Clinical Trial Results:
TREATMENT OF IRON DEFICIENCY ANAEMIA IN ADOLESCENTS WITH INFLAMMATORY BOWEL DISEASE USING FERROUS SULPHATE OR COSMOFER: TOLERANCE AND EFFECTS ON HAEMOGLOBIN, DISEASE ACTIVITY, MOOD, QUALITY OF LIFE AND AUTONOMIC NERVOUS SYSTEM ACTIVITY. AN OPEN LABEL PHASE IV NON-INFERIORITY STUDY.
Summary
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EudraCT number |
2010-023797-39 |
Trial protocol |
GB |
Global end of trial date |
20 Aug 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Apr 2017
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First version publication date |
26 Apr 2017
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Other versions |
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Summary report(s) |
End of Trial report Oral iron treatment response |
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 |
v.2 21 July 2015
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01991314 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
CSP ref: 40738, EudraCT number: 2010-023797-39, REDA ref: 007495BLT, REC ref: 10/H0504/90 | ||
Sponsors
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Sponsor organisation name |
Barts Health NHS Trust
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Sponsor organisation address |
Joint Research Management Office, QM Innovations Building, 5 Walden Street , London, United Kingdom, E12EF
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Public contact |
Marie-Claire Rickard, Joint Research Management Office, +44 2078827272, m.rickard@qmul.ac.uk
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Scientific contact |
Prof DS Rampton, Blizard Institute, +44 2035943500, d.rampton@qmul.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 |
09 Jun 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
20 May 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Aug 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 |
To assess these hypotheses:
[1] there is no difference in the haemoglobin response to oral iron treatment of iron deficiency anaemia (IDA) in adolescent compared to adult IBD patients;
[2] oral iron does not worsen disease activity in IBD;
[3] response to oral iron is inversely related to serum hepcidin concentrations at baseline; and
[4] treatment of anaemia improves QOL, mood and fatigue in adolescent and adult patients with IBD.
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Protection of trial subjects |
Patients were fully informed of the aims of the trial verbally and with patient information sheets. Their usual outpatient care was undertaken (including routine blood samples before and after treatment with oral iron), the only extra procedures being collection of two stool samples (for measurement of faecal calprotectin) and completion of psychometric questionnaires. There was no pain or distress involved.
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Background therapy |
Patients were on a range of treatments for their inflammatory bowel disease (IBD). These are shown in Table 1 of the attached paper and were, in adolescents and adults respectively, the following: 5 ASA 32 [71%], 17 [40%]; prednisolone/budesonide 7 [16%], 7 [16%]; enteral nutrition 3 [7%], 0 [0%]; thiopurine 23 [51%], 20 [47%]; methotrexate or ciclosporine 2 [4%], 0 [0%]; anti-TNF 2 [4%], 3 [7%]; antidepressants 0 [0%], 3 [7%]. | ||
Evidence for comparator |
Iron deficiency anaemia [IDA] is a frequent complication of IBD. In children and adolescents IDA appears to be commoner than in adults and is often undertreated, perhaps reflecting paediatricians’ concerns about side effects, including worsening of disease activity, and about young people’s medication adherence. Quality of life [QOL] correlates negatively with severity of anaemia in IBD. Prospective studies of oral and intravenous iron in adults with IBD have shown improvements in QOL when the haemoglobin [Hb] is corrected but this effect has not been assessed in young people with IBD. Psychological distress and fatigue are common in people of all ages with IBD but to our knowledge there have been no prospective studies of the effects of oral iron supplementation on these factors in people with IBD. It is widely stated that the Hb response to oral iron is reduced in patients with active IBD: this has been confirmed in one but not all studies. Such an effect could be explained by involvement of hepcidin, which regulates iron homeostasis by inhibiting its uptake by enterocytes, macrophages and hepatocytes. Serum hepcidin levels are increased by pro-inflammatory cytokines; conversely, in iron deficiency, hepcidin levels fall. Serum hepcidin concentrations at baseline are related inversely to the Hb response to oral iron in patients with rheumatoid arthritis and other diseases, but whether this is true in IBD is unknown. We therefore undertook a prospective phase IV, open-label, parallel group, 6-week non-inferiority clinical trial using oral ferrous sulphate to assess the hypotheses that: [1] there is no difference in the Hb response to oral iron treatment of IDA in adolescent compared to adult IBD patients; [2] oral iron does not worsen disease activity in IBD; [3] response to oral iron is inversely to serum hepcidin concentrations at baseline; and [4] treatment of anaemia improves QOL, mood and fatigue in these patients | ||
Actual start date of recruitment |
04 Jan 2012
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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 |
United Kingdom: 88
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Worldwide total number of subjects |
88
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EEA total number of subjects |
88
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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) |
41
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Adults (18-64 years) |
46
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
Between January 2012 and April 2015, adolescent and adult patients with IBD (ulcerative colitis, Crohn's disease or IBD unclassified) were recruited at Barts and the Royal London Hospitals, Barts Health Trust or at Chelsea and Westminster Hospital, London , UK. | ||||||||||||||||||
Pre-assignment
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Screening details |
Patients who within the next month were due to attend the adult, young people's and paediatric IBD clinics were screened for the result of their haemoglobin concentration at their previous clinic attendance. Those found to be be anaemic were sent a letter of explanation about, and invitation to participate in the trial. | ||||||||||||||||||
Period 1
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Period 1 title |
Patients at baseline (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Adolescents aged 13-18 years | ||||||||||||||||||
Arm description |
Adolescents with IBD and IDA | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Ferrous sulphate
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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 |
200mg twice daily for 6 weeks
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Arm title
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Adults aged 19 or more | ||||||||||||||||||
Arm description |
Adults aged 19 or more with IBD and IDA | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Ferrous sulphate
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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 |
200mg twice daily for 6 weeks
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Baseline characteristics reporting groups
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Reporting group title |
Adolescents aged 13-18 years
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Reporting group description |
Adolescents with IBD and IDA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Adults aged 19 or more
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Reporting group description |
Adults aged 19 or more with IBD and IDA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Adolescents aged 13-18 years
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Reporting group description |
Adolescents with IBD and IDA | ||
Reporting group title |
Adults aged 19 or more
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Reporting group description |
Adults aged 19 or more with IBD and IDA |
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End point title |
Increase in haemoglobin concentration (1) | ||||||||||||
End point description |
Intention to treat analysis
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End point type |
Primary
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End point timeframe |
after 6 weeks on ferrous sulphate
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Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
To test the hypothesis of non-inferiority with maximal statistical power, ANCOVA was used to compare the change in mean haemoglobin levels between adults and adolescents after accounting for necessary covariates. 95% confidence intervals were established for the treatment effects to determine the status of the primary hypothesis.
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Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.8 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.79 | ||||||||||||
upper limit |
- | ||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
0.7
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End point title |
Increase in haemoglobin concentration (2) | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
6 weeks
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Statistical analysis title |
Student's t test (unpaired) | ||||||||||||
Statistical analysis description |
To compare the change in Hb produced by oral iron between the adolescent and adult groups
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Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.23 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Confidence interval |
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Notes [1] - See above. Statistical Package for the Social Sciences [SPSS] [version 16] was used for the statistical analysis. |
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End point title |
Numbers of patients normalising haemoglobin | ||||||||||||
End point description |
Using the chi-squared test, we compared the proportions of patients in each group in whom ferrous sulphate produced a normalisation of haemoglobin concentration by WHO criteria
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End point type |
Primary
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End point timeframe |
6 weeks
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Statistical analysis title |
Chi squared test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.5 | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
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End point title |
Increase in serum hepcidin concentration | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
= 0.6 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Confidence interval |
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Notes [2] - This test was to see if there was a difference in hepcidin resposne to oral iron between the two arms. |
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End point title |
Increase in transferrin saturation | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.98 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Confidence interval |
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End point title |
Change in C reactive protein | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.78 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Change in faecal calprotectin | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.96 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Change in SIBDQ | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.49 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Change in HADS-A | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.85 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Change in HADS-D | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.62 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Change in PSQ-G | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Change in MFI | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 weeks
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Statistical analysis title |
Unpaired Student's t test | ||||||||||||
Comparison groups |
Adolescents aged 13-18 years v Adults aged 19 or more
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.69 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
6 weeks
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
SNOMED CT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Adolescents
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Reporting group description |
Adolescents aged 13-18 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Adults aged 19 or more
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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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24 Apr 2012 |
Because of staffing reductions, we reduced the numbers of investigations (nutritional assessment, exercise tolerance testing and Neuroscope testing) which we had planned in the original version of the Protocol; in addition, we decided that we were no longer able to provide Cosmofer in the necessary time-frame for the patients who proved to be intolerant of oral ferrous sulphate.
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14 Sep 2012 |
1. We requested an increase in the number of patients to be approached for recruitment from 90 to 140, because a higher than expected number of patients had turned out not to meet the inclusion criteria at the time of planned recruitment because their post-consent blood test showed them either to be no longer anaemic by WHO standards, or no longer iron deficient (Fe saturation <18%) (ie, during the time between their previous out-patient appointment and the intended recruitment date, their haemoglobin and iron status had improved).
2. Because of Pharmacy staffing shortages, to save time and inconvenience for patients attending afternoon clinics at the Royal London or any clinics at St Bartholomew’s Hospital, we arranged for prescriptions for ferrous sulphate to be collected from the Pharmacy at the Royal London by one of the investigators before the potential participants attended the clinic to give their written consent, giving them their tablets if/when this was been obtained. |
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21 Jan 2013 |
Change of name of sponsor from Barts and the London NHS Trust to Barts Health NHS Trust |
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24 Jan 2013 |
Because the initial suppliers, Wockhardt Ltd, could no longer make or supply ferrous sulphate tablets, we had to obtain them from an alternative supplier, Teva UK Ltd. |
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10 Oct 2013 |
1. Because of staff changes, we altered the arrangements for obtaining and countersigning patients' consent. Consent was taken by suitably trained (including GCP training) medically qualified and delegated staff at each site. At each site the consent form was countersigned by the site PI.
2. We changed our protocol to record that we were storing stool and serum samples at -40 rather than -80 degrees C.
3. As recruitment was going more slowly than initially hoped, we requested an extension of the duration of the study beyond 31 Dec 2013.
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15 Jul 2015 |
1. We minimally changed the inclusion criteria so that iron deficiency was defined now by a transferrin saturation of <18% rather than <16%. We had noticed at a monitoring visit at Chelsea and Westminster Hospital that they were using a version of the protocol showing 16% rather than 18%.
2. The faecal calprotectin assays were to be done in the routine Barts Health NHS Trust immunology laboratory rather than at Kings College Hospital (as originally planned) because the assay had now been established here as a routine clinical test.
3. The hepcidin assays were now to be undertaken in the Gastroenterology Laboratory at the University of Birmingham, under the supervision of Dr Tariq Iqbal, rather than here, because the Birmingham assay was well-established and probably the most reliable in the UK.
4. The letter to patients' GPs about their recruitment was very minimally modified.
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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. | |||
For a description of the study's limitations, see the penultimate paragraph of the Discussion in the attached publication in Journal of Crohn's and Colitis, as well as Section 13 of the attached textual End of Trial Report. | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/27932449 |