Clinical Trials Register

Summary
EudraCT Number:	2013-002763-25
Sponsor's Protocol Code Number:	NT2013/Orv/Prot001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-08-01
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-002763-25

A.3

Full title of the trial

A randomised, double-blind, placebo-controlled study to evaluate the efficacy of two different dose levels of orvepitant (10 and 30 mg) compared with placebo on EGFRi-induced intense pruritus in oncology subjects
(The “RELIEVE 1” Study)

Studio randomizzato in doppio cieco e controllato verso placebo, per valutare l’efficacia di due livelli di dosaggio differenti di orvepitant (10 e 30 mg) rispetto al placebo su prurito intenso indotto da inibitori dell’EGFR in soggetti oncologici.” Studio “Relieve 1"

A.3.1

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

Study in random distribution of the treatments, one of which is placebo, where neither the Investigator nor the patient knows the study treatment taken by the patient, to evaluate the efficacy of two different dose levels of orvepitant (10 and 30 mg) compared to placebo on intense itching induced by inhibitors of epidermal growth factor receptor in patients with cancer.

Studio a distribuzione casuale dei trattamenti, uno dei quali placebo, in cui né il medico dello studio né il paziente conoscono il trattamento assunto dal paziente, per valutare l'efficacia di due livelli di dosaggio differenti di orvepitant (10 e 30 mg) rispetto al placebo su prurito intenso indotto da inibitori del recettore del fattore di crescita epidermico in soggetti oncologici.

A.3.2

Name or abbreviated title of the trial where available

RELIEVE 1

A.4.1

Sponsor's protocol code number

NT2013/Orv/Prot001

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	NeRRe Therapeutics Ltd
B.1.3.4	Country	United Kingdom
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	NeRRe Therapeutics Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CROMSOURCE SRL
B.5.2	Functional name of contact point	PROJECT MANAGEMENT DEPARTMENT
B.5.3	Address:
B.5.3.1	Street Address	Via Scuderlando 10
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37135
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390458222809
B.5.5	Fax number	+390458222812
B.5.6	E-mail	davide.garrisi@cromsource.com

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	Orvepitant
D.3.4	Pharmaceutical form	Tablet
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	Orvepitant
D.3.9.1	CAS number	579475-24-4
D.3.9.2	Current sponsor code	GW823296B
D.3.9.3	Other descriptive name	GW823296B
D.3.9.4	EV Substance Code	SUB30699
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	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Orvepitant
D.3.9.1	CAS number	579475-24-4
D.3.9.2	Current sponsor code	GW823296B
D.3.9.3	Other descriptive name	GW823296B
D.3.9.4	EV Substance Code	SUB30699
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	30
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	Tablet
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

Intense pruritus, in oncology subjects, induced by EGFRi

Prurito intenso indotto da inibitori dell'EGFR in soggetti oncologici

E.1.1.1

Medical condition in easily understood language

Intense pruritus, in oncology subjects, induced by Epidermal Growth Factor Receptor inhibitors

Prurito intenso in soggetti oncologici indotto da inibitori del recettore del fattore di crescita epidermico

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10023084
E.1.2	Term	Itching
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 orvepitant (10 and 30 mg given once daily [od], orally for 4 weeks) compared with placebo in reducing EGFRi-induced intense pruritus

Valutare l'efficacia di orvepitant (10 e 30 mg una volta al giorno per via orale per 4 settimane) in confronto a placebo nel ridurre prurito indotto da inibitori dell'EGFR

E.2.2

Secondary objectives of the trial

To assess the effects of orvepitant (10 and 30 mg od) compared with placebo on quality of life measures using the Skindex-16 Questionnaire
To assess the effects of orvepitant (10 and 30 mg od) compared with placebo on quality of sleep using the Leeds Sleep Evaluation Questionnaire (LSEQ)
To assess the safety and tolerability of orvepitant (10 and 30 mg od, orally for 4 weeks)

valutare gli effetti di orvepitant (10 e 30 mg una volta al giorno) in confronto a placebo sulla qualità della vita misurata con il questionario Skindex-16
valutare gli effetti di orvepitant (10 e 30 mg una volta al giorno) in confronto a placebo sulla qualità del sonno tramite Leeds Sleep Questionnaire (LSEQ)
valutare la sicurezza e la tollerabilità di orvepitant (10 e 30 mg una volta al giorno, per 4 settimane)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male and female subjects > 18 years of age
• Subjects with a diagnosis of malignant solid tumours and undergoing treatment with one of the following EGFRi medicines [cetuximab (Erbitux®), panitumumab (Vectibix®), erlotinib (Tarceva®), lapatanib (Tyverb®), gefitinib (Iressa®]. Subjects expected treatment duration with their EGFRi must exceed the study duration
• Subjects experiencing intense pruritus symptoms following treatment with one of the following EGFRi medicines [cetuximab (Erbitux®), panitumumab (Vectibix®), erlotinib (Tarceva®), lapatanib (Tyverb®), Gefitinib (Iressa®]. Intense pruritus symptoms are defined by subjects reporting a clinic visit NRS score ≥ 7, (where 0 = No Itch and 10 = Worst Itch Imaginable) at the Screening visit, confirmed again at Baseline visit:
• Willing to refrain from all non-permitted concomitant medication from the Screening visit through to the Week 8 visit
• Willing to refrain from all insomnia medication for the duration of the study
• ECOG performance status of 0 to 2
• Life expectancy of > 6 months in the opinion of the Investigator
• Female subjects of childbearing potential must have a negative serum pregnancy test at Screening and urine pregnancy test result at Baseline and practice a reliable method of contraception throughout the study. A female is considered of childbearing potential unless she is:
o postmenopausal for at least 12 months prior to study drug administration;
o without a uterus and/or both ovaries; or
o Has been surgically sterile for at least 6 months prior to study drug administration.
Reliable methods of contraception are:
o Hormonal methods or intrauterine device in use > 90 days prior to study drug administration;
o Barrier methods plus spermicide in use at least 14 days prior to study drug administration; or
o Vasectomized partner
• Female subjects of childbearing potential who are not sexually active may not be required to practice a reliable method of contraception. These subjects may be enrolled at the Investigator's discretion if they commit to remain sexually inactive during the study and understand the possible risks in getting pregnant during the study
• Able to understand and comply with the requirements of the study and sign the Informed Consent Form
• Laboratory values (Haematology, Biochemistry and Urinalysis values) will be appropriate for subjects with cancer diagnosis, under treatment with EGFRis and dependent on the Investigator’s clinical judgement, where the ranges are not specified below:
o Haematology:
 Haemoglobin
 Haematocrit
 Red blood cell (RBC), Mean Corpuscular Volume (MCV), Mean Corpuscular Haemoglobin (MCH), Mean Corpuscular Haemoglobin Concentration (MCHC)
 White blood cell (WBC) count and differential
 Neutrophils ≥ 1,500 /dL
 Platelets ≥ 100,000 /dL
o Biochemistry:
 Serum creatinine ≤ 1.5 mg/dL
 Total bilirubin < 2.0 mg/dL
 Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) and alanine transaminase (ALT [serum glutamate pyruvic transaminase, SGPT]) ≤ 2.5 x upper limit of normal (ULN)
 Uric acid, total protein, albumin, gamma glutamyl transpeptidase (gamma GT), glucose, phosphorous, potassium, sodium, calcium, and chloride
o Urinalysis:
 Dipstick test: protein, blood, ketones, glucose; microscopy will be done on urine samples if the result of the dipstick test for protein or blood is abnormal, but dependent on the site of the subject’s cancer (to be reviewed as not clinically significant by the Investigator)

E.4

Principal exclusion criteria

• Treatment for any other type of pruritus within the previous 3 months (e.g. pruritus in atopic eczema or non-EGFRi-related skin diseases, nephrogenic pruritus, cholestatic pruritus)
• Prior use of aprepitant (Emend®) or fosaprepitant (Ivemend®), NK-1 antagonists licensed as antiemetics in cancer therapy within 4 weeks of the Screening visit
• History of hypersensitivity or idiosyncratic reaction to any excipients/components of the test medication
• Female subjects who are pregnant (positive urine pregnancy test), breast-feeding, or who are of childbearing potential and not practicing a reliable method of birth control (except those who are not sexually active)
• Prior history of seizure or traumatic brain injury
• Subjects with known or suspected brain tumour or metastases
• Any current diagnosis or history of a clinically significant abnormality of the neurological system (including demyelinating disorders such as multiple sclerosis, peripheral neuropathic demyelinating or axonal disorders, dementia and other cognitive disorders or significant head injury)
• Any moderate to severe acute illness which in the opinion of the Investigator would interfere with the study procedures or study outcome
• History of unstable cardiac, endocrine, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major diseases deemed clinically significant by the Investigator, but consistent with diagnosis of solid tumours
• History of poor co-operation, non-compliance with medical treatment, or unreliability
• Participation in any clinical research study evaluating another investigational drug or therapy within 30 days or at least 5 half-lives (whichever is longer), of the investigational drug prior to consenting to study entry

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint will be the change from Baseline of the mean from the last 3 recordings of Week 4 assessed by subject recorded NRS-IVRS. The NRS-IVRS values are recorded in response to the question on the average pruritus intensity.
Baseline measurement will be the mean daily NRS-IVRS assessments collected between Screening and the first dose of study medication (prior to first bedtime dose).

E.5.1.1

Timepoint(s) of evaluation of this end point

4 weeks

E.5.2

Secondary end point(s)

• Change from Baseline at Weeks 1, 4 and 8 in the Skindex-16 QoL
• Change from Baseline at Weeks 1, 4 and 8 in the LSEQ
• The change from Baseline of the mean from the last 3 recordings of each week assessed by subject recorded NRS-IVRS
• The change from Baseline of the mean of all values for each week assessed by subject recorded NRS-IVRS
• The change from Baseline at Weeks 1, 4 and 8 assessed by clinic visit NRS
• The VRS at Weeks 1, 4 and 8
• Effect on pruritus intensity of orvepitant (10 and 30 mg) compared with placebo measured using NRS-IVRS as a change from Baseline at each day during Week 1 (Days 2, 3, 4, 5, 6, 7 & 8)
• Change from Week 4 to Weeks 5, 6, 7 and 8 assessed by NRS-IVRS and clinic visit NRS (Week 8)
• Rescue medication usage, EGFRi dose reductions, and withdrawal from the study due to intense uncontrolled pruritus

E.5.2.1

Timepoint(s) of evaluation of this end point

8 weeks

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

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

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

Last Patient Last Visit

Ultima visita ultimo paziente

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 months

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

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)

None

Nessuno

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

2013-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-24

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-06-16

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