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Clinical Trial Results:
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.

Summary
EudraCT number	2020-001099-14
Trial protocol	FR SK CZ BG IT
Global end of trial date	25 Apr 2023

Results information
Results version number	v1(current)
This version publication date	20 Sep 2024
First version publication date	20 Sep 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

HIDR-0320/DR

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

FAES FARMA, S.A.

Sponsor organisation address

Avenida Autonomía 10, Leioa (Bizkaia), Spain, 48940

Public contact

Clinical Research Derpartment, FAES FARMA, S.A., 0034 663626137, clinical_rd@faes.es

Scientific contact

Clinical Research Derpartment, FAES FARMA, S.A., 0034 663626137, clinical_rd@faes.es

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 Jul 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

21 Jul 2022

Global end of trial reached?

Yes

Global end of trial date

25 Apr 2023

Was the trial ended prematurely?

Main objective of the trial

The general objective of this clinical study was to determine the efficacy and safety of 3 new weekly doses (75 mcg, 100 mcg and 125 mcg) of calcifediol SGCs compared to placebo.

Protection of trial subjects

The study is conducted in accordance with the Declaration of Helsinki (2013) as well as with the valid national laws of the participating countries, with the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP) (E6), and with the Commission Directives 2001/20/EC, 2005/28/EC and 2001/83/EC.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Dec 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 243

Country: Number of subjects enrolled

Czechia: 316

Country: Number of subjects enrolled

France: 31

Country: Number of subjects enrolled

Italy: 35

Country: Number of subjects enrolled

Serbia: 108

Country: Number of subjects enrolled

Slovakia: 320

Country: Number of subjects enrolled

Spain: 235

Worldwide total number of subjects

1288

EEA total number of subjects

1180

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

926

From 65 to 84 years

347

85 years and over

Subject disposition

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Recruitment details

A total of 1288 subjects were enrolled at 55 study sites in 7 countries (Bulgaria, Czech Republic, Spain, France, Italy, Serbia, Slovakia). Of these, 614 subjects failed screening. In total 674 subjects of both cohorts (Cohort1: 398 subjects, Cohort2: 276 subjects) were randomised.

Screening details

614 subjects failed screening. In total 674 subjects of both cohorts (Cohort1: 398 subjects, Cohort2: 276 subjects) were randomised by 31 MAR 2022.

Number of subjects started

1288

Number of subjects completed

674

Reason: Number of subjects

Consent withdrawn by subject: 10

Reason: Number of subjects

Protocol deviation: 1

Reason: Number of subjects

Ineligibility/developm. of an excl./withdr. crit.: 549

Reason: Number of subjects

Lost to follow-up: 1

Reason: Number of subjects

At the specific request of the sponsor: 1

Reason: Number of subjects

Other: 50

Reason: Number of subjects

Persisting 25-OH-D level ≤ 10 ng/mL: 2

Period 1 title

Randomisation

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Overall - Placebo

Arm description

Oral administration of 75/100/125 mcg Calcifediol SGC matching Placebo once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Placebo SGCs (75 mcg, 100 mcg, 125 mcg) oral administration once per week

Overall - Calcifediol 75 mcg

Arm description

Oral administration of 75 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 75 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Overall - Calcifediol 100 mcg

Arm description

Oral administration of 100 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 100 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Overall - Calcifediol 125 mcg

Arm description

Oral administration of 125 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 125 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Number of subjects in period 1 ^[1]	Overall - Placebo	Overall - Calcifediol 75 mcg	Overall - Calcifediol 100 mcg	Overall - Calcifediol 125 mcg
Started	130	159	271	114
Completed	130	159	271	114

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Number of subjects in the baseline period are defined as subjects who met all the inclusion criteria and none of the exclusion criteria. Of the 1288 subjects enrolled in the trial, 614 subjects failed screening. In total 674 subjects of both cohorts (Cohort1: 398 subjects, Cohort2: 276 subjects) were randomised.

