Clinical Trials Register

Summary
EudraCT Number:	2010-023322-21
Sponsor's Protocol Code Number:	NP031112-10B04
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:	2011-02-14
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

2010-023322-21

A.3

Full title of the trial

A multicenter, Randomized, Double-blind, Placebo-controlled, 4-arm, 26 week Parallel-Group Study to evaluate the Efficacy, Safety and Tolerability of Two Oral Doses and Two Regimes of Tideglusib vs Placebo in Mild-to-Moderate Alzheimer Disease Patients

A.3.1

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

Efficacy, Safety and Tolerability of Tideglusib to Treat Mild-to-Moderate Alzheimer's Disease Patients (ARGO)

A.3.2

Name or abbreviated title of the trial where available

ARGO

A.4.1

Sponsor's protocol code number

NP031112-10B04

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	Noscira S.A
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	Noscira S.A
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	Noscira S.A
B.5.2	Functional name of contact point	Teodoro del Ser
B.5.3	Address:
B.5.3.1	Street Address	Avda de la Industria 52
B.5.3.2	Town/ city	Tres Cantos, Madrid
B.5.3.3	Post code	28760
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34918061130
B.5.5	Fax number	+34918064953
B.5.6	E-mail	tdelser@noscira.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	tideglusib
D.3.2	Product code	NP031112-F06-037
D.3.4	Pharmaceutical form	Powder for oral suspension
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	tideglusib
D.3.9.1	CAS number	865854-05-3
D.3.9.2	Current sponsor code	NP031112-F06-037
D.3.9.3	Other descriptive name	4-benzyl-2-naphtalen-1-yl-1,2,4-thiadiazolidine-3,5-dione
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	500
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	Powder for oral suspension
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

Alzheimer's Disease (mild to moderate)

E.1.1.1

Medical condition in easily understood language

AD is a progressive neurodegenerative illness leading to cognitive, functional and behavioural disturbances

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease
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 cognitive changes after administration of
tideglusib vs. placebo at two oral doses and two treatment
regimes for 26 weeks in patients with mild to moderate
Alzheimer’s disease.

E.2.2

Secondary objectives of the trial

Key Secondary Objective
• To evaluate the safety and tolerability of two doses and two
treatment regimes of tideglusib administered for 26 weeks in
patients with mild-to-moderate Alzheimer’s disease.

Other Secondary Objectives:
• To evaluate other clinical changes in these patients after
administration of tideglusib vs. placebo at 2 oral doses and 2
treatment regimes up to 26 weeks:
o patient daily functioning
o behavior and depressive mood
o overall clinical change
o health related quality of life
o caregiver time
o urinary incontinence
• To evaluate the safety and tolerability of tideglusib over
longer periods of time (more than 26 weeks (extension study).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Men and women (of non-childbearing potential) with a
diagnosis of probable Alzheimer’s disease, according to the
NINCDS-ADRDA clinical criteria of AD and DSM-IV
criteria of dementia.
2. Age of 50 to 85 years (patients out of this range could be
included after a previous assessment by the Investigator and
approval by the sponsor).
3. Brain MRI study within 12 months before the Baseline visit
supporting the clinical diagnosis (e.g. diffuse, symmetric,
brain atrophy predominating in medial temporal regions) and
excluding other potential causes of dementia, especially
cerebrovascular lesions (see exclusion criteria, number 2).
4. Mild to moderate stage of Alzheimer’s disease according to
MMSE score 14 to 26.
5. Evidence of cognitive and/or functional decline in the past 6
months (in comparison with previous assessments) based
either on a formal rating scale or a structured interview.
6. No relevant depression as indicated by score in Geriatric
Depression Scale below or equal to 10
7. Female patients must be either at least one year
postmenopausal (confirmed by FSH >20) or surgically
sterilized. Male patients must be willing to use barrier
contraception (condom) during the study and for six months
after the last treatment administration if their partners are
women of child-bearing potential.
8. Good general health, hydration and nutrition status for
participating in this clinical trial
9. Patients living at home or in long stay residential or care
settings not requiring continuous and extensive nursing care;
able to walk independently with or without a walking aid (e.g.
cane or walker)
10. Ability to swallow a water suspension.
11. The patient and the caregiver are fluent in the language used
for administration of the rating scales and cognitive tests and
have sufficient visual, hearing, reading and writing skills to
perform all the planned assessments.
12. Well-tolerated treatment with one of the approved
Acetylcholinesterase-Inhibitors (Donepezil, Galantamine or
Rivastigmine) and/or Memantine in a stable dose for at least 4
months prior to baseline evaluations. Any of these drugs must
be anticipated not to be started or adjusted during the ongoing
study
13. A caregiver/nurse is available and is living in the same
household or interacts with the patient at least 10 hours/week
to assure the correct storage, preparation and administration of
the study drug, as well as to provide information about
patient’s physical and behavioral symptoms and changes.
14. Patients and caregivers must be able to understand and agree
to comply with the prescribed dosage regimens and
procedures, attend regularly scheduled visits and reliably
communicate effectively with the investigator team.
15. Signed informed consent by patient (and/or legal
representative if applicable) and caregiver prior to the
initiation of any study-specific procedure.

