Clinical Trial Results:
Feasible strategy for preventing blood clots in critically ill patients with acute kidney Injury
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Summary
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EudraCT number |
2012-004368-23 |
Trial protocol |
DK |
Global end of trial date |
20 Feb 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Sep 2016
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First version publication date |
08 Sep 2016
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Other versions |
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Summary report(s) |
Journal article |
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 |
20121005
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Odense University Hospital
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Sponsor organisation address |
Sdr. Boulevard 29 , Odense , Denmark, DK 5000
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Public contact |
Professor Palle Toft, Odense University Hospital , 45 65413947, palle.toft@rsyd.dk
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Scientific contact |
Professor Palle Toft
, Odense University Hospital , 45 65413947, palle.toft@rsyd.dk
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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 |
02 Mar 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
20 Feb 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Feb 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To reduce the incidence of venous thromboembolism(VTE) among patients on continuous renal replacement therapy (CRRT) by using 1 mg/kg enoxaparin, versus the standard dose of 40 mg enoxaparin.
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Protection of trial subjects |
The trial was approved by the Danish national scientific ethical committee and the Danish health and medicine authority. The study was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki and monitored by Good Clinical Practice (GCP). The study was closed in February 2015-a decision made in conjunction with GCP and the project’s data monitoring committee owing to poor accrual despite intense efforts to increase recruitment.
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Background therapy |
All study patients were critically ill and received treatment therapies as indicated by their underlying conditions. As all study patients had acute kidney injury (AKI), they received CRRT. Once patients achieved diuresis of > 200 ml/day on CRRT, dialysis was discontinued. | ||
Evidence for comparator |
Despite ICU patients receiving recommended doses of prophylactic low- molecular-weight heparin (LMWH), between 5 and 15.5% develop proximal leg deep-vein thrombosis (DVT). | ||
Actual start date of recruitment |
01 Mar 2013
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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 |
Denmark: 19
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Worldwide total number of subjects |
19
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EEA total number of subjects |
19
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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) |
11
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From 65 to 84 years |
8
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85 years and over |
0
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Recruitment
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Recruitment details |
Research physicians on the ICUs of the study hospitals obtained written informed consent from all potential trial participants or their designated surrogates for participation in the study. | |||||||||
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Pre-assignment
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Screening details |
Daily screening for consecutive eligible patients. | |||||||||
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Period 1
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Period 1 title |
Baseline
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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, Data analyst, Assessor | |||||||||
Blinding implementation details |
Patients, family members, clinicians, research personnel, radiologists, laboratory technicians, and the trial biostatistician were unaware of study-group assignments. They remained blinded until the study database was locked at the end of the trial. Nurses who administered the drug were the only party
privy to the actual dose given to each patient as it was impossible to prepare an enoxaparin dose of 1 mg/kg beforehand.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Control arm | |||||||||
Arm description |
Patients received 40 mg enoxaparin sc QD upon commencement of CRRT | |||||||||
Arm type |
control | |||||||||
Investigational medicinal product name |
enoxaparin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
40 mg enoxaparin sc QD
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Arm title
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Treatment arm | |||||||||
Arm description |
Patients received 1 mg/kg enoxaparin sc QD upon commencement of CRRT | |||||||||
Arm type |
intervention | |||||||||
Investigational medicinal product name |
enoxaparin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
1 mg/kg enoxaparin sc QD
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Period 2
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Period 2 title |
Overall
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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, Data analyst, Assessor | |||||||||
Blinding implementation details |
Patients, family members,clinicians, research personnel, radiologists, laboratory technicians, and the trial biostatistician were unaware of study-group assignments. They remained blinded until the study database was locked at the end of the trial. Nurses who administered the drug were the only party privy to the actual dose given to each patient as it was impossible to prepare an enoxaparin dose of 1 mg/kg beforehand.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Control arm | |||||||||
Arm description |
Patients received 40 mg enoxaparin sc QD upon commencement of CRRT | |||||||||
Arm type |
control | |||||||||
Investigational medicinal product name |
enoxaparin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
40 mg enoxaparin sc QD
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Arm title
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Treatment arm | |||||||||
Arm description |
Patients received 1 mg/kg enoxaparin sc QD upon commencement of CRRT | |||||||||
Arm type |
intervention | |||||||||
Investigational medicinal product name |
enoxaparin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
1 mg/kg enoxaparin sc QD
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Baseline characteristics reporting groups
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Reporting group title |
Control arm
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Reporting group description |
Patients received 40 mg enoxaparin sc QD upon commencement of CRRT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Treatment arm
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Reporting group description |
Patients received 1 mg/kg enoxaparin sc QD upon commencement of CRRT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Control arm
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Reporting group description |
Patients received 40 mg enoxaparin sc QD upon commencement of CRRT | ||
Reporting group title |
Treatment arm
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Reporting group description |
Patients received 1 mg/kg enoxaparin sc QD upon commencement of CRRT | ||
Reporting group title |
Control arm
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Reporting group description |
Patients received 40 mg enoxaparin sc QD upon commencement of CRRT | ||
Reporting group title |
Treatment arm
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Reporting group description |
Patients received 1 mg/kg enoxaparin sc QD upon commencement of CRRT | ||
Subject analysis set title |
Renal Recovery
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Renal recovery refers to the complete independence from renal replacement therapy after dialysis was discontinued.
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Subject analysis set title |
Repeat Dialysis
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Repeat Dialysis group: patients with continued dependence on renal replacement therapy after dialysis was discontinued.
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End point title |
Venous thromboembolism (VTE) | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Patients underwent daily bedside clinical assessment for VTE using validated tools.Bilateral lower extremity CUS was conducted on the first, third, and seventh day of inclusion. CUS was repeated on a weekly basis (more frequently if DVT was suspected).
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Statistical analysis title |
Primary endpoint analysis | |||||||||
Statistical analysis description |
We estimated that with 133 patients in each group, the study would have 80% power to show a 40% reduction in the relative risk of VTE with 1 mg/kg enoxaparin sc QD, assuming an incidence rate of 40% in the control group, at a two-sided alpha level of 0.05.
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Comparison groups |
Treatment arm v Control arm
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
t-test, 2-sided | |||||||||
Parameter type |
Mean difference (final values) | |||||||||
Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
- | |||||||||
upper limit |
- | |||||||||
Variability estimate |
Standard deviation
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End point title |
Bleeding | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Patients underwent daily bedside clinical assessment for bleeding.
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Statistical analysis title |
analysis for secondary endpoints | |||||||||||||||
Statistical analysis description |
All baseline demographic values for these two groups were compared using the Student’s t-test or Mann-Whitney rank sum test for continuous variables, and Fisher’s exact test for categorical variables. The prediction ability of urine output and NGAL for successful discontinuation of CRRT was assessed with multiple regression analysis. We analyzed data from all patients according to their assigned group (intention-to-treat principle).
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Comparison groups |
Control arm v Treatment arm
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
< 0.05 | |||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||
Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
- | |||||||||||||||
upper limit |
- | |||||||||||||||
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End point title |
All other DVTs and catheter-related thrombus | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Patients underwent daily bedside clinical assessment for DVT using validated tools.
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Statistical analysis title |
analysis of secondary outcomes | |||||||||
Statistical analysis description |
All baseline demographic values for these two groups were compared using the Student’s t-test or Mann-Whitney rank sum test for continuous variables, and Fisher’s exact test for categorical variables. The prediction ability of urine output and NGAL for successful discontinuation of CRRT was assessed with multiple regression analysis. We analyzed data from all patients according to their assigned group (intention-to-treat principle).
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Comparison groups |
Control arm v Treatment arm
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
t-test, 2-sided | |||||||||
Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
- | |||||||||
upper limit |
- | |||||||||
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End point title |
Haematology laboratory endpoints | |||||||||||||||||||||
End point description |
Peak anti-Xa was 0.47 IU/ml for 1 mg/kg enoxaparin compared to 0.16 IU/ml for 40 mg enoxaparin (P=0.17). Trough anti-Xa was 0.14 IU/ml for 1 mg/kg enoxaparin compared to 0.003 IU/ml for 40 mg enoxaparin (P=0.05). There was no significant difference in highest APTT, AT or lowest platelet count between groups.
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End point type |
Secondary
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End point timeframe |
Peak and trough anti-Xa were measured on day three, and once weekly. Ativated partial thromboplastin time (APTT), platelets and antithrombin (AT) were all measured at baseline. Daily platelet count was measured; AT and APTT as per department's norm.
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Statistical analysis title |
secondary endpoints analysis | |||||||||||||||||||||
Statistical analysis description |
All baseline demographic values for these two groups were compared using the Student’s t-test or Mann-Whitney rank sum test for continuous variables, and Fisher’s exact test for categorical variables. The prediction ability of urine output and NGAL for successful discontinuation of CRRT was assessed with multiple regression analysis. We analyzed data from all patients according to their assigned group (intention-to-treat principle).
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Comparison groups |
Control arm v Treatment arm
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||
P-value |
< 0.05 | |||||||||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||||||||
Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
- | |||||||||||||||||||||
upper limit |
- | |||||||||||||||||||||
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End point title |
Heparin - induced thrombocytopenia | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
All patients had daily platelet count measured during the study period and were evaluated by the 4 T’s clinical scoring system.
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Statistical analysis title |
secondary endpoints analysis | |||||||||
Statistical analysis description |
All baseline demographic values for these two groups were compared using the Student’s t-test or Mann-Whitney rank sum test for continuous variables, and Fisher’s exact test for categorical variables. The prediction ability of urine output and NGAL for successful discontinuation of CRRT was assessed with multiple regression analysis. We analyzed data from all patients according to their assigned group (intention-to-treat principle).
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Comparison groups |
Control arm v Treatment arm
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
t-test, 2-sided | |||||||||
Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
- | |||||||||
upper limit |
- | |||||||||
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End point title |
ICU endpoints | ||||||||||||||||||
End point description |
No significant difference was observed in ICU length of stay or ventilator free days.
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End point type |
Secondary
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End point timeframe |
Trial period.
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Statistical analysis title |
secondary endpoints analysis | ||||||||||||||||||
Statistical analysis description |
All baseline demographic values for these two groups were compared using the Student’s t-test or Mann-Whitney rank sum test for continuous variables, and Fisher’s exact test for categorical variables. The prediction ability of urine output and NGAL for successful discontinuation of CRRT was assessed with multiple regression analysis. We analyzed data from all patients according to their assigned group (intention-to-treat principle).
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Comparison groups |
Treatment arm v Control arm
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||||||||
upper limit |
- | ||||||||||||||||||
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End point title |
CRRT-related outcomes | |||||||||||||||||||||
End point description |
Patients in the group that received 40 mg enoxaparin showed a trend towards needing higher doses of regional UFH during CRRT (P=0.06) , and five patients in that group compared with none in the group that received 1 mg/kg enoxaparin needed regional citrate (P= 0.03).
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End point type |
Secondary
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End point timeframe |
Trial period.
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Statistical analysis title |
secondary endpoints analysis | |||||||||||||||||||||
Statistical analysis description |
All baseline demographic values for these two groups were compared using the Student’s t-test or Mann-Whitney rank sum test for continuous variables, and Fisher’s exact test for categorical variables. The prediction ability of urine output and NGAL for successful discontinuation of CRRT was assessed with multiple regression analysis. We analyzed data from all patients according to their assigned group (intention-to-treat principle).
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Comparison groups |
Treatment arm v Control arm
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||
P-value |
< 0.05 | |||||||||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||||||||
Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
- | |||||||||||||||||||||
upper limit |
- | |||||||||||||||||||||
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End point title |
Renal outcomes: general | ||||||||||||||||||||||||||||||
End point description |
The main cause of AKI was sepsis or septic shock (42%). In 63% of the patients, the reason for starting dialysis was either anuria or electrolyte disturbances. 26% of patients were dialysis-dependent after the first dialysis-free period on the ICU. Eight patients in the enoxaparin 1 mg/kg group, and six patients in the enoxaparin 40 mg group experienced renal recovery. The number of patients needing vasopressors did not differ significantly between the renal recovery and non-renal recovery groups (P =1), mean arterial pressure was not significantly different (P = 0.18), and patients had similar fluid balances before CRRT was discontinued (P = 0.4). The number of patients with sepsis was evenly distributed between non-renal recovery and renal recovery groups (P = 0.6). During the dialysis -free interval, the mean urine volume was similar but, non-renal recovery patients had a trend towards needing higher doses of furosemide to maintain urine volume (P = 0.05).
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End point type |
Secondary
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End point timeframe |
Trial period.
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Statistical analysis title |
secondary endpoints analysis | ||||||||||||||||||||||||||||||
Statistical analysis description |
All baseline demographic values for these two groups were compared using the Student’s t-test or Mann-Whitney rank sum test for continuous variables, and Fisher’s exact test for categorical variables. The prediction ability of urine output and NGAL for successful discontinuation of CRRT was assessed with multiple regression analysis. We analyzed data from all patients according to their assigned group (intention-to-treat principle).
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Comparison groups |
Renal Recovery v Repeat Dialysis
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||||||||||||
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End point title |
Renal outcomes:NGAL | ||||||||||||||||||
End point description |
Plasma NGAL levels were higher in non-renal recovery (1074 [± 694] ng/mL) compared to renal recovery patients (296[± 197] ng/mL; P = 0.01) during the dialysis-free interval (Figure 1). Urine NGAL levels were higher in non-renal recovery (3885 [± 2722] ng/mL) compared to renal recovery patients (597 [± 565] ng/mL; P= 0.006) during dialysis -free interval (Figure 2). Though both plasma and urine NGAL levels appear to be significantly related to renal recovery, multiple regression analysis showed that only urine NGAL could independently predict recovery from AKI (P = 0.006).
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End point type |
Secondary
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End point timeframe |
Urine and plasma NGAL were measured at baseline and during CRRT-free intervals.
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Attachments |
Chart 2 Chart 1 |
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Statistical analysis title |
secondary endpoints analysis | ||||||||||||||||||
Statistical analysis description |
All baseline demographic values for these two groups were compared using the Student’s t-test or Mann-Whitney rank sum test for continuous variables, and Fisher’s exact test for categorical variables. The prediction ability of urine output and NGAL for successful discontinuation of CRRT was assessed with multiple regression analysis. We analyzed data from all patients according to their assigned group (intention-to-treat principle).
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Comparison groups |
Repeat Dialysis v Renal Recovery
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Number of subjects included in analysis |
19
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||||||||
upper limit |
- | ||||||||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Recording of adverse events was from time of enrolment in the study until 24 hours after end of study. All serious adverse events were immediately reported to the sponsor. The immediate reports were followed within 24 hours by detailed written reports.
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Adverse event reporting additional description |
The investigator complied with regulatory requirements for reporting unexpected serious adverse drug reactions to the Danish national scientific ethical committee and the Danish Health and Medicines Authority. The sponsor expedited the reporting of all adverse drug reactions that were both serious and unexpected within the timeframe specified.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
ICD | |||||||||||||||||||||||||||||||||
Dictionary version |
9
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Reporting groups
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Reporting group title |
Control arm
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Reporting group description |
Patients received 40 mg enoxaparin sc QD upon commencement of CRRT | |||||||||||||||||||||||||||||||||
Reporting group title |
Treatment arm
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Reporting group description |
Patients received 1 mg/kg enoxaparin sc QD upon commencement of CRRT | |||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Heparin - induced thrombocytopenia was reported as a secondary endpoint, not as an adverse event, as per our protocol. |
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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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31 Aug 2012 |
This was the first amendment made on a version of the protocol that had been submitted to the Danish Health and Medicines Authority and the Danish national scientific ethical committee. At the request of Danish Health and Medicines Authority changes were made to the exclusion criteria so that patients with chronic renal failure or acute-on-chronic renal failure were ineligible. The methods section was also updated to indicate that a patient who changed from CRRT to intermittent hemodialysis would have reached the end of the study period. In addition, further details about the reporting of adverse events were included. The comparator dose which was unconfirmed until this point was included in this new protocol version. |
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21 Jan 2013 |
At the request of the Danish national scientific ethical committee a separate information sheet for the designated surrogates was developed. The methods section was also revised due to the acquisition of new dialysis machines at Odense University Hospital. |
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06 Jun 2013 |
A change in the exclusion criteria: platelet count of <75× 109/l, changed to <50 × 109/l and INR or APTT ≥1½ times the upper limit of normal changed to ≥2 times the upper limit of normal. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
| Our study did not recruit enough patients to test the primary hypothesis, and this is an obvious limitation. It is also possible that the characteristics of NGAL may not be the same in clinical settings. Urine NGAL was in absolute concentration. | |||||||
