Clinical Trials Register

Summary
EudraCT Number:	2017-000695-28
Sponsor's Protocol Code Number:	VitDURO-AECC17-01
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-05-21
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

Spain - AEMPS

A.2

EudraCT number

2017-000695-28

A.3

Full title of the trial

Pilot study of Vitamin D biological effects in patients with resectable urinary tract urothelial carcinoma.

Estudio piloto de los efectos biológicos de la vitamina D en pacientes con
carcinoma urotelial del tracto urinario resecable

A.3.1

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

Study to assess the effects of vitamin D on tumor tissue in urinary bladder cancer

Estudio para valorar los efectos de la vitamina D sobre el tejido del tumor en cáncer de vejiga urinaria

A.4.1

Sponsor's protocol code number

VitDURO-AECC17-01

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	Hospital Universitari Germans Trias i Pujol
B.1.3.4	Country	Spain
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	Fundación Asociación Española contra el Cáncer
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Spanish Clinical Research Network
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fundació Institut d'Investigació Germans Trias i Pujol
B.5.2	Functional name of contact point	Clinical Trial Unit (UPIC)
B.5.3	Address:
B.5.3.1	Street Address	Carretera del Canyet s/n
B.5.3.2	Town/ city	Badalona
B.5.3.3	Post code	08916
B.5.3.4	Country	Spain
B.5.4	Telephone number	34934978488
B.5.5	Fax number	34934978778
B.5.6	E-mail	arodrigueza@igtp.cat

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	Viatmin D3 Farmasierra 50.000 UI comprimidos
D.2.1.1.2	Name of the Marketing Authorisation holder	Farmasierra Manufacturing S.L
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Colecalciferol (Vitamin D)
D.3.4	Pharmaceutical form	Tablet
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	COLECALCIFEROL
D.3.9.3	Other descriptive name	Vitamin D
D.3.9.4	EV Substance Code	SUB06794MIG
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	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.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	Vitamin D3 Farmasierra 10.000 UI comprimidos
D.2.1.1.2	Name of the Marketing Authorisation holder	Farmasierra Manufacturing S.L
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Colecalciferol (Vitamin D)
D.3.4	Pharmaceutical form	Tablet
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	COLECALCIFEROL
D.3.9.3	Other descriptive name	Vitamin D
D.3.9.4	EV Substance Code	SUB06794MIG
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	10.000
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with resectable urinary tract urothelial carcinoma candidates to radical cystectomy o nephroureterectomy.

Pacientes con carcinoma urotelial resecable de tracto urinario candidatos a cistectomía o nefroureterectomía.

E.1.1.1

Medical condition in easily understood language

Patients with operable urinary bladder cancer.

Pacientes con cáncer de vejiga urinaria operable.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10046718
E.1.2	Term	Urothelial carcinoma bladder stage I, with cancer in situ
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10046720
E.1.2	Term	Urothelial carcinoma bladder stage II
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10046721
E.1.2	Term	Urothelial carcinoma bladder stage III
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10046724
E.1.2	Term	Urothelial carcinoma ureter local
E.1.2	System Organ Class	100000004864

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 determine the biological effect of weekly treatment with Vitamin D3 (10.000 UI or 50.000 UI according baseline levels) on tumor phenotype (sample comparison between transurethral resection and cystectomy or nephroureterectomy).

Determinar el efecto biológico del tratamiento semanal con vitamina D3 (10.000 UI o 50.000 UI según los niveles basales de día 1) sobre el fenotipo tumoral (comparación de muestra de la resección transuretral con la muestra de la cistectomía o nefroureterectomía).

E.2.2

Secondary objectives of the trial

1. To determine the biological effect of Vitamin D3 treatment on peripheral blood leukocyte gene expression as a marker of treatment sensitivity.
2. To compare the biological effects of Vitamin D3 on tumor phenotype and peripheral blood leukocyte gene expression, regarding plasma levels prior and after Vitamin D3 administration.

