Clinical Trials Register

Summary
EudraCT Number:	2021-006817-12
Sponsor's Protocol Code Number:	2031-38
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-02-03
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

France - ANSM

A.2

EudraCT number

2021-006817-12

A.3

Full title of the trial

Evaluation of the efficacy of an intra-articular injection of autologous microfat combined with autologous platelet-enriched plasma in the treatment of radiocarpal osteoarthritis: a randomized controlled non-inferiority trial versus total wrist denervation (established standard treatment).

Evaluation de l’efficacité de l’injection intra-articulaire d’un mélange de micrograisse autologue associée à du plasma autologue enrichi en plaquettes dans le traitement de l’arthrose radio-carpienne : essai randomisé contrôlé de non-infériorité versus dénervation totale du poignet (traitement de référence).

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

AMIPREP II

A.4.1

Sponsor's protocol code number

2031-38

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	ASSITANCE PUBLIQUE HOPITAUX DE MARSEILLE
B.1.3.4	Country	France
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	AP HM
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASSISTANCE PUBLIQUE HOPITAUX DE MARSEILLE
B.5.2	Functional name of contact point	ALEXANDRA GIULIANI
B.5.3	Address:
B.5.3.1	Street Address	DRS 80 rue Brochier
B.5.3.2	Town/ city	Marseille
B.5.3.3	Post code	13354
B.5.3.4	Country	France
B.5.4	Telephone number	0491382747
B.5.6	E-mail	alexandra.giuliani@ap-hm.fr

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	melange de Plasma Autologue riche en plaquette et de micrograisse autologue
D.3.2	Product code	PRP et micrograisse
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular 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)	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

radiocarpal osteoarthritis

l’arthrose radio-carpienne

E.1.1.1

Medical condition in easily understood language

radiocarpal osteoarthritis

l’arthrose radio-carpienne

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

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 demonstrate the non-inferiority in terms of efficiency of intra-articular injection of autologous microfat and PRP in patients suffering from radiocarpal osteoarthritis resistant to medical treatment on pain evaluated by the visual analog scale (VAS) at 6 months in comparison with total wrist denervation (established standard treatment)

Démontrer la non infériorité de l’efficacité de l’injection intra-articulaire de micrograisse et PRP autologues chez des patients souffrant d’arthrose radio-carpienne résistante au traitement médical sur la douleur évaluée par l’échelle visuelle analogique (EVA) à 6 mois en comparaison de la dénervation totale du poignet (traitement de référence

E.2.2

Secondary objectives of the trial

- Assess the safety of the treatment under study at D7, M3, M6, M12, compared to the established standard treatment group by monitoring adverse events and post-operative follow-up data.
- To assess the non-inferiority of the treatment under study compared to the established standard treatment on the secondary efficacy endpoints:
At M3, M6 and M12:
 PRWE functional score (non-inferiority limit: 11.5 points)
 DASH functional score (non-inferiority limit: 10.83 points),
 Strength measured by the Jamar dynamometer (non-inferiority limit: 6.5kg).
At M3 and M12
 Intensity of pain measured by the VAS (limit: 14mm).

- To evaluate the efficiency of the treatment under study at M3, M6 and M12:
 Wrist joint ranges,
 Patients' Global Impression of Change (PGIC)

- Evaluate patient satisfaction at D7 and M3.

- Evaluer la tolérance du traitement à l’étude à J7, M3, M6, M12, en comparaison au groupe traitement de référence : Evénements indésirables et données du suivi post-opératoire.

- Evaluer la non-infériorité du traitement à l’étude en comparaison au traitement de référence sur les critères secondaires de jugement d’efficacité :
A M3, M6 et M12 :
 Le score fonctionnel PRWE (limite non infériorité : 11.5 points),
 Le score fonctionnel DASH (limite non infériorité : 10.83 points),
 La force mesurée par le dynamomètre de Jamar (limite non infériorité : 6.5kg).
A 3 mois et 12 mois :
 La douleur mesurée par l’Echelle Visuelle Analogique (limite : 14mm).

- Evaluer l’efficacité du traitement à l’étude à M3, M6 et M12 sur :
 Les amplitudes articulaires du poignet,
 L’impression globale du changement perçu par le patient (Patients’ Global Impression of Change (PGIC))

