Clinical Trials Register

Summary
EudraCT Number:	2010-023048-34
Sponsor's Protocol Code Number:	NT-KO-003-2010-01
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:	2011-05-10
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

Germany - BfArM

A.2

EudraCT number

2010-023048-34

A.3

Full title of the trial

A Phase IIa Multicenter Double Blind Study to Evaluate the Efficacy and Safety of low doses of oral Diazoxide for the treatment of Multiple Sclerosis.

A.3.1

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

A Phase IIa Multicenter Double Blind Study to Evaluate the Efficacy and Safety of low doses of oral Diazoxide for the treatment of Multiple Sclerosis.

A.3.2

Name or abbreviated title of the trial where available

NeuroAdvan

A.4.1

Sponsor's protocol code number

NT-KO-003-2010-01

A.5.4

Other Identifiers

Name:

NeuroAdvan

Number:

NT-KO-003-2010-01

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	NEUROTEC PHARMA, S.L
B.1.3.4	Country	Spain
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	NEUROTEC PHARMA, S.L
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	ADVANCELL, Advanced In Vitro Cell Technologies SA
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	TFS Develop
B.5.2	Functional name of contact point	Marta León
B.5.3	Address:
B.5.3.1	Street Address	Consell de Cent, 334-336, 4ª planta
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08009
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34 93 185 02 00
B.5.5	Fax number	+34 93 185 02 57
B.5.6	E-mail	marta.leon@tfscro.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	Diazoxide
D.3.2	Product code	Diazoxide
D.3.4	Pharmaceutical form	Film-coated tablet
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	Diazoxide
D.3.9.1	CAS number	364-98-7
D.3.9.2	Current sponsor code	Diazoxide
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	4
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Diazoxide
D.3.2	Product code	Diazoxide
D.3.4	Pharmaceutical form	Film-coated tablet
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	Diazoxide
D.3.9.1	CAS number	364-98-7
D.3.9.2	Current sponsor code	Diazoxide
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	0.3
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
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.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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)	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	Film-coated tablet
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

Multiple Sclerosis Treatment.

E.1.1.1

Medical condition in easily understood language

Multiple Sclerosis

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10063399
E.1.2	Term	Relapsing-remitting multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system 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

To evaluate the efficacy of Diazoxide on patients with Relapsing Remitting MS (RRMS), measured as the cumulative number of new lesions observed in all MRIs, with exception of baseline.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of Diazoxide in patients with RRMS, measured as the cumulative number of new lesions (gadolinium enhancing lesions and T2 lesions) in all MRIs. To evaluate the clinical efficacy of Diazoxide in patients with RRMS, measured as relapses rates and EDSS scale.To evaluate the safety of treatment of Diazoxide in patients with RRMS, measured as the incidence of adverse events. Other objectives: 1a. Functional response markers (macrophage cells): Macrophage cells assays will be used for ex vivo functional studies (TNF-alfa and IL-1beta production after stimulation with lipopolysaccharide in pre-treated cells with Diazoxide) that will classify patients based on their good or poor response to treatment. 1b. Drug levels: Drug levels will be evaluated at baseline and time 3 and 6 months.

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

Genetic Substudy (Biomarkers): V4.0 15 April 2011. to assess the biomarkers efficacy of treatment in patients with RRMS: RNA to analyze the expressions of genes involved in disease progression and drug efficiency. DNA to identify the polymorphisms associated with metabolism and activity of Diazoxide, genes related to the mechanism of action or drug metabolism. In order to assess neuroprotection a sub-study using OCT will be performed.

E.3

Principal inclusion criteria

1. Patients who meet the diagnosis criteria for MS according to guidelines provided by McDonald et al (1).
2. Patients who meet the diagnosis criteria for RRMS.
3.Patients with clinical disability measured by EDSS score between 0 and 5.0 inclusive.
4.Patients who present at least 1 relapse in the previous 2 years or presence of at least 1 gadolinium-enhanced lesion in the previous 1 year.
5. Patients aged between 18 to 55 years old, either gender.
6. Patients who have signed the Informed consent/s (it has to be obtained prior to start any procedure related to study protocol)

