Clinical Trials Register

Summary
EudraCT Number:	2018-001227-39
Sponsor's Protocol Code Number:	779322
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-11-02
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

Denmark - DHMA

A.2

EudraCT number

2018-001227-39

A.3

Full title of the trial

A randomized controlled clinical trial to assess the efficacy of a combination of autologous mesenchymal stem cells and biomaterial in jaw bone regeneration prior to dental implant placement in comparison to autologous bone block grafting.

En randomiseret klinisk undersøgelse med formål at evaluere effekten af anvendelse af autologe mesenkymale stamceller og biomateriale for knogle regeneration før tand implantat installation sammenlignet med sædvanlige autologe knogle blok transplantat anvendelse

A.3.1

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

A study to evaluate if the use of the patients own stem cells in combination with a biomaterial is as good as the standard treatment, bone transplantation.

Et studie med formål at undersøge om anvendelsen af patientens egne stamceller kombineret med biomateriale er lige så god som sædvanlige anvendelse , knogletransplantat.

A.3.2

Name or abbreviated title of the trial where available

Maxibone

A.4.1

Sponsor's protocol code number

779322

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 of Bergen, Faculty of Medicin, Department of Clinical Dentistry
B.1.3.4	Country	Norway
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	University of Bergen, Faculty of Medicin, Department of Clinical Dentistry
B.4.2	Country	Norway
B.4.1	Name of organisation providing support	Inserm UMR 1238, PHY-OS Faculty of Medicine, University of Nantes
B.4.2	Country	France
B.4.1	Name of organisation providing support	Universidad Complutense de Madrid
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Syddansk Universitet SDU
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Haukeland University Hospital, Clinical trial unit
B.4.2	Country	Norway
B.4.1	Name of organisation providing support	Universitat Internacional De Catalunya Fundacio Privada
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Assistance Publique - Hôpitaux De Paris
B.4.2	Country	France
B.4.1	Name of organisation providing support	Institute for Transfusion Medicine and Immunogenetic Ulm, University Hospital Ulm (IKT Ulm) and German Red Cross Blood T
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Universitaet Ulm
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Biomatlante
B.4.2	Country	France
B.4.1	Name of organisation providing support	Straumann
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Bergen, Faculty of Medicin, Department of Clinical Dentistry
B.5.2	Functional name of contact point	Cecilie Gjerde
B.5.3	Address:
B.5.3.1	Street Address	Aarstadveien 19
B.5.3.2	Town/ city	Bergen
B.5.3.3	Post code	5009
B.5.3.4	Country	Norway
B.5.4	Telephone number	+4755586441
B.5.6	E-mail	cecilie.gjerde@uib.no

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	Mesenchymal stem cells and microporous Bi-phasic calcium phosphate (MBCP+)
D.3.2	Product code	Maxibone-1
D.3.4	Pharmaceutical form	Granules
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Dental use Implantation Periosseous use
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)	Yes
	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)	Yes
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

Patients in need of dental implant(s) in the upper and lower jaws with presence of bone defects with loss in vertical height and < than 4 mm in lateral width

Patienter med behov for knogleopbygning før tandimplantat installation, hvor kæbekams bredde og højde er mindre end 4 mm

E.1.1.1

Medical condition in easily understood language

Lack of bone width (and sometimes hight), so that it is not possible to place dental implants.

Tab af knoglevolumen, som medfører at det ikke er muligt at installere tandimplantat

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10005958
E.1.2	Term	Bone disorder NOS
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Principal objective: To compare linear changes in bone width between
the tested interventions aimed for vertical and lateral bone
augmentation; test (combination of autologous culture expanded
mesenchymal stem cells and biomaterials) and control groups
(autologous bone block graft from ramus fixed with osteosynthesis
screws)

primære formål er at sammenligne lineære forandringer efter lateral og vertikal knogleforøgelse ved test gruppe, hvor der anvendes autologe stamceller i kombination med biomaterialer og kontrol gruppe, hvor der anvendes autolog knogleblok transplantat, som er høstet fra underkæben og fikseret med miniskruer

