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Clinical Trial Results:
The Link between Obesity And Vitamin D in bariatric patients with omega-loop bypass surgery: a randomized controlled, double-blinded clinical supplementation trial - LOAD

Summary
EudraCT number	2013-003546-16
Trial protocol	AT
Global end of trial date	03 Jun 2016

Results information
Results version number	v1(current)
This version publication date	12 Aug 2017
First version publication date	12 Aug 2017
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

1.4

ISRCTN number

US NCT number

NCT02092376

WHO universal trial number (UTN)

Sponsor organisation name

Medical University of Vienna

Sponsor organisation address

Spitalgasse 23, Vienna, Austria,

Public contact

Michael Krebs, Klin. Abt. für Endokrinologie & Stoffwechsel, Univ.klinik für Innere Medizin III, 0043 1404004364, maria.luger@meduniwien.ac.at

Scientific contact

Maria Luger, Klin. Abt. für Endokrinologie & Stoffwechsel, Univ.klinik für Innere Medizin III, 0043 1404004364, maria.luger@meduniwien.ac.at

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 Jun 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Jun 2016

Was the trial ended prematurely?

Main objective of the trial

To test whether administering up to three doses of 100 000 IU vitamin D3 in the first month postoperatively (loading dose), followed by 3420 IU/day (intervention group LMD) in bariatric patients will increase significantly 25-hydroxyvitamin D levels 24 weeks after surgery, compared with a control group receiving placebo, followed by the standard daily doses of 3420 IU/ day (control group ST).

Protection of trial subjects

The trial subjects were protected by performing anamneses every visit and if necessary forward the patient to specific clinics in our university hospital.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 50

Worldwide total number of subjects

EEA total number of subjects

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

In- and out-patients of the Obesity Clinics at the Department of Internal Medicine III or the Department of Surgery in the General Hospital of Vienna were recruited between April 2014 and April 2015.

Screening details

After collecting baseline data or screening for in- and exclusion criteria, eligibility was assessed. Bariatric patients with following inclusion criteria were recruited: men and women aged 18–100 years with planned OLGB surgery, serum 25(OH)D concentrations of <75 nmol/L, and body weight <140 kg (due to body weight limitation of the DXA).

Period 1 title

Baseline period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Treatment arm

Arm description

The first loading dose of 100,000 IU vitamin D3 (cholecalciferol) was given on day 1 or 2 after surgery, followed by the second (2 weeks) and third administrations (4 weeks postoperatively) if 25(OH)D serum concentration remained below 75 nmol/L. The maximum loading dose for the intervention group was 300,000 IU. After the last loading dose, a maintenance dose of 3420 IU/day (approximately translating to 24,000 IU/week) was given.

Arm type

Experimental

Investigational medicinal product name

Oleovit D3-Tropfen

Investigational medicinal product code

A11CC05

Other name

Pharmaceutical forms

Oral drops

Routes of administration

Oral use

Dosage and administration details

Loading dose: 100 000 IU of cholecalciferol per dose and up to 3 doses (maximum 300 000 IU) in the first month after gastric bypass surgery Maintenance dose: 3420 IU per week (over 46 weeks) and starting after loading dose

Placebo/control arm

Arm description

The control group received placebo as loading dose and subsequently the maintenance dose, the same way as the intervention group.

Arm type

Placebo

Investigational medicinal product name

Oil (medium-chain-Triglyceride)

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral drops

Routes of administration

Oral use

Dosage and administration details

The placebo loading dose (without vitamin D) is divided into three administrations and will be given over the first months (the same as treatment arm). After the last placebo loading dose a maintenance dose of 3420 IU per day is given (the same dosage as the treatment arm).

Number of subjects in period 1	Treatment arm	Placebo/control arm
Started	25	25
Completed	25	25

Period 2 title

Active/ intervention period (6 months)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Treatment arm

Arm description

Arm type

Experimental

Investigational medicinal product name

Oleovit D3-Tropfen

Investigational medicinal product code

A11CC05

Other name

Pharmaceutical forms

Oral drops

Routes of administration

Oral use

Dosage and administration details

Placebo/control arm

Arm description

The control group received placebo as loading dose and subsequently the maintenance dose, the same way as the intervention group.

Arm type

Placebo

Investigational medicinal product name

Oil (medium-chain-Triglyceride)

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral drops

Routes of administration

Oral use

Dosage and administration details

The control group received placebo as loading dose and subsequently the maintenance dose, the same way as the intervention group.

Number of subjects in period 2	Treatment arm	Placebo/control arm
Started	25	25
Received allocated intervention	23	23
Completed	21	22
Not completed	4	3
Lost to follow-up	2	1
Protocol deviation	2	2

Baseline characteristics

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Reporting group title

Baseline period

Reporting group description

50 patients with mean age of 42 (SD 13) years and 80% were female. Mean BMI was 43.8 (4.3) kg/m2 and mean 25-hydroxy vitamin D was 39.0 (16.2) nmol/l.

Reporting group values	Baseline period	Total
Number of subjects	50	50
Age categorical
Units: Subjects
In utero		0
Preterm newborn infants (gestational age < 37 wks)		0
Newborns (0-27 days)		0
Infants and toddlers (28 days-23 months)		0
Children (2-11 years)		0
Adolescents (12-17 years)		0
Adults (18-64 years)		0
From 65-84 years		0
85 years and over		0
Age continuous
Units: years
arithmetic mean (standard deviation)	42 ± 13	-
Gender categorical
Units: Subjects
Female	40	40
Male	10	10

Subject analysis set title

Baseline assessment

Subject analysis set type

Full analysis

Subject analysis set description

All randomized patients were analysed.

