Clinical Trial Results:
Prevention of Glucocorticoid induced impairment of bone metabolism – A Randomized, Placebo-Controlled, Single Centre Clinical Trial
Summary
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EudraCT number |
2021-000275-36 |
Trial protocol |
SE |
Global end of trial date |
12 Dec 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
31 Dec 2023
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First version publication date |
31 Dec 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CSUB0202
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04767711 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Sahlgrenska University Hospital
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Sponsor organisation address |
Göteborgsvägen 31, Mölndal, Sweden, 43180
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Public contact |
Mattias Lorentzon, Sahlgrenska University Hospital, mattias.lorentzon@medic.gu.se
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Scientific contact |
Mattias Lorentzon, Sahlgrenska University Hospital, mattias.lorentzon@medic.gu.se
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Dec 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Dec 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Dec 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to determine if the administration of L.Reuteri could prevent the changes in bone turnover markers induced by oral glucocorticoid (GC) treatment. The primary outcome was investigated as between group percent change in bone turnover markers between baseline (day 16, prior to the glucocorticoid (GC) treatment start) and day 23 (7 days after starting oral GC).
1. Serum osteocalcin
2. Serum CTX
3. Serum P1NP
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Protection of trial subjects |
To minimize the risk of adverse events of the oral glucocorticoid (GC) treatment, the exposure time was limited to 7 days, and extensive testing to exclude participants with prediabetes or diabetes at screening was performed. The inclusion criteria ensured that only young participants without skeletal disease, and with a very low risk of bone fractures were included. Thus, all included participants had a very low risk of developing known GC-associated adverse events, as a result of highly stringent inclusion and exclusion criteria.
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Background therapy |
All participants (in both treatment arms) were given 25 mg oral glucocorticoid treatment for 7 days. | ||
Evidence for comparator |
Glucocorticoid (GC) therapy is used to treat a variety of inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease and bronchial asthma. Despite the well-known side-effects, GC treatment is widely used and approximately over 1.2% of the US population are being prescribed long-term GC therapy. Oral GC therapy leads to rapid and deleterious effects on bone metabolism, which results in bone loss, and a subsequent increased fracture risk. Long-term oral GC also increases the risk of increased blood glucose levels and diabetes. The gut microbiota is involved in regulating bone metabolism and we recently demonstrated that Lactobacillus reuteri ATCC PTA 6475 (L. reuteri) could reduce bone loss over 12 months by half in older women. L. reuteri supplementation was generally well tolerated. In a recent study, it was discovered that mice treated either with broad spectrum antibiotics, eradicating gut microbiota, or with L. reuteri did not experience GC induced bone loss in the spine and femur. GC was found to induce intestinal barrier breaches, an effect that could also be prevented with L. reuteri. We therefore, hypothesize that L.reuteri could be able to prevent the negative effects on bone metabolism, gut permeability and blood glucose regulation in humans. Primary research hypothesis: The aim of this randomized, double-blind, placebo-controlled trial is to investigate if daily supplementation with L. reuteri, compared to placebo, can prevent the negative effects of oral glucocorticoid (GC) on bone turnover and blood glucose regulation in healthy young adult men and women. | ||
Actual start date of recruitment |
03 May 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Sweden: 50
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Worldwide total number of subjects |
50
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EEA total number of subjects |
50
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
50
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Study participants were screened between May18th and November 8th 2022. | |||||||||||||||
Pre-assignment
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Screening details |
63 men and women were screened. 50 fulfilled all inclusion criteria, had no exclusion criteria, and were included in the study. | |||||||||||||||
Period 1
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Period 1 title |
Baseline (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Assessor | |||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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L.reuteri+oral prednisolone | |||||||||||||||
Arm description |
L.reuteri 5x109 colony-forming units (CFU) mixed with maltodextrin powder, taken twice daily, yielding a total daily dose of 1x1010 CFU/day for 30 days + oral prednisolone 25 mg daily for 7 days (starting 11-14 days after initiation of the L.reuteri treatment). | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Prednisolone
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Investigational medicinal product code |
H02AB06
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
25 mg daily for 7 days. The whole dose was taken in the morning.
