Clinical Trial Results:
A randomised controlled trial of continuous subcutaneous insulin infusion(CSII) compared to multiple daily injection(MDI) regimens on insulin in children and young people at diagnosis of type I diabetes mellitus (TIDM).
Summary
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EudraCT number |
2010-023792-25 |
Trial protocol |
GB |
Global end of trial date |
30 Jan 2017
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Results information
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Results version number |
v2(current) |
This version publication date |
08 Feb 2019
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First version publication date |
17 Aug 2017
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Other versions |
v1 |
Version creation reason |
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Summary report(s) |
SCIPI Final analysis report v3.0 |
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 |
HTA08/14/39
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Additional study identifiers
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ISRCTN number |
ISRCTN29255275 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
CTA no: 21362/0002/001-0001, REC no: 10/H1002/80, Funder Reference No: HTA 08/14/39 | ||
Sponsors
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Sponsor organisation name |
Alder Hey Children's NHS Foundation Trust
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Sponsor organisation address |
Eaton Road, Liverpool, United Kingdom, L12 2AP
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Public contact |
Carrol Gamble, Clinical Trials Research Centre, University of Liverpool, +44 151 795 8751, ctrcqa@liverpool.ac.uk
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Scientific contact |
Carrol Gamble, Clinical Trials Research Centre, University of Liverpool, +44 151 795 8751, ctrcqa@liverpool.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 |
31 Mar 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Mar 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jan 2017
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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 |
Inbuilt pilot: The primary objective for the inbuilt pilot is to acquire an understanding of the acceptability of randomisation to multiple daily injections or infusion pumps at diagnosis of type 1 diabetes mellitus in children and young people.
Full study: The primary objective for the full study is to compare the control of the blood glucose levels, measured by glycosylated haemoglobin (HbA1c), at 12 months after diagnosis of type 1 diabetes mellitus in children and adolescents receiving infusion pumps with those receiving multiple daily injections.
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Protection of trial subjects |
SCIPI was a pragmatic trial set in routine clinical practice. All interventions were in common use in the age range of the trial. No additional measures were required.
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Background therapy |
No additional interventions were provided. | ||
Evidence for comparator |
This study is designed to provide an evidence base to inform future NHS investment in health care services for children and young people with TIDM. The role of intensive insulin therapy in optimizing glycaemic control and thereby reducing the risk of vascular complications of TIDM is unquestioned however the optimal way in which to achieve this and the cost effectiveness of the tools currently available is unknown. This study will compare two methods of insulin delivery during childhood and adolescence to identify which facilitates superior glycaemic control, and examine the impact of treatment modalities on other predictors of vascular complications of TIDM, adverse events and QoL. Both methods are currently available and used within the SCIPI target population. | ||
Actual start date of recruitment |
16 May 2011
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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: 293
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Worldwide total number of subjects |
293
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EEA total number of subjects |
293
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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) |
14
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Children (2-11 years) |
198
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Adolescents (12-17 years) |
81
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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 |
Participants were recruited from 15 children’s diabetes services in England and Wales with experience of treating ten of more patients with CSII. The study opened to recruitment on 16/05/2011, and was closed on 30/01/2017. | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
976 patients were screened. 98 (10%) were not eligibile. 189 (22%) were not approached about participation due to time or clinical reason. 689 approached, 294 consented (1 withdrew). 395 eligible who declined consent 36 (9%) cited a preference for CSII therapy and 259 (66%) a preference for MDI. | |||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
976 [1] | |||||||||||||||||||||||||||
Number of subjects completed |
293 | |||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 1 | |||||||||||||||||||||||||||
Reason: Number of subjects |
Not eligible: 98 | |||||||||||||||||||||||||||
Reason: Number of subjects |
Eligible Consent not sought: Lack of trained staff: 52 | |||||||||||||||||||||||||||
Reason: Number of subjects |
Eligible Consent not sought: Reason not recorded: 22 | |||||||||||||||||||||||||||
Reason: Number of subjects |
Eligible Consent not sought: Consultant decision: 115 | |||||||||||||||||||||||||||
Reason: Number of subjects |
Eligible Consent sought: MDI preference: 259 | |||||||||||||||||||||||||||
Reason: Number of subjects |
Eligible Consent sought: Pump preference: 36 | |||||||||||||||||||||||||||
Reason: Number of subjects |
Eligible Consent sought: Other: 100 | |||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 976 patients screened with 293 randomised. Please override warning. |
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Period 1
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Period 1 title |
Main trial (visits at: 0m/3m/6m/9m/12m) (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 |
Trial was open-label. Blood samples sent to the laboratory did not indicate allocated intervention.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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CSII group | |||||||||||||||||||||||||||
Arm description |
Roche CSII Insulin pump. Medtronic and Omnipod could also be used as per clinical judgement. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Novorapid 100 U/ml solution for injection (Insulin Aspart)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for solution for infusion
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Insulin aspart will be administered using CSII insulin pumps (Refer to Insulin Pump Manual Guide). Participants will be given insulin aspart using basal insulin infusion with bolus doses of insulin aspart when 5g or more carbohydrate is consumed.
