Clinical Trials Register

Summary
EudraCT Number:	2013-001601-85
Sponsor's Protocol Code Number:	UKM10_0037
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-11-14
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

Germany - BfArM

A.2

EudraCT number

2013-001601-85

A.3

Full title of the trial

Aprepitant in histamine-refractory chronic pruritus:
a multicenter, randomized, double-blind, placebo-controlled, cross-over, phase II trial

A.3.1

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

Aprepitant in chronic itching in the case of unsuccessful pretreatment with antihistamines:
a multicenter, randomized, double-blind, placebo-controlled, cross-over, phase II trial

A.3.2

Name or abbreviated title of the trial where available

APREPRU

A.4.1

Sponsor's protocol code number

UKM10_0037

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1140-6701

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	University Hospital Münster
B.1.3.4	Country	Germany
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	Federal Ministry of Education and Research (BMBF)
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Münster, Department of Dermatology
B.5.2	Functional name of contact point	Competence Center Chronic Pruritus
B.5.3	Address:
B.5.3.1	Street Address	Von-Esmarch-Str. 58
B.5.3.2	Town/ city	Münster
B.5.3.3	Post code	48149
B.5.3.4	Country	Germany
B.5.6	E-mail	sonja.staender@ukmuenster.de

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	EMEND® 80 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Ltd.
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.3.4	Pharmaceutical form	Capsule, hard
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	Aprepitant
D.3.9.3	Other descriptive name	APREPITANT
D.3.9.4	EV Substance Code	SUB20017
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	80
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, hard
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

Patients with generalized chronic pruritus (> 6 weeks duration) and showing prurigo nodularis refractory to pretreatment with antihistamines (normal dosage, four weeks)

E.1.1.1

Medical condition in easily understood language

Patients with generalized chronic itching (> 6 weeks duration) and itchy nodules in the case of unsuccessful pretreatment with antihistamines (normal dosage, four weeks)

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10037084
E.1.2	Term	Prurigo nodularis
E.1.2	System Organ Class	100000004858

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10018123
E.1.2	Term	Generalized pruritus
E.1.2	System Organ Class	100000004858

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 efficacy of aprepitant relative to placebo in reducing chronic pruritus according to the Patient Global Assessment (PGA) as measured by the Visual Ana-logue Scale (VAS, average itch, visit-obtained)

E.2.2

Secondary objectives of the trial

•To evaluate the efficacy of aprepitant relative to placebo in reducing chronic pruritus according to the PGA as measured by the
-VRS concerning itch, burning, stinging (visit-obtained)
-VAS (worst itch, visit-obtained)
-Global and dynamic score (visit-obtained)
-VRS concerning itch (diary-obtained)
-NRS (average itch, diary-obtained)
-NRS (worst itch, diary-obtained)
-Global question concerning presence of pruritus (diary-obtained)
•To evaluate the efficacy of aprepitant relative to placebo in reducing chronic pruritus as measured by the
-DLQI (visit-obtained)
-HADS (visit-obtained)
-PBI-P (visit-obtained)
-PAS of skin lesions of prurigo nodularis (visit-obtained)
•To assess the safety of aprepitant
•Subanalysis of response in atopic and non-atopic patients
•To compare the results obtained by PAS and VAS with VRS and NRS in order to analyze the sensitivity of the tools and to validate the diary-obtained measurements

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age: 18 - 70 years, both gender
2. Patients with generalized chronic pruritus (being actively present for at least 6 weeks prior to screening) AND showing prurigo nodularis of dermatological, systemic or mixed origin
3. Pruritus was refractory* to a four-week systemic antihistamine therapy (by history, any antihistamine; *no reduction of pruritus by more than two points on VAS)
4. VAS ≥ 7 (in average during one of the past two days) at Baseline
5. Signed informed consent
6. Male patients agree to use a reliable method of birth control during the study.
7. If the subject is a female of childbearing potential who:
- has been strictly abstinent 1 month prior to baseline (V2) and agrees to continue for the duration of the clinical trial and for 2 months after end of study
- and/or agrees to use a highly effective and approved contraceptive method(s) for the duration of the study and for 2 months after end of the study.
A highly effective method of contraception is defined as:
- combined oral contraceptives (estrogens and progesterone) or implanted or in-jectable contraceptives with a stable dose for at least 1 month prior to Baseline visit AND use of preservative or
- bilateral tubal ligation
- or hormonal intra-uterine device (IUD) inserted at least 1 month prior to Base-line visit AND use of preservative
- or vasectomized partner for at least 3 months prior to baseline
Or
Female of non-childbearing potential, defined as post menopausal (absence of menstrual bleeding for one year without any other medical reasons), hysterectomy or bilateral oophorectomy at Screening and Baseline visit

