Clinical Trial Results:
Fractures and Bisphosphonates: A double-blind, randomised controlled trial on the effect of alendronic acid on healing and clinical outcomes of wrist fractures.
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Summary
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EudraCT number |
2011-000988-28 |
Trial protocol |
GB |
Global end of trial date |
02 Nov 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Aug 2020
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First version publication date |
08 Aug 2020
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Other versions |
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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 |
19403
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Additional study identifiers
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ISRCTN number |
ISRCTN62133820 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
ACCORD (University of Edinburgh and NHS Lothian)
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Sponsor organisation address |
47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
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Public contact |
Edinburgh Clinical Trials Unit, University of Edinburgh, +44 01315373855, ectu@ed.ac.uk
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Scientific contact |
Edinburgh Clinical Trials Unit, University of Edinburgh, +44 01315373855, ectu@ed.ac.uk
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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 |
19 Jul 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 May 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Nov 2015
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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 aim of the study is to determine if alendronic acid - the drug most commonly used in the UK as treatment of osteoporosis (thinning bones) - affects fracture healing. Participants will be randomised to receive either alendronic acid or a placebo (a tablet that contains no active drug).
The main objective will be to look at the x-rays that are taken 4 weeks into the study and compare the number of healed fractures in each group (alendronic acid or placebo). We will also look at how long it takes a fracture to heal, using the x-rays taken at weeks 2, 4, 6 and 8.
One person will analyse all the x-rays in the study. The x-rays will be anonymised so that the reviewer is unaware of individual details or the treatment that the participant received.
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Protection of trial subjects |
The trial was conducted in accordance with all relevant data protection, ethical and regulatory requirements to ensure the privacy and security of patient information and to ensure the rights, safety and well-being of the patients and the quality of the research data. Unblinding procedures were in place for situations where the safe management of the participant’s medical condition necessitated knowledge of the study medication by the person(s) responsible for the participant’s care.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Apr 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United Kingdom: 421
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Worldwide total number of subjects |
421
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EEA total number of subjects |
421
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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) |
239
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From 65 to 84 years |
179
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85 years and over |
3
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Recruitment
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Recruitment details |
Participants were randomised from 2 April 2012 to 29 September 2013 at 16 UK hospitals. Randomisation (1:1 ratio) took place following baseline assessment and prior to commencing study drug (alendronate or placebo). Randomisation was stratified by site, gender and fracture status (displaced or undisplaced). | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
8,707 patients screened. 4,913 were ineligible; 1,727 declined; 885 were missed; 739 not consented for other reasons. Of the 3,794 eligible patients, 443 consented but 11 withdrew, 8 were ineligible and 3 were withdrawn by the clinician prior to randomisation. 421 were randomised. | ||||||||||||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
421 | ||||||||||||||||||||||||||||||
Number of subjects completed |
421 | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Assessor, Subject | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Alendronic Acid | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Alendronic Acid
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Investigational medicinal product code |
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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 |
Participants commenced study drug (70mg tablet) within 14 days following fracture or within 7 days following randomisation, whichever come first. Ideally participants took their 1st dose the morning after randomisation. Participants took 1 tablet of alendronate once a week for 24 weeks. Alendronate was taken on the same day each week.
Alendronic acid was taken after getting up for the day and before taking any food, drink or medicine. The tablet was taken with a full glass of water only (not less than 200ml). Participants waited at least 30 minutes after taking alendronate before taking any other oral medicinal product.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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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 |
Participants commenced placebo within 14 days following fracture or within 7 days following randomisation, whichever come first. Ideally Placebo was taken on the same day each week.
Placebo was taken after getting up for the day and before taking any food, drink or medicine. The tablet was taken with a full glass of water only (not less than 200ml). Participants waited at least 30 minutes after taking placebo before taking any other oral medicinal product.
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Period 2
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Period 2 title |
In Study
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Assessor | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Alendronic Acid | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Alendronic Acid
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Investigational medicinal product code |
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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 |
Participants commenced study drug (70mg tablet) within 14 days following fracture or within 7 days following randomisation, whichever come first. Ideally participants took their 1st dose the morning after randomisation. Participants took 1 tablet of alendronate/placebo once a week for 24 weeks. Alendronate/placebo was taken on the same day each week.
Alendronic acid was taken after getting up for the day and before taking any food, drink or medicine. The tablet was taken with a full glass of water only (not less than 200ml). Participants waited at least 30 minutes after taking alendronate before taking any other oral medicinal product.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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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 |
Participants commenced placebo within 14 days following fracture or within 7 days following randomisation, whichever come first. Ideally participants took their 1st dose the morning after randomisation. Participants took 1 tablet of placebo once a week for 24 weeks. Placebo was taken on the same day each week.
Placebo was taken after getting up for the day and before taking any food, drink or medicine. The tablet was taken with a full glass of water only (not less than 200ml). Participants waited at least 30 minutes after taking placebo before taking any other oral medicinal product.
