Clinical Trials Register

Summary
EudraCT Number:	2008-004794-18
Sponsor's Protocol Code Number:	KF6005/02
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-11-17
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

UK - MHRA

A.2

EudraCT number

2008-004794-18

A.3

Full title of the trial

A randomized Phase IIa trial evaluating the safety and efficacy of a new centrally acting analgesic in subjects with pain due to diabetic polyneuropathy

A.4.1

Sponsor's protocol code number

KF6005/02

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Grünenthal GmbH
B.1.3.4	Country	Germany
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	GRT6005 hemi-citrate oral solution in Macrogol 400 (400 µg GRT6005 / mL)
D.3.2	Product code	GRT6005
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	GRT6005
D.3.9.3	Other descriptive name	6’-Fluoro-4’,9’-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1’(3’H)-pyrano[3,4-b]indol]-4-amin
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	400
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	MST Continus
D.2.1.1.2	Name of the Marketing Authorisation holder	Mundipharma GmbH
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.3.1	Product name	Over-encapsulated Morphine sulphate prolonged-release capsules 60 mg (MST Continus®)
D.3.4	Pharmaceutical form	Capsule*
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	MORPHINE SULPHATE
D.3.9.3	Other descriptive name	MORPHINE SULPHATE
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	60
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Oral solution
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
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

painful diabetic polyneuropathy

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10012685
E.1.2	Term	Diabetic polyneuropathy

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 analgesic efficacy of GRT6005 in subjects with moderate to severe pain due to diabetic polyneuropathy

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of GRT6005 and to evaluate the relationship between plasma concentration and analgesic efficacy of GRT6005

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects must already have signed an Informed Consent Form. Subjects willing to participate in DNA research must have signed the separate Informed Consent Form for DNA research (where local regulations permit).
2. Male or female Caucasian or Hispanic subjects aged 18 years to 75 years inclusive.
3. All subjects must have type 1 or type 2 diabetes mellitus, and must have a documented clinical diagnosis of painful DPN with symptoms and signs for at least 3 months, and pain present at the time of Enrollment.
4. The Investigator considers the subject’s blood glucose to be well controlled by a diet, oral hypoglycemics, or insulin for at least 3 months prior to enrolling in the trial. This control should be documented by a concentration of glycosylated hemoglobin (HbA1C) no greater than 11% at the Enrollment Visit.
5. Subjects that have been taking opioid or non opioid analgesic medication for the painful DPN before the Enrollment Visit must be dissatisfied with their current treatment.
6. A daily average pain intensity score of ≥4 on the 11 point NRS on at least 3 consecutive days without the use of rescue medication within the 5 day Enrollment Pain Intensity Evaluation Period.
7. Male subjects have to use barrier contraception (condom) during sexual intercourse with females, and no sex with females who are pregnant or lactating will be allowed from the time of dosing of GRT6005 hemi-citrate until 1 month after the final Treatment Period.
Sexually active female subjects must be postmenopausal for at least 2 years, surgically sterile, or practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and 1 month after the final Treatment Period.
Women of childbearing potential must have a negative urine β-human chorionic gonadotropin (β-hCG) pregnancy test at the Enrollment Visit and at the Baseline Visit.

