Clinical Trials Register

Summary
EudraCT Number:	2016-001715-21
Sponsor's Protocol Code Number:	S59102
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-07-08
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2016-001715-21

A.3

Full title of the trial

Intravenous ketamine for Treatment Resistant Depression: Exploring biomarkers of response and relapse
A double-blind, randomized controlled trial

A.3.1

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

Ketamine for depression

A.4.1

Sponsor's protocol code number

S59102

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	UZ Leuven
B.1.3.4	Country	Belgium
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	IWT Agentschap voor Innovatie door Wetenschap en Technologie
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UZ Leuven
B.5.2	Functional name of contact point	PhD student
B.5.3	Address:
B.5.3.1	Street Address	Kapucijnenvoer 33 blok i - box 7001
B.5.3.2	Town/ city	Leuven
B.5.3.3	Post code	3000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	0032465273027
B.5.6	E-mail	carmen.schiweck@kuleuven.be

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	Ketamine (Ketalar by Pfizer)
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Major depressive disorder and Bipolar Disorder I and II

E.1.1.1

Medical condition in easily understood language

depression

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10037180
E.1.2	Term	Psychiatric symptoms NEC
E.1.2	System Organ Class	100000005195

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1) To replicate efficacy of intravenous ketamine in Treatment resistant depressed patients in a Belgian sample

E.2.2

Secondary objectives of the trial

2) To distinguish responders to ketamine from non-responders by different biological markers.
3) To identify markers of relapse after improvement of depressive symptoms

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Must be a man/woman of 18 or above
• Meet the DSM-IV-TR diagnostic criteria for MDD, without psychotic features (DSM-IV 296.22, 296.23, 296.32, or 296.33) or BPD Type I or II (DSM-IV 296.89), currently in a depressed episode based upon clinical assessment at Screening.
• Patients with BPD I or II should not be in a current mixed episode and should not have experienced mood incongruent psychotic features for at least 4 weeks.
• Be medically stable on the basis of physical examination, 12-lead ECG, and vital signs, performed at Screening.
• Be medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study.
• Patients should have an Inventory of Depressive Symptomatology-Clinician Rated (HAMD-17) total score ≥ 17 at Screening and/or at day 1 (pre-dose)
• Patients with major depressive disorder should have failed at least two adequate treatment courses (dose and duration) with antidepressant therapy, one of which is in the current episode. The definition of adequate antidepressant therapy can be reviewed in section 4.2..
• Subjects recently started on a new antidepressant or a new adjunctive treatment (e.g., quetiapine, lithium, etc), are eligible provided none/minimal improvement of symptoms is seen after 4 weeks of dosing.
• For patients who receive a higher/lower dose of an antidepressant medication that has previously been stable for at least 4 weeks, a duration of 2 weeks should lie between change of medication dose and screening.
• For patients who recently stopped their antidepressant medication, a washout period of 14 days applies.
• Patients may have received ECT (at least 2 weeks between last ECT and ketamine administration), or may be scheduled for ECT
• Patients with bipolar depression (BPD) Type I or II can participate if they have had 2 different mood-stabilizing therapies or antidepressants in the past.
• Patients with BPD I or II must have been taking a stable dose of a mood-stabilizing medication (see table in section 4.2.) ) for at least 4 weeks prior to ketamine infusion (day 8), dosed clinically to target the therapeutic range. If dose of the mood stabilizing medication was changed, they may participate given that no or minimal improvement is seen after 2 weeks of dosing.
• Doses of current antidepressant therapies should remain the same for the duration of the study.
• Benzodiazepines (Alprazolam, diazepam etc.) are permitted after consultation of the treating doctor. Daily doses of benzodiazepines or antipsychotic medication may vary if prescribed by the doctor but should be documented throughout the study period.
• Inpatient or outpatient, and agrees to be admitted to the study site for IV ketamine administration and remain at the study site for 4 hours post-dose
• Subjects with non-insulin dependent diabetes mellitus who are adequately controlled (not on insulin) may participate in the study.
• Patients may have received ketamine in the past if used as anesthetic, but should not have participated in another clinical trial using ketamine.

Participants must agree to use an effective method of birth control (implant, intrauterine device, male or female partner sterilization, the contraceptive pill, injectable, ring, diaphragm) for the entire period
of the study and 1 months after the last administration of the study drug.
• Heterosexually active men must inform their partner who must agree to use an effective method of birth control.
• If a woman of childbearing potential, she must have a negative urine human chorionic gonadotropin (hCG) pregnancy test at screening; and a negative urine pregnancy test at predose (day 1) before receiving any study drug.
• Be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
• Sign an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

E.4

Principal exclusion criteria

• Subject has a history of drug or alcohol abuse or dependence according to Diagnostic and Statistical Manual of Mental Disorders (4th edition) (DSM-IV) criteria, except nicotine or caffeine, within 6 months before screening.
• Subject has positive test result(s) for drugs of abuse (including opiates, cocaine, barbiturates, methadone, and amphetamine/methamphetamine) at screening or day 1 (predose).
Subjects with a positive test result at screening due to prescribed amphetamines or opioids may be enrolled in case no abuse history is known and no further indication for risk or abuse is evident to the researcher or known interactions occur with ketamine. Subjects with a positive alcohol breath test at screening may have the test repeated once during the screening phase, based on the investigator’s discretion. This determination, and the reason for permitting a repeat test, must be recorded in the subject's source documents and initialed by the investigator. A positive, repeat alcohol breath test is exclusionary.
• Subject is currently taking > 4 psychotropic medications at day 1 (predose).
• Has an autoimmune disorder such as Crohn’s disease, rheumatoid arthritis, psoriasis currently treated with/requiring treatment with immunomodulatory therapies ( interleukins, chemokines, cytokines or IMiDs). Participation depends on the study physician’s judgement.
• Has any significant cardiovascular (including a history of myocardial infarction within 6 months prior to first dose administration), respiratory (including chronic obstructive pulmonary disease), neurologic (including seizures or significant cerebrovascular disorders), renal, hepatic, endocrine, or immunologic diseases currently or within 6 months prior to the study; glaucoma; hypothyroidism or hyperthyroidism (a normal thyroid-stimulating hormone [TSH] is required at screening; subjects with hypothyroidism who are on stable treatment with normal TSH may participate) based on Screening examination.
• Has uncontrolled hypertension (diastolic blood pressure > 90 mmHg), despite diet, exercise or a stable dose of an allowed antihypertensive treatment, at screening or day 8 (predose).
• Has planned vaccination within 2 weeks prior to the first dose of study medication through 2 weeks after the last dose of study medication.
• Has an acute infectious disease/current infection based on laboratory assessment at screening. Inclusion can still be permitted if the study doctor does not estimate any health risks associated with the use of ketamine and/or participation in the study.
• Has received systemic corticosteroids within 21 days before day 1.
• Has known allergies, hypersensitivity, or intolerance to ketamine or its excipients (refer to SmPC)
• Has contraindications to the use of ketamine per local prescribing information
• Has received an investigational drug (including vaccines) or used an investigational medical device within 3 months before the planned start of study or are currently enrolled in an investigational study.
• Female subjects only: is pregnant or breastfeeding.
• Has any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements.
• Has donated 1 or more units (approximately 450 mL) of blood or had acute loss of an equivalent amount of blood within 90 days prior to study drug administration.
• Is an employee of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.

E.5 End points

E.5.1

Primary end point(s)

-Efficacy: Relief of depressive symptoms

E.5.1.1

Timepoint(s) of evaluation of this end point

At Screening (Day 1), after the IV ketamine injection (day 8), at final visit ( day 15), at follow-up: Day 21

E.5.2

Secondary end point(s)

-Experience Sampling Method
-Predicors of Response and Relapse: Biomarkers
-Psychophysiology of Stress

E.5.2.1

Timepoint(s) of evaluation of this end point

At Screening (Day 1), after the IV ketamine injection (day 8), final study visit ( day 15), at follow-up: Day 21

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

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

Identification of Biomarkers for response/relapse

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

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 with the last visit of the last subject

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)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

120

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)

Standard Care

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

2016-07-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-01-29

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