Clinical Trials Register

Summary
EudraCT Number:	2015-004438-93
Sponsor's Protocol Code Number:	CT-ORZY-NPC-002
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-03-11
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

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2015-004438-93

A.3

Full title of the trial

Arimoclomol prospective double blind, randomised, placebo-controlled study in patients diagnosed with Niemann Pick disease type C

A.3.1

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

A clinical study to investigate the study drug Arimoclomol in a double blind, randomised, placebo-controlled study in patients diagnosed with Niemann Pick disease type C.

A.3.2

Name or abbreviated title of the trial where available

Investigate study drug Arimoclomol with patients diagnosed with Niemann Pick disease type C.

A.4.1

Sponsor's protocol code number

CT-ORZY-NPC-002

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	Orphazyme A/S
B.1.3.4	Country	Denmark
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	Orphazyme A/S
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	Orphazyme A/S
B.5.2	Functional name of contact point	Clinical Trial Manager
B.5.3	Address:
B.5.3.1	Street Address	Ole Maaløes Vej 3
B.5.3.2	Town/ city	Copenhagen N
B.5.3.3	Post code	DK-2200
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004561715350
B.5.6	E-mail	mcc@orphazyme.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/3/14/1376
D.3 Description of the IMP
D.3.1	Product name	Arimoclomol
D.3.2	Product code	_
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Arimoclomol citrate
D.3.9.2	Current sponsor code	BRX-345
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	25
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.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/3/14/1376
D.3 Description of the IMP
D.3.1	Product name	Arimoclomol
D.3.2	Product code	_
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Arimoclomol citrate
D.3.9.2	Current sponsor code	BRX-345
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	50
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.IMP: 3
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/3/14/1376
D.3 Description of the IMP
D.3.1	Product name	Arimoclomol
D.3.2	Product code	_
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ARIMOCLOMOL
D.3.9.2	Current sponsor code	BRX-345
D.3.9.4	EV Substance Code	SUB192526
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	100
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Niemann Pick disease type C

E.1.1.1

Medical condition in easily understood language

Niemann-Pick Type C is a rare and inherited disease in which quantities of fatty substances accumulate in the brain and other organs. The brain, central nervous system, liver and spleen are affected.

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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	10029403
E.1.2	Term	Niemann-Pick disease
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

MAIN STUDY:
To evaluate therapeutic response to arimoclomol versus placebo, both in addition to best available standard of care, at 12 months.

E.2.2

Secondary objectives of the trial

MAIN STUDY:
•To evaluate the therapeutic response to arimoclomol through clinical,
biological and imaging assessments at 6 and 12 months;
•To evaluate the long term therapeutic response (clinical and biological
assessments) at 18 months and every 6 months thereafter until End of
Extension Phase at 60 months and hereafter annually until
study end;
•To evaluate the safety of arimoclomol.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PAEDIATRIC SUBSTUDY:
(within the same protocol, under the same title)
Primary:
• To evaluate the safety and tolerability of arimoclomol in patients aged
6 to <24 months at study enrolment.
Secondary:
• To evaluate the therapeutic response to arimoclomol in patients aged
6 to <24 months at study enrolment through clinical, biological and
imaging assessments.
• To assess the PK [AUC0-8,SS] of arimoclomol, and if relevant also of
metabolites in patients aged 6 to <24 months at study enrolment.

E.3

Principal inclusion criteria

• Diagnosis of NPC1 or NPC2;
• NPC diagnosis confirmed by:
o Genetically confirmed (deoxyribonucleic acid [DNA] sequence
analysis) by mutations in both alleles of NPC1 or NPC2,
OR
Mutation in only one allele of NPC1 or NPC2 plus either positive filipin
staining or elevated cholestane triol/oxysterols (>2 x upper limit of
normal [ULN]).
• Main study: Males and females aged from 2 years to 18 years and 11
months;
• Paediatric substudy: Males and females aged 6 to <24 months; with a cap of maximum 3 patients above 18 months
• Treated or not treated with miglustat;
o Main study: If a patient is under prescribed treatment with miglustat,
it has to be under stable dose of the medication for at least 6 continuous
months prior to inclusion in the CT ORZY NPC 002 study;
o Main study: If a patient has been discontinued from prescribed
treatment with miglustat, they must have been discontinued for at least
3 continuous months prior to inclusion in the CT-ORZY-NPC-002 study;
o Paediatric substudy: If a patient is on prescribed treatment with
miglustat, the dose must have been stable for at least 1 month prior to
inclusion in the paediatric substudy;
o Paediatric substudy: If a patient has been discontinued from
prescribed treatment with miglustat, they must have been discontinued
for at least 1 month prior to inclusion in the paediatric substudy.