1. Determinar el efecto biológico del tratamiento con vitamina D3 sobre la expresión génica en leucocitos de sangre periférica como marcador de sensibilidad al tratamiento.
2. Comparar los efectos biológicos de la vitamina D3 sobre el fenotipo tumoral y sobre la expresión génica en leucocitos de sangre periférica, en relación con los niveles plasmáticos previos y posteriores a su administración.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Men and women older than 18 years.
2. Patients are willing and able to read and understand the patient’s information sheet and give their consent for participation in the study, before initiating any protocol specific procedure.
3. Histologically confirmed diagnosis of urothelial non-muscle-invasive bladder cancer (T1 high grade and/or carcinoma in situ), and patients with muscle-invasive or high urinary tract carcinoma without evidence of distant metastasis (T2-4N0M0).
4. Candidate patients to undergo treatment by radical cystectomy or nephroueterectomy as part of conventional tumor treatment.
5. Not having received any antitumor treatment during the 4 weeks prior the administration of Vitamin D3.
6. Life expectancy longer than 6 months.
7. Karnofsky Index > 70%.
8. Confirmed adequate bone marrow, kidney and liver functions by:
- Leukocyte count > 4.000.
- Platelet count > 100.000.
- Haemoglobin levels > 10 gr/dL.
- Serum Bilirubin levels < 1,5X the upper limit of normality.
- AST and ALT levels <2,5X the upper limit of normality.
- Alkaline Phosphatase levels <5X the upper limit of normality.
- Serum creatinine levels ≤2 mg/dL, and/or Glomerular Filtration Rate ≥45 mL/min/1,73m2 estimated by MDRD-4 IDMS or CKD-EPI evaluation.
9. Plasma calcium levels between 8,8 and 10,6 mg/dL, and 24 hours urine calcium levels between 100 and 300 mg/24h.
10. Women of childbearing potential should use a highly effective contraceptive method according the Clinical Trial Facilitation Group (such as combined hormonal contraceptives or IUD), and should continue its use for 90 days after the last dose of Vitamin D3.
11. Males in fertile age, with a potentially fertile partner, should use a contraceptive method such as sexual abstinence or barrier method (condom), throughout the clinical trial and up to 90 days after the end of treatment, or be vasectomized.

1. Hombres y mujeres >18 años.
2. Consentimiento informado antes de someterse a ninguna prueba relacionada con el estudio.
3. Diagnóstico histológicamente confirmado de cáncer urotelial de vejiga no-músculo-invasivo (T1 alto grado y/o carcinoma in situ) y pacientes con carcinoma de vejiga músculo-invasivo o del tracto urinario alto, sin evidencia de metástasis a distancia (T2-4N0M0).
4. Pacientes candidatos a someterse a un tratamiento mediante cistectomía radical o con nefroureterectomía como parte del tratamiento convencional del tumor.
5. No haber recibido ningún tratamiento antitumoral en las 4 semanas previas a la administración de la vitamina D3.
6. Esperanza de vida >6 meses.
7. Indice de Karnofsky >70%.
8. Funciones de médula ósea, renal y hepática adecuadas confirmadas por:
- Recuento de leucocitos >4.000
- Recuento de plaquetas >100.000
- Niveles de hemoglobina >10 g/dl
- Niveles de bilirrubina sérica <1.5 x el límite superior de la normalidad
- Niveles de AST y ALT <2.5 x límite superior de la normalidad
- Niveles de fosfatasa alcalina <5 veces el límite superior de la normalidad
- Niveles de creatinina sérica ≤2 mg/dl y/o Filtrado Glomerular ≥45 mL/min/1.73m2 calculado a través de estimación de MDRD-4 IDMS o de CKD-EPI.
9. Niveles de calcio plasmático entre 8,8 y 10,6 mg/dl y de calcio en orina de 24h entre 100 y 300 mg/24 h.
10. Las mujeres en edad fértil deberán usar un método anticonceptivo de alta efectividad de acuerdo con el Clinical Trial Facilitation Group (como anticonceptivos hormonales combinados o DIU) y continuar su uso durante 90 días tras la administración de la última dosis de vitamina D3.
11. Los varones en edad fértil, con pareja potencialmente fértil, deberán utilizar un método anticonceptivo como la abstinencia sexual, o de barrera (preservativo), durante todo el ensayo clínico y hasta 3 meses después de finalizado el tratamiento, o estar vasectomizados.