E.2.2

Secondary objectives of the trial

(1) To evaluate efficacy of treatment and formation of new bone by:
assessing the possibility to insert an implant 5 months after the grafting procedure (3D CBCT)
Measuring clinical changes in alveolar bone width.
evaluating the collected core biopsies using μCT, SRμCT and histology.
evaluting outcomes after implant placement
(2) To evaluate the safety of the interventions by:
assessing adverse effects (AEs) and soft tissue healing at 2 and 4 weeks and 5 months
assessing the morbidity associated with both procedures by measuring the usage of postoperative anti-inflammatory medication and degree of reported pain using a VAS scale
assessing fate of the transplanted MSCs by liquid biopsy (blood samples and plasma/sera at screening and 2 weeks after bone augmentation surgery)
(3) To assess patient’s satisfaction with surgical intervention and prosthetic outcome by patient reported outcomes (PROMs). Impact of treatment on the patient’s overall quality of life (QoL) will be assessed

1) Evaluering af effektivitet af behandling og knoglenydannelse ved:
-- tilstrækkeligt knoglevolumen til implant installation efter 5 måneder (3D CBCT)
-- måle kliniske knoglebredde
-- evaluere samlede knoglebiopsier med micro CT, Synchrotron Røntgen micro CT og histologi
-- ordinære kliniske implantat parametre efter installation
2)Evaluering af sikkerhed af behandlingerne ved:
--uønskede effekter (AEs) og blødtvævsheling efter 2-, 4- og 5 måneder
--morbiditet ved begge procedurer i form af mål af forbrug af anti-inflammatoriske medikamenter og grad af smerte ved VAS-skala
--Transplanterede stamcellers skæbne målt ved flydende biopsi i form af blodprøver og plasma/sera ved screening og 2 uger efter knogle
opbygningen.
3)Patienttilfredshed af kirurgiske og protetiske procedurer ved PROMs ( patient rapporterede outcomes). Livskvalitets ved QoL (Quality of Life) spørgeskemaer

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Written informed consent
 Patient should be able to understand and complete the informed consent
 Age 18 years or older
 Insufficient bone ridge width (≤ than 4 mm) and or height at the recipient site for
titanium dental implant placement
 Patient should be eligible for bone marrow harvest and bone transplant
 Healthy oral mucosa, at least 2 mm keratinized mucosa
 Female candidates of child bearing potential (WOCBP) -as defined by CTFG 2- must be
referred to their physician for a pregnancy test 1,2 before inclusion in the study. In
case of a negative preganancy test their physician will be asked to prescribe one of
the highly effective birth control methods recommended by CTFG 2 which includes:
1. Combined estrogen and progestogen containing contraceptives that are
associated with inhibition of ovulation (oral, intravaginal or transdermal).
2. Progestogen-only hormonal contraceptives associated with inhibition of
ovulation (oral, injectable or implantable).
3. Intrauterine devices.
4. Intrauterine hormone-releasing system.
5. Bilateral tubal occlusion.
 The WOCBP candidates will only be included in the study if the pregnency tests are
negative. These patients must continue using the contraceptives until the placement
of dental implants (5 months after bone augmentation procedure considering that
pregnancy is not considered as a contraindication for normal dental implant).
 Female candidates that have entered menopause for less than 12 months must also
be referred to confirm post-menopausal state by testing the level of follicle
stimulating hormone (FSH).

Skriftlig samtykkeerklæring:
Patienten skal
-- være istand til at forstå og udfylde informeret samtykke erklæringen
-- 18 år eller ældre
-- have utilstrækkeligt volumen af kæbekam i region for planlagt titanium tandimplantat installation (højde og bredde < 4mm)
-- være egnet for knoglemarvshøst og knogletransplantation
-- have sund mundslimhinde og mindst 2 mm keratiniseret mundslimhinde i implantatregion.
Kvindelige kandidater i fødedygtige alder (WOCBPs) - som defineret af CTFG2 - skal henvises til egen læge for graviditetstest 1,2 før inklusion. Ved negativ test vil egen læge blive anmodet om at ordinere en af virksomme antigraviditets metoder rekommanderet af CTFG2:
1. Kombineret østrogen og progesteron kontraceptivum som hæmmer ægløsning (tablet, intravaginal eller transdermal)
2. Progesteron hormon contraceptivum som hæmmer ægløsning (tablet, injektabelt eller implantabelt)
3. Intrauterine spiral
4. Intrauterine hormone frigivende system
5. Sterilisering
--De fødedygtige kvindelige kandidater vil kun blive inkluderet i studiet ved negativ graviditets tests. Disse patienter må fortsætte med at anvende contraceptive midler indtil tandimplant installation ( 5 måneder efter knogleopbygnong) , da denne ikke er kontraindiceret ved graviditiet.
-- Menopausale kvinder der erindtrådt i menopause indenfor 12 måneder af aktuel forsøg skal også henvises til egen læge for at få konfirmeret der menopausale status ved follikel stimulerende hormon test (FSH)

E.4

Principal exclusion criteria

General contraindications for dental and/or surgical treatments
· Contraindications for both bone marrow harvesting and bone grafts:
o General:
§ Patients with severe bone marrow diseases such as leukemias, lymphomas, and myelodysplastic syndromes.
§ Patients with severe respiratory disease, chronic respiratory failure, medical history of generalized allergic manifestation.
§ Patients with a history of severe osteoporosis.
§ Patients suffering from any serious coagulation disorders that could require substitution therapy.
§ Patients receiving anticouagulant treatment should be adjusted in collaboration with the treating physician.
§ Patients with total hip prothesis
o Local:
§ Patients with active infection at the harvest site
§ Patients with previous pathology or trauma at the harvest site
· History of any malignant diseases
· Concurrent or previous radiotherapy of head and neck region
· History of contagious diseases (HIV, HTLV and/or syphilis seropositivity, hepatitis B or C infection)
· Uncontrolled diabetes mellitis, e.g. patients with diabetes not regulated with medications or diet. This will be verified based on patient`s history and concurrent HbA1c levels (HbA1c > 53 mmol/mol).
· Inflammatory and autoimmune disease of the oral cavity.
· Concurrent or previous immunosuppressant, bisphosphonate or high dose corticosteroid therapy.
· Patients with a history of drug addiction.
· Patients with known hypersensitivity against paracetamol, codein or xylocaine.
· Thin keratinized mucosa (< 1mm)
· Current smokers and those who have quitted smoking in the last 4 weeks (there is evidence that nicotine and cotinine levels disappear after 4 weeks of non-smoking).
· Pregnant or lactating women.
· Participation in an investigational device, drug or biologics study within the last 24 weeks prior to the study start

Generelle kontraindikationer for dental og/eller kirurgiske behandlinger
-- Kontraindikatioer for både knoglemarvshøst og knogletransplantation:
--- Generelle:
Patienter med
§Svær knoglemarvs sygdom i form af leukæmi, lymfom og myelodysplastisksyndrom
§Svær respiratorisk sygdom, kronisk respiratorisk sygdom, generel allergisk manifestation
§svær osteoporose
§Seriøs koagulations sygdom som kræver substitution behandling
§Antikoagulations behandling skal justeres i samarbejde med behandlende læge
§total hofte protese
--Lokale:
Patienter med
§Aktiv infektion i region for høst af stamceller eller knogletransplantat
§ Tidligere patologi eller traume i region for høst af stamceller eller knogletransplantat
--- Malignitet
--- tidligere eller aktiv terapeutisk røntgenbestråling til hoved- og hals region
--- Smitsom sygdom - HIV; HTLV og/eller syfilis seropositiv, hepatitis B eller C infektion.
---ukontrolleret Diabetes mellitus feks ikke reguleret medicinsk eller ved diæt. Dette verificeres via anamnese og aktuelle HbA1c niveau (HbA1c > 53 mol/mol)

E.5 End points

E.5.1

Primary end point(s)

Principal assessment is linear change in bone width 2 mm below alveolar crest measured by
means of CBCT images from baseline to 5 months after the regenerative surgery, immediately
prior to implant placement.

Primære mål er evaluering af lineære forandring i knoglekams bredden, som måles 2 mm under toppen af kæbekammen på Cone Beam CT (CBCT) vurderet fra baseline til 5 måneder efter den regenerative knogleprocedure umiddelbart før implantat installationen

E.5.1.1

Timepoint(s) of evaluation of this end point

After 5,5 +- 14 days

E.5.2

Secondary end point(s)

PROMS, implant stability, QoL, AE assessment

Patient oplevede evalueringer via spørgeskemaer (PROMS), QoL, implantat stabilitet og bivirkninger (AE)

E.5.2.1

Timepoint(s) of evaluation of this end point

At 21 months.

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)

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

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

Bone transplantation

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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

F.3.3.2

Women of child-bearing potential using contraception

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.4.2

For a multinational trial

F.4.2.1

In the EEA

110

F.4.2.2

In the whole clinical trial

150

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)

Standard operating procedures for these patients

Standard behandlings procedurer for disse patienter

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

2019-11-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-11

P. End of Trial
P.	End of Trial Status	Ongoing

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