Clinical Trials Register

Summary
EudraCT Number:	2013-003357-17
Sponsor's Protocol Code Number:	Ketamin_SST01
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-11-04
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

Denmark - DHMA

A.2

EudraCT number

2013-003357-17

A.3

Full title of the trial

RESET Trial

A randomized, double-blinded, single-centre, parallel-group, placebo-controlled, prospective trial of S-ketamine for pain treatment in chronic pancreatitis (RESET trial)

”RESET trial” - A randomized, double-blinded, single-centre, parallel-group, placebo-controlled, prospective trial of S-ketamine for pain treatment in chronic pancreatitis.e enter information in other language that is applicable

A.3.1

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

The Ketamine - a novel approach to treating painful chronic pancreatitis.

Ketaminstudiet. En ny tilgang til behandling af smerter på grund af kronisk betændelse i bugspytkirtlen

A.3.2

Name or abbreviated title of the trial where available

RESET Trial

A.4.1

Sponsor's protocol code number

Ketamin_SST01

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	Prof. Asbjørn Mohr Drewes
B.1.3.4	Country	Denmark
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	Center of Mech-Sense, Department of Gastroenterology, Aalborg University Hospital
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Center of Mech-Sense, Department of Gastroenterology, Aalborg University Hospital
B.5.2	Functional name of contact point	Anne Estrup Olesen
B.5.3	Address:
B.5.3.1	Street Address	Mølleparkvej 4
B.5.3.2	Town/ city	Aalborg
B.5.3.3	Post code	9000
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4597663523
B.5.6	E-mail	aneso@rn.dk

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	S-Ketamin
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	S-ketamin
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral 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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Midazolam
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord, Matrix, B. Braun, ViroPharma
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Midazolam
D.3.4	Pharmaceutical form	Solution for injection/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

Chronic Pancreatitis

Kronisk pankreatitis

E.1.1.1

Medical condition in easily understood language

Chronic Pancreatitis

Kronisk betændelse i bugspytkirtlen.

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10009093
E.1.2	Term	Chronic pancreatitis
E.1.2	System Organ Class	100000004856

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	HLT
E.1.2	Classification code	10033646
E.1.2	Term	Acute and chronic pancreatitis
E.1.2	System Organ Class	100000004856

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

In the clinical part the aim is to investigate the analgesic effect of S-ketamine on clinical pain resulting from CP. Hence, the primary clinical objective is to understand the effect of S-ketamine on the daily pain experienced by patients with CP as documented in a pain diary. The experimental part of the study aims at evaluating the effect of S-ketamine in controlled and standardized circumstances. Hence, using an experimental pain model the primary objective of the experimental study is to understand the analgesic and anti-hyperalgesic mechanisms of action underlying S-ketamine’s efficacy. In addition, basic pain mechanisms in CP will be explored and experimental pain models will be used to predict the clinical efficacy of s-ketamine based on patients’ sensory profile prior to treatment. Subjects will have a brain MR-I at baseline, end of study medication and at the end of the study.

E.2.2

Secondary objectives of the trial

Secondary objectives are to understand the effect of S-ketamine on quality of life, physical functioning including symptoms of anxiety and depression. Further secondary objectives are to understand the safety, tolerability and absorption of S-ketamine in this patient population.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

 Patients from the ages of 18 with a diagnosis of CP diagnosed using the Mayo Clinic diagnostic criteria. Both diabetic and non-diabetic patients will be allowed to enter the study.
 The participants must be able to read and understand Danish.
 The patients must suffer from chronic abdominal pain characteristic for CP, meet the criteria for chronic pain (pain ≥ 3 days per week in at least 3 months) and must consider their pain as insufficiently treated with their usual analgesic treatment.
 Personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.
 Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests and other trial procedures.

E.4

Principal exclusion criteria

 Patients with any clinically significant laboratory abnormalities that in the opinion of the investigator may increase the risk associated with trial participation or may interfere with the interpretation of the trial results.
 Undiagnosed or untreated severe hypertension.
 Unstable angina.
 Congestive heart failure.
 Any condition with elevated intracranial pressure.
 Untreated thyrotoxicosis.  Alcohol dependence (Alcohol use in accordance with the recommendations by the Danish Health and Medicines Authority are allowed).
 Illegal drug dependencies.
 Patients with evidence or history of medical or surgical disease of importance for this study as judged by investigator.
 Patients treated with S-ketamine during the previous 4 months.
 Treatment with an investigational drug within 4 months preceding the first dose of study medication of importance for this study as judged by investigator.
 Female patients who are pregnant or lactating, or intend to become pregnant and male patients who intend to father a child during the course of the study. A pregnancy test will be conducted at baseline and after 4 weeks to ensure that female patients are not pregnant during the study medication period. The investigator will have to ensure that fertile female patients use a safe contraception method during the study and for at least 15 hours after termination of the study medication period. The following methods are considered as safe contraception methods:
o The combined oral contraceptive pill
o Intra uterine device
o Gestagen injection
o Subdermal implantation
o Hormone vaginal ring
o Transdermal plaster
 Patients must not suffer from painful conditions other than CP that make them unable to distinguish the pain associated with CP from chronic pain of other origin.
 Patients with known hypersensitivity to S-ketamine or any of its components.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy parameter to be evaluated is pain relief. In the clinical part of the study the efficacy is assessed as changes in the daily experience of pain, which will be measured using a patient pain diary based on the visual analog scale (VAS). Maximum intensity and average daily VAS will be recorded on daily basis.

E.5.1.1

Timepoint(s) of evaluation of this end point

After termination of the study at day 91.

E.5.2

Secondary end point(s)

Experimental endpoints:

Recording of experimental pain measures will be employed at baseline, during s-ketamine or placebo infusion, after four weeks of S-ketamine or placebo, and during the last visit at day 91 to unravel the mechanisms underlying anti-hyperalgesic and analgesic effects of S-ketamine. Furthermore, experimental baseline recordings will be compared to recordings from a group of healthy controls to evaluate general aspects of pain processing in CP.
The following experimental pain measures will be employed:
 Tetanic electric stimulation (pancreatic viscerotome and control area).
 Pressure stimulation (pancreatic viscerotome and control area) and muscle (quadriceps).
 Electric stimulation (pancreatic viscerotome and control area) with recording of evoked brain potentials (EPs).
 Contact heat evoked potentials (CHEPS) (pancreatic and control area).
 Somatosensory EPs with recovery cycle estimation (median nerve).
 Nociceptive reflexes.
 Temporal summation to repetitive electric stimulations (pancreatic and control area).
 Resting state electroencephalography (EEG).
 Conditioned pain modulation (CPM).
 Offset-analgesia with recording of EPs
The slope of the stimulus response curves and latency/amplitude of the EPs are considered secondary efficacy parameters. The analgesic effect is assessed as changes in the experimental endpoints. Pharmacokinetic parameters will also be secondary endpoints in this study. These parameters will be compared and associated to relevant experimental and clinical endpoints.

Secondary clinical endpoints:

 The ratio of responders versus non-responders defined by a decrease in VAS > 30% after four weeks compared to baseline.
 Change in opioid consumption.
 Change in quality of life using the European Organization for Research and Treatment of Cancer Quality of Life questionnaire EORTC-C30.15
 Changes in pain and physical functioning composite scores of the modified brief pain inventory-short form (mBPI-sf).16
 Change in Izbicki pain score.17
 Patient Global Impression of Change (PGIC).18
 Change in Beck’s Depression Inventory (BDI) to track changes in depressive symptoms19.
 Change in Edmonton Symptom Assessment System (ESAS) for monitoring side-effects and tolerability

E.5.2.1

Timepoint(s) of evaluation of this end point

After termination of the study at day 91.

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

Yes

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)

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

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

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

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

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.1.1.1

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

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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)

Provided in the protocol. The patients will be followed in the Out-Patients Department.

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

2013-11-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-02-28

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