Period 2 title

Treatment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Treatment - Placebo

Arm description

Oral administration of 75/100/125 mcg Calcifediol SGC matching Placebo once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Placebo SGCs (75 mcg, 100 mcg, 125 mcg) oral administration once per week

Treatment - Calcifediol 75 mcg

Arm description

Oral administration of 75 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 75 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Treatment - Calcifediol 100 mcg

Arm description

Oral administration of 100 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 100 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Treatment - Calcifediol 125 mcg

Arm description

Oral administration of 125 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 125 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Number of subjects in period 2	Treatment - Placebo	Treatment - Calcifediol 75 mcg	Treatment - Calcifediol 100 mcg	Treatment - Calcifediol 125 mcg
Started	130	159	271	114
Completed	107	142	239	94
Not completed	23	17	32	20
Consent withdrawn by subject	8	6	15	7
Adverse event, non-fatal	1	4	2	4
Persisting 25-OH-D level ≤ 10 ng/mL	1	-	-	-
Other	1	-	-	-
Pregnancy	1	-	1	-
At the specific request of the sponsor	2	-	-	-
Ineligibility/developm. of an excl./withdr. crit.	5	3	5	9
Use of prohibited concomitant medication	2	3	6	-
Lost to follow-up	2	1	2	-
Protocol deviation	-	-	1	-

Period 3 title

Safety Follow-Up

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Safety Follow-Up - Placebo

Arm description

Oral administration of 75/100/125 mcg Calcifediol SGC matching Placebo once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period. Due to technical issues of EudrCT database only the 107 subjects of the Placebo treated arm could be stated, that completed treatment period and did Follow-Up Visit 8. In total 117 subjects of this arm had a Follow-Up Visit 8.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Placebo SGCs (75 mcg, 100 mcg, 125 mcg) oral administration once per week

Safety Follow-Up - Calcifediol 75 mcg

Arm description

Oral administration of 75 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period. Due to technical issues of EudrCT database only the 142 subjects treated with Calcifediol 75 mcg could be stated, that completed treatment period and did Follow-Up Visit 8. In total 150 subjects of this arm had a Follow-Up Visit 8.

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 75 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Safety Follow-Up - Calcifediol 100 mcg

Arm description

Oral administration of 100 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period. Due to technical issues of EudrCT database only the 239 subjects treated with Calcifediol 100 mcg could be stated, that completed treatment period and did Follow-Up Visit 8. In total 248 subjects of this arm had a Follow-Up Visit 8.

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 100 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Safety Follow-Up - Calcifediol 125 mcg

Arm description

Oral administration of 125 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period. Due to technical issues of EudrCT database only the 94 subjects treated with Calcifediol 125 mcg could be stated, that completed treatment period and did Follow-Up Visit 8. In total 102 subjects of this arm had a Follow-Up Visit 8.

Arm type

Active comparator

Investigational medicinal product name

Calcifediol (25-OH-D)

Investigational medicinal product code

Calcifediol

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of 125 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Number of subjects in period 3	Safety Follow-Up - Placebo	Safety Follow-Up - Calcifediol 75 mcg	Safety Follow-Up - Calcifediol 100 mcg	Safety Follow-Up - Calcifediol 125 mcg
Started	107	142	239	94
Completed	107	142	239	94

Baseline characteristics

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Subject analysis set title

Overall - Placebo x Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who took at least one dose of IP

Subject analysis set title

Overall - Calcifediol 75 mcg x Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who took at least one dose of IP

Subject analysis set title

Overall - Calcifediol 100 mcg x Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who took at least one dose of IP

Subject analysis set title

Overall - Calcifediol 125 mcg x Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who took at least one dose of IP

Subject analysis set title

Overall - Placebo x Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who took at least one dose of IP and who had at least one post baseline assessment of the primary efficacy measurement (25‑OH-D level).

Subject analysis set title

Overall - Calcifediol 75 mcg x Full Analsysis Set

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who took at least one dose of IP and who had at least one post baseline assessment of the primary efficacy measurement (25‑OH-D level).

Subject analysis set title

Overall - Calcifediol 100 mcg x Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who took at least one dose of IP and who had at least one post baseline assessment of the primary efficacy measurement (25‑OH-D level).

Subject analysis set title

Overall - Calcifediol 125 mcg x Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who took at least one dose of IP and who had at least one post baseline assessment of the primary efficacy measurement (25‑OH-D level).

