Clinical Trials Register

Summary
EudraCT Number:	2018-001153-27
Sponsor's Protocol Code Number:	PenVe
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-10-11
Trial 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

2018-001153-27

A.3

Full title of the trial

A feasibility study of a prospective randomised controlled trial comparing the use of open label pentoxifylline and tocopherol versus current standard of care for the prevention of fibrosis related outcomes in irradiated head and neck oncology patients. PenVe

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

PenVe

A.4.1

Sponsor's protocol code number

PenVe

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN74484952

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	Guy's and St Thomas' NHS Foundation Trust
B.1.3.4	Country	United Kingdom
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	NIHR Central commissioning facility (CCF) Research for patient benefit
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	Guy's and St Thomas' NHS Foundation Trust
B.5.2	Functional name of contact point	Mr Vinod Patel,
B.5.3	Address:
B.5.3.1	Street Address	Oral Surgery Dept, Tower Wing, Guys Dental Hospital,
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SE1 9RT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	440207188 3885
B.5.6	E-mail	vinod.patel@gstt.nhs.uk

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	Pentoxifylline 200mg/5ml solution
D.3.4	Pharmaceutical form	Oral suspension
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	PENTOXIFYLLINE
D.3.9.1	CAS number	6493-05-6
D.3.9.3	Other descriptive name	3,7-dimethyl-1-(5-oxohexyl)purine-2,6-dione
D.3.9.4	EV Substance Code	SUB09705MIG
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	40
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	Trental 400
D.2.1.1.2	Name of the Marketing Authorisation holder	Aventis Pharma Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Modified-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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: 3
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	Vitamin E Suspension 100mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Alliance Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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: 4
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	Auxina E
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi Espana, S.A.U.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Osteoradionecrosis, trismus and dysphagia

E.1.1.1

Medical condition in easily understood language

Bone death and scarring of tissue in the jaw and mouth following radiotherapy cancer treatment

E.1.1.2

Therapeutic area

Diseases [C] - Mouth and tooth diseases [C07]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10067352
E.1.2	Term	Osteoradionecrosis
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10044684
E.1.2	Term	Trismus
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10013950
E.1.2	Term	Dysphagia
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

E.2.2

Secondary objectives of the trial

•To assess the presence of osteoradionecrosis compared to the non-intervention arm
•To assess an improved mouth opening compared to the non-intervention arm
•To assess an improved swallowing capacity compared to the non-intervention arm
•To assess an improved quality of life compared to the non-intervention arm

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients (≥18yrs) presenting with a primary head and neck (H&N) tumour requiring radiotherapy treatment and placing them in the highest risk group for developing osteoradionecrosis, trismus and dysphagia. These include:
o Oropharynx (Tonsil, Base of Tongue)
o Nasopharynx
o Oral cavity
o Maxillary sinus
o Salivary glands
o Unknown primary of the neck
o Hypopharynx

•Oncology treatment aiming for the intent to cure
•Patients able to consent and willing to participate

E.4

Principal exclusion criteria

• Previous history of H&N cancer
• Patients treated with any drug implicated to cause medication related osteonecrosis of the jaw (MRONJ). These include bisphosphonates, denosumab, radium 223, tyrosine kinase inhibitors and bevacizumab
• Any patient with significant medical history where taking part in this study may potentially compromises their health.
• Women who are pregnant or breast feeding or of child bearing age not on adequate contraception
• Patients lacking capacity to consent.
• Oncology treatment for palliative care
• Patients deemed to have a high risk of recurrent tumour
• • Patients with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial infarction, severe cardiac arrhythmias and /or impaired renal function, impaired liver function which in the expert opinion of the principal investigator present a risk to the patient
• Known drug allergy or sensitivity to pentoxifylline (or methyl xanthines) and alpha-tocopheryl or any constituents of the medication (e.g. methyl and propyl hydroxybenzoates or a rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency)
• Patients taking theophylline or oestrogens
• Patients with metastatic disease
• Patients participating in other drug (CTIMP) trials

E.5 End points

E.5.1

Primary end point(s)

To assess the feasibility of a randomised controlled trial of pentoxifylline in combination with vitamin E (PVe) for the prevention of radiation induced fibrosis outcomes in head and neck radiotherapy patients compared to best standard of care, through:

Assessing patients preference for pentoxifylline and vitamin E formulation, in a liquid vs tablet format
- The time point that the participant agrees to swap from liquid to tablet formulation of pentoxifylline and vitamin E.
- Patients self reported preference for tablet or liquid

Assessing patients subsequent side effects related to the pentoxifylline and vitamin E
- The presence and number of side effects using standard adverse event reporting.

Assessing the recruitment into the trial
- Number of participants consented, as a proportion of the number of patients eligible and invited.
- Number of participants who attend their month 6 post randomisation visit (visit 4) as a proportion of the number of patients randomised.

Assessing retention of the participants in the trial
- Number of visits attended and phone calls answered

Assessing patient adherence to pentoxifylline and vitamin E
- Sustained and elevated levels of Vitamin E levels (higher than natural variation/standard range) at months 3 and month 6 in comparison to participants baseline, through blood test for vitamin E and recording levels of Vitamin E present.
- Patients self-reported adherence

Assessing the acceptability to participants of the outcome measurement tools
- Number of questionnaires completed by participants.

E.5.1.1

Timepoint(s) of evaluation of this end point

All endpoints will be obtained by measurements taken during the study visits and through patient contact.

E.5.2

Secondary end point(s)

To assess the presence of osteroradionecrosis
- Proportion of patients with osteoradionecrosis at month 6 post randomisation

To assess the improvement in mouth opening
- Difference in mouth opening measurements from baseline to month 6 post randomisation

To assess improvement in swallowing capacity
- Difference in swallowing scores from baseline to month 6 post randomisation

To assess improvement in quality of life
- Difference in quality of life scores from baseline to month 6 post randomisation

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, month 3 (post randomisation) and month 6 (post randomisation).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Basic standard of care

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

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

The end of trial will be defined as the date when the data has been fully cleaned and the trial database is locked.

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

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

Information not present in EudraCT

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)

Patients will return back to receiving the basic standard of care from their oncology team and be referred to the dental team in the future if clinically required.

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

2018-11-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-22

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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