Clinical Trial Results:
Development of chronic disease in newly diagnosed Idiopathic Thrombocytopenic Purpura of Childhood. A randomized controlled study on the influence of treatment with intravenous gammaglobulin on the course of the disease.
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Summary
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EudraCT number |
2008-001597-33 |
Trial protocol |
NL |
Global end of trial date |
12 Jul 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Jan 2020
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First version publication date |
15 Jan 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 |
20081203
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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 |
UMC Utrecht
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Sponsor organisation address |
Heidelberglaan 100, Utrecht, Netherlands, 3584 CX
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Public contact |
KMJ Heitink-Polle, UMC Utrecht, +31 887555555, k.m.j.heitink-polle@umcutrecht.nl
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Scientific contact |
KMJ Heitink-Polle, UMC Utrecht, +31 887555555, k.m.j.heitink-polle@umcutrecht.nl
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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 Jun 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Jul 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Jul 2016
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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 is to investigate the hypothesis that early IVIG treatment in children with newly diagnosed acute ITP reduces the risk of development of chronic disease.
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Protection of trial subjects |
Standard Operation Procedures were created to cope with bleeding complications.
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Background therapy |
Childhood immune thrombocytopenia (ITP) is an immune-mediated disease characterized by an isolated low platelet count (peripheral blood platelet count <100 x 109/L) in the absence of other causes that are associated with thrombocytopenia. Most children recover within 6-12 months and chronic ITP, until 2009 defined as a platelet count < 150 x 109/L at 6 months after diagnosis, occurs in about 20-25%. Since 2009, chronic ITP is defined as a platelet count < 100 x 109/L at 12 months after diagnosis and the rate of occurrence is not yet determined. Observational studies have suggested a lower incidence of chronic ITP in children that were treated with intravenous immunoglobulin (IVIg), but randomized studies are lacking. Since chronic ITP has a huge impact on children and their families, being able to prevent a chronic course of the disease would be of major importance. To address the question whether IVIg treatment can prevent a chronic course of the disease in children with ITP, the multicenter randomized ‘Treatment with or without IVIg for Kids with ITP’ (TIKI) trial was performed. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 May 2009
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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 |
Netherlands: 200
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Worldwide total number of subjects |
200
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EEA total number of subjects |
200
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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) |
36
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Children (2-11 years) |
143
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Adolescents (12-17 years) |
21
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Adults (18-64 years) |
0
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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 |
From May 2009 through April 2015, 206 patients from 48 different sites were registered on the Web site. Two were ineligible and 4 declined participation. Twelve sites did not enroll patients. Two hundred patients were included in the intention-to-treat analysis: 100 patients were allocated to receive IVIg and 100 to receive careful observation. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Children aged 3 months to 16 years with newly diagnosed ITP, a platelet count of 20 x 109/L or less and with mild to moderate bleeding (grade 1-3 on the adapted Buchanan bleeding score) were screened by participating pediatricians. If they met inclusion criteria and did not met exclusion criteria they could be enrolled within 72 hours. | ||||||||||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Blinding implementation details |
Since there was no placebo, patients and physicians were aware of the allocated treatment. However, since the primary outcome parameter, namely platelet count, was not influenced by this knowledge, we did not consider this as a problem.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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IVIg | ||||||||||||||||||
Arm description |
All patients randomized to the intervention arm of the study received a single dose of IVIg (Nanogam ®) of 0.8 gram/kg bodyweight once of Nanogam. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Nanogam
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Name: Nanogam ®, manufactured by Sanquin.
Substance: liquid human normal immunoglobulin for intravenous use
Product presentation: 50 ml= 2.5 g human protein of which is at least 95% IgG
200 ml= 10 g human protein of which is at least 95% IgG
Dose: 0.8 gram per kilogram bodyweight
Infusion rate: 0-20 min: 0.5 ml/kg/hr
if well tolerated : next 20 ml gradually increase to 1.0 ml/kg/hr
if well tolerated : increase to a maximum of 3.0 ml/kg/hr
Since Nanogam ® is registered for use in children with ITP, Nanogam® could be prescribed from the regular stock. The local investigators have noted the batch number that was given to the patient on the CRF’s.
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Arm title
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observation | ||||||||||||||||||
Arm description |
Patients randomized to the observational arm of the study received careful observation and immune-modulating treatment only in case of severe bleeding (grade 4-5). | ||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
IVIg
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Reporting group description |
All patients randomized to the intervention arm of the study received a single dose of IVIg (Nanogam ®) of 0.8 gram/kg bodyweight once of Nanogam. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
observation
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Reporting group description |
Patients randomized to the observational arm of the study received careful observation and immune-modulating treatment only in case of severe bleeding (grade 4-5). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
IVIg
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Reporting group description |
All patients randomized to the intervention arm of the study received a single dose of IVIg (Nanogam ®) of 0.8 gram/kg bodyweight once of Nanogam. | ||
Reporting group title |
observation
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Reporting group description |
Patients randomized to the observational arm of the study received careful observation and immune-modulating treatment only in case of severe bleeding (grade 4-5). | ||
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End point title |
Development of chronic ITP | ||||||||||||||||||
End point description |
Chronic ITP was defined as a platelet count < 150 x 10E9/L at 6 months after diagnosis.
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End point type |
Primary
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End point timeframe |
6 months
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| Notes [1] - intention to treat analysis; 3 subjects no available platelet count at 6 months [2] - intention to treat analysis; 3 subjects no available platelet count at 6 months |
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Statistical analysis title |
risk ratio with 95% confidence interval | ||||||||||||||||||
Statistical analysis description |
risk ratio with 95% confidence interval
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Comparison groups |
IVIg v observation
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Number of subjects included in analysis |
194
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||||||||
P-value |
= 0.09 | ||||||||||||||||||
Method |
Chi-squared | ||||||||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||||||||
Point estimate |
0.64
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.38 | ||||||||||||||||||
upper limit |
1.08 | ||||||||||||||||||
Variability estimate |
Standard deviation
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| Notes [3] - no comment |
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Adverse events information [1]
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Timeframe for reporting adverse events |
1 year
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Adverse event reporting additional description |
Since this was a phase 3 study for an already registered treatment and indication, we did not collect adverse effect data, but only severe adverse events. There was a standard operating procedure developed about reporting severe adverse events. Local investigators were asked to fill out SAE forms within 24 hours after the SAE occurred.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
not applicable | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
0
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Reporting groups
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Reporting group title |
IVIg
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Reporting group description |
Group thta was randomized to IVIg | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
observation
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Reporting group description |
group randomized to observation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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: Since this was a phase 3 study for an already registered treatment and indication, we did not collect adverse effect data, but only severe adverse events. |
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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10 Feb 2010 |
- exclusion criteria are more extensively explained
- the infusion rate of Nanogam is adjusted to the guidelines in the IB-1
text
- paragraph 11.3 regarding Quality Assurance has been changed
according to the monitoring plan of the study.
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06 Aug 2012 |
- Paragraph 4.4: due to a too stringent alpha (0.01 instead of 0.05) sample size
was miscalculated. This has been corrected and sample size now is 100 subjects in each group.
- Paragraphs 5.3, 7.4 and 7.5: patients that receive rescue medication for
severe bleeding or immunomodulating therapy for other conditions will NOT
be withdrawn from the study, since they are included in the intention to treat
analysis. This has been corrected in the abovementioned paragraphs. |
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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/29945954 |
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