Clinical Trials Register

Summary
EudraCT Number:	2012-000845-11
Sponsor's Protocol Code Number:	TIRCON2012V1
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-30
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

Germany - BfArM

A.2

EudraCT number

2012-000845-11

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled trial of deferiprone in patients with pantothenate kinase-associated neurodegeneration (PKAN)

Eine randomisierte, doppelblinde, plazebokontrollierte Studie zur Untersuchung von Deferiprone bei Patienten mit Pantothenat-Kinase assoziierter Neurodegeneration (PKAN)

A.3.1

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

An international trial of deferiprone in patients with iron storage brain disorders

Eine internationale Studie mit Deferiprone bei Patienten, die eine Erkrankung haben, welche durch Eisenablagerungen im Gehirn verursacht wird

A.3.2

Name or abbreviated title of the trial where available

TIRCON

A.4.1

Sponsor's protocol code number

TIRCON2012V1

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	ApoPharma Inc.
B.1.3.4	Country	Canada
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	European Commission (Main monetary support)
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	ApoPharma (Investigational Medicinal Products support)
B.4.2	Country	Canada
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ApoPharma Inc.
B.5.2	Functional name of contact point	John Connelly
B.5.3	Address:
B.5.3.1	Street Address	200 Barmac Drive
B.5.3.2	Town/ city	Toronto, Ontario
B.5.3.3	Post code	M9L 2Z7
B.5.3.4	Country	Canada
B.5.4	Telephone number	+14164017296
B.5.5	Fax number	+14164013869
B.5.6	E-mail	jconnell@apopharma.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Deferiprone 80 mg/mL oral solution
D.3.4	Pharmaceutical form	Oral solution
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	Deferiprone
D.3.9.1	CAS number	30652-11-0
D.3.9.2	Current sponsor code	V03AC02
D.3.9.3	Other descriptive name	Deferiprone
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	80
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	Yes
D.3.11.13.1	Other medicinal product type	Iron chelating Agent

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	Oral solution
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

Pantothenate kinase-associated neurodegeneration (PKAN)

E.1.1.1

Medical condition in easily understood language

Neurodegeneration with brain iron accumulation

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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

- To evaluate the change in severity of dystonia (BAD scale) in patients with PKAN treated with deferiprone for 18 months compared to placebo.
- To evaluate the patient’s global impression of condition’s improvement in patients treated with deferiprone for 18 months compared to placebo (PGI-I).

E.2.2

Secondary objectives of the trial

- To evaluate the effect of deferiprone compared to placebo on the change in globus pallidus iron levels (MRI) (subset of patients).
- To evaluate the effect of deferiprone compared to placebo on motor symptoms (UPDRS);
- To evaluate the effect of deferiprone compared to placebo on a measure of functional independence (WeeFIM or FIM);
- To evaluate the effect of deferiprone compared to placebo on quality of life (PedsQL);
- To evaluate the effect of deferiprone compared to placebo on the patient’s quality of sleep (PSQI);
- To evaluate the pharmacokinetics of deferiprone and its 3-O-glucuronide metabolite (subset of patients);
- To evaluate the safety and tolerability of deferiprone in patients with PKAN.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females 4 years of age and older at screening visit;
2. Patients must have PKAN, confirmed by genetic testing;
3. Patients having a BAD total score ≥ 3 at the screening visit;
4. Patients who have Deep Brain Stimulation (DBS) systems or Baclofen pumps in place will be eligible for the study, but they must have had a stable setting for at least two months prior to the screening visit and every effort should be made to maintain the stable setting for the duration of the study:
• Enrollment of non-DBS patients will be given priority, to maximize the proportion that can undergo imaging;
5. Sexually active female patients of childbearing potential must have a negative pregnancy test result at Screening Visit (if applicable; In cases where the Investigator determines there is no reasonable risk of pregnancy because of significant incapacity, pregnancy testing will not be performed);
6. Fertile sexually active males must use an effective method of contraception or must confirm partner’s use of effective contraception;
7. Informed consent/assent obtained before any study-related activities are undertaken;
8. Ability and willingness to adhere to the protocol including appointments and evaluation schedule