E.4

Principal exclusion criteria

Subjects who meet any of the following criteria will be excluded from participating in the trial:
General:
1. Concurrent participation in another trial, or within 3 months of enrollment into this trial.
2. Previous participation in this or other trials with GRT6005.
3. History of alcohol or drug abuse according to the Investigator’s judgment, based on subject history and physical examination.
4. Known or suspected of not being able to comply with the protocol and with the use of the IMP.
5. Female subjects who are pregnant or breastfeeding.
6. Any clinically significant disease that in the Investigator's opinion may affect efficacy or safety assessments or may compromise the subject’s safety during trial participation, such as, e.g., significant pulmonary, gastrointestinal, endocrine, metabolic (with the exception of diabetes mellitus), neurological, psychiatric disorders (resulting in disorientation, memory impairment or inability to report accurately; for instance, schizophrenia, Alzheimer’s disease).
7. Employees of the Investigator or trial site, with direct involvement in the proposed trial or other trials under the direction of that Investigator or trial site, as well as family members of employees or the Investigator.
8. Subjects with impaired hepatic function determined by international normalized ratio of prothrombin time greater than 1.7 and bilirubin greater than 2.0 mg/dL and albumin lower than 2.8 g per dL or impaired hepatic function with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3-fold the upper limit of normal (ULN).
9. History of moderate to severe hepatic impairment; chronic hepatitis B or C, presence of active hepatitis B or C within the past 3 months.
10. Subjects with impaired renal function as determined by chronic kidney disease stage higher than 2 (K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease 2002).
11. Any chronic gastrointestinal disease or previous major abdominal surgery (e.g., Billroth procedure or enteroanastomosis) that might affect drug absorption, or excretion.
12. Significant cardiac disease (e.g., unstable angina pectoris, angina pectoris Canadian Cardiovascular Society (CCS) Class III IV, acute myocardial infarction within the last 3 months, cardiac insufficiency New York Heart Association (NYHA) Class III IV).
13. At the Enrollment Visit and the Baseline Visit, electrocardiogram (ECG) with clinically relevant findings, e.g., marked repolarization abnormality (e.g., suspicious or definite congenital long QT syndrome) and/or QT values of: QTcF for females ≥450 ms, QTcF for males ≥430 ms, uncorrected QT ≥500 ms.
14. Any of the following within 1 year: mild/moderate traumatic brain injury, stroke, transient ischemic attack, brain neoplasm. Severe traumatic brain injury within the last 15 years (consisting of 1 or more of the following: brain contusion, intracranial hematoma, either unconsciousness or posttraumatic amnesia lasting more than 24 h) or residual sequelae suggesting transient changes in consciousness. Life long history of seizure disorder or epilepsy.
15. History of malignancy within the past 2 years, with the exception of basal cell carcinoma that has been treated and is no longer present.
16. Subjects unable to discontinue any of the prohibited medications.
17. Subjects whose body weight is lower than 50 kg.
Trial specific
1. Past or pending litigation due to chronic pain or disability.
2. Any scheduled surgery or painful procedure during the course of the trial that, in the opinion of the Investigator, may affect efficacy or safety assessments.
3. Clinically relevant history of hypersensitivity, allergy, or contraindications to opioids, paracetamol and Macrogol 400 Ph.Eur.
4. Presence of conditions other than painful DPN that could contribute to pain or confound the assessment of self-evaluation of pain, for instance fibromyalgia, complex regional pain syndrome, phantom pain, significant skin conditions such as abscesses, significant osteoarthritis, low back pain, inflammation (e.g., rheumatoid arthritis, ankylosing spondylitis), and vasculitis.
5. Significant vascular disease (e.g., peripheral occlusive arterial disease, Fontaine Class III–IV; venous insufficiency, post thrombotic syndrome, Stage III/IV).
6. Severe or extensive diabetic ulcers or amputations (more than 2 toes) of the limbs, or Charcot joints.
7. Conditions which require treatment with prohibited medication.

E.5 End points

E.5.1

Primary end point(s)

Reduction from Baseline in average daily pain intensity score (over the last 24 h) measured with the 11 point NRS at the final treatment day of each treatment period, in comparison to placebo.
On the basis of data from different doses, a dose response relationship will be assessed. When plasma levels are above the lower limit of quantification, the concentration response relationship will be assessed as well.

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

Yes

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

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)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

Information not present in EudraCT

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.1.1.1

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.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

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.4.2.1

In the EEA

108

F.4.2.2

In the whole clinical trial

108

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)

Subjects will return to normal treatment end of the trial.

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

2009-01-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-01-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2010-05-24

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