Clinical Trials Register

Summary
EudraCT Number:	2012-002302-43
Sponsor's Protocol Code Number:	CHDR1209
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-05-30
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

Netherlands - Competent Authority

A.2

EudraCT number

2012-002302-43

A.3

Full title of the trial

A study to investigate the analgesic effects of buprenorphine and milnacipram in healthy volunteers.

A.3.1

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

A study of the effect of buprenorphine in combination with milnacipran in a pain model in healthy volunteers.

A.3.2

Name or abbreviated title of the trial where available

Interaction pain study between buprenorphine and milnacipran.

A.4.1

Sponsor's protocol code number

CHDR1209

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	Dr. Reddy's Laboratories Ltd.
B.1.3.4	Country	India
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	Dr. Reddy's Laboratories Ltd.
B.4.2	Country	India
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cente for Human Drug Research
B.5.2	Functional name of contact point	Geert Jan Groeneveld
B.5.3	Address:
B.5.3.1	Street Address	Zernikedreef 10
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333CL
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31715246400
B.5.5	Fax number	31715246499
B.5.6	E-mail	GGroeneveld@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	Temgesic
D.2.1.1.2	Name of the Marketing Authorisation holder	RB Pharmaceuticals Limited
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.3.1	Product name	Buprenorpine
D.3.2	Product code	RVG 08725
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous drip use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BUPRENORPHINE
D.3.9.1	CAS number	52485-79-7
D.3.9.2	Current sponsor code	Temgesic
D.3.9.3	Other descriptive name	Buprenorphine
D.3.9.4	EV Substance Code	SUB05985MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.2
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	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	Ixel
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre
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.3.1	Product name	milnacipran
D.3.2	Product code	2217180
D.3.4	Pharmaceutical form	Capsule
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	MILNACIPRAN
D.3.9.1	CAS number	92623-85-3
D.3.9.2	Current sponsor code	Ixel
D.3.9.3	Other descriptive name	Milnacipran
D.3.9.4	EV Substance Code	SUB08965MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	25 to 50
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 infusion
D.8.4	Route of administration of the placebo	Intravenous drip use (Noncurrent)
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

Pain therapeutics, neuropathic pain, nociceptive pain, synergism between opioids and TCA.

E.1.1.1

Medical condition in easily understood language

Long term pain treatment, acute term pain treatment, combination treatment.

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	10054095
E.1.2	Term	Neuropathic pain
E.1.2	System Organ Class	10029205 - Nervous system disorders

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	10066714
E.1.2	Term	Acute pain
E.1.2	System Organ Class	10018065 - General disorders and administration site conditions

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 determine if co-administration of acute milnacipran with acute buprenorphine potentiates or synergises with the analgesic effects of buprenorphine in healthy volunteers or vice versa.

E.2.2

Secondary objectives of the trial

• To determine if co-administration of multiple-dose milnacipran with acute buprenorphine potentiates or synergises with the analgesic effects of buprenorphine in healthy volunteers.
• To investigate the safety and tolerability of co-administration of iv buprenorphine and oral milnacipran in healthy subjects.
• To examine the potential pharmacokinetic interactions between of i.v. buprenorphine and oral milnacipran in healthy subjects.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Caucasian (white) males aged between 18 and 45 years (inclusive) at screening with no clinically significant findings on the physical examination.
2. Signed informed consent prior to any study-mandated procedure.
3. Body mass index (BMI) between 18 and 30 kg/m2 (inclusive) at screening.
4. Systolic blood pressure (SBP) 100–140 mmHg, diastolic blood pressure (DBP) 60–90 mmHg, and heart rate (HR) 45–90 b.p.m. (all inclusive).
5. 12-lead electrocardiogram (ECG) without clinically relevant abnormalities at screening.
6. Haematology and clinical chemistry results within normal range to a clinically relevant extent at screening.
7. Negative results from urine drug screen at screening.
8. Ability to communicate well with the investigator and to understand and comply with the requirements of the study.

All clinical judgments will be done by the study physician and he or she will decide eligibility of the subjects based on individual evaluation for each case.

E.4

Principal exclusion criteria

1. Known hypersensitivity to any excipients of the drug formulations.
2. Previous treatment with any prescribed or OTC medications (including herbal medicines such as St John’s Wort), within 7 days prior to screening.
3. Treatment with another investigational drug within 3 months prior to screening.
4. History or clinical evidence of alcoholism or drug abuse.
5. Treatment with or consumption of inducers or inhibitors of CYP3A4 (e.g. grapefruit (juice), star fruit) or CYP2C8.
6. Excessive caffeine consumption, defined as ≥ 800 mg per day at screening.
7. History or clinical evidence of any disease, and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs.
8. Smoking within 3 months prior to screening and inability to refrain from smoking during the course of study.
9. Loss of 250 mL or more of blood within 3 months prior to screening.
10. Positive results from the hepatitis serology (except in the case of VHB for vaccinated subjects) at screening.
11. Positive results from the HIV serology at screening.
12. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
13. Legal incapacity or limited legal capacity at screening.

E.5 End points

E.5.1

Primary end point(s)

Safety & Tolerability
Change from baseline:
• vital signs (supine blood pressure [BP] and HR, SpO2 (saturation)) and body weight;
• ECG variables;
• clinical laboratory tests including urinalysis.
• simple breath count/flow spirometry

Treatment-emergent
• ECG abnormalities 24 hours after study drug administration in each treatment period.
• AEs up to 96 hours after study drug administration in each treatment period.
• SAEs from (first) study drug administration up to EOS.

Pharmacodynamics
• Cold pressor test
o Tolerance time (s)
o Intensity x time AUC (%s)
Pharmacokinetics
• Buprenorphine and nor-buprenorphine PK (LLOQ 0.2 ng/mL)
• Milnacipran PK (1-1000 ng/mL, no separation of enantiomers)

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline and around 15 minutes after the end of the medication infusion.

E.5.2

Secondary end point(s)

SECONDARY ENDPOINTS
Pharmacodynamics
• Pupil size (pupil:iris ratio) [opioid sensitive] (2 min)
• Pain threshold and tolerance levels for each nociceptive test:
o Thermal grill (VAS) [neuropathic pain model] (2 min)
o Pressure pain (muscle) (kPa), [fibromyalgia model (?)] (4 min)
o Electrical pain (skin) (mA) single stimulus [SNRI sensitive] (4 min)
o Cold pressor pain (seconds) (6 min)
o Diffuse Noxious Inhibitory Control (difference of electrical pain before and after cold pressor task) (4 min)
• Other CNS effects
o Saccadic eye movement [SNRI sensitive] (3 min)
o Body sway (postural stability) [opioid, SNRI sensitive] (3 min)
o Adaptive Tracking (Motor Co-ordination/Attention) [opioid, SNRI sensitive] (4 min)

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline and around 15 minutes after the end of the medication infusion.

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)

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)

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

After completion of the four occasions planned for the trial, PI decides to withdraw the healthy volunteer (any reason) or subjects withdraws.

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

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)

Just follow-up visit will be planned after the study completion.

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

2012-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-08

P. End of Trial
P.	End of Trial Status	Completed

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