E.4

Principal exclusion criteria

1. Evidence of iron deficiency defined by Fe:TIBC ratio<15%, or serum ferritin <12 ng/mL;
2. Treatment with deferiprone in the past 12 months;
3. Previous failure of treatment with deferiprone, or previous discontinuation of treatment with deferiprone due to adverse events;
4. Evidence of abnormal liver or renal function (serum liver enzyme level(s) > 3 times upper limit of normal at screening) or clinically significant abnormal creatinine levels at screening visit;
5. Disorders associated with neutropenia (ANC < 1.5 x 109/L) or thrombocytopenia (platelet count < 50 x 109/L) in the 12 months preceding the initiation of the study medication. Exception: for patients whose neutropenia was attributed by the treating physician to episodes of infection or to drugs associated with a decline in the neutrophil count and in whom the ANC has fully recovered at the screening visit;
6. Pregnant or nursing females, females planning to become pregnant, and females of childbearing potential who are sexually active and are unwilling, or unable, to use an acceptable method of contraception
according to local requirements;
7. Initiation or discontinuation of treatment with baclofen, trihexyphenidyl, clonazepam, tizanidine within 30 days prior to baseline; treatment with botox within 60 days of baseline; and initiation or discontinuation of treatment with tetrabenazine within 90 days prior to baseline;
8. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the baseline visit;
9. Currently taking iron chelators;
10. Patients who, in the opinion of the physician, represent a high medical or psychological risk;
11. History of or active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements;
12. Patients and patient’s legal representative (if applicable) with a mental incapacity, unwillingness or language barriers precluding adequate understanding or co-operation;
13. Baclofen pump placement less than two months prior to the beginningof the study.

E.5 End points

E.5.1

Primary end point(s)

Efficacy Endpoints:
Co-Primary:
- Change in the Barry-Albright Dystonia Scale (BAD) total score from baseline to Month 18 in patients treated with deferiprone compared to placebo, as assessed by central blinded evaluation of video-tapes;
- Patient’s Global Impression of Improvement (PGI-I) from baseline to Month 18 in patients treated with deferiprone compared to placebo.
Study will be considered positive if both co-primary endpoints reach statistical significance.

E.5.1.1

Timepoint(s) of evaluation of this end point

BAD: Baseline, 6m, 12m, 18m.
PGI-I: 6m, 12m, 18m.

E.5.2

Secondary end point(s)

Efficacy Endpoints:
Secondary (deferiprone vs. placebo):
1. Proportion of patients with improved or unchanged BAD scale total score between baseline and Month 18 (responder analysis).
2. Change from baseline to Month 18 in BAD scale score per body region (eyes, mouth, neck, trunk, each upper and lower extremity), as assessed by central blinded evaluation of video-tapes
3. Proportion of patients showing an improvement on PGI-I at the Month 18 visit (responder analysis);
4. Change from baseline to Month 18 in globus pallidus iron levels as measured by MRI R2* (subset of patients).
5. Change from baseline to Month 18 in UPDRS Parts I, II, III and VI scores, respectively;
6. Change from baseline to Month 18 in global WeeFIM score (or FIM for patients > 18 years);
7. Change from baseline to Month 18 in WeeFIM (or FIM for patients > 18 years) score per item;
8. Change from baseline to Month 18 in quality of life (PedsQL);
9. Change from baseline to Month 18 in quality of sleep (PSQI).

Safety Endpoints:
1. Frequency of Adverse Events (AEs);
2. Frequency of Serious Adverse Events (SAEs);
3. Discontinuation due to AEs;
4. Hematology assessments;
5. Blood clinical biochemistry assessments;
6. ECG.

Pharmacokinetic Endpoints:

Steady state pharmacokinetics of deferiprone and its 3-O-glucuronide metabolite will be assessed in a subset of up to 24 patients over 12 hours. The following standard pharmacokinetic parameters will be derived from plasma concentrations of deferiprone:
- Cmax
- Tmax
- Cmin
- AUCSS
- T½
- Vd/F

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints: Baseline, and 2m, 3m, 6m, 9m, 12m, 15m, 18m and follow-up; except Brain MRI: Baseline and 18m.
Safety endpoints
- Physical examination: at Screening, 1.5m, 3m, 6m, 12m,18m and Follow-up.
- Hematology: at Screening, weekly after dosing starts, 1.5m, 3m, 6m, 12m,18m and Follow-up.
- Biochemistry: at Screening, 1.5m, 3m, 6m, 12m, 18m.
- ECG: at Screening and 18m.
- Adverse events and SAEs: at each study visits and by phone at weeks 1, 2, 3, 4, 5, 6 and 2m, 3m, 6m, 9m, 15m, 18m and Follow-up.

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

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

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

Yes

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

Italy

Germany

Poland

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

Based on the total individual study duration of 18 months, the last patient will have their final study visit at month 34, followed by analysis and interpretation of the results.

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