and completing the study, or interfere with the interpretation of study results. Or Subjects who have other conditions rendering them unsuitable for inclusion as judged by the investigator.

E.5 End points

E.5.1

Primary end point(s)

Percent change from baseline in BMD at the lumbar spine to Week 52 (D365).
Note: The percent change in BMD is calculated as: (Test value − Baseline value) / (Baseline Value) × 100%

E.5.1.1

Timepoint(s) of evaluation of this end point

365 days

E.5.2

Secondary end point(s)

1. Fracture rate from baseline to Week 52 (D365).
2. Percent change in BMD at lumbar spine from baseline to Week 26 (D183).
3. Percent change in BMD at total hip from baseline to Week 26 (D183) and Week 52 (D365).
4. Percent change in BMD at the femoral neck from baseline to Week 26 (D183) and Week 52 (D365).
Note: The fracture rate is calculated as (Number of subjects with a history of fracture as of D365 −
Number of subjects with a fracture at baseline) / Number of subjects with a fracture at baseline × 100%
The percent change in BMD is calculated as (test value - baseline value) ÷ (baseline value) × 100%

E.5.2.1

Timepoint(s) of evaluation of this end point

365 days

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

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

Australia

China

Hong Kong

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

The End-of-Study is defined as the last visit of the last subject.

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:

478

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

478

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

F.4.2.2

In the whole clinical trial

478

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)

Local standard of care.

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

2022-11-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-11-21

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

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