E.4

Principal exclusion criteria

1. Age older than 80 years.
2. Patients with non-urothelial histology. Those with mixed histology (urothelial histology combined with another histological type) may be included if the urothelial component is the predominant (>50%).
3. Administration of neoadjuvant chemotherapy.
4. Administration of radiotherapy during the period between TUR and surgery.
5. Medical history of another neoplasm diagnosed in the previous 3 years (except carcinoma in situ or non-melanoma cutaneous carcinoma). It may be included those patients with history of other neoplasms, provided that after receiving radical treatment do not relapsed.
6. History of hypersensitivity to Vitamin D.
7. History of renal lithiasis larger than 5 mm or symptomatic in the year prior its inclusion in the study, and/or nephrocalcinosis.
8. History of hypercalcemia and/or hypercalciuria.
9. Situation of hypervitaminosis (25-OH Vitamin D > 50 ng/mL).
10. Previous treatment with Vitamin D3 in the last 6 months.
11. Chronic treatment with corticosteroids.
12. Other serious diseases or medical processes such as:
- Infection that requires systemic anti-infective treatment.
- Not controlled serious medical process, including severe heart disease (episodes of ischemic heart disease in the last 6 months, cardiac arrhythmia or heart failure).
13. Medical history of sarcoidosis or parathyroid disease.
14. History of malabsorption syndrome (for example pancreatic insufficiency, celiac disease or Crohn’s disease), history of small bowel resection or any medical condition that may interfere with Vitamin D absorption.
15. Patients who are expected to administer nutritional supplements containing Vitamin D, or who are being treated with drugs (or combination of drugs) that contain Vitamin D.
16. Pregnancy.

1. Pacientes >80 años de edad.
2. Pacientes con histología no-urotelial. Los pacientes con histología mixta (carcinoma urotelial combinado con otro tipo histológico) podrán ser incluidos si predomina el componente urotelial (>50%).
3. Administración de quimioterapia neoadyuvante.
4. Administración de radioterapia durante el período comprendido entre la RTU y la cirugía.
5. Antecedentes de otra neoplasia diagnosticada en los 3 años previos (excepto carcinoma in situ o carcinoma cutáneo no melanoma). Se podrán incluir pacientes que hayan tenido otras neoplasias, que habiendo recibido un tratamiento radical no hayan presentado recidiva.
6. Antecedentes de hipersensibilidad a la vitamina D.
7. Antecedentes de litiasis renal de tamaño >5mm o sintomática en el año previo a su inclusión en el estudio, y/o nefrocalcinosis
8. Antecedentes de hipercalcemia y/o hipercalciuria
9. Situación de hipervitaminosis (niveles en la selección de 25-OH vitamina D >50 ng/ml)
10. Tratamiento previo con vitamina D3 en los últimos 6 meses.
11. Tratamiento crónico con corticoides.
12. Otras enfermedades graves o procesos médicos como:
- Infección que requiera tratamiento anti-infeccioso sistémico
- Proceso médico grave, no controlado, incluyendo cardiopatía severa (episodios de cardiopatía isquémica en los últimos 6 meses, arritmia cardiaca o insuficiencia cardiaca).
13. Antecedentes de sarcoidosis o enfermedad paratiroidea.
14. Antecedentes de síndrome de malabsorción (p.ej., insuficiencia pancreática, enfermedad celiaca o enfermedad de Crohn), antecedentes de resección de intestino delgado o cualquier condición médica que pueda interferir en la absorción de vitamina D.
15. Pacientes a los que se prevea administrar suplementos nutricionales que contengan Vitamina D o que estén en tratamiento con fármacos o combinaciones de fármacos que contengan Vitamina D.
16. Embarazo.

E.5 End points

E.5.1

Primary end point(s)

Tumor expression of differentiation and Vitamin D response markers (RNA and protein), comparing pre- versus post- intervention with Vitamin D.

Expresión de marcadores de diferenciación y respuesta a vitamina D en el tumor (RNA y proteína), comparación pre- vs. post-intervención con vitamina D3.

E.5.1.1

Timepoint(s) of evaluation of this end point

Post-surgical intervention.

Post-intervención quirúrgica.

E.5.2

Secondary end point(s)

- Expression of Vitamin D target genes in peripheral blood leukocytes (RNA), comparing pre- versus post-intervention with Vitamin D.
- Vitamin D plasma levels, comparing pre- versus post- study inclusion.

- Expresión de genes diana de vitamina D en leucocitos de sangre periférica (RNA), comparación pre- vs. post-intervención con vitamina D3.
- Niveles de vitamina D plasmática, comparación pre- vs. post-inclusión en el estudio.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the study.

Al final del estudio.

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

E.8.1.1

Randomised

E.8.1.2

Open

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

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

Last visit last subject.

Última visita del último paciente.

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

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.

Ninguno.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Spanish Clinical Research Network
G.4.3.4	Network Country	Spain

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-07-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-22

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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