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Arm title
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Placebo + oral prednisolone | |||||||||||||||
Arm description |
Maltodextrin powder capsules, taken twice daily, as placebo + oral prednisolone 25 mg daily for 7 days (starting 11-14 days after initiation of the L.reuteri treatment). | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Prednisolone
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Investigational medicinal product code |
H02AB06
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
25 mg daily for 7 days. The whole dose was taken in the morning.
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Baseline characteristics reporting groups
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Reporting group title |
L.reuteri+oral prednisolone
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Reporting group description |
L.reuteri 5x109 colony-forming units (CFU) mixed with maltodextrin powder, taken twice daily, yielding a total daily dose of 1x1010 CFU/day for 30 days + oral prednisolone 25 mg daily for 7 days (starting 11-14 days after initiation of the L.reuteri treatment). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo + oral prednisolone
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Reporting group description |
Maltodextrin powder capsules, taken twice daily, as placebo + oral prednisolone 25 mg daily for 7 days (starting 11-14 days after initiation of the L.reuteri treatment). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Baseline characteristics
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Data is being analyzed.
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Subject analysis set title |
ITT Analysis
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
ITT analysis is ongoing.
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Subject analysis set title |
Per protocol analysis
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Per protocol analysis is ongoing.
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End points reporting groups
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Reporting group title |
L.reuteri+oral prednisolone
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Reporting group description |
L.reuteri 5x109 colony-forming units (CFU) mixed with maltodextrin powder, taken twice daily, yielding a total daily dose of 1x1010 CFU/day for 30 days + oral prednisolone 25 mg daily for 7 days (starting 11-14 days after initiation of the L.reuteri treatment). | ||
Reporting group title |
Placebo + oral prednisolone
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Reporting group description |
Maltodextrin powder capsules, taken twice daily, as placebo + oral prednisolone 25 mg daily for 7 days (starting 11-14 days after initiation of the L.reuteri treatment). | ||
Subject analysis set title |
Baseline characteristics
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Data is being analyzed.
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Subject analysis set title |
ITT Analysis
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
ITT analysis is ongoing.
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Subject analysis set title |
Per protocol analysis
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per protocol analysis is ongoing.
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End point title |
Bone turnover markers | ||||||||||||||||||||
End point description |
Results are being analyzed.
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End point type |
Primary
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End point timeframe |
Between group per cent change in bone turnover markers between baseline (day 16, prior to glucocorticoid (GC) treatment start) and day 23 (7 days after starting oral GC).
1. Serum osteocalcin
2. Serum CTX
3. Serum P1NP
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Statistical analysis title |
ANCOVA | ||||||||||||||||||||
Statistical analysis description |
Log-normally distributed variables (osteocalcin, CTX, and P1NP) will be analysed using ANCOVA on log-transformed variables, adjusting for log-baseline values
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Comparison groups |
L.reuteri+oral prednisolone v Placebo + oral prednisolone
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Number of subjects included in analysis |
50
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||||||||||
P-value |
< 0.05 [2] | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Confidence interval |
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95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||||||||||
upper limit |
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Variability estimate |
Standard deviation
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Notes [1] - Analysis is ongoing. [2] - P-value composed of fractions for each coprimary outcome, according to the SAP. |
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Adverse events information
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Timeframe for reporting adverse events |
From randomization to end of trial (last study subject, last visit).
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Adverse event reporting additional description |
There were no serious adverse events. The proportion of adverse events (AEs) was similar between the two arms (36% in the active treatment arm and 36% in the placebo arm). Details of AEs are being analyzed.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
CTCAEv5.0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
5.0
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Reporting groups
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Reporting group title |
L.reuteri+oral prednisolone
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Reporting group description |
L.reuteri 5x109 colony-forming units (CFU) mixed with maltodextrin powder, taken twice daily, yielding a total daily dose of 1x1010 CFU/day for 30 days + oral prednisolone 25 mg daily for 7 days (starting 11-14 days after initiation of the L.reuteri treatment). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo + prednisolone
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Reporting group description |
Maltodextrin powder capsules, taken twice daily, as placebo + oral prednisolone 25 mg daily for 7 days (starting 11-14 days after initiation of the L.reuteri treatment). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |