Clinical Trials Register

Summary
EudraCT Number:	2014-004349-29
Sponsor's Protocol Code Number:	01-10-2014
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-02-04
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

Denmark - DHMA

A.2

EudraCT number

2014-004349-29

A.3

Full title of the trial

Mesenchymal stem cells for radiation-induced xerostomia (MESRIX) in previous HPV-positive oropharyngeal head and neck cancer patients

Mesenkymale stamceller til behandling af stråleinduceret xerostomi hos tidligere HPV-positive oropharyngeale hoved hals cancer patienter - Et sikkerhedsstudie

A.3.1

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

Stemcell treatment of drymouth after radiation therapy of HPV induced cancer in the tonsils or base of tongue

Stamcelle behandling af mundtørhed efter strålebehandlet HPV- positiv svælgkræft

A.3.2

Name or abbreviated title of the trial where available

MESRIX

A.4.1

Sponsor's protocol code number

01-10-2014

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	Rigshospitalet
B.1.3.4	Country	Denmark
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	Candy Foundation
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dept. of Otolaryngology, Head and Neck surgery
B.5.2	Functional name of contact point	Rigshospitalet
B.5.3	Address:
B.5.3.1	Street Address	Blegdamsvej 9
B.5.3.2	Town/ city	Copenhagen
B.5.3.3	Post code	2100
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004535452071
B.5.6	E-mail	christian.von.buchwald@regionh.dk

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	Autologous adipose-derived stem cells / Mesenchymale stem cells (MSC)
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Other use (Noncurrent) Route of administration not applicable
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EXPANDED HUMAN AUTOLOGOUS MESENCHYMAL ADULT STEM CELLS EXTRACTED FROM ADIPOSE TISSUE
D.3.9.3	Other descriptive name	EXPANDED HUMAN AUTOLOGOUS MESENCHYMAL ADULT STEM CELLS EXTRACTED FROM ADIPOSE TISSUE (EASCS)
D.3.9.4	EV Substance Code	SUB30158
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	-10 to +10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Isotonic NaCl
D.3.9.3	Other descriptive name	STERILE PYROGEN-FREE ISOTONIC NACL SOLUTE (0.9% W / V)
D.3.9.4	EV Substance Code	SUB79490
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0,9
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Albumin
D.3.9.1	CAS number	8000043-98-3
D.3.9.3	Other descriptive name	ALBUMIN HUMAN SALT-POOR
D.3.9.4	EV Substance Code	SUB12761MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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 injection
D.8.4	Route of administration of the placebo	Other use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The study will include participants with xerostomi (International
Classification of Diseases-10: DQ 838A) and oropharyngeal cancer (DC 10).

Studiet vil inkl. forsøgsdeltagere med xerostomi (DQ 838A) og oropharyngeal cancer (DC10)

E.1.1.1

Medical condition in easily understood language

This study will include participants with dry-mouth after radiation therapy of cancer in the tonsils and base of tongue.

Studiet vil inkludere deltagere med mundtørhed og kræft i mundsvælget (mandlerne og tungeroden).

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10031103
E.1.2	Term	Oropharyngeal cancer stage unspecified
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10048223
E.1.2	Term	Xerostomia
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objective is to examine whether enrichment of the submandibular gland with injection of autologous ASC will improve the result of salivary function in radiation-induced gland hypofunction.

Formålet er et undersøge hvorvidt stamcelle behandling af mundtørhed efter strålebehandling forbedrer spytkirtlens funktion.

E.2.2

Secondary objectives of the trial

Screening of radiological and histological changes in the gland after stem cell-enriched fat injection as based on MRI and biopsy.

Screening af radiologiske og histologiske ændringer i kirtlen efter stamcelle-behandling vurderet ved MRI og biopsi.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Previous radiotherapy for HPV-positive oropharyngeal head and neck cancer with bilateral irradiation of the neck.
• 2 years follow-up without recurrence
• Clinically reduced hyposalivation and hyposalivation, evaluated by a screening
o Unstimulated salivary flow rate between less than 0.2ml/min and above 0.05ml/min
• Only participants with previous T1-T2 and N0, N1 or N2a.
• Informed consent
• Grade 1-43 xerostomia as evaluated by the UKU side effect rating scale

Tidligere strålebehandlet for HPV-positiv svælgkræft, T1-T2 og N0, N1 eller N2a.
2 års opfølgning uden recidiv
Klinisk mundtørhed og nedsat spytsekretion evalueret ved anerkendt screeningsmetode.
Informeret samtykke underskrevet

E.4

Principal exclusion criteria

• Any cancer in the previous 2 years
• Xerogenic medications
• Any previous other diseases in of the salivary glands, e.g. Sjögrens syndrome, sialolithiasis, etc.
• Pregnancy or planned pregnancy within the next 2 years
• Breastfeeding
• Any other disease/condition judged by the investigator to be grounds for exclusion
• Treatment with anticoagulant that cannot be stopped during the intervention period.

Hvilken som helst kræft de sidste 2 år.
Medicinsk behandling af mundtørhed
Andre sygdomme i spytkirtlerne Sjögrens, sialolithiasis, etc.
Gravid eller planlagt graviditet de næste 2 år
Igangværende amning
Anden sygdom som vurderes uhensigtsmæssig ift mulige risici (f.eks. svære immunologiske sygdomme, svær hjerte/ lunge syg)
Antikoagulant behandling som ikke kan pauseres.