E.4

Principal exclusion criteria

Main exclusion criteria:
• Severe liver insufficiency (defined as hepatic laboratory parameters,
AST and/or ALT greater than three-times the ULN for age and gender
[central laboratory assessment]);
• Renal insufficiency, with serum creatinine level greater than 1.5 times
the ULN (central laboratory assessment);
• Paediatric substudy: Patients with known causes of active liver
disease or prolonged icterus or malformation of organs other than NPC (e.g. Gaucher disease, chronic viral hepatitis, Gilbert syndrome, blood group incompatibilities);
• Paediatric substudy: Patient was born before 37 weeks gestation;
• Paediatric substudy: Patient weight <5 kg at study enrolment;
• Paediatric substudy: Patient was diagnosed with severe intra-uterine growth restriction.

E.5 End points

E.5.1

Primary end point(s)

• Change in the NPC disease severity based on the 5 domain NPCCSS
scores (ambulation, speech, swallow, fine motor skills and cognition)
from baseline (Visit 1) to 12 months;
• Safety and tolerability.

MAIN STUDY:
•Change in the NPC disease severity based on the 5 domain NPCCSS scores (ambulation, speech, swallow, fine motor skills and cognition) from baseline (Visit 1) to 12 months;
PAEDIATRIC SUB-STUDY:
•Safety and tolerability.

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 6 (12 months)

E.5.2

Secondary end point(s)

MAIN STUDY:
Key Secondary Endpoints:
• Responder analysis of patient's CGI-I score remains stable or shows
improvement at 12 months (for the United States Food and Drug
Administration [FDA] submission, this endpoint is considered
coprimary);
• Responder analysis of patient's 5 domain NPCCSS score remains
stable or improves at 12 months compared to baseline;
• Time to worsening (as defined by reaching the minimal clinically
important difference [MCID] on patient's 5 domain NPCCSS). The
MCID will be determined and documented prior to unblinding the
study;
• Proportion of patients worsening (as defined by reaching the MCID on
patient's 5 domain NPCCSS) at 6 and 12 months
• Change in full scale NPCCSS score apart from hearing domains (i.e.
Hearing and Auditory Brainstem Response) at 12 months.
Other Secondary Endpoints:
• Change in 5 domain NPCCSS score at 6 and 18 months and every
6 months thereafter until End of Extension Phase at 60 months;
• Change in full scale NPCCSS score apart from hearing domains(i.e.
Hearing and Auditory Brainstem Response) at 6 and 18 months and
every 6 months thereafter until End of Extension Phase at 60 months;
• Responder analysis of the CGI-I score remains stable or shows
improvement at 6 and 18 months and every 6 months thereafter until
End of Extension Phase at 60 months;
• Responder analysis of 5 domain NPCCSS score remains stable or
improves at 6 and 18 months and every 6 months thereafter until End
of Extension Phase at 60 months compared to baseline;
• Proportion of patients worsening (as defined by reaching the MCID on
patient's 5 domain NPCCSS) at 18 months and every 6 months
thereafter until End of Extension Phase at 60 months;
• Changes in each individual domain of the NPCCSS at 6, 12 and
18 months and every 6 months thereafter until End of Extension Phase
at 60 months;
• Change in the Niemann Pick type C Clinical Database (NPC-cdb)
score (modified "Stampfer Score" [Stampfer et al., 2013]) at 6, 12 and
18 months and every 6 months thereafter until End of Extension Phase
at 60 months;
• Change in Quality of Life (EQ-5D-Y) at 6, 12 and 18 months and every
6 months thereafter until End of Extension Phase at 60 months;
• Change in the SARA score at 6, 12 and 18 months and every 6 months
thereafter until End of Extension Phase at 60 months;
• Change in the 9HPT time at 6, 12 and 18 months, and every 6 months
thereafter until End of Extension Phase at 60 months;
• CGI-S score at 6, 12 and 18 months and every 6 months thereafter
until
End of Extension Phase at 60 months;
• CGI-I score at 6, 12 and 18 months and every 6 months thereafter
until
End of Extension Phase at 60 months.
PAEDIATRIC SUBSTUDY:
• Clinical signs and symptoms captured through physical examination;
• Change from baseline in patient weight and height;
• Change in Bayley III score: Developmental delay scoring.

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints will be at 6 months, 12 months, 18 months and every 6
months thereafter until End of Extension Phase at 60 months.

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

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)

Yes

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.8.5

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

United States

Switzerland

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

LSLV

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.2.1

Number of subjects for this age range:

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

Patients on this study will involve minors and adult patients where brain/ central nervous
system are affected and could impact their ability to give consent.

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 this study, all patients will be offered to continue into the extension phase of the study where every patient will receive arimoclomol and be followed up on an annual basis. The extension phase runs until arimoclomol has received European Union (EU) marketing authorisation (MA) or until the analysis of data from the controlled, blinded phase 12 month study period does not support the efficacy and/or safety of arimoclomol.

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

2016-05-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-19

P. End of Trial
P.	End of Trial Status	Completed

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
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