Clinical Trials Register

Summary
EudraCT Number:	2008-001252-52
Sponsor's Protocol Code Number:	CZOL446H2337
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-12-24
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2008-001252-52

A.3

Full title of the trial

A multicenter, randomized, double-blind, placebo controlled efficacy and safety trial of intravenous zoledronic acid twice yearly compared to placebo in osteoporotic children treated with glucocorticoids

A.3.1

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

A one-year multi-center study, to evaluate safety and efficacy of zoledronic acid given every six months compared to placebo in children with weakened bone treated with long-term steroids

A.4.1

Sponsor's protocol code number

CZOL446H2337

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/140/2013

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma Services AG
B.1.3.4	Country	United States
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma AG
B.5.2	Functional name of contact point	Clinical trial Information desk
B.5.3	Address:
B.5.3.1	Street Address	Forum 1, Novartis Campus
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	41613241111
B.5.5	Fax number	41613248001
B.5.6	E-mail	clinicaltrial.enquiries@novartis.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	Yes
D.2.1.1.1	Trade name	Aclasta®
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Aclasta®
D.3.2	Product code	ZOL446
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ZOLEDRONIC ACID
D.3.9.1	CAS number	118072-93-8
D.3.9.2	Current sponsor code	ZOL446
D.3.9.4	EV Substance Code	SUB00176MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of osteoporosis in a paediatric population (aged 5 to 17 years old) treated with systemic glucocorticoids (i.v. or oral)

E.1.1.1

Medical condition in easily understood language

Disease of bones that leads to an increase 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	17.1
E.1.2	Level	SOC
E.1.2	Classification code	10028395
E.1.2	Term	Musculoskeletal and connective tissue disorders
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

The primary efficacy objective:
The primary efficacy objective of the study is to demonstrate that zoledronic acid administered every 6 months 0.05 mg/kg (max 5 mg) is superior to placebo for the change in lumbar spine (LS) areal bone mineral density (BMD) Z-score at Month 12 relative to baseline.

The safety objectives are:
- to demonstrate that zoledronic acid is safe for the treatment of osteoporotic children treated with glucocorticoids through the monitoring of relevant clinical and laboratory safety parameters
- to measure urinary concentration of zoledronic acid at Month 12

E.2.2

Secondary objectives of the trial

▪ To evaluate between-treatment differences for the change in LS areal BMD Z-score at Month 6 relative to baseline
▪ To evaluate between-treatment differences for the change from baseline in LS and total body BMC at 6 and 12 months
▪ To evaluate between-treatment differences for the change in serum P1NP, NTX, BSAP & TRAP-5b at Months 6 and 12 relative to baseline
▪ To evaluate between-treatment differences for the proportion of patients with new vertebral fractures at Month 12 relative to baseline
▪ To evaluate the between-treatment differences for change in vertebral morphometry at Month 12 relative to baseline
▪ To evaluate the between-treatment differences for change in pain using the Faces Pain Scale-Revised (FPS-R) at months 3 6, 9 and 12 relative to baseline
▪ To evaluate the between-treatment differences for change in 2nd metacarpal cortical width at month 12 relative to baseline.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

▪ Children, male or female, between 5 and 17 years of age at visit 1 of the study
▪ Confirmed diagnosis of non-malignant conditions requiring treatment with systemic glucocorticoids receiving systemic glucocorticoids (i.v. or oral) within the 12 months preceding enrollment in the study (any duration)
▪ Lumbar Spine areal BMD Z-score of -0.5 or worse
▪ Evidence of at least 1 vertebral compression fracture (at least Genant Grade 1 vertebral compression or radiographic signs of vertebral compression*) seen in X-ray and asymptomatic within 1 month of or at screening visit confirmed by central reading
OR
One or more, low-trauma, lower extremity long-bone fracture which occurred sometime within the 2 years preceding enrollment in the study, confirmed by central reading or radiological report.
OR
Two or more, low-trauma, upper extremity long-bone fractures which occurred sometime within the 2 years preceding enrollment in the study, confirmed by central reading or radiological report. Low trauma fracture is defined as falling from standing height or less
▪ Willingness to consent/assent to study participation