Starting Dose Calculations:
Total daily starting dose of insulin will be calculated from body weight. In pre pubertal subjects 0.5units/kg body weight/day with 50% of calculated dose given as a continuous 24hour infusion (0.5x kg body weight, ÷ 2 ÷ 24 = hourly rate) (CSII). The remaining 50% will be given as 3 divided pre-prandial doses at meal times. If the doses are not equal more insulin will be given before breakfast and the evening meal than at lunch time to account for diurnal variation in insulin sensitivity. In pubertal participants the initial dose calculation will be based on 0.7units/kg body weight /day.
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Arm title
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MDI group | |||||||||||||||||||||||||||
Arm description |
Insulin delivered subcutaneously using an insulin pen injection device in accordance with manufacturer instructions for use. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Insulin Glargine (Lantus 100 units/ml solution for injection)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled injector
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Insulin glargine was delivered subcutaneously using an insulin pen injection device in accordance with manufacturer instructions for use. Participants were given insulin glargine (long acting analog) once or twice daily according to their needs.
Starting Dose Calculations: Total daily starting dose of insulin will be calculated from body weight. In pre pubertal subjects 0.5units/kg body weight/day with 50% of calculated dose given as insulin glargine injection into the anterior-lateral aspect of the thigh, arm, abdomen or the upper outer quadrant of the buttocks (MDI). The remaining 50% will be given as 3 divided pre-prandial doses at meal times. If the doses are not equal more insulin will be given before breakfast and the evening meal than at lunch time to account for diurnal variation in insulin sensitivity. In pubertal participants the initial dose calculation will be based on 0.7units/kg body weight /day.
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Investigational medicinal product name |
Insulin Aspart (Novorapid 100 U/ml solution for injection)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled injector
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Insulin aspart was delivered subcutaneously using an insulin pen injection device in accordance with manufacturer instructions for use. Participants were given boluses of insulin aspart (short acting analog) when 10g or more of carbohydrate were consumed.
Starting Dose Calculations:
Total daily starting dose of insulin was calculated from body weight. In pre pubertal subjects 0.5units/kg body weight/day with 50% of calculated dose given either as insulin injection into the anterior-lateral aspect of the thigh, arm, abdomen or the upper outer quadrant of the buttocks (MDI). The remaining 50% will be given as 3 divided pre-prandial doses at meal times. If the doses are not equal more insulin will be given before breakfast and the evening meal than at lunch time to account for diurnal variation in insulin sensitivity. In pubertal participants the initial dose calculation will be based on 0.7units/kg body weight /day.
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Investigational medicinal product name |
Insulin Detimir. Levemir Cartridge 100 units/ml - Penfill, Levemir Pre-filled Pen 100 units/ml - FlexPen and InnoLet
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled injector
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Insulin detimir was delivered subcutaneously using an insulin pen injection device in accordance with manufacturer instructions for use.
Starting Dose Calculations: Total daily starting dose of insulin will be calculated from body weight. In pre pubertal subjects 0.5units/kg body weight/day with 50% of calculated dose given as insulin glargine injection into the anterior-lateral aspect of the thigh, arm, abdomen or the upper outer quadrant of the buttocks (MDI). The remaining 50% will be given as 3 divided pre-prandial doses at meal times. If the doses are not equal more insulin will be given before breakfast and the evening meal than at lunch time to account for diurnal variation in insulin sensitivity. In pubertal participants the initial dose calculation will be based on 0.7units/kg body weight /day.
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Baseline characteristics reporting groups
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Reporting group title |
CSII group
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Reporting group description |
Roche CSII Insulin pump. Medtronic and Omnipod could also be used as per clinical judgement. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MDI group
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Reporting group description |
Insulin delivered subcutaneously using an insulin pen injection device in accordance with manufacturer instructions for use. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
CSII group
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Reporting group description |
Roche CSII Insulin pump. Medtronic and Omnipod could also be used as per clinical judgement. | ||
Reporting group title |
MDI group
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Reporting group description |
Insulin delivered subcutaneously using an insulin pen injection device in accordance with manufacturer instructions for use. | ||
Subject analysis set title |
Per protocol - CSII
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The primary endpoint will be analysed a second time using the per protocol approach. The per protocol analysis will only be considered in the event of major protocol deviations in more than 10% of the ITT analysis population and apply to a secondary analysis of the primary outcome only.
The per protocol analysis set is defined as those participants without a major protocol deviation or less than three minor deviations as specified within the monitoring plan.
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Subject analysis set title |
Per protocol - MDI
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The primary endpoint will be analysed a second time using the per protocol approach. The per protocol analysis will only be considered in the event of major protocol deviations in more than 10% of the ITT analysis population and apply to a secondary analysis of the primary outcome only.
The per protocol analysis set is defined as those participants without a major protocol deviation or less than three minor deviations as specified within the monitoring plan.
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End point title |
Primary outcome: HbA1c measured 12 months after randomisation | ||||||||||||||||||||||||||||||||||||||||
End point description |
HbA1c is measured from a blood sample taken at the 12-month follow-up appointment . Unit of measurement: mmol/mol. Two measurements are recorded for each blood sample: a local measurement arising from measurement in situ using a portable machine in clinic; and a measurement made at a central lab at Alder Hey. Local measurements will be used when central measurements are not available.
HbA1c will be compared between the trial groups using mixed-model regression with 12-month HbA1c as the dependent variable, treatment group as an explanatory factor and the stratification variables: age-group and centre as covariates. Centre will be fitted as a random effect.
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End point type |
Primary
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End point timeframe |
Measured 12 months after randomisation.
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Attachments |
All tables and figures for outcome |
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Statistical analysis title |
HbA1c at 12 months - Mixed model analysis (ITT) | ||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
HbA1c will be compared between the trial groups using mixed-model regression with 12-month HbA1c as the dependent variable, treatment group as an explanatory factor and the stratification variables: age-group and centre as covariates. Centre will be fitted as a random effect.
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Comparison groups |
CSII group v MDI group
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Number of subjects included in analysis |
285
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.09 [1] | ||||||||||||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||||||||||||||||||
Point estimate |
2.4
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.4 | ||||||||||||||||||||||||||||||||||||||||
upper limit |
5.3 | ||||||||||||||||||||||||||||||||||||||||
Notes [1] - Not significant. |
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Statistical analysis title |
HbA1c at 12 months - Mixed model analysis (PP) | ||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
HbA1c will be compared between the trial groups using mixed-model regression with 12-month HbA1c as the dependent variable, treatment group as an explanatory factor and the stratification variables: age-group and centre as covariates. Centre will be fitted as a random effect.
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Comparison groups |
Per protocol - CSII v Per protocol - MDI
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Number of subjects included in analysis |
153
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.67 [2] | ||||||||||||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||||||||||||||||||
Point estimate |
0.9
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-3.2 | ||||||||||||||||||||||||||||||||||||||||
upper limit |
5 | ||||||||||||||||||||||||||||||||||||||||
Notes [2] - Not significant. Confirms the robustness of the ITT analysis result. |
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End point title |
Secondary outcome 1: Percentage of participants in each group with 12-month HbA1c < 6.5% | |||||||||
End point description |
HbA1c < 6.5% is equivalent to HbA1c < 48 mmol/mol.
Number of participants in each group with 12-month HbA1c less than 48 mmol/mol.
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End point type |
Secondary
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End point timeframe |
Measured 12 months after randomisation.
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Attachments |
Secondary outcome 1 |
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Statistical analysis title |
12-month HbA1c < 48 mmol/mol | |||||||||
Statistical analysis description |
The number and percentage of participants with 12-month HbA1c less than 48 mmol/mol (equivalent to 6.5%) will be reported overall and for each treatment group. The difference between the two percentages will be presented with a 95% confidence interval and significance tested using the chi-squared test. RR with 95% confidence interval will also be presented. A precision of 1 decimal place will be used for all statistics.
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Comparison groups |
CSII group v MDI group
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Number of subjects included in analysis |
285
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.28 [3] | |||||||||
Method |
Chi-squared | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.75
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.46 | |||||||||
upper limit |
1.25 | |||||||||
Notes [3] - Not significant. |
||||||||||
Statistical analysis title |
12-month HbA1c < 58.5 mmol/mol | |||||||||
Statistical analysis description |
The number and percentage of participants with 12-month HbA1c less than 48 mmol/mol (equivalent to 7.5%) will be reported overall and for each treatment group. The difference between the two percentages will be presented with a 95% confidence interval and significance tested using the chi-squared test. RR with 95% confidence interval will also be presented. A precision of 1 decimal place will be used for all statistics.
|
|||||||||
Comparison groups |
CSII group v MDI group
|
|||||||||
Number of subjects included in analysis |
285
|
|||||||||
Analysis specification |
Post-hoc
|
|||||||||
Analysis type |
superiority [4] | |||||||||
P-value |
= 0.16 [5] | |||||||||
Method |
Chi-squared | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.84
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.67 | |||||||||
upper limit |
1.06 | |||||||||
Notes [4] - Analysis not post-hoc as such as was detailed in earlier version of SCIPI trial protocol. See substantial amendment (01/08/2016): "Updated the HbA1c recommendations in line with the recent NICE guidance: Change to the Secondary Objective. HbA1c reduced from 7.5% to 6.5% and HbA1c also provided in mmol. Change to secondary endpoint - Percentage of participants in each group with HbA1c reduced from <7.5% to <6.5%. Added partial remission and height as endpoints." [5] - Not significant which matches conclusion from the < 48 mmol/mol analysis. |
|
||||||||||
End point title |
Secondary outcome 2: Incidence of severe hypoglycaemia | |||||||||
End point description |
Severe hypoglycaemia is a type of related adverse event. Participants that experience at least one instance of severe hypoglycaemia will be identified.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Measured 12 months after randomisation.
|
|||||||||
|
||||||||||
Attachments |
All tables and figures for outcome |
|||||||||
Statistical analysis title |
Incidence of severe hypoglycaemia | |||||||||
Statistical analysis description |
The number and percentage of participants in each group that experience at least one instance of severe hypoglycaemia will be reported overall and for each treatment group. The difference between the two percentages will be presented with a 95% confidence interval and significance tested using the chi-squared test. RR with 95% confidence interval will also be presented. A precision of 1 decimal place will be used for all statistics.
|
|||||||||
Comparison groups |
MDI group v CSII group
|
|||||||||
Number of subjects included in analysis |
293
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.17 [6] | |||||||||
Method |
Chi-squared | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
3.1
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.6 | |||||||||
upper limit |
15.1 | |||||||||
Notes [6] - Not significant. |
|
||||||||||
End point title |
Secondary outcome 3: Incidence of diabetic ketoacidosis | |||||||||
End point description |
Diabetic ketoacidosis is a type of related adverse event. Participants that experience at least one instance of severe hypoglycaemia will be identified.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Measured 12 months after randomisation.