E.4

Principal exclusion criteria

1. Patients who are candidates for treatment with drugs modifying the course of the disease according to the criteria of the Regulatory Agencies in each country, unless the patient refuses to initiate such therapy or decide to postpone the start of this therapy.
2. Patients with relapse in the 30 days period before baseline visit.
3. Patients in treatment with Diazoxide.
4. Medical conditions such as hypotension, insulinome, hyperuricemia.
5. Patients with Diabetes defined by ADA criteria (2).
6. Other conditions: drug abuse, inability to consent, or inability to perform all the procedures for the Clinical Trial.
7. Contraindications for MRI studies: claustrophobia, heart pacemaker or any other condition that would preclude proximity to strong magnetic field.
8. Contraindications for treatment with Diazoxide or excipients: Allergies, hypersensitivity, or others.
9. Patients with known allergy or with contraindications to the administration of intravenous gadolinium-based agents (chronic or acute renal failure according to The Renal Association or NICE guidelines (3)).
10. Corticosteroid therapy in the last month.
11. Interferon-beta or Glatiramer acetate therapy in the last 3 months.
12. Natalizumab therapy in the last 6 months.
13. Patients treated with chemotherapy (Mitroxantone, Azathioprine, Cyclophosphamide, Cladribine, Methotrexate) or monoclonal antibodies that deplete populations of cells (rituximab, alentuzumab, ocrelizumab, daclizumab) in the last 12 months or have entered in previous trials with treatments in development in the last 3 months.
14. Patients participating in another Clinical Trial at the moment of the screening visit.
15. Patient who had received a liver transplantation or candidates for liver transplantation.
16. Positive pregnancy test, breast feeding women or of childbearing potential not using highly effective methods of contraception. Note: For women of childbearing potential, a highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (intrauterine device, hormonal), sexual abstinence or vasectomised partner).
17. Male patients that do not follow adequate contraceptive measurements.
18. Fingolimod therapy in the last 6 months
19. Persons who have been committed to an institution by virtue of an order issued either by the judicial or administrative authorities

E.5 End points

E.5.1

Primary end point(s)

Efficacy variables:
Primary: Efficacy (by Magnetic Resonance imaging, MRI), MRI with double dose of contrast (A gadolinium compound at a dose of 0.2mmol/kg using the same contrast compound for all patients from the same center, delay time 10 minutes). Cumulative number of new lesions that enhanced with gadolinium on T1-weighted sequences (specifically the addition of new lesions observed in all MRIs, with the exception of baseline MRI).

E.5.1.1

Timepoint(s) of evaluation of this end point

six months of treatment

E.5.2

Secondary end point(s)

1. MRI

• Cumulative number of new / enlarged lesions on T2-weighted sequences in all MRIs.
• Cumulative number of new / increased lesions on T2-weighted sequences in the sixth month of starting therapy (compared to baseline MRI).
• Cumulative number of CUAL: addition of new or enlarged lesions on T2-weighted sequences that do not enhance with gadolinium and new lesions that enhance with gadolinium in all MRIs.
• Cumulative number of CUAL: addition of new or enlarged lesions on T2-weighted sequences that do not enhance with gadolinium and new lesions that enhance with gadolinium in the sixth month of starting therapy (compared to baseline MRI).
• Number of patients without lesions in gadolinium-enhancing T1-weighted sequences in the sixth month of starting therapy.

2. Efficacy (by clinical assessments), in the sixth month of starting therapy:
• Relapse-free status.
• Relapse rate.
• Number of relapses requiring corticosteroids treatment.
• Time to first relapse (during the trial).
• Change in EDSS scale.
• Quality of life, using Short form 36 Healthy Survey Questionnaire (SF-36)

3. Safety (Incidence, nature, and severity of adverse events): during the six month duration of therapy and until 15 days after the last dose of Diazoxide or placebo.
• Presence of adverse effects: control of glucose levels, glycated hemoglobin, blood pressure, presence of hirsutism.
• Presence of severe adverse effect

E.5.2.1

Timepoint(s) of evaluation of this end point

six 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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

The trial ends when 99 patients in the study have completed 6 months of treatment and visit 7 to 15 days after last dose of treatment. If a subject wants to continue with the treatment until the study ends, he/she is allowed to do so (same arm, blinded way, after resign Informed Consent, followed up separately).
The patient can continue until finalization of the core study + 3 months for data analyzing and assessment of risk/benefit. The total permitted treatment will be 21 months.

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

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero