Clinical Trials Register

Summary
EudraCT Number:	2012-002773-64
Sponsor's Protocol Code Number:	RP103-07
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-09-28
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

France - ANSM

A.2

EudraCT number

2012-002773-64

A.3

Full title of the trial

A Long-Term Open-Label, Safety and Superior Effectiveness Study of
Cysteamine Bitartrate Delayed-release Capsules (RP103) in Patients with
Cystinosis

A.3.1

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

A Long-Term Open-Label, Safety and Superior Effectiveness Study of
Cysteamine Bitartrate Delayed-release Capsules (RP103) in Patients with
Cystinosis

A.3.2

Name or abbreviated title of the trial where available

RP103-07

A.4.1

Sponsor's protocol code number

RP103-07

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	Raptor Therapeutics 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	Raptor Pharmaceuticals Europe BV
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PSR Goupr BV
B.5.2	Functional name of contact point	Peter van Twuyver
B.5.3	Address:
B.5.3.1	Street Address	Planetenweg 5
B.5.3.2	Town/ city	Hoofddorp
B.5.3.3	Post code	2132 HN
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	003102355632203224
B.5.5	Fax number	00310235563230
B.5.6	E-mail	peter.vantwuyver@psr-group.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/3/10/778
D.3 Description of the IMP
D.3.1	Product name	Cysteamine bitartrate (INN: mercaptamine bitartrate )
D.3.2	Product code	RP103
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
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	mercaptamine bitartrate
D.3.9.1	CAS number	CAS 27761-19
D.3.9.2	Current sponsor code	RP103
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, 75
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	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	Cystagon
D.2.1.1.2	Name of the Marketing Authorisation holder	Orphan Europe
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Cystagon
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
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	MERCAPTAMINE bitartrate
D.3.9.1	CAS number	60-23-1
D.3.9.4	EV Substance Code	SUB08770MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	50 to 150
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Cystinosis

E.1.1.1

Medical condition in easily understood language

Cystinosis

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10011777
E.1.2	Term	Cystinosis
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

Primary Objective:
To demonstrate superiority of RP103 versus Cystagon® in controlling white blood cell cystine (WBC) levels over 24 hours in patients with cystinosis and to assess long-term safety and tolerability of RP103

E.2.2

Secondary objectives of the trial

Secondary Objectives:

To compare WBC cystine measurements provided by a central
laboratory versus sites’ local (regional, not associated with the
clinical trial) laboratories.
To assess long-term quality of life and sleep using instruments
appropriate to the subjects’ age and region (US or Europe).
To assess subject dosing compliance with two different
cysteamine bitartrate formulations, Q6H immediate-release
Cystagon® versus Q12H delayed-release RP103.
To assess halitosis during Cystagon® and RP103 treatment in a
subgroup of subjects

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female with a documented diagnosis of cystinosis.
2. On a stable dose of Cystagon® for at least 21 days prior to
Screening.
3. WBC cystine level > 1 nmol ½ cystine/mg of protein on
average over at least 2 measurements collected during the 2
years prior to Screening.
4. No clinically significant change in liver function tests, i.e. 1.5
times ULN for ALT and AST, and/or 1.5 times ULN for total
bilirubin, within 6 months prior to Screening.
5. No clinically significant change in renal function, i.e.
estimated GFR within 6 months prior to Screening.
6. Must have an estimated GFR > 20 mL/minute/1.73 m2 (using
the equation from Schwartz 2009 J Am Soc Nephrol 20:629-
637) 1.
7. Female subjects who are sexually active and of childbearing
potential, i.e. not surgically sterile (tubal ligation, bilateral
oopherectomy, or hysterectomy) or at least 2 years naturally
postmenopausal must agree to use an acceptable form of
contraception from Screening through completion of the
study. Acceptable forms of contraception for this study
include hormonal contraceptives (oral, implant, transdermal
patch, or injection) at a stable dose for at least 3 months prior
to Screening, barrier (spermicidal condom or diaphragm with
spermicide), IUD, or a partner who has been vasectomized
for at least 6 months.
8. Subject or their parent or guardian must provide written
informed consent and assent (where applicable) prior to
participation in the study.

E.4

Principal exclusion criteria

Exclusion Criteria:
1. Younger than 12 years of age.
2. Current history of the following conditions or any other
health issues that make it, in the opinion of the Investigator,
unsafe for study participation:
- Inflammatory bowel disease if currently active, or
prior resection of small intestine;
- Heart disease (e.g. myocardial infarction, heart
failure, unstable arrhythmias, or poorly controlled
hypertension) within 90 days prior to Screening;
-Active bleeding disorder within 90 days prior to
Screening;
- History of malignant disease within 2 years prior to
Screening.
3. Hemoglobin level of < 9 g/dL at Screening or, in the opinion
of the Investigator, a hemoglobin level that would make it
unsafe for study participation.
4. Known hypersensitivity to cysteamine and penicillamine.
5. Female subjects who are nursing, planning a pregnancy, or
are known or suspected to be pregnant.
6. Subjects who, in the opinion of the Investigator, are not able
or willing to comply with study requirements.

E.5 End points

E.5.1

Primary end point(s)

Comparison of steady-state cysteamine-trough WBC cystine
levels between Cystagon® and RP103 over 3 months for each
treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

study visits will occur every month during both the 3 month Cystagon® treatment and the 4 month RP103 treatment period, with one additional study visit at Month 3.5 to assess WBC cystine levels for potential dose increase(s) during the first month
taking RP103. Months 1-2-3 vs. Months 5-6-7 (comparing the Cystagon and RP103 3-month treatment periods)

E.5.2

Secondary end point(s)

Safety Endpoints:
- The safety profile of RP103 will be investigated by changes
from the last study visit as noted in the following safety
assessments: physical examination, vital signs, ECG and
clinical laboratory testing. Incidence of adverse event report
(including attribution of treatment-emergent non-serious and
serious adverse events) will be recorded.

Pharmacokinetic Endpoint:
- Halitosis Substudy participants only: Cmax, Tmax and AUCs
for plasma cysteamine and expired air DMS concentrations
will be determined.

Pharmacodynamic Endpoint:
-The WBC cystine content will be measured from samples
collected within 15 minutes pre-dose under Cystagon® or 30
minutes post-dose under RP103 at each study visit.

Exploratory Endpoints:
-Central laboratory versus local laboratory WBC cystine
values.
-The longitudinal change in the use of concomitant gastric
acid reduction therapies, quality of life questionnaires, and
VAS swallowing difficulty and sleep rating scale scores.

E.5.2.1

Timepoint(s) of evaluation of this end point

Monthly Study Visits are only for patients who completed Study RP103-03 and will begin within 1 month (± 7 days) after study entry. Each patient will complete a minimum of 6 consecutive Monthly visits.
Quarterly Study Visits will commence for each patient ≥ 1 month and < 4 months after the patient has completed at least 6 consecutive Monthly visits.
Each Quarterly visit will take place by the middle of the first month (± 7 days) of each calendar quarter (i.e., January 15, April 15, July 15 and October 15).
Depending on enrollment timing, up to 6 Quarterly visits may occur over this 3 year study

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

Yes

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

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

Yes

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

Cystagon

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

Information not present in EudraCT

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

Belgium

France

Italy

Netherlands

United Kingdom

United States

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

last visit of last subject undergoing the trial.

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

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)

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)

Yes

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

Children and adolescents

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

2013-05-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-07-10

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