Clinical Trials Register

Summary
EudraCT Number:	2018-003888-56
Sponsor's Protocol Code Number:	20192022
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-06-02
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

Denmark - DHMA

A.2

EudraCT number

2018-003888-56

A.3

Full title of the trial

Treatment of adynamic bone disorder with parathyroid hormone in patients with chronic kidney disease

Diagnostik og behandling af knoglesygdom hos patienter med nedsat nyrefunktion

A.3.1

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

Diagnosis and treatment of bone disease in patients with chronic kidney disease

A.4.1

Sponsor's protocol code number

20192022

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	Department of Nephrology, Herlev & Gentofte Hospital, Herlev Hospital
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Augustinusfonden, Helen & Ejnar Bjoernows Fond, Danish Society of Nephrology, Herlev & Gentofte Hospital
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Herlev & Gentofte Hospital
B.5.2	Functional name of contact point	Resarch unit, Nephrology
B.5.3	Address:
B.5.3.1	Street Address	Ib Juuls Vej 1
B.5.3.2	Town/ city	Herlev
B.5.3.3	Post code	2730
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004538682877

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	Yes
D.2.1.1.1	Trade name	Terrosa 20 micrograms/80 microliters solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Gedeon Richter Plc.
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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
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	TERIPARATIDE
D.3.9.1	CAS number	52232-67-4
D.3.9.4	EV Substance Code	SUB10925MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/µl microgram(s)/microlitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.25
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

E.1.1.1

Medical condition in easily understood language

Bone disease with low activity of the boneforming cells

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10060881
E.1.2	Term	Adynamic bone disease
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The study will explore if treatment with recombinant human parathyroid hormone (PTH) improves bone turnover and bone mineral density (BMD) and thereby prevent the high risk of fracture in patients with chronic kidney disease (CKD).

E.2.2

Secondary objectives of the trial

Disturbed bone metabolism is related to increased risk of cardiovascular disease in patients with CKD. The study will examine if treatment with recombinant PTH improves cardiovascular parameters.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

○ Age ≥18 years
○ CKD stage 4-5D (eGFR ≤2930 ml/min) according to KDIGO (Kidney Disease Improving Global Outcome) definition
○ DEXA scan with a T-score at the total hip, femoral neck or lumbar spine (L1-4) ≤-2 (or Z-score ≤-2) in a minimum of 2 vertebraes and/or former fragility fracture (vertebral, hip, for- or upper arm, ankle) assessed with VFA or x-ray of the columna
○ Patients with expected adynamic bone disorder, based on BSAP≤21 µg/l or biopsy-verified low bone turnover

E.4

Principal exclusion criteria

○ Hypercalcemia defined as sustained ionized calcium >1.35 mmol/l
○ Previous fracture within the last 6 months * Patients may be rescreened after the 6 months
○ Previous calciphylaxis
○ Thyroid disturbances not adequately treated based on the opinion by the clinician
○ Treatment with digoxin
○ Paget’s disease or other metabolic bone disorders
○ Antiresorptive or bone anabolic medication during the last 24 months (for bisphosphonates it is only during the last 12 months)
○ Former or present malignant disease (except skin basal or planocellular carcinoma)
○ Previous external beam or implant radiation therapy to the skeleton
○ Kidney transplanted patients
○ Oral prednisolone treatment exceeding a total of 450 mg during the last 6 months or active oral prednisolone treatment with a daily dose of > 5 mg
○ 25 hydroxyvitamin D2 and D3 <50 nmol/l *Patients may be rescreened after correction
○ Inability to administer teriparatide
○ Reduced liver function *ALAT >3x upper limit of normal or bilirubin > 2x upper limit of normal
○ Pregnancy, lactation or fertile women * Post-menopausal females are not considered fertile not using safe anticonception (the following contraceptive methods are considered appropriate: Intrauterine device (IUD) or hormonal anticontraceptive (oral contraceptives, implant, transdermal patches, vaginal ring or depot injection)).
○ Hypersensitivity to the active substance in teriparatide or to any of the excipients or content
○ Inability to provide informed consent
○ Medical conditions or treatments that may interfere with assessments of the outcomes of the trial
○ Drug or alcohol abuse
○ Unable to participate in a clinical study based on the judgement by the local investigator

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the difference between the two groups (treated versus controls) in changes in BSAP after 18 months.

E.5.1.1

Timepoint(s) of evaluation of this end point

Evalutaion of this endpoint is after 18 months after inclusion

E.5.2

Secondary end point(s)

Changes between baseline and 18 months as well as differences between treated and untreated in:
○ Number of patients who no longer have adynamic bone disorder based on a BSAP >21 µg/l
○ BMD at the lumbar spine, antebrachium, femoral neck and total hip
○ Incidence of fragility fractures and vertebral fractures assessed using vertebral fracture assessment (VFA) or x-ray of columna
○ Bone microarchitecture, volumetric BMD, bone geometry and bone strength assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT)
○ Regional bone formation using 18F-NAF PET/CT
○ P-parathyroid hormone (intact, whole and nonoxidated-PTH), p-ionised calcium, p-phosphate, p-magnesium, p-FGF-23 and p-sclerostin
○ Bone microstructure by micro-computer tomography (µCT) of the bone biopsy
○ Static and dynamic bone histomorphometry classified by the TMV classification assessed by bone biopsy
○ Detailed histology of underSlying cellular mechanisms using a combination of immunostainings and advanced in situ hybridizations on the bone biopsy
○ Bone turnover markers i.e. intact PINP, TRAP5b, osteocalcin, RANKL and OPG
○ 24-hour blood pressure and pulse wave measurements including velocity
○ T50 (30), NT-proBNP as well as other cardiovascular biomarkers
○ The incidence of adverse reactions

E.5.2.1

Timepoint(s) of evaluation of this end point

After 18 months after inclusion and for some also after 30 months after inclusion (DEXA, X-ray, blood samples)

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

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

The lack of treatment / an untreated control group

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

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

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:

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.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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Herlev Hospital, Department of Endocrinology
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Herlev Hospital, Department of Clinical Physiology
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Herlev Hospital, Department of Clinical Physiology
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	Odense University Hospital, Department of Nephrology
G.4 Investigator Network to be involved in the Trial: 5
G.4.1	Name of Organisation	Steno Diabetes Center Copenhagen
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 6
G.4.1	Name of Organisation	Herlev Hospital, Department of Nephrology
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 7
G.4.1	Name of Organisation	Herlev Hospital, Department of Bone and joint surgery
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 8
G.4.1	Name of Organisation	Odense University Hospital, Department of Pathology
G.4.3.4	Network Country	Denmark

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-06-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-30

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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