E.4

Principal exclusion criteria

1. Hospitalization within 4 weeks prior to or during screening period or change of chronic concomitant medication (except vitamins or nutritional supplements) within 4 weeks prior to baseline.

2. Clinical, laboratory or neuroimaging findings consistent with :

- other primary degenerative dementia

- cerebrovascular disease as major, cortical, strategic infarction or more than 2 lacunar infarcts, or extensive white matter lesions scoring 3, or multi-infarct dementia.

- other central nervous system lesions

- other relevant infectious, metabolic or systemic diseases affecting central nervous system

3. A current DSM-IV diagnosis of schizophrenia, bipolar disorder or active major depression.

4. Any chronic liver disease as indicated by out of range values of ALAT, ASAT or direct bilirubin, clinically relevant hepatic steatosis or other clinical manifestations of liver disease

5. Clinical or historical evidence of active hepatitis or positive serology for hepatitis B or C

6. History of hepatic drug intolerance or any significant drug allergy

7. Any clinically significant, advanced or unstable disease that may interfere with evaluations, may bias the assessment of patient's clinical or mental status or put the patient at special risk, such as:

- uncontrolled diabetes mellitus ( Hb1Ac >8.5%)

- renal insufficiency (serum creatinine >2mg/dl and creatinine clearance ≤ 60 mL/min according to Cockgroft-Gault formula)

- respiratory insuficiency

- myocardial infarction, unstable angina within 3 months before screening

- heart failure, cardiomyopathy

- persistent bradycardia (heart beat <50/min) or tachycardia (heart beat >100/min)

- episodes of unstable or uncontrolled blood pressure (systolic >160 or <90 mm Hg, or diastolic >100 or <45 mm Hg) in the 2 months prior to Baseline visit.

- atrioventricular block (type II/Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or marked prolongation of QTc F interval (>450 msec for males and >470 msec for females).

- active, peptic ulceration or gastrointestinal bleeding within 6 months

- malignant tumors or metastases within 3 years except indolent prostate or skin malignancies (other than melanoma)

8. Chronic daily drug intake of:

- drugs metabolized by the CYP3A4 with narrow therapeutic window

- systemic anticholinergics with relevant action on central nervous system

- tricyclics, MAO inhibitors or opiod analgesics

- sedatives with the exception of sleep inducers

- neuroleptics except quetiapine (max 25 mg/d) or risperidone (max 1 mg/d)

- nootropics

- paracetamol (more than 1000 mg/day)

- centrally active anti-hypertensive drugs

- immunosuppressants

- systemic cortico-steroids

- tacrine, lithium or valproic acid within 3 months prior to the baseline visit.

9. Drug abuse or excessive alcohol intake.

10. Allergy to any components of the study treatments.

11. Enrollment in another study within 3 months.

12. Investigator opinion that makes the patient to be non-compliant.

E.5 End points

E.5.1

Primary end point(s)

The changes from Baseline of the 3 active study medication
groups will be compared with the placebo group in:
• Alzheimer’s Disease Assessment Scale – Cognitive subscale
(ADAS-Cog+)

E.5.1.1

Timepoint(s) of evaluation of this end point

Core study: baseline, week 6, w12 and w26

Extension period: w39, w52. w65(final)

E.5.2

Secondary end point(s)

The changes from Baseline of the 3 active study medication
groups will be compared with the placebo group in the following
scales:

• Alzheimer’s Disease Cooperative Study Unit Activities of
Daily Living (ADCS-ADL).
• Mini Mental State Examination (MMSE)
• Word Fluency test
• Neuropsychiatric Inventory (NPI)
• Geriatric Depression Scale (GDS)
• Clinical Global Impression of Change (CGIC)
• Clinical Global Impression of Severity (CGIS)
• European Quality of life Instrument (EQ-5D)
• Caregiver time (RUD Lite)
• Questionnaire on urinary incontinence

E.5.2.1

Timepoint(s) of evaluation of this end point

Core study: baseline, w12 and w26

Extension period: w39, w52. w65(final)

Some of the sencondary end points are not assesed on week 39 and 52 (word fluency, Neuropsychiatric Inventory, EQ-5D y Clinical Global Impression of Severity-Change)

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

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

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

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

Last patient last visit

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