Clinical Trials Register

Summary
EudraCT Number:	2019-003907-37
Sponsor's Protocol Code Number:	DON3
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-21
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-003907-37

A.3

Full title of the trial

The effects of vitamin D on bone, muscle and adipose tissue: a phase IV randomized double-blind study.

Gli effetti della vitamina D sull’osso, muscolo e tessuto adiposo: uno studio di fase IV randomizzato in doppio cieco.

A.3.1

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

The effects of vitamin D on bone, muscle and adipose tissue: a phase IV randomized double-blind study.

Gli effetti della vitamina D sull’osso, muscolo e tessuto adiposo: uno studio di fase IV randomizzato in doppio cieco.

A.4.1

Sponsor's protocol code number

DON3

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	Università Campus Bio-Medico
B.1.3.4	Country	Italy
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	Abiogen Pharma S.p.A
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Università Campus Bio-Medico
B.5.2	Functional name of contact point	U.O. di Endocrinologia e Diabetolog
B.5.3	Address:
B.5.3.1	Street Address	Via Álvaro del Portillo, 21
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00128
B.5.3.4	Country	Italy
B.5.4	Telephone number	003906225419151
B.5.5	Fax number	00390622541456
B.5.6	E-mail	n.napoli@unicampus.it

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	Yes
D.2.1.1.1	Trade name	Dibase
D.2.1.1.2	Name of the Marketing Authorisation holder	ABIOGEN PHARMA S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Dibase
D.3.4	Pharmaceutical form	Oral solution
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	colecalciferolo (vitamina D3)
D.3.9.1	CAS number	67-97-0
D.3.9.3	Other descriptive name	VITAMIN D
D.3.9.4	EV Substance Code	SUB129580
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50.000
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Obese elderly patients with vitamin D deficiency who have scheduled either hip replacement due to osteoarthritis or bariatric surgery.

Pazienti anziani obesi con carenza vitaminica D che hanno programmato o un intervento di sostituzione d’anca dovuta a osteoartrite o un intervento di chirurgia bariatrica.

E.1.1.1

Medical condition in easily understood language

Endocrinology and Diabetology

Endocrinologia e Diabetologia

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

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	10047626
E.1.2	Term	Vitamin D deficiency
E.1.2	System Organ Class	10027433 - Metabolism and nutrition 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

Evaluate the effect on inflammation of cholecalciferol supplementation in obese elderly patients with vitamin D deficiency.

Valutare l’effetto sull’infiammazione della supplementazione di colecalciferolo in pazienti anziani obesi con carenza vitaminica D.

E.2.2

Secondary objectives of the trial

Evaluate the inflammatory processes of muscle and adipose tissue following cholecalciferol supplementation; evaluate the effects of cholecalciferol supplementation on the modulation of the WNT pathway in bone, muscle and adipose tissue in obese elderly subjects; evaluate the safety of cholecalciferol supplementation

Valutare i processi infiammatori del muscolo e del tessuto adiposo a seguito della supplementazione con colecalciferolo; valutare gli effetti della supplementazione di colecalciferolo sulla modulazione del WNT pathway nell’osso, del muscolo e del tessuto adiposo in soggetti obesi anziani; valutare la sicurezza della supplementazione con colecalciferolo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Availability to comply with the requirements of the protocol as reported in the written informed consent;
2. Post-menopausal women between 55 and 75 years of age and men of equal age for whom one of the two surgical procedures has been scheduled.
3. BMI> = 30 kg / m2
4. Levels of 25 (OH) D <20 ng / ml

1. Disponibilità aderire ai requisiti del protocollo come riportato dal consenso informato scritto;
2. Donne in età post-menopausale tra i 55 e i 75 anni e uomini di pari età per i quali è stata programmata una delle due procedure chirurgiche.
3. BMI >= 30 kg/m2
4. Livelli di 25(OH)D < 20 ng/ml

E.4

Principal exclusion criteria

1. eGFR <40 ml / min. / 1.72 m2 estimated by the EPI formula (8)
2. Hypercalcaemia (> 10.5 mg / dL)
3. Nephrolithiasis known to the anamnesis
4. Conditions that can alter the metabolism of calcium and vitamin D (primary hyperparathyroidism, hyperthyroidism, chronic renal failure, liver failure, hypercortisolism, malabsorption, HIV);
5. Use of drugs that can alter bone metabolism (estrogen, raloxifene, tamoxifen, bisphosphonates, denosumab, teriparatide, GnRH analogues, use of at least 5 mg per day of glucocorticoids for ≥ 3 months, anabolic steroids, dilantin, antiretrovirals, therapy radiant);
6. Immobilized patients;
7. Alcohol and / or tobacco abuse;
8. Clinical history of bone metastases or neoplastic bone diseases;
9. Paget's disease;
10. Pathologies at the surgical site;
11. Participation in interventional clinical studies in the past 3 months.

1. eGFR < 40 ml/min./1.72 m2 stimato tramite formula EPI (8)
2. Ipercalcemia (> 10,5 mg/dL)
3. Nefrolitiasi nota all’anamnesi
4. Condizioni che possono alterare il metabolismo del calcio e della vitamina D (iperparatirodismo primitivo, ipertirodismo, insufficienza renale cronica, insufficienza epatica, ipercortisolismo, malassorbimento, HIV);
5. Utilizzo di farmaci che possono alterare il metabolismo osseo (estrogeni, raloxifene, tamoxifene, bisfosfonati, denosumab, teriparatide, analoghi del GnRH, uso di almeno 5 mg al giorno di glucocorticoidi per ≥ 3 mesi, steroidi anabolici, dilantin, antiretrovirali, terapia radiante);
6. Pazienti immobilizzati;
7. Abuso di alcool e/o tabacco;
8. Storia clinica di metastasi ossee o malattie neoplastiche dell’osso;
9. Malattia di Paget;
10. Patologie al sito dell’intervento chirurgico;
11. Partecipazione a studi clinici interventistici nei 3 mesi pregressi.

E.5 End points

E.5.1

Primary end point(s)

Serum: Changes in the pro-inflammatory cytokine TNF-a will be evaluated by ELISA

Siero: Verranno valutati tramite saggio ELISA cambiamenti a carico della citochina pro-infiammatoria TNF-a

E.5.1.1

Timepoint(s) of evaluation of this end point

Beginning (T0), during (T1) and at the end of the study (T2)

Inizio (T0), durante (T1) e al termine dello studio (T2)

E.5.2

Secondary end point(s)

Muscle tissue: Nuclear magnetic resonance imaging of the ileo-psoas muscle (MRN). Through RT-PCR the gene expression of inflammatory cytokines (IL-6; IL-8; IL-10; TNF-a; MCP-1) eadiponectin, myogenic proteins (myogenin, myo-D, MHC-2) and myostatin and expression of WNT pathway genes such as: WNT10b, WNT5a, GSK-3b and sFRP5. Protein expression analysis will be performed via Western-Blot for the following elements: TNF-a; IL-6, adiponectin, myostatin, WNT10b, WNT5a, GSK-3b and sFRP5.
Adipose tissue: Analysis of gene and protein expression of IL-6 cytokines; IL-8; IL-10; TNF-a; IGF-1, of adiponectin, markers inherent in the WNT pathway such as WNT5a, WNT10b, sFRP5 and GSK-3b and of the differentiation factor PPAR-gamma through RT-PCR and Western-Blot, respectively.
Bone tissue: RT-PCR will be used to evaluate the expression of the following genes: WNT5a, WNT10b, GSK-3b, SOST, DKK-1 RUNX2, IGF-1 and osteocalcin.
Serum: The following cytokines and adipokines will be evaluated by ELISA: IL-6; IL-8; IL-10 and adiponectin as well as bone turnover markers: CTX, P1NP, active and inactive osteocalcin, BSAP. Serum 25-hydroxy-vitamin D concentration will be assessed by radioimmunoassays. WNT pathway biomarkers will be evaluated by ELISA assays such as: serum sclerostin, DKK-1 and sFRP.
In order to monitor the safety of cholecalciferol supplementation, the patient will also be subjected to the calcium at each time point of the study.
Intra-medullary fat: Intra-medullary fat will be quantified by spectroscopic magnetic resonance imaging (MRS)

TTessuto muscolare: Risonanza magnetica nucleare del muscolo ileo-psoas (MRN). Tramite RT-PCR verrà valutata l’espressione genica di citochine infiammatore (IL-6; IL-8; IL-10; TNF-a; MCP-1) eadiponectina, proteine miogeniche (miogenina, myo-D, MHC-2) e miostatina nonché l’espressionedi geni del WNT pathway quali: WNT10b, WNT5a, GSK-3b e sFRP5. L’analisi dell’espressione proteica verrà eseguita tramite Western-Blot per i seguenti elementi: TNF-a; IL-6, adiponectina, miostatina, WNT10b, WNT5a, GSK-3b e sFRP5.
Tessuto adiposo: Analisi di espressione genica e proteica delle citochine IL-6; IL-8; IL-10; TNF-a; IGF-1, dell’adiponectina, marker inerenti al pathway di WNT quali WNT5a, WNT10b, sFRP5 e GSK-3b e del fattore di differenziamento PPAR-gamma tramite RT-PCR e Western-Blot, rispettivamente.
Tessuto osseo: La RT-PCR verrà utilizzata per valutare l’espressione dei seguenti geni: WNT5a, WNT10b, GSK-3b, SOST, DKK-1 RUNX2, IGF-1 e osteocalcina.
Siero: Verranno valutati tramite saggi ELISA le seguenti citochine e adipochine: IL-6; IL-8; IL-10 e adiponectina nonché i markers di turnover osseo: CTX, P1NP, osteocalcina attiva e non attiva, BSAP. Tramite saggi radioimmunologici verrà valutata la concentrazione sierica di 25-idrossi-vitamina D. Tramite saggi ELISA verranno valutati biomarcatori del pathway di WNT quali: sclerostina sierica, DKK-1 e sFRP.
Al fine di monitorare la sicurezza della supplementazione con il colecalciferolo al paziente verrà inoltre dosata la calcemia ad ogni time-point dello studio.
Grasso intra midollare: La quantificazione del grasso intra-midollare avverrà tramite risonanza magnetica spettroscopica (MRS)

E.5.2.1

Timepoint(s) of evaluation of this end point

Beginning (T0), during (T1) and at the end of the study (T2)

Inizio (T0), durante (T1) e al termine dello studio (T2)

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

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

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.6

Cross over

Yes

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

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.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)

At the end of the study, patients will be advised to periodically check the serum vitamin D levels with particular attention during the winter and will be advised to have these analyzes viewed by the attending or competent doctor.

Al termine dello studio ai pazienti verrà raccomandato di verificare periodicamente i livelli sierici di vitamina D con particolare riguardo nei periodi invernali e verrà suggerito di far visionare tali analisi al medico curante o competente.

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

2020-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-08

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

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