- Evaluer la satisfaction des patients à J7 et M3.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1 Patients of both gender, minimum age 18-year-old
2 Patient suffering from wrist osteoarthritis that must be:
-Symptomatic: pain ≥ 40 mm on the VAS (0 to 100 mm), associated or not with a loss of strength measured by the Jamar dynamometer and/or a loss of wrist mobility leading to discomfort in daily life activities and an impaired quality of life.
-Shown on radiographs and arthroscan: stylo-scaphoid and/or global radiocarpal and/or scapho-capital and/or luno-capital joint pinch, associated or not with osteophytic and subchondral changes equivalent to a grade 3 of the Kellgren and Lawrence classification. Depending on the aetiology of the wrist osteoarthritis, the following findings may be identified: an adaptive carpal defect (DISI: Dorsal intercalated segmental instability), a rupture of the scapholunate or pisotiquetral ligaments, a pseudarthrosis of the scaphoid, a necrosis of the proximal pole of the scaphoid, a vicious callus of the radius, or an avascular necrosis of another carpal bone.
-Not responding to medical treatment for at least 1 year: painkillers of the appropriate level, non-steroidal anti-inflammatory drugs, wearing of an analgesic brace, rehabilitation by a physiotherapist +/- intra-articular injections of corticoids or hyaluronic acid.

3 Informed consent form must be signed by the patient
4 Women of childbearing age must have a negative pregnancy test (serum or urine) (detection threshold (sensitivity): 25 mIU hCG/ml). Patients of both genders must use reliable contraception.
5 Beneficiaries or members of the French social security scheme

Hommes et femmes d’âge ≥ 18 ans
Patients présentant une arthrose du poignet :
- Symptomatique : douleurs ≥ 40 mm sur l’échelle visuelle analogique (EVA 0-100 mm) plus ou moins associées à une perte de force objectivée par le dynamomètre de Jamar et/ou de mobilité du poignet entrainant une gêne dans les activités de la vie quotidienne et une altération de la qualité de vie.
- Objectivée sur des radiographies et un arthroscanner : pincement articulaire stylo-scaphoïdien et/ou radio-carpien global et/ou scapho-capital et/ou luno-capital, plus ou moins associés à des remaniements osteophytiques et sous chondraux équivalents à un grade 3 de la classification de de Kellgren et Lawrence (cf chapitre I). En fonction de l’étiologie de l’arthrose du poignet pourront être associés : un carpe adaptatif (DISI), une rupture des ligaments scapholunaire ou pisotiquetral, une pseudarthrose du scaphoïde, une nécrose du pole proximal du scaphoïde, un cal vicieux du radius, une nécrose avasculaire d’un os du carpe.
- En échec du traitement médical bien conduit pendant au moins un an : antalgiques de palier adapté à la douleur, AINS, port d’une orthèse antalgique, rééducation par un kinésithérapeute +/- injections intra-articulaires de corticoïdes ou d’acide hyaluronique.
Formulaire de consentement éclairé signé par le patient
Les femmes en âge de procréer doivent présenter un test (sérique ou urinaire) de grossesse négatif (seuil de détection (sensibilité) : 25 mIU hCG/ml)). Les patients des deux sexes doivent utiliser une méthode de contraception fiable.
Bénéficiaires ou affiliés à un régime de sécurité sociale

E.4

Principal exclusion criteria

1. Use of antiplatelet agents, aspirin, or anti-vitamin K drugs less than 15 days prior to inclusion that may interfere with the quality or therapeutic effect of the treatment under study
2. Chronic treatment with oral corticosteroids or the use of such treatment less than 2 weeks prior to inclusion
3. Intra-articular corticosteroid injection less than 2 months prior to inclusion
4. Intra-articular injection of hyaluronic acid less than 2 months prior to inclusion
5. Non-steroidal anti-inflammatory drugs less than 15 days prior to inclusion
6. Fever or recent infection (bacterial or viral) less than one month prior to inclusion
7. Current or chronic infectious diseases (viral or bacterial) identified by clinical and/or biological evidence (inflammatory marker: ESR, CRP, Fibrinogen)
8. Autoimmune diseases attested by clinical and/or biological evidence (inflammatory marker: ESV, CRP, fibrinogen) that may interfere with the quality or therapeutic effect of the drug under study
9. Inflammatory arthritis
10. Microcrystalline arthritis
11. History of surgery for treatment of wrist osteoarthritis: total wrist denervation, first row carpal resection, arthrodesis, arthroplasty
12. Congenital or acquired immune deficiency
13. Malignant tumours or history of malignant tumours less than 5 years prior to inclusion
14. Contraindications to MRI: metallic foreign bodies (ferromagnetic material) and metallic implants (pacemakers, heart valves, vascular clips, surgical clips or staples, cochlear implants, any implanted electronic medical material or device (e.g. insulin pump), orthopaedic medical prosthetics.
15. Contraindications to local anaesthetics drugs
16. Contraindications to local anaesthesia or surgery
17. Positive markers for the following active infectious diseases: HIV 1 and HIV 2 human immunodeficiency virus infection; HTLV I virus infection; Hepatitis B virus infection; Hepatitis C virus infection; Syphilis causative agent infection. (Order of November 4, 2014 on screening for infectious diseases during autologous therapeutic samples provided for in Article R. 1211-22-1 of the French Public Health Code and amending the order of May 14, 2010 setting the content of information allowing the use of human body elements and products for therapeutic purposes)
18. Body mass index (BMI) of less than 18 kg/m2 not allowing to obtain a sufficient quantity of adipose tissue for the manufacturing of the experimental “hospital exemption” and exposing the patient to a significant discomfort during the liposuction procedure
19. Coagulation disorders that may interfere with the quality or therapeutic effect of the drug under study: Thrombocytopenia < 150 G/L, thrombocytosis > 450 G/L, known thrombopathy, PT < 70%, patient to Witness APTT ratio > 1.20, anaemia < 10g/dl contraindicating peripheral venous blood sampling.

o Prise d’antiagrégant plaquettaire, d’aspirine, d’anti vitamine K datant de moins de 15 jours avant l’inclusion pouvant interférer sur la qualité ou sur l’effet thérapeutique du médicament expérimental
o Traitement chronique par corticoïdes per os ou datant de moins de 2 semaines
o Injection intra-articulaire de corticoïde datant de moins de 2 mois
o Injection intra-articulaire d’acide hyaluronique datant de moins de 2 mois
o Prise d’AINS datant de moins de 15 jours
o Fièvre ou infection récente (bactérienne ou virale) datant de moins d’un mois
o Maladies infectieuses en cours ou chroniques (virale ou bactérienne) attestées par des éléments cliniques et/ou biologiques (bilan inflammatoire : VS, CRP, Fibrinogène)
o Maladies auto immunes attestées par l’interrogatoire, ou des éléments cliniques et/ou biologiques (bilan inflammatoire : VS, CRP, fibrinogène) et pouvant interférer sur la qualité ou sur l’effet thérapeutique du médicament expérimental
o Arthrite inflammatoire
o Arthrite microcristalline
o Antécédent de chirurgie pour le traitement de l’arthrose du poignet testé : dénervation totale du poignet, résection de la première rangée du carpe, arthrodèse, arthroplastie
o Déficit immunitaire congénital ou acquis
o Tumeurs malignes en cours de traitement ou antécédent de tumeurs malignes de moins de 5 ans
o Contre-indications à l’IRM : corps étrangers métalliques (matériel ferromagnétique) et implants métalliques (pacemakers, valves cardiaques, clips vasculaires, clips ou agrafes chirurgicales, implants cochléaires, tout matériel ou dispositif médical électronique implanté (ex. pompe à insuline), prothèses médicales orthopédiques.
o Contre-indications aux anesthésiques locaux.
o Contre-indications à l’anesthésie locale ou à la chirurgie
o Marqueurs positifs des maladies infectieuses actives suivantes : L’infection par les virus de l’immunodéficience humaine VIH 1 et VIH 2; L’infection à virus HTLV I; L’infection par le virus de l’hépatite B; L’infection par le virus de l’hépatite C; L’infection par l’agent responsable de la syphilis. (Arrêté du 4 novembre 2014 relatif au dépistage des maladies infectieuses lors des prélèvements à des fins thérapeutiques autologues prévu à l’article R. 1211-22-1 du code de la santé publique et modifiant l’arrêté du 14 mai 2010 fixant le contenu des informations permettant d’utiliser des éléments et produits du corps humain à des fins thérapeutiques)
o Indice de masse corporelle (IMC) inférieur à 18kg/m2 ne permettant pas l’obtention d’une quantité de tissu adipeux suffisante pour la fabrication du MTI-PP expérimental et exposant le patient à un inconfort important lors de la procédure de lipoaspiration
o Troubles de la coagulation pouvant interférer sur la qualité ou sur l’effet thérapeutique du médicament expérimental :
o Thrombocytopénie < 150 G/L
o Thrombocytose > 450 G/L
o Thrombopathie connue
o TP < 70%
o Rapport TCA Patient/Témoin > 1,20
o Anémie < 10g/dl contre-indiquant la réalisant d’un prélèvement de sang veineux périphérique

E.5 End points

E.5.1

Primary end point(s)

pain intensity measured on the VAS

l’intensité de la douleur mesurée sur l’EVA

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mois

E.5.2

Secondary end point(s)

Assessment of upper limb function by the DASH score
Assessment of wrist strength by dynamometry

Evaluation de la fonction du membre supérieur par le score DASH (Disabilities of the Arm, Shoulder and Hand)
Evaluation de la force du poignet par dynamométrie

E.5.2.1

Timepoint(s) of evaluation of this end point

3 months, 6months and 12 months

3 mois ,, 6 mois , 12 mois

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

dénervation totale du poignet

total wrist denervation surgery.

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

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

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

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

2022-06-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-14

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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