Clinical Trials Register

Summary
EudraCT Number:	2014-003956-30
Sponsor's Protocol Code Number:	CHDR1429
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-10-07
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

Netherlands - Competent Authority

A.2

EudraCT number

2014-003956-30

A.3

Full title of the trial

A single-centre randomized double-blind, double-dummy, placebo-controlled, four-way crossover study in healthy subjects to investigate the effect of ethanol 0.5 and 1.0 g/L and alprazolam 1 mg on a driving simulator and to compare the results with the NeuroCart CNS test battery.

A.3.1

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

Validate a driving simulator by determining the sensitivity of a driving simulator test battery to the effects of ethanol 0.5 and 1.0 g/L and alprazolam 1 mg, and compare results with CNS test battery scores and to explore the relationships with historical results from actual driving performance.

A.4.1

Sponsor's protocol code number

CHDR1429

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	Centre for Human Drug Research
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Centre for Human Drug Research
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	Centre for Human Drug Research
B.5.2	Functional name of contact point	J.M.A. van Gerven
B.5.3	Address:
B.5.3.1	Street Address	Zernikedreef 8
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 CL
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31715246400
B.5.5	Fax number	+31715246499
B.5.6	E-mail	clintrials@chdr.nl

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	Yes
D.2.1.1.1	Trade name	Alprazolam 1 PCH (The Netherlands)
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmachemie B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	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	Alprazolam
D.3.9.1	CAS number	28981-97-7
D.3.9.3	Other descriptive name	ALPRAZOLAM
D.3.9.4	EV Substance Code	SUB05370MIG
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	1
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
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

A total of 24 healthy subjects, both male and female, will be enrolled into the study following satisfactory completion of a screening visit where eligibility for the study will be checked.
Subjects will be recruited via media advertisement or from the subjects’ database of the Centre for Human Drug Research, Leiden, the Netherlands.

E.1.1.1

Medical condition in easily understood language

Healthy subjects aged 18 to 55, inclusive.

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Investigative Techniques [E05]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objectives:
• To assess the effect of ethanol compared to placebo on a driving simulator performance tests;
• To assess the effect of alprazolam compared to placebo on a driving simulator performance tests;

E.2.2

Secondary objectives of the trial

Secondary objectives:
• To assess the effect of alprazolam compared to ethanol on driving simulator performance tests;
• To establish the relationship between driving simulator and NeuroCart performances;
• To study the suitability of additional complex parameters of driving simulation on the assessment of drug effects.
• To explore the relationships between driving simulator and historical results from actual driving performance.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Eligible subjects must meet all of the following inclusion criteria:
1. Healthy subjects, aged 18 to 55 years, inclusive; healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including 12-lead ECG, and clinical laboratory tests.
2. Subjects are in possession of a valid driver’s license and are active and experienced drivers; this is to be determined by the investigators;
3. Evidence of a personally signed and dated informed consent form indicating that the study subject has been informed of all pertinent aspects of the study.
4. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.
5. Female subjects of childbearing potential must have a negative (β-hCG) test (at screening and before the start of each occasion) and be willing and able to use one of the following double-barrier methods of birth control: hormonal intrauterine device with condom, or oral contraceptives with condom from the screening visit to the end of study.

E.4

Principal exclusion criteria

Eligible subjects must meet none of the following exclusion criteria:
1. Confirmed or suspected myasthenia gravis, severe respiratory insufficiency, sleep apnoea syndrome, severe hepatic insufficiency or hypersensitivity to benzodiazepines;
2. Evidence or history of clinically significant haematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
3. Any condition possibly affecting drug absorption (e.g., gastrectomy).
4. A positive urine drug screen for cocaine, amphetamine, morphine, benzodiazepine and THC.
5. Subject is not able to perform the drive simulator tests.
6. History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor) within 6 months of Screening.
7. Treatment with an investigational drug within 3 months prior to screening or having participated in more than 4 investigational drug studies within 1 year prior to screening.
8. Use of (non-)prescription medications that are believed to affect subject safety or the overall results of the study following judgment by the investigator.
9. Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening.
10. Unwilling or unable to comply with the Lifestyle Guidelines described in this protocol.
11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
12. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects directly involved in the conduct of the study.

E.5 End points

E.5.1

Primary end point(s)

Pharmacodynamic driving simulator endpoints:
1. Primary driving simulator outcome: SDLP

Pharmacodynamic CNS test battery primary endpoints:
1. Adaptive tracking (average performance %);
2. Saccadic eye movements (saccadic reaction time (sec), saccadic peak velocity (deg/sec), and saccadic inaccuracy (%));
3. Smooth pursuit eye movements (percentage of the time that subject’s eyes are in smooth pursuit of the target (%));
4. Body sway (antero-posterior sway (mm/2min));
5. Visual verbal learning test (VVLT);
6. Visual Analogue Scales according to Bond and Lader (alertness, mood, and calmness subscales (mm)).

E.5.1.1

Timepoint(s) of evaluation of this end point

This is a single-centre, randomized, double-blind, double-dummy, placebo-controlled, crossover study with ethanol and alprazolam in healthy subjects while performing neurocognitive and psychomotor tests on the NeuroCart and a driving simulator. The tests will be conducted on four separate study days with a wash out period of at least three days. On each study day subjects arrive at the clinic in the morning (8AM) and perform baseline assessments. After the administration of the study drug, driving tests and CNS tests will be performed at intervals (+2, +4, +5 and +6 hours post-dosing).

E.5.2

Secondary end point(s)

Secondary driving simulator endpoints:
a. Automative behaviour (tracking, steering, vigilance, sustained attention);
b. Control behaviour (maintaining distance, passing, motor performance, maneuvers, divided attention, perception);
c. Executive planning behaviour (risk taking, impulsivity, information processing, attention, cognition, judgement).

E.5.2.1

Timepoint(s) of evaluation of this end point

Tests will be conducted on four (4) separate study days with a wash out period of at least three days. On each study day subjects arrive at the clinic in the morning (8AM) and perform baseline assessments. After the administration of the study drug, driving tests and CNS tests will be performed at intervals (+2, +4, +5 and +6 hours post-dosing).

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

E.6.5

Efficacy

E.6.6

Pharmacokinetic

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

Yes

E.6.13.1

Other scope of the trial description

This is a validation study. The purpose of the study is to determine the sensitivity of a driving simulator test battery to the effects of ethanol 0.5 and 1.0 g/L and alprazolam 1 mg, and to explore the relationships with historical results from actual driving performance. In addition, the results will also be compared with those of the NeuroCart, a validated test battery that quantifies a large range of drug-sensitive CNS-functions.

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Ethanol 0.5 and 1.0 g/L

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

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

LVLS

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

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

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

Telephonic follow-up

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

2014-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-13

P. End of Trial
P.	End of Trial Status	Ongoing

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