Subject analysis set title

Overall - Placebo x Safety Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Calcifediol 75 mcg x Safety Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Calcifediol 100 mcg x Safety Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Placebo x Safety Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Calcifediol 100 mcg x Safety Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Calcifediol 125 mcg x Safety Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Placebo x Full Analysis Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Full Analysis Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Full Analysis Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Full Analysis Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Placebo x Full Analysis Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Full Analysis Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Full Analysis Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Full Analysis Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis sets values	Overall - Placebo x Safety Set	Overall - Calcifediol 75 mcg x Safety Set	Overall - Calcifediol 100 mcg x Safety Set	Overall - Calcifediol 125 mcg x Safety Set	Overall - Placebo x Full Analysis Set	Overall - Calcifediol 75 mcg x Full Analsysis Set	Overall - Calcifediol 100 mcg x Full Analysis Set	Overall - Calcifediol 125 mcg x Full Analysis Set	Overall - Placebo x Safety Set (Cohort 1)	Overall - Calcifediol 75 mcg x Safety Set (Cohort 1)	Overall - Calcifediol 100 mcg x Safety Set (Cohort 1)	Overall - Placebo x Safety Set (Cohort 2)	Overall - Calcifediol 100 mcg x Safety Set (Cohort 2)	Overall - Calcifediol 125 mcg x Safety Set (Cohort 2)	Overall - Placebo x Full Analysis Set (Cohort 1)	Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1)	Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1)	Overall - Placebo x Full Analysis Set (Cohort 2)	Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2)	Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2)
Number of subjects	128	158	266	113	128	156	263	110	73	158	162	55	104	113	73	156	159	55	104	110
Age Categorical
Age Categorical Characteristic
Units: Subjects
In Utero									0	0	0	0	0	0
Preterm newborn- gestational age < 37 wk									0	0	0	0	0	0
Newborns (0-27days)									0	0	0	0	0	0
Infants and toddlers (28days – 23months)									0	0	0	0	0	0
Children (2-11 years)									0	0	0	0	0	0
Adolescents (12-17 year)									0	0	0	0	0	0
From 18 - 64 years									58	119	122	42	71	75
From 65 – 84 years									15	39	40	13	33	35
Over 85 years									0	0	0	0	0	3
Age Continuous
Age Continuous Characteristic
Units: years
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )	( )	( )	50.1 ( 15.43 )	52.7 ( 15.81 )	51.3 ( 16.43 )	53.8 ( 12.9 )	55.4 ( 15.97 )	56.3 ( 16.41 )	56.3 ( 16.41 )	56.3 ( 16.41 )	56.3 ( 16.41 )	56.3 ( 16.41 )	56.3 ( 16.41 )	56.3 ( 16.41 )
Gender Categorical
Gender Categorical Characteristic
Units: Subjects
Female									51	124	116	43	79	79
Male									22	34	46	12	25	34

End points

Top of page

Reporting group title

Overall - Placebo

Reporting group description

Oral administration of 75/100/125 mcg Calcifediol SGC matching Placebo once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Reporting group title

Overall - Calcifediol 75 mcg

Reporting group description

Oral administration of 75 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Reporting group title

Overall - Calcifediol 100 mcg

Reporting group description

Oral administration of 100 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Reporting group title

Overall - Calcifediol 125 mcg

Reporting group description

Oral administration of 125 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Reporting group title

Treatment - Placebo

Reporting group description

Oral administration of 75/100/125 mcg Calcifediol SGC matching Placebo once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Reporting group title

Treatment - Calcifediol 75 mcg

Reporting group description

Oral administration of 75 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Reporting group title

Treatment - Calcifediol 100 mcg

Reporting group description

Oral administration of 100 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Reporting group title

Treatment - Calcifediol 125 mcg

Reporting group description

Oral administration of 125 mcg Calcifediol SGC once per week on Sunday morning (at least 48 hours before next blood sample extraction) during the treatment period

Reporting group title

Safety Follow-Up - Placebo

Reporting group description

Reporting group title

Safety Follow-Up - Calcifediol 75 mcg

Reporting group description

Reporting group title

Safety Follow-Up - Calcifediol 100 mcg

Reporting group description

Reporting group title

Safety Follow-Up - Calcifediol 125 mcg

Reporting group description

Subject analysis set title

Overall - Placebo x Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who took at least one dose of IP

Subject analysis set title

Overall - Calcifediol 75 mcg x Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who took at least one dose of IP

Subject analysis set title

Overall - Calcifediol 100 mcg x Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who took at least one dose of IP

Subject analysis set title

Overall - Calcifediol 125 mcg x Safety Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who took at least one dose of IP

Subject analysis set title

Overall - Placebo x Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who took at least one dose of IP and who had at least one post baseline assessment of the primary efficacy measurement (25‑OH-D level).

Subject analysis set title

Overall - Calcifediol 75 mcg x Full Analsysis Set

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who took at least one dose of IP and who had at least one post baseline assessment of the primary efficacy measurement (25‑OH-D level).

Subject analysis set title

Overall - Calcifediol 100 mcg x Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who took at least one dose of IP and who had at least one post baseline assessment of the primary efficacy measurement (25‑OH-D level).

Subject analysis set title

Overall - Calcifediol 125 mcg x Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who took at least one dose of IP and who had at least one post baseline assessment of the primary efficacy measurement (25‑OH-D level).

Subject analysis set title

Overall - Placebo x Safety Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Calcifediol 75 mcg x Safety Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Calcifediol 100 mcg x Safety Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Placebo x Safety Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Calcifediol 100 mcg x Safety Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Calcifediol 125 mcg x Safety Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Placebo x Full Analysis Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Full Analysis Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Full Analysis Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of of Full Analysis Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Subject analysis set title

Overall - Placebo x Full Analysis Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Full Analysis Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Full Analysis Set, having 25-OH-D baseline level ≤ 10 ng/mL

Subject analysis set title

Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects of Full Analysis Set, having 25-OH-D baseline level ≤ 10 ng/mL

Primary: 25-OH-D response level of ≥ 30 ng/mL at endpoint (Visit 4 [Week 16])

Top of page

End point title

25-OH-D response level of ≥ 30 ng/mL at endpoint (Visit 4 [Week 16])

End point description

The primary endpoint of this trial was 25-OH-D response level of ≥ 30 ng/mL at endpoint (Visit 4 [Week 16]). Subjects were allocated to two cohorts based on their 25-OH-D baseline level at Visit 1

End point type

Primary

End point timeframe

16 weeks

End point values	Overall - Placebo x Full Analysis Set (Cohort 1)	Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1)	Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1)	Overall - Placebo x Full Analysis Set (Cohort 2)	Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2)	Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2)
Number of subjects analysed	73	156	159	55	104	110
Units: [%]
number (not applicable)
Response Rate	11	74.4000000000	89.9	0	49	76.4000000000

z-test

Statistical analysis description

The percentage of 25-OH-D responders was analysed using a large-sample normal approximation test of proportions, also known as a z-test. For the primary efficacy analysis, responders were those subjects who achieved 25 OH D levels of ≥ 30 ng/mL at Visit 4/16 weeks of treatment. For confirmatory testing of 25-OH-D response rate, as a primary approach, subjects with missing 25-OH-D level at 16 weeks for any reason, including discontinuation prior to Visit 4, were regarded as non-responders.

Comparison groups

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1) v Overall - Placebo x Full Analysis Set (Cohort 1)

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

z-test

Statistical analysis description

Comparison groups

Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1) v Overall - Placebo x Full Analysis Set (Cohort 1)

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

z-test

Statistical analysis description

Comparison groups

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2) v Overall - Placebo x Full Analysis Set (Cohort 2)

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

z-test

Statistical analysis description

Comparison groups

Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2) v Overall - Placebo x Full Analysis Set (Cohort 2)

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

z-test

Statistical analysis description

Comparison groups

Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2) v Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2)

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

z-test

Statistical analysis description

Comparison groups

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1) v Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1)

Number of subjects included in analysis

315

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

z-test

Confidence interval

Primary: 25-OH-D response level of ≥ 20 ng/mL at endpoint (Visit 4 [Week 16])

Top of page

End point title

25-OH-D response level of ≥ 20 ng/mL at endpoint (Visit 4 [Week 16])

End point description

The primary endpoint of this trial was 25-OH-D response level of ≥ 20 ng/mL at endpoint (Visit 4 [Week 16]). Subjects were allocated to two cohorts based on their 25-OH-D baseline level at Visit 1

End point type

Primary

End point timeframe

16 weeks

End point values	Overall - Placebo x Full Analysis Set (Cohort 1)	Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1)	Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1)	Overall - Placebo x Full Analysis Set (Cohort 2)	Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2)	Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2)
Number of subjects analysed	73	156	159	55	104	110
Units: [%]
number (not applicable)
Response Rate	50.7	93.6	98.7	7.3	92.3	91.8

z-test

Statistical analysis description

The percentage of 25-OH-D responders was analysed using a large-sample normal approximation test of proportions, also known as a z-test. For the primary efficacy analysis, responders were those subjects who achieved 25 OH D levels of ≥ 20 ng/mL at Visit 4/16 weeks of treatment. For confirmatory testing of 25-OH-D response rate, as a primary approach, subjects with missing 25-OH-D level at 16 weeks for any reason, including discontinuation prior to Visit 4, were regarded as non-responders.

Comparison groups

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1) v Overall - Placebo x Full Analysis Set (Cohort 1)

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

z-test

Statistical analysis description

The percentage of 25-OH-D responders was analysed using a large-sample normal approximation test of proportions, also known as a z-test. For the primary efficacy analysis, responders were those subjects who achieved 25 OH D levels of ≥ 20 ng/mL at Visit 4/16 weeks of treatment. For confirmatory testing of 25-OH-D response rate, as a primary approach, subjects with missing 25-OH-D level at 16 weeks for any reason, including discontinuation prior to Visit 4, were regarded as non-responders.

Comparison groups

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 1) v Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1)

Number of subjects included in analysis

315

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0002

Method

z-test

Confidence interval

z-test

Statistical analysis description

The percentage of 25-OH-D responders was analysed using a large-sample normal approximation test of proportions, also known as a z-test. For the primary efficacy analysis, responders were those subjects who achieved 25 OH D levels of ≥ 20 ng/mL at Visit 4/16 weeks of treatment. For confirmatory testing of 25-OH-D response rate, as a primary approach, subjects with missing 25-OH-D level at 16 weeks for any reason, including discontinuation prior to Visit 4, were regarded as non-responders.

Comparison groups

Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2) v Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2)

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0464

Method

z-test

Confidence interval

z-test

Statistical analysis description

The percentage of 25-OH-D responders was analysed using a large-sample normal approximation test of proportions, also known as a z-test. For the primary efficacy analysis, responders were those subjects who achieved 25 OH D levels of ≥ 20 ng/mL at Visit 4/16 weeks of treatment. For confirmatory testing of 25-OH-D response rate, as a primary approach, subjects with missing 25-OH-D level at 16 weeks for any reason, including discontinuation prior to Visit 4, were regarded as non-responders.

Comparison groups

Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2) v Overall - Placebo x Full Analysis Set (Cohort 2)

Number of subjects included in analysis

159

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

z-test

Statistical analysis description

The percentage of 25-OH-D responders was analysed using a large-sample normal approximation test of proportions, also known as a z-test. For the primary efficacy analysis, responders were those subjects who achieved 25 OH D levels of ≥ 20 ng/mL at Visit 4/16 weeks of treatment. For confirmatory testing of 25-OH-D response rate, as a primary approach, subjects with missing 25-OH-D level at 16 weeks for any reason, including discontinuation prior to Visit 4, were regarded as non-responders.

Comparison groups

Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2) v Overall - Calcifediol 100 mcg x Full Analysis Set (Cohort 2)

Number of subjects included in analysis

214

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8946

Method

z-test

Confidence interval

z-test

Statistical analysis description

The percentage of 25-OH-D responders was analysed using a large-sample normal approximation test of proportions, also known as a z-test. For the primary efficacy analysis, responders were those subjects who achieved 25 OH D levels of ≥ 20 ng/mL at Visit 4/16 weeks of treatment. For confirmatory testing of 25-OH-D response rate, as a primary approach, subjects with missing 25-OH-D level at 16 weeks for any reason, including discontinuation prior to Visit 4, were regarded as non-responders.

Comparison groups

Overall - Calcifediol 75 mcg x Full Analysis Set (Cohort 1) v Overall - Placebo x Full Analysis Set (Cohort 1)

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

z-test

Statistical analysis description

The percentage of 25-OH-D responders was analysed using a large-sample normal approximation test of proportions, also known as a z-test. For the primary efficacy analysis, responders were those subjects who achieved 25 OH D levels of ≥ 20 ng/mL at Visit 4/16 weeks of treatment. For confirmatory testing of 25-OH-D response rate, as a primary approach, subjects with missing 25-OH-D level at 16 weeks for any reason, including discontinuation prior to Visit 4, were regarded as non-responders.

Comparison groups

Overall - Calcifediol 125 mcg x Full Analysis Set (Cohort 2) v Overall - Placebo x Full Analysis Set (Cohort 2)

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

z-test

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

In this clinical trial TEAEs were defined as all untoward events with onset or worsening after the first intake of the IP until 30 days after the last IP intake.

Adverse event reporting additional description

In this clinical trial TEAEs were defined as all untoward events with onset or worsening after the first intake of the IP until 30 days after the last IP intake.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Overall - Placebo x Safety Set (Cohort 1)

Reporting group description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Reporting group title

Overall - Calcifediol 75 mcg/week x Safety Set (Cohort 1)

Reporting group description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Reporting group title

Overall - Calcifediol 125 mcg/week x Safety Set (Cohort 2)

Reporting group description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Reporting group title

Overall - Placebo x Safety Set (Cohort 2)

Reporting group description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Reporting group title

Overall - Calcifediol 100 mcg/week x Safety Set (Cohort 2)

Reporting group description

Subjects of Safety Set, having 25-OH-D baseline level ≤ 10 ng/mL

Reporting group title

Overall - Calcifediol 100 mcg/week x Safety Set (Cohort 1)

Reporting group description

Subjects of of Safety Set, having 25-OH-D baseline level > 10 to < 20 ng/mL

Serious adverse events	Overall - Placebo x Safety Set (Cohort 1)	Overall - Calcifediol 75 mcg/week x Safety Set (Cohort 1)	Overall - Calcifediol 125 mcg/week x Safety Set (Cohort 2)	Overall - Placebo x Safety Set (Cohort 2)	Overall - Calcifediol 100 mcg/week x Safety Set (Cohort 2)	Overall - Calcifediol 100 mcg/week x Safety Set (Cohort 1)
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 73 (8.22%)	7 / 158 (4.43%)	4 / 113 (3.54%)	3 / 55 (5.45%)	3 / 104 (2.88%)	3 / 162 (1.85%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Meniscus injury
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dementia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Sudden death
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis acute
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peptic ulcer haemorrhage
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated umbilical hernia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 73 (1.37%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Tubulointerstitial nephritis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	2 / 73 (2.74%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Overall - Placebo x Safety Set (Cohort 1)	Overall - Calcifediol 75 mcg/week x Safety Set (Cohort 1)	Overall - Calcifediol 125 mcg/week x Safety Set (Cohort 2)	Overall - Placebo x Safety Set (Cohort 2)	Overall - Calcifediol 100 mcg/week x Safety Set (Cohort 2)	Overall - Calcifediol 100 mcg/week x Safety Set (Cohort 1)
Total subjects affected by non serious adverse events
subjects affected / exposed	27 / 73 (36.99%)	52 / 158 (32.91%)	40 / 113 (35.40%)	21 / 55 (38.18%)	32 / 104 (30.77%)	66 / 162 (40.74%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Vascular disorders
Aortic arteriosclerosis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Hot flush
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Hypertension
subjects affected / exposed	0 / 73 (0.00%)	5 / 158 (3.16%)	2 / 113 (1.77%)	2 / 55 (3.64%)	1 / 104 (0.96%)	2 / 162 (1.23%)
occurrences all number	0	6	2	2	1	2
Hypotension
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	1	0	0	0
Thrombosis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	3	0	0	0	0
Post thrombotic syndrome
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Thrombophlebitis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Peripheral venous disease
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	2
Asthenia
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	1 / 113 (0.88%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	2	1	0	1	0
Vaccination site pruritus
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Pyrexia
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	2	0	0	0	2
Hyperpyrexia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	2	0	0	0
Fatigue
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Cyst
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Chest pain
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	0	0	1	1	1
Oedema peripheral
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	2	1	0	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Allergy to animal
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Gynaecomastia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Sexual dysfunction
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Prostatism
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Vulvovaginal discomfort
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Vulvovaginal inflammation
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Epistaxis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	1	0
Dysphonia
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	2	0	0	0	0
Cough
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	2	0	1	0	1
Bronchitis chronic
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Asthmatic crisis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	2	0
Asthma
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Pharyngeal disorder
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Rhinitis allergic
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	2 / 104 (1.92%)	1 / 162 (0.62%)
occurrences all number	0	1	0	0	2	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	1	0	0
Confusional state
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Mixed anxiety and depressive disorder
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	1	1
Depression
subjects affected / exposed	2 / 73 (2.74%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	2	0	1	0	1	1
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood 25-hydroxycholecalciferol decreased
subjects affected / exposed	7 / 73 (9.59%)	0 / 158 (0.00%)	0 / 113 (0.00%)	5 / 55 (9.09%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	8	0	0	5	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	0	0	0	2
Alanine aminotransferase increased
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	0	1	0	1
Blood parathyroid hormone increased
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Occult blood
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Heart rate irregular
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	1	1	0	0	2
Coronavirus test positive
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood pressure diastolic increased
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	1	1
Blood potassium increased
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Transaminases increased
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Weight decreased
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Weight increased
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	0	0	0	2
Injury, poisoning and procedural complications
Foot fracture
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	0	1	0	2
Fibula fracture
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Contusion
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Ankle fracture
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Head injury
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Post vaccination syndrome
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Limb fracture
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Ligament sprain
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Cardiac disorders
Extrasystoles
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Cardiac failure
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Carotid artery stenosis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	1	0	0
Carotid arteriosclerosis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Sciatica
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	1	0	0	0
Piriformis syndrome
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Paraesthesia
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Migraine
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypersomnia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Headache
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	1 / 113 (0.88%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	1	1	0	1	1
Essential tremor
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Epilepsy
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Dizziness
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Carpal tunnel syndrome
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1	0	0	2
Secondary thrombocytosis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Leukopenia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Iron deficiency anaemia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Tinnitus
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Ear pain
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Cerumen impaction
subjects affected / exposed	1 / 73 (1.37%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	1	0	0	0	0
Eye disorders
Vitreous floaters
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Vision blurred
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Blepharitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Gastrointestinal disorders
Constipation
subjects affected / exposed	2 / 73 (2.74%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	2	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	1	1	0	0	1
Abdominal pain lower
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Abdominal pain
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	2	0	0	1	1
Abdominal distension
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Diarrhoea
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	1	0	0	0	2
Dry mouth
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Vomiting
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Toothache
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	1	0
Pancreatic steatosis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Odynophagia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Nausea
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	1 / 113 (0.88%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	1	1	0	0
Hyperchlorhydria
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Hiatus hernia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Haemorrhoids
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Gingival bleeding
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastric ulcer
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Dyspepsia
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	2	0	0	0	1
Hepatobiliary disorders
Hepatic steatosis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	1 / 113 (0.88%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	1	1	0	0
Cholelithiasis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	1	0
Skin and subcutaneous tissue disorders
Seborrhoeic dermatitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	0	0	0	2
Rash
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	2	0	0	0	1
Perioral dermatitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Hyperhidrosis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	1	1
Erythema
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Ecchymosis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Dermatitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	1	0	1
Angioedema
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Acne
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Skin lesion
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Renal and urinary disorders
Urinary tract discomfort
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Renal cyst
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal colic
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Pollakiuria
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Microalbuminuria
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Dysuria
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Chronic kidney disease
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Nephropathy
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Endocrine disorders
Autoimmune thyroiditis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Thyroid mass
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	1	0
Hypothyroidism
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	1	0
Hyperparathyroidism secondary
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	1	0	0
Musculoskeletal and connective tissue disorders
Fibromyalgia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Intervertebral disc protrusion
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Limb discomfort
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Lumbar spinal stenosis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Muscle contracture
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	1	0	0	0
Connective tissue disorder
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Chondropathy
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Back pain
subjects affected / exposed	0 / 73 (0.00%)	4 / 158 (2.53%)	1 / 113 (0.88%)	0 / 55 (0.00%)	1 / 104 (0.96%)	2 / 162 (1.23%)
occurrences all number	0	5	1	0	1	2
Arthritis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	0	0	0	2
Arthralgia
subjects affected / exposed	0 / 73 (0.00%)	3 / 158 (1.90%)	4 / 113 (3.54%)	2 / 55 (3.64%)	0 / 104 (0.00%)	3 / 162 (1.85%)
occurrences all number	0	4	5	2	0	3
Muscular weakness
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Myalgia
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	2	0	0	0	0
Osteitis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Osteopenia
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Pain in extremity
subjects affected / exposed	1 / 73 (1.37%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	1	1	0	0	1	1
Pain in jaw
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Patellofemoral pain syndrome
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Plantar fasciitis
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	2	0	0	0	1
Rheumatoid arthritis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	1	0	0
Spinal pain
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Synovial cyst
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Tendonitis
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	2	0	1	0	0
Infections and infestations
Abscess limb
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Abscess
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastroenteritis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	3 / 113 (2.65%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	1	3	0	1	1
Acute sinusitis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	1	0	0	0	0	1
Balanitis candida
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Bronchitis
subjects affected / exposed	2 / 73 (2.74%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	2 / 162 (1.23%)
occurrences all number	2	3	0	0	1	3
COVID-19
subjects affected / exposed	6 / 73 (8.22%)	13 / 158 (8.23%)	18 / 113 (15.93%)	4 / 55 (7.27%)	9 / 104 (8.65%)	18 / 162 (11.11%)
occurrences all number	6	15	18	4	9	18
Clostridium difficile colitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Cystitis
subjects affected / exposed	0 / 73 (0.00%)	3 / 158 (1.90%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	3	0	0	1	1
Dermatophytosis of nail
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Erysipelas
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Escherichia urinary tract infection
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Fungal infection
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	0	0	0	0	2
Furuncle
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Genital herpes
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	0	0
Helicobacter infection
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Herpes simplex
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	1	1
Oral herpes
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	0	2	0	0	0	3
Laryngitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	1	0
Lyme disease
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	2 / 104 (1.92%)	1 / 162 (0.62%)
occurrences all number	0	1	0	0	2	1
Onychomycosis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Influenza
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	1 / 55 (1.82%)	2 / 104 (1.92%)	3 / 162 (1.85%)
occurrences all number	0	1	0	1	2	3
Respiratory tract infection
subjects affected / exposed	1 / 73 (1.37%)	2 / 158 (1.27%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	1	2	1	0	0	2
Post viral fatigue syndrome
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Tonsillitis
subjects affected / exposed	2 / 73 (2.74%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	4	1	0	0	1	1
Sinusitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	1	0	0	1
Schistosomiasis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Rhinitis
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0
Oral infection
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	1	0
Otitis externa
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Periodontitis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Pharyngitis
subjects affected / exposed	1 / 73 (1.37%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	1	0	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Tonsillitis streptococcal
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Viral infection
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	1 / 104 (0.96%)	2 / 162 (1.23%)
occurrences all number	0	0	0	1	1	2
Urinary tract infection
subjects affected / exposed	1 / 73 (1.37%)	3 / 158 (1.90%)	2 / 113 (1.77%)	1 / 55 (1.82%)	0 / 104 (0.00%)	2 / 162 (1.23%)
occurrences all number	1	3	2	1	0	2
Upper respiratory tract infection
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Tracheobronchitis
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Tooth abscess
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	1	1
Metabolism and nutrition disorders
Obesity
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	2	0	0	0	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	1 / 162 (0.62%)
occurrences all number	0	0	0	0	0	1
Hypernatraemia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	1 / 113 (0.88%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	1	0	1	0
Hypercholesterolaemia
subjects affected / exposed	0 / 73 (0.00%)	2 / 158 (1.27%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	2	0	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	2 / 113 (1.77%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	2	0	0	0
Folate deficiency
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Fluid retention
subjects affected / exposed	0 / 73 (0.00%)	1 / 158 (0.63%)	0 / 113 (0.00%)	0 / 55 (0.00%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	1	0	0	0	0
Dyslipidaemia
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	1 / 55 (1.82%)	0 / 104 (0.00%)	0 / 162 (0.00%)
occurrences all number	0	0	0	1	0	0
Diabetes mellitus
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	4 / 113 (3.54%)	0 / 55 (0.00%)	2 / 104 (1.92%)	5 / 162 (3.09%)
occurrences all number	0	0	4	0	2	5
Overweight
subjects affected / exposed	0 / 73 (0.00%)	0 / 158 (0.00%)	0 / 113 (0.00%)	0 / 55 (0.00%)	1 / 104 (0.96%)	0 / 162 (0.00%)
occurrences all number	0	0	0	0	1	0

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
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.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 25-OH-D response level of ≥ 30 ng/mL at endpoint (Visit 4 [Week 16])

Primary: 25-OH-D response level of ≥ 30 ng/mL at endpoint (Visit 4 [Week 16])

Primary: 25-OH-D response level of ≥ 20 ng/mL at endpoint (Visit 4 [Week 16])

Primary: 25-OH-D response level of ≥ 20 ng/mL at endpoint (Visit 4 [Week 16])

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: 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.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 25-OH-D response level of ≥ 30 ng/mL at endpoint (Visit 4 [Week 16])

Primary: 25-OH-D response level of ≥ 30 ng/mL at endpoint (Visit 4 [Week 16])

Primary: 25-OH-D response level of ≥ 20 ng/mL at endpoint (Visit 4 [Week 16])

Primary: 25-OH-D response level of ≥ 20 ng/mL at endpoint (Visit 4 [Week 16])

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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.