Other protocol-defined inclusion criteria may apply

E.4

Principal exclusion criteria

▪ Any prior use bisphosphonates, sodium fluoride
▪ History of malignancy
▪ History of primary bone disease (osteogenesis imperfecta, idiopathic juvenile osteoporosis, rickets/osteomalacia).
▪ Any medical condition that might interfere with the evaluation of LS BMD, such as severe scoliosis or spinal fusion
▪ Hypocalcemia and hypophosphatemia: any value (age-matched) below the normal range at screening
▪ Vitamin D deficiency (serum 25-hydroxy vitamin D concentrations of < 16ng/mL or < 40 nmol/L) at screening
▪ Renal impairment defined as an estimated glomerular filtration rate (GFR) < 35ml/min/1.73 m2 at screening based on the Schwartz formula
▪ A serum creatinine increase between Visit 1 and Visit 2 greater than 0.5 mg/dL (44.2mmol/L)
▪ Duchenne Muscular Dystrophy patients with history of serious renal disease
▪ Duchenne Muscular Dystrophy patients with history of symptomatic cardiac involvement
▪ History of hyperparathyroidism or hyperthyroidism within 1 year of screening
▪ History of hypothyroidism unless on a stable treatment regimen for > 6 months, with at least one documented normal TSH and FT4 levels during this 6 month period
▪ History of sarcoidosis
▪ Diagnosis of active uveitis (symptomatic or asymptomatic) at the time of enrollment of the study
▪ Female patients of child bearing potential are eligible only if they are:
(1) not pregnant/ non-lactating;
(2) are sexually abstinent or are surgically sterile
(3) if sexually active, must be practicing a medically acceptable form of birth control for greater than 2 months prior to screening visit. Females of child bearing potential who are sexually active must agree to continue to practice their birth control during the trial and at least 1 year after completing the trial and must consent to a pregnancy test prior to every dose administration and at the End of Study (EOS) Visit.
▪ History of primary bone disease (osteogenesis imperfecta, idiopathic juvenile osteoporosis, rickets/osteomalacia)

Other protocol-defined exclusion criteria may apply

E.5 End points

E.5.1

Primary end point(s)

LS areal BMD Z-score measurement.

E.5.1.1

Timepoint(s) of evaluation of this end point

At screening and month 12.

E.5.2

Secondary end point(s)

Secondary efficacy assessments:
a. LS areal BMD Z-score.
b. LS and total body BMC.
c. Serum P1NP and BSAP.
d. Serum NTx and TRAP5b.
e. new vertebral fractures based on a lateral thoracolumbar spine x-ray.
f. vertebral morphometry, based on a lateral thoracolumbar spine x-ray.
g. Pain using the Faces Pain Scale-Revised (FPS-R).
h. Metacarpal cortical width.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary efficacy assessments:
a. at Month 6 (visit 5).
b. at 6 and 12 months (visits 5 and 8/EOS).
c. at months 6 and 12 (visits 5 and 8/EOS).
d. at months 6 and 12 (visits 5 and 8/EOS).
e. at month 12 relative to baseline (visit 8/EOS).
f. at month 12 relative to baseline (visit 8/EOS).
g. at months 3, 6, 9 and 12 relative to baseline (visits 4,5,7 and 8/EOS).
h. at month 12 relative to baseline (visit 8/EOS).

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

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

E.8.1.4

Double blind

Yes

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

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Belgium

Brazil

Canada

Finland

Germany

Hungary

Italy

New Zealand

Poland

Romania

Russian Federation

South Africa

Sweden

Turkey

Ukraine

United Kingdom

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 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 months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Minors under the age of 18 years old

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

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)

Following the completion of CZOL446H2337study (identified as “Core” study), patient can enter a one-year Extension study (CZOL446H2337E1) where all patients will be receiving zoledronic acid regardless of previous treatment arm in the core (placebo vs. zoledronic acid) and all adverse events will be monitored.

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

2015-01-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-03-05

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