E.4

Principal exclusion criteria

1. Patients with
a. chronic pruritus of paraneoplastic, neurogenic, and psychogenic origin
b. pruritus of dermatologic origin with severe skin inflammation necessitating systemic anti-inflammatory therapy, for example urticaria, bullous pemphigoid, acute generalized flaring up in atopic dermatitis.
c. localized pruritus (only a single area involved)
2. Current clinically significant cardiovascular, respiratory, neurologic, hepatic, hematopoiet-ic, renal, gastrointestinal or metabolic dysfunction and/or disease unless currently con-trolled and stable
3. Subjects with an underlying known disease, a surgical or medical condition, which in the judgement of the Investigator, would put the subjects at risk (e.g., uncontrolled chronic or serious diseases which would normally prevent participation in any clinical study or might confound the study assessments (e.g. other dermatological diseases), or might interfere with the subject’s study participation (e.g. planned hospitalization during the study) at Screening and Baseline visits
4. Subjects with clinically significant abnormal laboratory values according to the Investigator at Screening visit
5. Current psychosomatic and psychiatric diseases
6. Current malignant disease and chemotherapy (e.g., hodgkins lymphoma during therapy)
7. Chemotherapy with etoposide, vinorelbine
8. Current and past use of topical (washout period 2 weeks) or systemic steroids (washout period 4 weeks) before baseline
9. Current and past use before baseline of topical and systemic antihistamines such as cetirizine or loratadine (washout period 2 weeks) [remark: During the study the intake of cetirizine as rescue medication is allowed.]
10. Current and past use before baseline of the following systemic drugs or phototherapie (washout period 4 weeks): ultraviolet A or B light therapie, cyclosporin A and other immunosuppressants, antiepileptics (e.g., midazolam) and anti-cholinergics, antidepressants, pain modulators (gabapentin/pregabalin), opioid receptor agonists or antagonists, anti-anxiety drugs, tranquilizers, hypnotics, antipsychotic drugs (e.g., pimozide)
11. Current and past use before baseline and planned intake during the study of the following drugs (washout period 4 weeks):
- drugs strongly inducing CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort (Hypericum perforatum, “Johanniskraut”),
- ketoconazole, itraconazole, voriconazol, posaconazol, clarithromycin, telithromycin, nefazodon, protease inhibitors, irinotecan
- pimozid, terfenadine, astemizole, cisapride
- tacrolimus, sirolimus, everolimus, alfentanil, dihydroergotamin, ergotamin, fentanyl, chinidin
- warfarin, phenprocoumon, midazolam, alprazolam, triazolam, acenocoumarol, tolbutamide
12. Pregnancy, breast feeding
13. Subjects currently enrolled in another investigational drug or device study or participated in such a study in the month prior to Baseline visit.
14. Known hypersensitivity to aprepitant or to any of the excipients, especially sucrose (e.g. patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency).

E.5 End points

E.5.1

Primary end point(s)

Baseline-adjusted VAS (average itch, visit-obtained) according to the PGA;
i.e., intra-individual difference in VAS at visit 4 minus Baseline visit 2, and at visit 7 minus “Baseline” visit 5, respectively

E.5.1.1

Timepoint(s) of evaluation of this end point

at visit 4 minus Baseline visit 2, and at visit 7 minus “Baseline” visit 5

E.5.2

Secondary end point(s)

1. Baseline-adjusted VRS concerning itch, burning, and stinging (visit-obtained) according to the PGA; i.e., intra-individual difference in VRS at visit 4 minus Baseline visit 2, and at visit 7 minus “Baseline” visit 5, respectively
2. Baseline-adjusted VAS (worst itch, visit-obtained) according to the PGA; i.e., intra-individual difference in VAS at visit 4 minus Baseline visit 2, and at visit 7 minus “Baseline” visit 5, respectively.
3. Global and dynamic score (visit-obtained) according to the PGA at visit 4 and at visit 7, respectively
4. Time course changes in VAS, VRS and Global/dynamic score according to the PGA (visit-obtained)
5. Time course changes in VRS concerning itch, NRS (average itch and worst itch), and global question concerning presence of pruritus according to the PGA (diary-obtained)
6. Time course changes in DLQI and HADS (visit-obtained)
7. PBI-P index (visit-obtained) at visits 4 and 5, and at visits 7 and 8, respectively, compared to Baseline visit 2
8. Baseline-adjusted PAS of skin lesions of prurigo nodularis (visit-obtained); i.e., intra-individual difference in PAS at visit 4 minus Baseline visit 2, and at visit 7 minus “Baseline” visit 5, respectively;
9. Time course changes in PAS (visit-obtained)
10. Use of rescue medication

E.5.2.1

Timepoint(s) of evaluation of this end point

1. at visit 4 minus Baseline visit 2, and at visit 7 minus “Baseline” visit 5
2.at visit 4 minus Baseline visit 2, and at visit 7 minus “Baseline” visit 5
3. at visit 4 and at visit 7
4. -
5. -
6. -
7. at visits 4 and 5, and at visits 7 and 8
8. at visit 4 minus Baseline visit 2, and at visit 7 minus “Baseline” visit 5
9. -
10. -

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

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

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

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

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

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception