Clinical Trials Register

Summary
EudraCT Number:	2013-000971-34
Sponsor's Protocol Code Number:	01052013
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:	2013-08-01
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

2013-000971-34

A.3

Full title of the trial

Mucosal immune regulation by high dose vitamin D treatment in Crohn’s disease

A.3.1

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

High dose vitamin D treatment in Crohn's disease affects the gut immune cells

A.3.2

Name or abbreviated title of the trial where available

MirViDiC

A.4.1

Sponsor's protocol code number

01052013

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	Jørgen Agnholt
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	Aarhus University
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Hepatology and Gastroenterology department V, Aarhus University Hospital
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	Hepatology and Gastroenterology department V, Aarhus University Hospital
B.5.2	Functional name of contact point	Jørgen Agnholt
B.5.3	Address:
B.5.3.1	Street Address	Noerrebrogade 44 building 7, 2. floor
B.5.3.2	Town/ city	Aarhus C
B.5.3.3	Post code	8000
B.5.3.4	Country	Denmark
B.5.6	E-mail	joeragnh@rm.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	Yes
D.2.1.1.1	Trade name	Dekristol 20.000 ie
D.2.1.1.2	Name of the Marketing Authorisation holder	mibe GmbH Arzneimittel, Münchener Str. 15, 06796 Brehna
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	cholecalciferol
D.3.9.3	Other descriptive name	CHOLECALCIFEROL
D.3.9.4	EV Substance Code	SUB34314
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20000
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	Remicade
D.2.1.1.2	Name of the Marketing Authorisation holder	MSD Denmark ApS
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INFLIXIMAB
D.3.9.1	CAS number	170277-31-3
D.3.9.4	EV Substance Code	SUB02681MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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)	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	Yes
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	Remsima
D.2.1.1.2	Name of the Marketing Authorisation holder	Celltrion Healthcare Hungary Kft.
D.2.1.2	Country which granted the Marketing Authorisation	Hungary
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	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INFLIXIMAB
D.3.9.1	CAS number	170277-31-3
D.3.9.4	EV Substance Code	SUB02681MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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)	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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
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

Active Crohn's Disease in colon and/or terminal ileum

E.1.1.1

Medical condition in easily understood language

Active chronic inflammatory bowel disease present in the large intestine and/or in the terminal end of the small intestines.

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10011408
E.1.2	Term	Crohns disease aggravated
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

• Mucosal T cell and macrophage VDR expression is increased by high dose vitamin D treatment and inflammation in CD compared to CD in remission and placebo.
• High dose vitamin D treatment to patients with active CD down regulates the Th17 cell inflammatory cytokine production in the intestinal mucosa.
• Increased VDR expression in active CD leads to an increased cathelicidin production in patients receiving vitamin D treatment.
• High dose vitamin D treatment modulates the macrophage function and phenotype in mucosa.

E.2.2

Secondary objectives of the trial

not applicable

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Mucosal immune regulation by high dose vitamin D in healthy subjects (13.11.13 version 1.0)
Purpose/aim
The purpose of this project is to investigate whether vitamin D supplementation affect the immune cells of the healthy intestine.

Hypotheses:
An increased blood level of 25-OH vitamin D, will affect the following in healthy intestinal mucosa
1. Vitamin D receptor (VDR) expression.
2. VDR pathway, including the expression of vitamin D dependent genes (cathelicidin, VDR, DERB4 and others).
3. Potential low grade inflammation, as measured by the production of proinflammatory cytokines.

E.3

Principal inclusion criteria

CD patients:
Age ≥ 18 years and < 80 years

Negative pregnancy test (serum-HCG) for women of childbearing age before the start of the study. (Women not of childbearing age are defined as postmenopausal for at least 1 year or surgically sterilised (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)). Women of childbearing age included in the study will be required to use contraception during the entire study period (i.e. one of the following: contraceptive pills, intrauterine device, depot injection of gestagen, sub dermal implant, hormonal vaginal ring or transdermal patch). If contraceptive medicine is contraindicated the women must use condom for protection during the study period.

Known colon and/or ileoceacal Crohn’s disease according to established diagnostic criteria (clinical criteria plus endoscopic verification with colon- capsule endoscopy, and/or histology)

Active disease with HBI score > 5 and CRP > 8 or calprotectin > 100 mg/g

CDEIS score > 5

Healthy controls:
Age ≥ 18 years and < 80 years

Negative pregnancy test (serum-HCG) for women of childbearing age before the start of the study. (Women not of childbearing age are defined as postmenopausal for at least 1 year or surgically sterilised (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)). Women of childbearing age included in the study will be required to use contraception during the entire study period (i.e. one of the following: contraceptive pills, intrauterine device, depot injection of gestagen, sub dermal implant, hormonal vaginal ring or transdermal patch). If contraceptive medicine is contraindicated the women must use condom for protection during the study period.

