Clinical Trials Register

Summary
EudraCT Number:	2020-001099-14
Sponsor's Protocol Code Number:	HIDR-0320/DR
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-09-17
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

2020-001099-14

A.3

Full title of the trial

Randomised, double-blind, double-dummy, multicentre trial to evaluate the efficacy and safety of three different weekly dosages of calcifediol versus placebo in subjects with either vitamin D deficiency or insufficiency

A.3.1

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

Study to investigate the efficacy and safety of 3 different weekly dosages of calcifediol (versus placebo) in patients suffering from Vitamin D deficiency or insufficiency

A.3.2

Name or abbreviated title of the trial where available

WORFEROL

A.4.1

Sponsor's protocol code number

HIDR-0320/DR

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	FAES FARMA S.A.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	FAES FARMA S.A.
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	FAES FARMA S.A.
B.5.2	Functional name of contact point	R&D+i Department
B.5.3	Address:
B.5.3.1	Street Address	Av. Autonomía 10
B.5.3.2	Town/ city	Leioa (Bizkaia)
B.5.3.3	Post code	48940
B.5.3.4	Country	Spain
B.5.4	Telephone number	3494481 83 00
B.5.5	Fax number	3494481 83 23
B.5.6	E-mail	clinical_rd@faes.es

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	Calcifediol monohydrate
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	Calcifediol Monohydrate
D.3.9.1	CAS number	63283-36-3
D.3.9.2	Current sponsor code	Calcifediol
D.3.9.4	EV Substance Code	SUB06045MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
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	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	Calcifediol monohydrate
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	Calcifediol Monohydrate
D.3.9.1	CAS number	63283-36-3
D.3.9.2	Current sponsor code	Calcifediol
D.3.9.4	EV Substance Code	SUB06045MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(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	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: 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	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	Calcifediol monohydrate
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	Calcifediol Monohydrate
D.3.9.1	CAS number	63283-36-3
D.3.9.2	Current sponsor code	Calcifediol
D.3.9.4	EV Substance Code	SUB06045MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	125
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	Capsule, soft
D.8.4	Route of administration of the placebo	Oral 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
D.8 Placebo: 3
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

Vitamin D deficiency or insufficiency

E.1.1.1

Medical condition in easily understood language

Blood vitamin D levels are lower than the recomended ones.

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10053828
E.1.2	Term	Blood 1,25-dihydroxy vitamin D decreased
E.1.2	System Organ Class	100000004848

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 assess efficacy for each cohort in terms of percentage of subjects who achieve 25-OH-D levels ≥ 30 ng/mL and/or ≥ 20 ng/mL at 16 weeks of treatment.

E.2.2

Secondary objectives of the trial

1. To assess efficacy in terms of further parameters based on 25-OH-D levels at different time points, also by age and BMI subgroups, as well as by treatment cohorts
2. To assess safety by treatment cohort

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female subjects ≥ 18 years of age.
2. Evidence of serum 25-OH-D levels < 20 ng/mL or ≤ 10 ng/mL, for each cohort respectively.
3. Written informed consent given freely after the nature of the clinical trial and disclosure of data has been explained to the subject.
4. For females of childbearing potential only: willing to perform pregnancy tests, must agree to use highly effective methods of birth control throughout the study. Highly effective methods of birth control include: combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner (provided that partner is the sole sexual partner of the clinical trial participant and has documentation of azoospermia) or sexual abstinence (if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment). The investigator is responsible for determining whether the subject has adequate birth control for study participation.

