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Clinical Trial Results:
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)

Summary
EudraCT number	2013-002763-25
Trial protocol	IT GB
Global end of trial date	10 Jul 2015

Results information
Results version number	v1(current)
This version publication date	16 Jul 2016
First version publication date	16 Jul 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

NT2013/Orv/Prot001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

NeRRe Therapeutics Ltd

Sponsor organisation address

SBC, Incubator Building, Gunnels Wood Rd, Stevenage, United Kingdom, SG1 2FX

Public contact

Elizabeth Ballantyne, NeRRe Therapeutics Ltd, +44 07826 846960, Elizabeth.Ballantyne@nerretherapeutics.com

Scientific contact

Elizabeth Ballantyne, NeRRe Therapeutics Ltd, +44 07826 846960, Elizabeth.Ballantyne@nerretherapeutics.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Jan 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Jul 2015

Global end of trial reached?

Yes

Global end of trial date

10 Jul 2015

Was the trial ended prematurely?

Yes

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 the intensity of Epidermal Growth Factor Receptor Inhibitors (EGFRi)-induced intense pruritus.

Protection of trial subjects

The study was conducted in accordance with all applicable regulatory requirements including the ‘International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use’ (ICH) guidelines on GCP, all applicable subject privacy requirements, and, the guiding principles of the Declaration of Helsinki and all applicable amendments laid down by the world assemblies. This included, but was not limited to, the following: - IRB/IEC review and favourable opinion/approval to conduct the study and of any subsequent relevant amended documents - Written informed consent (and any amendments) to be obtained from each subject before participation in the study - Investigator reporting requirements (e.g. reporting of AEs/SAEs to IRB/IEC).

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Nov 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Italy: 40

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Adult patients experiencing intense pruritus symptoms following treatment with any EGFRi medicines for malignant solid tumours. Patients were not to have received treatment for any other type of pruritus within the previous 3 months.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

This was a double-blind study in which orvepitant 30 mg, orvepitant 10 mg and matching placebo were identical in appearance and presented as white round tablets. The randomization number for each patient was provided at the Baseline visit via randomization by connection to the Interactive Response Technology (IRT). The randomization schedule was not to be broken until the study has completed and all data queries were resolved.

Are arms mutually exclusive

Yes

Orvepitant 10 mg Tablet

Arm description

Arm type

Experimental

Investigational medicinal product name

Orvepitant 10 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg orvepitant tablets administered once daily for 4 weeks.

Orvepitant 30 mg Tablet

Arm description

Arm type

Experimental

Investigational medicinal product name

Orvepitant 30 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orvepitant 30 mg Tablets once daily for 4 weeks.

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily for 4 weeks.

Number of subjects in period 1	Orvepitant 10 mg Tablet	Orvepitant 30 mg Tablet	Placebo
Started	14	16	14
Completed	11	12	12
Not completed	3	4	2
Consent withdrawn by subject	1	1	-
Adverse event, non-fatal	1	1	-
EGFRi dose reduction / delay	1	-	1
Disease Progression	-	1	1
Protocol deviation	-	1	-

Baseline characteristics

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Reporting group title

Overall trial

Reporting group description

Reporting group values	Overall trial	Total
Number of subjects	44	44
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	12	12
From 65-84 years	32	32
85 years and over	0	0
Gender categorical
Units: Subjects
Female	18	18
Male	26	26
Race
Units: Subjects
Caucasian	44	44

End points

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Reporting group title

Orvepitant 10 mg Tablet

Reporting group description

Reporting group title

Orvepitant 30 mg Tablet

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: Change in Pruritus Intensity from Baseline to Week 4

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End point title

Change in Pruritus Intensity from Baseline to Week 4

End point description

Change in pruritus intensity assessed by patient-recorded numerical rating score.

End point type

Primary

End point timeframe

Change from Baseline to Week 4.

End point values	Orvepitant 10 mg Tablet	Orvepitant 30 mg Tablet	Placebo
Number of subjects analysed	11	13	14
Units: N/a
arithmetic mean (standard deviation)	-3.04 ± 3.062	-2.78 ± 2.644	-3.21 ± 1.768

Orvepitant 30 mg v Placebo

Comparison groups

Orvepitant 30 mg Tablet v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.12

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

2.95

Orvepitant 10 mg v Placebo

Comparison groups

Orvepitant 10 mg Tablet v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.194

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

2.96

Adverse events

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Timeframe for reporting adverse events

AEs were collected from the moment the ICF was signed until the Follow-up visit.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Orvepitant 10 mg Tablet

Reporting group description

Reporting group title

Orvepitant 30 mg Tablet

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Orvepitant 10 mg Tablet	Orvepitant 30 mg Tablet	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 14 (0.00%)	0 / 16 (0.00%)	0 / 14 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0

Frequency threshold for reporting non-serious adverse events: 0.05%

Non-serious adverse events	Orvepitant 10 mg Tablet	Orvepitant 30 mg Tablet	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 14 (92.86%)	11 / 16 (68.75%)	10 / 14 (71.43%)
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 14 (14.29%)	3 / 16 (18.75%)	3 / 14 (21.43%)
occurrences all number	2	5	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 14 (7.14%)	2 / 16 (12.50%)	0 / 14 (0.00%)
occurrences all number	1	3	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 14 (0.00%)	1 / 16 (6.25%)	3 / 14 (21.43%)
occurrences all number	0	1	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 14 (7.14%)	1 / 16 (6.25%)	1 / 14 (7.14%)
occurrences all number	1	1	1
Skin and subcutaneous tissue disorders
Skin toxicity
subjects affected / exposed	3 / 14 (21.43%)	2 / 16 (12.50%)	2 / 14 (14.29%)
occurrences all number	4	3	5
Rash
subjects affected / exposed	3 / 14 (21.43%)	0 / 16 (0.00%)	0 / 14 (0.00%)
occurrences all number	3	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

29 Apr 2014

Protocol Amendment Number 01 (Protocol Version 2.0, dated 29 April 2014): This protocol amendment included the following: - Inclusion Criteria modified to allow patients with a moderate level of EGFRi-induced pruritus to be recruited as reflected by a reduction of the Numerical Rating Scale (NRS) score at entry from ≥ 7 to ≥ 5. - Removal of measurement of Substance P as an Exploratory Biomarker. - Afatinib (Giotrif®) added to the list of approved EGFRi monotherapies in the Inclusion Criteria. - Minor updates made to reflect changes in the Medical Monitor and Sponsor Contact Information personnel. - Addition of details about the Data Safety Monitoring Board (DSMB).

12 Aug 2014

Protocol Amendment Number 02 (Protocol Version 2.1, dated 12 August 2014): This was a UK specific amendment to address the medical points raised in a ‘nonacceptance’ letter from the MHRA. Specifically, these were to: - Add further detail regarding actions to be taken for unblinding in the event of a medical emergency. - Provide cautionary information relating to a potential cytochrome P450 3A4 drug-drug interaction (DDI) risk with orvepitant when co-administered with drugs with a narrow therapeutic window primarily metabolised by the same route.

24 Feb 2015

Protocol Amendment Number 03 (Protocol Version 3.0 dated 24 February 2015): This amendment included: - Removal of 10 mg dose arm - Reduction of number of patients from a total of 30 patients randomised to each of 3 arms, to 20 patients randomised to each of 2 arms arm (to give a total of 17 patients completing dosing and critical assessments in each arm). This was based on a reduction in the power of the study to 80% from 90% consistent with that needed for an investigational medicine study at the Phase II stage of development. - Option added for patients to use a Paper Diary for their patient-reported NRS scores, instead of the NRS-IVRS. - Insomnia medication removed from list of prohibited medications. - Double-barrier method removed from the list of acceptable contraceptive methods as this is not recognised as a highly effective birth control method. - The allowable window for the Week 1 (Visit 3) visit was extended by 1 day. - Chief Medical Officer (CMO) – Dr Ajay Duggal added as signatory to the protocol.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in Pruritus Intensity from Baseline to Week 4

Primary: Change in Pruritus Intensity from Baseline to Week 4

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: 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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in Pruritus Intensity from Baseline to Week 4

Primary: Change in Pruritus Intensity from Baseline to Week 4

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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)