Clinical Trials Register

Summary
EudraCT Number:	2018-004364-66
Sponsor's Protocol Code Number:	BMR111-208
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-09-11
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2018-004364-66

A.3

Full title of the trial

A Phase 2 Open-Label Long-Term Extension Study to Evaluate the Safety
and Efficacy of BMN 111 in Children with Achondroplasia

A.3.1

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

A Phase 2 open-label long-term study of BMN 111 in children with Achondroplasia

A.4.1

Sponsor's protocol code number

BMR111-208

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/379/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	BioMarin Pharmaceutical Inc.
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	BioMarin Pharmaceutical Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	BioMarin Pharmaceutical Inc.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	105 Digitial Drive
B.5.3.2	Town/ city	Novato
B.5.3.3	Post code	94949
B.5.3.4	Country	United States
B.5.6	E-mail	clinicaltrials@bmrn.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/12/1094
D.3 Description of the IMP
D.3.1	Product name	Modified recombinant human c-type
D.3.2	Product code	Natriuretic peptide
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	Yes
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	Vosoritide
D.3.9.1	CAS number	1480721-61-5
D.3.9.2	Current sponsor code	BMN 111
D.3.9.3	Other descriptive name	MODIFIED RHCNP
D.3.9.4	EV Substance Code	SUB120857
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	0.8
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	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	Yes
D.2.5.1	Orphan drug designation number	EU/3/12/1094
D.3 Description of the IMP
D.3.1	Product name	Modified recombinant human c-type
D.3.2	Product code	Natriuretic peptide
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	Yes
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	Vosoritide
D.3.9.1	CAS number	1480721-61-5
D.3.9.2	Current sponsor code	BMN 111
D.3.9.3	Other descriptive name	MODIFIED RHCNP
D.3.9.4	EV Substance Code	SUB120857
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	2.0
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

Achondroplasia

E.1.1.1

Medical condition in easily understood language

Dwarfism

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	LLT
E.1.2	Classification code	10000452
E.1.2	Term	Achondroplasia
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the long-term safety, tolerability of BMN 111
Evaluate change in height/length z-score in children with ACH treated
with BMN 111

E.2.2

Secondary objectives of the trial

Evaluate the effect of BMN 111 on AGV
• Evaluate the pharmacokinetics of BMN 111
• Evaluate the effect of BMN 111 on body proportions and ratios of the
extremities
• Evaluate the effect of BMN 111 on bone morphology/quality by X-ray
and dual X-ray absorptiometry (DXA)
• Evaluate the long-term effect of BMN 111 on health-related quality of
life, developmental status and functional independence , using agespecific
QoL and functional independence questionnaires
• Evaluate bone metabolism and pharmacodynamic biomarkers
• Evaluate immunogenicity of BMN 111 and assess impact on safety, PK,
and efficacy measures
• Describe the incidence of surgical and medical interventions related to
achondroplasia
• Assess effect on sleep disordered breathing by polysomnography in
patients up to 5 years old.
• Evaluate the effect of BMN 111 on skull and brain morphology,
including foramen magnum, ventricular and brain parenchymal
dimensions by MRI in patients up to 3 years old.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Must have completed Study 111-206 (eligible to enroll in 111-208 within 3 months after completing 111-206 at the discretion of the principal investigator and medical monitor).
2.Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, subjects under the age of majority are willing and able to provide written assent (if required by local regulations or the IRB/IEC) after the nature of the study has been explained and prior to performance of any research-related procedure. Subjects who reach the age of majority in their country while the study is ongoing will be asked to provide their own written consent again upon reaching the legal age of majority.
3.Are willing and able to perform all study procedures as physically possible