|
|||||||||
|
||||||||||
Attachments |
All tables and figures for outcome |
|||||||||
Statistical analysis title |
Incidence of diabetic ketoacidosis | |||||||||
Statistical analysis description |
The number and percentage of participants in each group that experience at least one instance of diabetic ketoacidosis will be reported overall and for each treatment group. The difference between the two percentages will be presented with a 95% confidence interval and significance tested using the chi-squared test. RR with 95% confidence interval will also be presented. A precision of 1 decimal place will be used for all statistics.
|
|||||||||
Comparison groups |
CSII group v MDI group
|
|||||||||
Number of subjects included in analysis |
293
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.24 [7] | |||||||||
Method |
Chi-squared | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
5.2
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.3 | |||||||||
upper limit |
106.8 | |||||||||
Notes [7] - Not significant. |
|
|||||||||||||
End point title |
Secondary outcome 4: Change in BMI SDS | ||||||||||||
End point description |
BMI SDS will be derived using the 2006 WHO growth standard (for children <5 years) and 2007 WHO growth reference (for children ≥5 years) from the age (years), weight (kg) and height (m) measurements taken at baseline and at 12 months post diagnosis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and at 12 months post diagnosis.
|
||||||||||||
|
|||||||||||||
Attachments |
All tables and figures for outcome |
||||||||||||
Statistical analysis title |
Change in BMI SDS mixed model ANCOVA | ||||||||||||
Statistical analysis description |
Change in BMI SDS (12-month follow‐up minus baseline) will be analysed using mixed model ANCOVA.
The outcome in the ANCOVA model will be change in BMI SDS with baseline BMI SDS, age-strata and treatment included as covariates in the model. Centre will be fitted as a random effect.
The ANCOVA model will not adjust for gender as a confounder (age is adjusted for in the calculation of BMI SDS) but age-strata will be because randomisation was stratified by this.
|
||||||||||||
Comparison groups |
CSII group v MDI group
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.13 [8] | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0 | ||||||||||||
upper limit |
0.3 | ||||||||||||
Notes [8] - Not significant. |
|
|||||||||||||
End point title |
Secondary outcome 5: Height | ||||||||||||
End point description |
Height SDS will be derived using the 2006 WHO growth standard (for children <5 years) and 2007 WHO growth reference (for children ≥5 years) from the age (years), and height (m) measurements taken at baseline and at 12 months post diagnosis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and at 12 months post diagnosis.
|
||||||||||||
|
|||||||||||||
Attachments |
All tables and figures for outcome |
||||||||||||
Statistical analysis title |
Change in height SDS mixed model ANCOVA | ||||||||||||
Statistical analysis description |
Change in height SDS (12-month follow‐up minus baseline) will be analysed using mixed model ANCOVA.
The outcome in the ANCOVA model will be change in height SDS with baseline height SDS, age-strata and treatment included as covariates in the model. Centre will be fitted as a random effect.
The ANCOVA model will not adjust for gender as a confounder (age is adjusted for in the calculation of height SDS) but age-strata will be because randomisation was stratified by this.
|
||||||||||||
Comparison groups |
CSII group v MDI group
|
||||||||||||
Number of subjects included in analysis |
244
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.1 [9] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.2 | ||||||||||||
upper limit |
0 | ||||||||||||
Notes [9] - Not significant |
|
|||||||||||||||||||||||||
End point title |
Secondary outcome 6: Insulin requirements | ||||||||||||||||||||||||
End point description |
Insulin usage is recorded at each follow-up appointment, reflecting the insulin usage for the 4 weeks preceding the appointment. The unit of measurement is units/kg/day. It can be obtained in a number of ways, with data directly available from pump devices for the CSII arm. For the purpose of this analysis, insulin usage will be obtained from a single source type for both arms, i.e. from glucometers; and only data obtained at the 12-month appointment will be analysed.
Insulin requirement (IR) is calculated as per SAP.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Measured 12 months after randomisation.
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Attachments |
All tables and figures for outcome |
||||||||||||||||||||||||
Statistical analysis title |
Insulin requirements mixed model analysis | ||||||||||||||||||||||||
Statistical analysis description |
Insulin requirement will be compared between the trial groups using mixed-model regression with 12-month HbA1c as the dependent variable, treatment group as an explanatory factor and the stratification variables: age-group and centre as covariates. Centre will be fitted as a random effect.
|
||||||||||||||||||||||||
Comparison groups |
CSII group v MDI group
|
||||||||||||||||||||||||
Number of subjects included in analysis |
151
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.01 [10] | ||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
0.1
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0 | ||||||||||||||||||||||||
upper limit |
0.2 | ||||||||||||||||||||||||
Notes [10] - Significant. |
|
||||||||||||||||||||||||||||||||||
End point title |
Secondary outcome 7: Paediatric Quality of Life (PedsQL) | |||||||||||||||||||||||||||||||||
End point description |
PedsQL is a standardised age-targeted questionnaire, generating an overall score between 0 and 100 representing patients’ perceived health-related quality of life. Values for each question of each age-specific questionnaire will be uploaded and the overall score calculated as per PedsQL guidelines: “Scaling And Scoring Of The Paediatric Quality of Life Inventory™ PedsQL” found at http://www.pedsql.org /PedsQL-Scoring.pdf. This also provides a strategy for handling missing data: if > 50% of questions are unanswered, then the total score should not be calculated; otherwise, impute the mean score of the questions that have been answered in for the missing ones.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
Measured 12 months after randomisation.
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Attachments |
All tables and figures for outcome |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Children - Overall QoL at 12m - Mixed model | |||||||||||||||||||||||||||||||||
Statistical analysis description |
Overall QoL score will be compared between the trial groups using mixed-model regression with 12-month Overall QoL score as the dependent variable, treatment group as an explanatory factor and the stratification variables: questionnaire age-group and centre as covariates. Centre will be fitted as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
CSII group v MDI group
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
293
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||||||||||||||
P-value |
= 0.1 [11] | |||||||||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||||||||||||||||||||
Point estimate |
3.1
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
-0.6 | |||||||||||||||||||||||||||||||||
upper limit |
6.8 | |||||||||||||||||||||||||||||||||
Notes [11] - Not significant. |
||||||||||||||||||||||||||||||||||
Statistical analysis title |
Parent - Overall QoL at 12m - Mixed model | |||||||||||||||||||||||||||||||||
Statistical analysis description |
Overall QoL score will be compared between the trial groups using mixed-model regression with 12-month Overall QoL score as the dependent variable, treatment group as an explanatory factor and the stratification variables: questionnaire age-group and centre as covariates. Centre will be fitted as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
CSII group v MDI group
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
293
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||||||||||||||
P-value |
= 0.02 [12] | |||||||||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||||||||||||||||||||
Point estimate |
4.1
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
0.6 | |||||||||||||||||||||||||||||||||
upper limit |
7.6 | |||||||||||||||||||||||||||||||||
Notes [12] - Not significant. The Estimated G matrix was not positive definite which indicates that the variance component in the RANDOM statement (site) are estimated to be zero so were removed from the model. |
|
||||||||||
End point title |
Secondary outcome 8: Cost effectiveness | |||||||||
End point description |
This analysis is reported separately by Health Economists at Bangor. See HTA report for full detail once published.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
This analysis is reported separately by Health Economists at Bangor. See HTA report for full detail once published.
|
|||||||||
|
||||||||||
Attachments |
All tables and figures for outcome |
|||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Secondary efficacy outcome 9: Partial Remission | |||||||||
End point description |
Insulin dose-adjusted HbA1c (IDAA1c) is a measure used to define partial remission in children recently diagnosed with Type I diabetes. This is a transient phase in which children partially recover in response to treatment, before they enter the chronic phase of the disease. IDAA1c was proposed by Mortensen et al (2009). The variables included in the calculation are HbA1c, daily insulin dose (units) up to 4 weeks before the follow-up visit and weight (kg). See SAP for details.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Measured at 12 months after randomisation.
|
|||||||||
|
||||||||||
Attachments |
All tables and figures for outcome |
|||||||||
Statistical analysis title |
Partial remission at 12m | |||||||||
Statistical analysis description |
The number and percentage of participants with partial remission at 12 months will be reported overall and for each treatment group. The difference between the two percentages will be presented with a 95% confidence interval and significance tested using the chi-squared test. RR with 95% confidence interval will also be presented. A precision of 1 decimal place will be used for all statistics.
|
|||||||||
Comparison groups |
MDI group v CSII group
|
|||||||||
Number of subjects included in analysis |
150
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.28 [13] | |||||||||
Method |
Chi-squared | |||||||||
Parameter type |
Mean difference (final values) | |||||||||
Point estimate |
0.74
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.45 | |||||||||
upper limit |
1.24 | |||||||||
Notes [13] - Not significant. |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Serious ARs/AEs: Reported to the CTU within 24 hours.
Non serious ARs/AEs: Reported to the CTU as per routine schedule.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Participants AEs/SAEs are included in the method of insulin delivery they were actually receiving at the time of AE/SAE onset to take into account any participants that temporarily/permanently changed their mode of insulin delivery at any point throughout the trial.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
CSII group
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Total person years (total patients) = 144.1 (144) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MDI group
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Total person years (total patients) = 151.9 (149) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
30 Mar 2011 |
Inclusion criteria amendment to include patients and parents able to complete study material.
HbA1c samples will be collected, analysed and destroyed according to local clinical practice rather than analysis at a central laboratory
Pharmacovigilence: Only related SAEs and related AEs will be reported for this trial. RUSAEs related to medical devices will be reported as per user vigilance reporting |
||
01 Jul 2011 |
The time period to start the randomised treatment was changed from within 3-5 days to within 10 days. The study information will be provided and the consent should occur as close to the time of diagnosis as possible, ideally between the time of diagnosis (Day 0) and Day 5.
Timelines for providing information and approaching the patient for consent will be recorded on the screening log.
Web randomisation system to be used instead of telephone, with randomisation envelopes as a back-up. Up to this point all randomisations completed using backup envelopes.
PedsQL (Quality of life) questionnaire booklets were removed from baseline and will only be administered at 6 and 12 month study visit.
|
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17 Aug 2012 |
Revision to the inclusion criteria, change to patients and parents able to comply with the treatment regimen and study visits.
Addition to exclusion criteria list:
g. Known thyroid condition in a non Euthyroid state and;
h. Known coeliac disease unable to maintain a gluten free diet.
Exclusions previously specified within the protocol but not numbered within the exclusion criteria.
Revision to the exclusion criteria change to: a. have a sibling with existing TIDM rather than first degree relative
Additional guidance and change to recruitment window period to 14 days and further guidance on patients being approached and consented as soon after diagnosis as possible.
HbA1c samples to be collected, analysed and destroyed at a central laboratory.
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21 Jan 2015 |
Removal of the following from the eligibility criteria: Patient aged 8 years and over are able to comply with the treatment regimen and study visits.
Addition of Omnipod as a pump that can be supplied in line with normal clinical practice
Addition of text permitting use of the insulin Detemir
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01 Aug 2016 |
Updated the HbA1c recommendations in line with the recent NICE guidance: Change to the Secondary Objective. HbA1c reduced from 7.5% to 6.5% and HbA1c also provided in mmol.
Change to secondary endpoint - Percentage of participants in each group with HbA1c reduced from <7.5% to <6.5%. Added partial remission and height as endpoints
Outcomes may be presented as mmol/mol or equivalent %
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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. | |||
N/A |