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Baseline characteristics reporting groups
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Reporting group title |
Alendronic Acid
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Reporting group description |
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Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intention to treat population
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The intention-to-treat (ITT) population will include all patients who have been randomised into the FaB study.
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Subject analysis set title |
Per-protocol population
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The per-protocol (PP) population will comprise those members of the ITT population who completed the study without a major protocol violation and who complied adequately with the administered treatment .
Compliance will be assessed in terms of the pill counts recorded at the 4, 8 and 26 week visits. A patient will be regarded as being 'compliant' if they miss at most one dose up to the Week 4 visit. If the Week 4 pill count is missing then the patient will be classified as ‘compliant’ if the Week 8 pill count indicates that at most one dose was missed up to the Week 8 visit. If the Week 4 and Week 8 pill counts are missing then the patient will be classified as ‘compliant’ if the Week 26 pill count indicates that at most one dose was missed up to the Week 26 visit.
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End points reporting groups
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Reporting group title |
Alendronic Acid
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Reporting group description |
- | ||
Reporting group title |
Placebo
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Reporting group description |
- | ||
Reporting group title |
Alendronic Acid
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Reporting group description |
- | ||
Reporting group title |
Placebo
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Reporting group description |
- | ||
Subject analysis set title |
Intention to treat population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intention-to-treat (ITT) population will include all patients who have been randomised into the FaB study.
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Subject analysis set title |
Per-protocol population
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The per-protocol (PP) population will comprise those members of the ITT population who completed the study without a major protocol violation and who complied adequately with the administered treatment .
Compliance will be assessed in terms of the pill counts recorded at the 4, 8 and 26 week visits. A patient will be regarded as being 'compliant' if they miss at most one dose up to the Week 4 visit. If the Week 4 pill count is missing then the patient will be classified as ‘compliant’ if the Week 8 pill count indicates that at most one dose was missed up to the Week 8 visit. If the Week 4 and Week 8 pill counts are missing then the patient will be classified as ‘compliant’ if the Week 26 pill count indicates that at most one dose was missed up to the Week 26 visit.
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End point title |
Fracture healing at 4 weeks | ||||||||||||||||||||||||||||||
End point description |
X-ray assessment at visit 2, 4 weeks post-randomisation.
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End point type |
Primary
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End point timeframe |
Week 4 visit.
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Statistical analysis title |
Primary Outcome analysis | ||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Alendronic Acid v Intention to treat population v Per-protocol population
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Number of subjects included in analysis |
1135
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||
P-value |
= 0.36 | ||||||||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||
Point estimate |
4
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Confidence interval |
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95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-4.7 | ||||||||||||||||||||||||||||||
upper limit |
12.8 | ||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were documented from date of randomisation to last study visit. Any adverse events ongoing at last study visit were followed up until resolution or no longer medically indicated.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
Study bespoke | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
n/a
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Reporting groups
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Reporting group title |
Alendronic Acid
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Reporting group description |
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Reporting group title |
Placebo
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Reporting group description |
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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? Yes | |||
Date |
Amendment |
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23 Jan 2012 |
Change to Protocol: change to the manufacture of the IMP and placebo because of the size of the tablet made which was considered too large so could potentially be a major barrier to recruitment.
Two other changes to the protocol in the “Exclusion Criteria” section:
1. Removal of the adjusted serum calcium value of 2.2mmol/L from the hypocalcaemia exclusion to take account of the fact that different laboratories have different lower limits of normal and different algorithms for adjusting serum calcium for albumin. Also, the normal reference range for serum calcium differs with age (Gardner & Scott J Clin Path 1980;33:380-385). Therefore, “Hypocalcaemia” listed in the revised protocol (v2) as the exclusion criterion which brought the study in line with the wording in the Summary of Product Characteristics (SmPC) for Alendronic acid. It allowed for variations between institutions without impacting on safety.
2. Removal of the MDRD formula as the method for calculating GFR since in routine clinical practice it is usual to calculate GFR values on the basis of age, gender and serum creatinine. Patients who had a GFR below 35ml/min were excluded from the study. This also brought the wording in line with the SmPC for alendronic acid which does not stipulate a specific method of calculating GFR. |
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13 Jul 2012 |
Change to protocol: change in the process so participants could be randomised before the results of their safety bloods. This gave sites flexibility to complete all baseline procedures and dispense medication in one day, reducing the number of extra visits a participant needed to make. Participants were instructed not to commence study medication until the blood results were back and showed no contraindication to take alendronic acid. The change affected the exclusion criteria to only exclude known hypocalcaemia and renal impairment at the time of randomisation. If blood tests showed renal impairment the participant would not start therapy but would still have the opportunity to be followed up within the trial if they wished. Any post-randomisation exclusions would be replaced. |
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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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/30845365 |
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