E.4

Principal exclusion criteria

1. Subjects receiving any treatment with calcifediol, vitamin D analogues, vitamin complexes or vitamin D supplements within the last week before screening or planned during the clinical trial (except clinical trial rescue medication).
2. Subjects taking drugs that could modify vitamin D levels, i.e. phenobarbital, phenytoin, primidone, digoxin, rifampin, thiazide diuretics (hydrochlorothiazide), some antibiotics (penicillin, neomycin and chloramphenicol), antiretrovirals (tenofovir, adefovir), long-term corticosteroids (defined as a dose of prednisolone ≥ 5 mg per day (or equivalent) for more than 3 months), verapamil, paraffin, mineral oil laxatives, magnesium salts, actinomycin, and antifungic imidazoles, within the last week before screening or planned during the clinical trial. Subjects taking orlistat, cholestyramine or colestipol who do not respect an interval of at least 2 hours before IP intake.
3. Subjects taking calcium supplements within the last week before screening or planned during the clinical trial.
4. Uncorrected hypercalcaemia (calcium > 10.5 mg/dL), known hypercalciuria or nephrolithiasis.
5. Severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) by CKD-EPI < 30 mL/min/1.73m2
6. Subjects diagnosed with liver or biliary failure, congestive heart failure, malabsorption, primary hyperparathyroidism, hypoparathyroidism, prolonged immobilisation, sarcoidosis, tuberculosis or other granulomatous diseases or hyperthyroidism.
7. Any present or previous malignancy within the last 5 years prior to the screening visit.
8. Known contraindications or sensitivities to the use of the IP or any of its components.
9. Pregnant woman, breastfeeding woman or woman planning a pregnancy.
10. Subject has received an IP (including investigational vaccines) or used an invasive investigational medical device within 30 days (or five half-lives of that IP, whichever is longer) before the start of the screening or is currently enrolled in an investigational interventional study.
11. Any condition that, in the opinion of the investigator, may jeopardise the clinical trial conduct according to the protocol (for example, evidence of diseases, medications or laboratory abnormalities that could alter the conduct of the study).
12. Employees of the investigator or clinical trial site, with direct involvement in the proposed study or other studies under the direction of that investigator or clinical trial site, as well as family members of the employees or the principal investigator.
13. Person committed to an institution by virtue of an order issued either by judicial or other authorities.

E.5 End points

E.5.1

Primary end point(s)

Percentage of responders by cohort, defined as a subject who achieves 25-OH-D levels ≥ 30 ng/mL and/or ≥ 20 ng/mL at 16 weeks of treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

At 16 weeks of treatment

E.5.2

Secondary end point(s)

1. Percentage of subjects achieving 25-OH-D levels ≥ 20 ng/mL at 4, 24, 32 and 52 weeks of treatment.
2. Percentage of subjects achieving 25-OH-D levels ≥ 30 ng/mL at 4, 24, 32 and 52 weeks of treatment.
3. Mean change from baseline in 25-OH-D levels at 4, 16, 24, 32 and 52 weeks of treatment.
4. Time to achieve 25-OH-D levels ≥ 30 ng/mL.
5. Time to achieve 25-OH-D levels ≥ 20 ng/mL.
6. Percentage of subjects in need of rescue medication, i.e. with 25-OH-D level ≤ 10 ng/mL at 16, 24 and 32 weeks of treatment..
7. Percentage of responders regarding seasonal variations.
8. Correlation between parathyroid hormone (PTH) and 25-OH-D levels at 16, 24 and 32 weeks of treatment.
9. Mean change from baseline in bone and mineral metabolism parameters (total serum calcium (tCa), PTH, albumin, phosphorus and total alkaline phosphatase levels) at 4, 16, 24, 32 and 52 weeks, as well as frequencies for values out of range and in range.
10. Percentage of treatment-emergent adverse events (TEAEs).
11. Percentage of related TEAEs
12. Percentage of TEAEs by severity
13. Percentage of serious TEAEs (related/unrelated), including TEAEs resulting in death
14. Frequency of TEAEs leading to discontinuation of study drug.
15. Haematology, frequencies for values out of range and in range.
16. Biochemistry, frequencies for values out of range and in range.
17. Physical examination and vital signs, clinically significant changes from baseline at 16, 24 and 52 weeks.
18. Percentage of subjects withdrawn from the study due to safety concerns.
19. Percentage of subjects reaching 25-OH-levels above 50, 60 and 70 ng/mL.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. At 4, 24, 32 and 52 weeks of treatment.
2. At 4, 24, 32 and 52 weeks of treatment.
3. At 4, 16, 24, 32 and 52 weeks of treatment
4. + 5. At any time during the 52 weeks of treatment
6. + 8. At 16, 24 and 32 weeks of treatment
9. At 4, 16, 24, 32 and 52 weeks of treatment
7. no timepoint applicable
17. At 16, 24 and 52 weeks
Safety endpoints (9.-19.) will be assessed throughout the study.

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

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

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

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Double-dummy

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

Yes

E.8.2.3.1

Comparator description

Benferol as rescue medication for subjects with 25-OH-D levels ≤ 10 ng/mL at V4 (or V5, V6)

E.8.2.4

Number of treatment arms in the trial

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Bulgaria

Czech Republic

France

Italy

Romania

Serbia

Slovakia

Spain

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

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:

525

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

270

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.4.2

For a multinational trial

F.4.2.1

In the EEA

705

F.4.2.2

In the whole clinical trial

795

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)

After the end of the trial, the subjects will be treated according to local standard practice. No further post-trial therapy will be offered by the sponsor.

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

2020-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-04-25

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