E.5 End points

E.5.1

Primary end point(s)

• Safety
All measures of adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) [26]. Since this is a local treatment with MSCs the primary safety measures are:
• Pain at injection site (Grade 1: Mild pain, grade 2: Moderate pain; limiting instrumental activities of daily living (ADL), grade 3: Severe pain; limiting self care ADL)
• Oral discomfort (Grade 1: Mild discomfort; not interfering with oral intake, grade 2: Moderate pain; interfering with oral intake, 3: Disabling pain; tube feeding or TPN indicated)
• Infection (Grade 1: Localized; local intervention indicated, grade 2: Oral intervention indicated (antibiotic, antifungal, antiviral), grade 3: IV antibiotic, antifungal or antiviral indicated; or radiologic, endoscopic or operative intervention indicated, grade 4: life threatening consequences; urgent intervention needed)

• Sikkerhed
Alle foranstaltninger af uønskede hændelser vil blive gradueret i henhold til en fælles terminologi Kriterier for bivirkninger (CTCAE) [26]. Da dette er en lokal behandling med MSC'er de primære sikkerhedsforanstaltninger er:
• Smerter på injektionsstedet (Grad 1: Mild smerte, grad 2: Moderat smerte, begrænsning instrumentale dagligdags aktiviteter (ADL), grad 3: Svære smerter, begrænsning af egenomsorg ADL)
• Oral ubehag (Grad 1: Mild ubehag, ikke interfererer med oral indtagelse, klasse 2: Moderat smerte; forstyrre oral indtagelse, 3: Deaktivering smerte, sondeernæring eller TPN angivet)
• Infektion (Grad 1: Lokaliseret; lokale interventioner angivet, klasse 2: Oral medicin ngivet (antibiotika, svampedræbende, antiviral), grad 3: IV antibiotika, svampedræbende eller antiviral angivet; eller radiologisk, endoskopisk eller operative indgreb angivet, klasse 4: life truende konsekvenser hasteindgreb nødvendigt)

E.5.1.1

Timepoint(s) of evaluation of this end point

3-4 weeks and 3-4 months after intervention.

3-4 uger og 3-4 måneder efter intervention.

E.5.2

Secondary end point(s)

• Significant increase in unstimulated and stimulated whole saliva flow rate in the group receiving MSCs, compared with the group of participants receiving placebo (control group). Salivary flow rate will be calculated as a change in the participant's saliva flow rate from before intervention (baseline) to four months after.
• Significant decrease in complaints of xerostomia in the group receiving MSCs compared with the group of participants receiving placebo as evaluated by a physician and patient questionnaire.
• Measurement of 4-months volume change of submandibular glands based on magnetic resonance imaging (MRI). Calculated as a change after 4 months compared to MRI before intervention (baseline).
Registration of all unexpected side effects of the intervention.
• Estimation of change in the amount of fibrosis from the MRI-scan between intervention and placebo group.
• Estimation of the change in the amount of serous and mucinous gland tissue in histological sections from the biopsies taken pre- (baseline) and post-interventional.
• Estimation in the change in fibrosis in histological sections from the biopsies taken pre- (baseline) and post-interventional.
• Estimation in the change in vascularisation in histological sections from the biopsies taken pre- (baseline) and post-interventional.

• Betydelig stigning i ikke-stimulerede og stimuleret hele spyt flow i gruppen, der fik MSC'er sammenlignet med gruppen af deltagere, der fik placebo (kontrolgruppe). Spyt flow vil blive beregnet som en ændring i deltagerens spyt flow fra før intervention (baseline) til fire måneder efter.
• Signifikant fald i klager over xerostomi i gruppen, der modtog MSC'er sammenlignet med gruppen af deltagere, der fik placebo som vurderes af en læge og patient spørgeskema.
• Måling af 4-måneders volumen ændring af submandibulære kirtler baseret på magnetisk resonans (MRI). Beregnet som en ændring efter 4 måneder sammenlignet med MRI før intervention (baseline).
Registrering af alle uventede bivirkninger af interventionen.
• Beregning af ændring i mængden af fibrose fra MR-scanning mellem intervention og placebogruppen.
• Estimering af ændring i mængden af serøs og mucinous kirtel væv i histologiske snit fra biopsier er taget før (baseline) og post-interventionel.
• Estimation i forandringen i fibrose i histologiske snit fra biopsier er taget før (baseline) og post-interventionel.
• Skøn af ændringen i vaskularisering i histologiske snit fra biopsier er taget før (baseline) og post-interventionel.

E.5.2.1

Timepoint(s) of evaluation of this end point

Biopsy and MRI: 3-4 weeks and 3-4 months after intervention.

Biopsi og MRI: 3-4 uger og 3-4 måneder after intervention.

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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

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

E.8.9.2

In all countries concerned by the trial years

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)

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

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)

The participants have yearly / 2-yearly checks at the oncologic department.

Forsøgsdeltagerne kommer til årlige / hvert andet års ambulante besøg på onkologisk klinik.

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

2015-04-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-04-07

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