Subject analysis set title

6-months outcome assessment

Subject analysis set type

Intention-to-treat

Subject analysis set description

The primary outcome variable 25(OH)D was analyzed according to the intention-to-treat (ITT) principle (including all randomized participants). To handle missing data, the multiple imputation (MI) method was used for the main analysis. Repeated measure analysis of covariance (ANCOVA) using random error (linear mixed model) was used to assess the effect of time and the interaction for changes in parameters between the groups, by using different covariance structure models as appropriate and were adjusted for baseline value, season, age, and sex to supply an unbiased estimate of the mean group difference. Moreover, a post hoc analysis with Bonferroni correction was used.

Subject analysis sets values	Baseline assessment	6-months outcome assessment
Number of subjects	50	43
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	42 ± 13	43 ± 12
Gender categorical
Units: Subjects
Female	40	40
Male	10	10

End points

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Reporting group title

Treatment arm

Reporting group description

Reporting group title

Placebo/control arm

Reporting group description

The control group received placebo as loading dose and subsequently the maintenance dose, the same way as the intervention group.

Reporting group title

Treatment arm

Reporting group description

Reporting group title

Placebo/control arm

Reporting group description

The control group received placebo as loading dose and subsequently the maintenance dose, the same way as the intervention group.

Subject analysis set title

Baseline assessment

Subject analysis set type

Full analysis

Subject analysis set description

All randomized patients were analysed.

Subject analysis set title

6-months outcome assessment

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: 25-hydroxy vitamin D

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End point title

25-hydroxy vitamin D

End point description

Primary outcome variable was measured at baseline, 0.5, 1, 2, 3, 4, 5, 6 months postoperatively.

End point type

Primary

End point timeframe

6 months after surgery

End point values	Treatment arm	Placebo/control arm
Number of subjects analysed	25 ^[1]	25 ^[2]
Units: nmol/l
arithmetic mean (standard deviation)	68.9 ± 21.6	56.4 ± 22.5

Attachments

Untitled (Filename: Primary_outcome.jpg)

Notes
[1] - ITT
[2] - ITT

Primary outcome

Statistical analysis description

The primary outcome variable was analyzed according to the intention-to-treat principle with repeated measure analysis of covariance (ANCOVA) using random error (linear mixed model) to assess the effect of time and the interaction for changes between the groups and were adjusted for age, sex, baseline values, dosing, and season. Moreover, a post hoc analysis with Bonferroni correction was used.

Comparison groups

Treatment arm v Placebo/control arm

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

≤ 0.05

Method

Mixed models analysis

Confidence interval

Adverse events

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Timeframe for reporting adverse events

Baseline until 6 months

Adverse event reporting additional description

After 2 weeks, 1, 2, 3, 4, 5, 6 month(s) postoperatively any signs or symptoms of vitamin D toxicity or other adverse events, including serious illness or hospitalizations were assessed.

Assessment type

Systematic

Dictionary name

ICD-10

Dictionary version

2.0

Reporting group title

Treatment arm

Reporting group description

Reporting group title

Placebo/control arm

Reporting group description

The control group received placebo as loading dose and subsequently the maintenance dose, the same way as the intervention group.

Serious adverse events	Treatment arm	Placebo/control arm
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 25 (4.00%)	1 / 25 (4.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Cardiac disorders
Myocardial infarction
Additional description: This SAE occurred before bariatric surgery and before administration of the study medication vitamin D3 (cholecalciferol) at baseline. Therefore it could not be related to the study medication. The patient was allocated to the treatment arm.
subjects affected / exposed	1 / 25 (4.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Liver injury
Additional description: This liver hematoma occurred as a consequence of liver biopsy during surgery and before administration of study medication vitamin D3 at baseline. Therefore it could not be related to the study medication. The patient was in placebo/control arm.
subjects affected / exposed	0 / 25 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Treatment arm	Placebo/control arm
Total subjects affected by non serious adverse events
subjects affected / exposed	24 / 25 (96.00%)	19 / 25 (76.00%)
General disorders and administration site conditions
Alopecia
subjects affected / exposed	7 / 25 (28.00%)	5 / 25 (20.00%)
occurrences all number	7	5
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	7 / 25 (28.00%)	7 / 25 (28.00%)
occurrences all number	7	7
Vomiting
subjects affected / exposed	6 / 25 (24.00%)	4 / 25 (16.00%)
occurrences all number	6	4
Reflux
subjects affected / exposed	4 / 25 (16.00%)	3 / 25 (12.00%)
occurrences all number	4	3

More information

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Were there any global substantial amendments to the protocol? Yes

13 May 2015

Change of principal investigator.

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

http://www.ncbi.nlm.nih.gov/pubmed/27837387

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Clinical trials

Clinical Trial Results:
The Link between Obesity And Vitamin D in bariatric patients with omega-loop bypass surgery: a randomized controlled, double-blinded clinical supplementation trial - LOAD

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 25-hydroxy vitamin D

Primary: 25-hydroxy vitamin D

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: The Link between Obesity And Vitamin D in bariatric patients with omega-loop bypass surgery: a randomized controlled, double-blinded clinical supplementation trial - LOAD

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 25-hydroxy vitamin D

Primary: 25-hydroxy vitamin D

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
The Link between Obesity And Vitamin D in bariatric patients with omega-loop bypass surgery: a randomized controlled, double-blinded clinical supplementation trial - LOAD