Serum 25-hydroxyvitamin D2+D3 < 60 nmol/l

E.4

Principal exclusion criteria

CD patients:

• Untreated infections, sepsis or opportunistic infections
• 25-hydroxyvitamin D2 + D3 > 100 nmol/l
• Biological treatment with Infliximab or Adalimumab within 3 month
• Unable to talk and understand Danish
• Allergy to Dekristol, peanuts or soya
• Allergy to Infliximab
• Infliximab antibodies detected at previous Infliximab treatment
• Active or suspicion of tuberculosis infection (positive T-spot, positive quantiferon gold-test or radiological changes on thoracic x-ray)
• Active and chronic viral hepatitis, present CMV or EBV infection
• Hypercalcaemia and/or hypercalcuria
• Pseudohypoparathyrodism
• Prior calcium-containing kidney stones
• Disorders of renal calcium and phosphate excretion
• Treatment with benzothiadiazine derivate, phenytoin, barbiturates or digoxin
• Immobilisation
• Sarcoidosis
• Moderate to severe heart failure (NYHA class 3 and 4)
• Present or former cancer
• Breastfeeding
• Demyelinating diseases inclusive Guillian-Barré and Multiple Sclerosis
• Vaccination with living vaccine within 4 weeks
• CD with untreated abscesses
• Changes in azathioprine treatment dose within 3 months
• Steroid dose > 20 mg/day (prednison) or > 3 mg/day budesonide
• P-sodium > 150 mmol/l
• P-chloride > 106 mmol/l
• Over hydration

Healthy controls:
• Hypercalcaemia or hypercalcuria
• Ongoing infection
• Known autoimmune disease
• Allergy to Dekristol (cholecalciferol), peanuts or soya
• Pseudohypoparathyrodism
• Prior calcium-containing kidney stones
• Disorders of renal calcium and phosphate excretion
• Treatment with benzothiadiazine derivate, phenytoin, barbiturates or digoxin
• Immobilisation
• Sarcoidosis
• Pregnancy or breast-feeding

E.5 End points

E.5.1

Primary end point(s)

Measurement of the VDR expression in mucosal T cells, DCs and macrophages before and after high dose vitamin D treatment and inflammation and compare to placebo treatment.

IL-17A, IL-17F, IFNγ, IL-4 and IL-22 expression in mucosal T cells before and after high dose vitamin D treatment and inflammation.

Investigate whether high dose vitamin D improve the effect of TNFalpha antibody treatment on the cytokines listed above

E.5.1.1

Timepoint(s) of evaluation of this end point

when all patients have finished the study period and the treatment is unblinded

E.5.2

Secondary end point(s)

•HBI score, CRP and faecal calprotectin before and after high dose vitamin D treatment
•The amount of dendritic cells and macrophages before and after high dose vitamin D treatment in inflamed and non-inflamed mucosa
•Cathelicidin concentrations before and after treatment of inflammation
•Cathelicidin concentration before and after vitamin D treatment
•Correlation between vitamin D binding protein concentration, Vitamin D binding protein phenotype and 25D3 levels before and after vitamin D treatment
•Correlation between VDR expression in mucosal macrophages, dendritic cells and T cells and vitamin D binding protein
•Changes in phenotypes within inflammation and vitamin D treatment in T cells, macrophages and dendritic cells.
•Changes in mucosal adherent bacteria measurement before and after inflammation.
•Changes in phenotype and function of T cells and dendritic cells before and after treatment in PBMCs.
•VDR expression and cathelicidin concentration measurements in epithelial cells
• Identify the micro biome in stool samples before and after treatment and compare to healthy controls

Helthy controls:
• Changes in mRNA expression of vitamin D dependent genes in healthy controls treated with high dose vitamin D
• VDR expression in mucosal T cells from healthy controls compared to CD patients
• Cytokine production in mucosal T cells from healthy controls compared to CD patients

E.5.2.1

Timepoint(s) of evaluation of this end point

when all patients have finished the study period and the treatment is unblinded

Healthy controls:
Helthy controls are included independent of the patients and the results are evaluated when all ten healthy controls are included.

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

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)

Yes

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

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

The study is unblinded when the last patient has ended the treatment study period (maximum 49 days). The patients are followed up afterwards up to week 52.

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

Yes

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)

When patients have ended the study period of 6 weeks + 1 to 7 days, patients are treated according to the following:
• Patients in remission are treated with Infliximab 5 mg/kg every 6 to 8 week.
• Patients who have not responded to treatment are unblinded regarding the infusion treatment and treated in the following order:
Placebo Infliximab treated patients are treated with 5 mg/kg Infliximab
Infliximab treated patients are switched in treatment according to guidelines and excluded.

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

2013-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-11-22

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