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Clinical Trial Results:
A phase II, randomised, double-blind, and parallel study to estimate the dose-response of vitamin D supplementation in chronic kidney disease patients with secondary hyperparathyroidism and vitamin D deficiency.

Summary
EudraCT number	2019-000640-10
Trial protocol	BG
Global end of trial date	18 Jun 2020

Results information
Results version number	v1(current)
This version publication date	02 Jul 2021
First version publication date	02 Jul 2021
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

GPR-II-18-1

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Laboratoires SMB S.A.

Sponsor organisation address

26-28, rue de la Pastorale, Brussels, Belgium, 1080

Public contact

CLINICAL DEPARTMENT, LABORATOIRES SMB S.A, 32 2411 48 28, dptclinique@smb.be

Scientific contact

CLINICAL DEPARTMENT, LABORATOIRES SMB S.A, 32 2411 48 28, dptclinique@smb.be

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

03 Feb 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Jun 2020

Global end of trial reached?

Yes

Global end of trial date

18 Jun 2020

Was the trial ended prematurely?

Main objective of the trial

To estimate the dose-response on iPTH and related markers of vitamin D3 in chronic kidney disease patients (CKD stage 3) with secondary hyperparathyroidism and vitamin D deficiency.

Protection of trial subjects

For this study, no particular measure was taken to protect the trial patients. The study treatment (Cholecalciferol/ vitamin D) was already on the European market and then were well known by the most of participating patients.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Oct 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 100

Worldwide total number of subjects

100

EEA total number of subjects

100

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in four sites in Bulgaria. The recruitment was adequate to meet the target of 100 patients. After the screening visit, the patients were randomized in one of the four groups of treatments. The study extended over 12 weeks of supplementation followed by a final visit 2 weeks after the last administration of study treatment.

Screening details

- Obtain signed ICF -Obtain demo data - Perform a medical history & physical examination -Take vital signs -Review prior/concomitant medications -Perform laboratory evaluation & pregnancy test -Review inclusion/exclusion criteria -Schedule the randomisation visit

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Monitor, Investigator

Are arms mutually exclusive

Yes

Group 1 : 25.000 IU/mL per week

Arm description

1 ampoule of cholecalciferol 25.000 IU/mL + 3 ampoules of placebo taken once a week during 12 weeks (total dose: 300.000 IU/mL)

Arm type

Experimental

Investigational medicinal product name

D-CURA 1 ml ampoule of 25.000 IU/mL

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

One ampoule of 25.000 IU/mL was taken every week during 12 weeks (+ 3 placebo ampoules/week). The ampoules of placebo were given to maintain the blind between treatment groups.

Group 2 : 50.000 IU/ml per week

Arm description

2 ampoules of cholecalciferol 25.000 IU/mL + 2 ampoules of placebo taken once a week during 12 weeks (total dose: 600.000 IU/mL)

Arm type

Experimental

Investigational medicinal product name

D-CURA 1 ml ampoule of 25.000 IU/mL

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Two ampoules of 25.000 IU/mL were taken every week during 12 weeks (+ 2 placebo ampoules/week). The ampoules of placebo were given to maintain the blind between treatment groups.

Group 3 : 75.000 IU/ml per week

Arm description

3 ampoules of cholecalciferol 25.000 IU/mL + 1 ampoule of placebo taken once a week during 12 weeks (total dose: 900.000 IU/mL)

Arm type

Experimental

Investigational medicinal product name

D-CURA 1 ml ampoule of 25.000 IU/mL

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Three ampoules of 25.000 IU/mL were taken every week during 12 weeks (+ 1 placebo ampoules/week). The ampoules of placebo were given to maintain the blind between treatment groups.

Group 4 : 100.000 IU/ml per week

Arm description

4 ampoules of cholecalciferol 25.000 IU/mL taken once a week during 12 weeks (total dose: 1.200,000 IU/mL)

Arm type

Experimental

Investigational medicinal product name

D-CURA 1 ml ampoule of 25.000 IU/mL

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Four ampoules of 25.000 IU/mL were taken every week during 12 weeks.

Number of subjects in period 1	Group 1 : 25.000 IU/mL per week	Group 2 : 50.000 IU/ml per week	Group 3 : 75.000 IU/ml per week	Group 4 : 100.000 IU/ml per week
Started	25	25	25	25
Completed	25	24	24	23
Not completed	0	1	1	2
Adverse event, serious fatal	-	-	-	1
Fear of COVID-19	-	-	-	1
Consent withdrawn by subject	-	1	1	-

Baseline characteristics

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Reporting group title

Overall Trial

Reporting group description

Reporting group values	Overall Trial	Total
Number of subjects	100	100
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	50	50
From 65-84 years	45	45
85 years and over	5	5
Age continuous
Units: years
arithmetic mean (standard deviation)	64.5 ( 12.9 )	-
Gender categorical
Units: Subjects
Female	42	42
Male	58	58

End points

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Reporting group title

Group 1 : 25.000 IU/mL per week

Reporting group description

1 ampoule of cholecalciferol 25.000 IU/mL + 3 ampoules of placebo taken once a week during 12 weeks (total dose: 300.000 IU/mL)

Reporting group title

Group 2 : 50.000 IU/ml per week

Reporting group description

2 ampoules of cholecalciferol 25.000 IU/mL + 2 ampoules of placebo taken once a week during 12 weeks (total dose: 600.000 IU/mL)

Reporting group title

Group 3 : 75.000 IU/ml per week

Reporting group description

3 ampoules of cholecalciferol 25.000 IU/mL + 1 ampoule of placebo taken once a week during 12 weeks (total dose: 900.000 IU/mL)

Reporting group title

Group 4 : 100.000 IU/ml per week

Reporting group description

4 ampoules of cholecalciferol 25.000 IU/mL taken once a week during 12 weeks (total dose: 1.200,000 IU/mL)

Primary: Change from baseline to week 12 in iPTH

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End point title

Change from baseline to week 12 in iPTH

End point description

End point type

Primary

End point timeframe

Baseline (week 0) and Week 12

End point values	Group 1 : 25.000 IU/mL per week	Group 2 : 50.000 IU/ml per week	Group 3 : 75.000 IU/ml per week	Group 4 : 100.000 IU/ml per week
Number of subjects analysed	25	25	24	23
Units: pg/mL
least squares mean (confidence interval 95%)	-29.7 (-43.6 to -12.4)	-15.3 (-27.7 to -0.9)	-30.2 (-42.4 to -15.5)	-19.2 (-38.9 to 6.7)

Mixed model

Comparison groups

Group 1 : 25.000 IU/mL per week v Group 2 : 50.000 IU/ml per week v Group 3 : 75.000 IU/ml per week v Group 4 : 100.000 IU/ml per week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.05

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Confidence interval

Secondary: Change from baseline to week 12 in 25(OH)D3

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End point title

Change from baseline to week 12 in 25(OH)D3

End point description

End point type

Secondary

End point timeframe

Baseline (Week 0) and week 12

End point values	Group 1 : 25.000 IU/mL per week	Group 2 : 50.000 IU/ml per week	Group 3 : 75.000 IU/ml per week	Group 4 : 100.000 IU/ml per week
Number of subjects analysed	25	25	24	23
Units: ng/mL
least squares mean (standard error)	22.66 ( 3.498 )	34.83 ( 5.027 )	33.58 ( 5.634 )	34.85 ( 5.199 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The AEs were recorded during the entire study period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Group 1 : 25.000 IU/mL per week

Reporting group description

1 ampoule of cholecalciferol 25.000 IU/mL + 3 ampoules of placebo taken once a week during 12 weeks (total dose: 300.000 IU/mL)

Reporting group title

Group 2 : 50.000 IU/ml per week

Reporting group description

2 ampoules of cholecalciferol 25.000 IU/mL + 2 ampoules of placebo taken once a week during 12 weeks (total dose: 600.000 IU/mL)

Reporting group title

Group 3 : 75.000 IU/ml per week

Reporting group description

3 ampoules of cholecalciferol 25.000 IU/mL + 1 ampoule of placebo taken once a week during 12 weeks (total dose: 900.000 IU/mL)

Reporting group title

Group 4 : 100.000 IU/ml per week

Reporting group description

4 ampoules of cholecalciferol 25.000 IU/mL taken once a week during 12 weeks (total dose: 1.200,000 IU/mL)

Serious adverse events	Group 1 : 25.000 IU/mL per week	Group 2 : 50.000 IU/ml per week	Group 3 : 75.000 IU/ml per week	Group 4 : 100.000 IU/ml per week
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 25 (0.00%)	0 / 25 (0.00%)	0 / 25 (0.00%)	2 / 25 (8.00%)
number of deaths (all causes)	0	0	0	1
number of deaths resulting from adverse events	0	0	0	1
Nervous system disorders
Cerebral infarction
subjects affected / exposed	0 / 25 (0.00%)	0 / 25 (0.00%)	0 / 25 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cerebral infarction caused by artery thrombosis
subjects affected / exposed	0 / 25 (0.00%)	0 / 25 (0.00%)	0 / 25 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Group 1 : 25.000 IU/mL per week	Group 2 : 50.000 IU/ml per week	Group 3 : 75.000 IU/ml per week	Group 4 : 100.000 IU/ml per week
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 25 (20.00%)	2 / 25 (8.00%)	3 / 25 (12.00%)	6 / 25 (24.00%)
Nervous system disorders
Headache
subjects affected / exposed	3 / 25 (12.00%)	2 / 25 (8.00%)	2 / 25 (8.00%)	6 / 25 (24.00%)
occurrences all number	3	2	2	6
Gastrointestinal disorders
Nausea
subjects affected / exposed	2 / 25 (8.00%)	0 / 25 (0.00%)	1 / 25 (4.00%)	0 / 25 (0.00%)
occurrences all number	2	0	1	0

More information

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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:
A phase II, randomised, double-blind, and parallel study to estimate the dose-response of vitamin D supplementation in chronic kidney disease patients with secondary hyperparathyroidism and vitamin D deficiency.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline to week 12 in iPTH

Primary: Change from baseline to week 12 in iPTH

Secondary: Change from baseline to week 12 in 25(OH)D3

Secondary: Change from baseline to week 12 in 25(OH)D3

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A phase II, randomised, double-blind, and parallel study to estimate the dose-response of vitamin D supplementation in chronic kidney disease patients with secondary hyperparathyroidism and vitamin D deficiency.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline to week 12 in iPTH

Primary: Change from baseline to week 12 in iPTH

Secondary: Change from baseline to week 12 in 25(OH)D3

Secondary: Change from baseline to week 12 in 25(OH)D3

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase II, randomised, double-blind, and parallel study to estimate the dose-response of vitamin D supplementation in chronic kidney disease patients with secondary hyperparathyroidism and vitamin D deficiency.