E.4

Principal exclusion criteria

1. Permanently discontinued BMN 111 or placebo prior to completion of
Study 111-206
2. Have a clinically significant finding or arrhythmia on ECG that
indicates abnormal cardiac function or conduction or QTc-F > 450 msec
3. Require any investigational agent (except BMN 111) prior to
completion of study period
4. Current therapy with antihypertensive medications, angiotensinconverting
enzyme (ACE) inhibitors, angiotensin II receptor blockers,
diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides,
systemic anticholinergic agents, GnRH agonists, any medication that
may impair or enhance compensatory tachycardia, diuretics, or other
drugs known to alter renal or tubular function (Table 9.3.4.1)
5. Pregnant or planning to become pregnant (self or partner) at any time
during the study
6. Concurrent disease or condition that, in the view of the investigator,
would interfere with study participation or safety evaluations, for any
reason
7. Have a condition or circumstance that, in the view of the investigator,
places the subject at high risk for poor treatment compliance

E.5 End points

E.5.1

Primary end point(s)

•Evaluate the incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: "Through study completion, an average of 5 years" ]
Number of study participants with treatment-emergent adverse events or serious adverse events

•Evaluate change in height/length z-score in children with ACH treated with BMN 111 [ Time Frame: "Through study completion, an average of 5 years" ]

E.5.1.1

Timepoint(s) of evaluation of this end point

Time Frame: "Through study completion, an average of 5 years"

E.5.2

Secondary end point(s)

•Evaluate the change from baseline of mean annualized growth velocity (AGV) [ Time Frame: "Through study completion, an average of 5 years" ]
•Characterize maximum concentration (Cmax) of BMN 111 in plasma [ Time Frame: "Through study completion, an average of 5 years" ]
•Characterize the area under the plasma concentration time-curve from time 0 to infinity (AUC0-∞) [ Time Frame: "Through study completion, an average of 5 years" ]
•Characterize the elimination half-life of BMN 111 (t½) [ Time Frame: "Through study completion, an average of 5 years" ]
•Characterize the apparent clearance of drug [ Time Frame: "Through study completion, an average of 5 years" ]
•Characterize the apparent volume of distribution based upon the terminal phase (Vz/F) [ Time Frame: "Through study completion, an average of 5 years" ]
•Characterize the amount of time BMN 111 is present at maximum concentration (Tmax) [ Time Frame: "Through study completion, an average of 5 years" ]
•Evaluate the change from baseline on body proportion ratios of the extremities [ Time Frame: "Through study completion, an average of 5 years" ]
•Effect of BMN 111 on bone morphology and quality by XRay [ Time Frame: "Through study completion, an average of 5 years" ]
•The effect of BMN 111 on bone morphology/quality will be assessed by measuring bone mineral density via Dual X-ray Absorptiometry [ Time Frame: "Through study completion, an average of 5 years" ]
•Potential Changes in health-related quality of life as measured by the quality of life in Short- statured youth [ Time Frame: "Through study completion, an average of 5 years" ]
Evaluate the long-term effect of BMN 111 on health-related quality of life, developmental status and functional independence, using age-specific QoL and functional independence questionnaires (Bayley-III, WeeFIM, ITQOL, QoLISSY, PedsQL, Child Behavior Checklist 1.5-5 [CBCL 1.5-5], Child Behavior Checklist 6-18 [CBCL 6-18]).

•BMN 111 activity will be assessed by measuring bone and collagen metabolism [ Time Frame: "Through study completion, an average of 5 years" ]
•Describe the incidence of surgical and medical interventions related to achondroplasia [ Time Frame: "Through study completion, an average of 5 years" ]
•Assess effect on sleep disordered breathing by polysomnography in patients up to 5 years old. [ Time Frame: "Through study completion, an average of 1 year" ]
•Evaluate the effect of BMN 111 on skull and brain morphology, including foramen magnum, ventricular and brain parenchymal dimensions by MRI in patients up to 3 years old. [ Time Frame: "Through study completion, an average of 1 year" ]

E.5.2.1

Timepoint(s) of evaluation of this end point

Time Frame: "Through study completion, an average of 5 years"

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

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

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

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

Japan

United Kingdom

United States

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

Until Subject attains near final adult height

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

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

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)

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

Subjects in this protocol will be not be able to read or write so subjects parent/guardian will be consenting on their behalf.

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)

None

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

2019-10-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-22

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials