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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
EudraCT number	2010-023792-25
Trial protocol	GB
Global end of trial date	30 Jan 2017

Results information
Results version number	v2(current)
This version publication date	08 Feb 2019
First version publication date	17 Aug 2017
Other versions	v1
Version creation reason	Correction of full data set Changes to summary attachments An error spotted during copy-editing stage of HTA final report submission needs to be corrected within EudraCT database. The value that needs to be corrected is the difference in percentages in ‘Table 6.6-13: Percentage of participants in each group with 12-month HbA1c < 58.5 mmol/mol – Results (ITT)’. This is presented as a secondary analysis within the attachment for the ‘Percentage of participants in each group with 12-month HbA1c < 48 mmol/mol’ secondary outcome.
Summary report(s)	SCIPI Final analysis report v3.0

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

HTA08/14/39

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

Sponsor organisation name

Alder Hey Children's NHS Foundation Trust

Sponsor organisation address

Eaton Road, Liverpool, United Kingdom, L12 2AP

Public contact

Carrol Gamble, Clinical Trials Research Centre, University of Liverpool, +44 151 795 8751, ctrcqa@liverpool.ac.uk

Scientific contact

Carrol Gamble, Clinical Trials Research Centre, University of Liverpool, +44 151 795 8751, ctrcqa@liverpool.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Mar 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Mar 2016

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2017

Was the trial ended prematurely?

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.

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.

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

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 293

Worldwide total number of subjects

293

EEA total number of subjects

293

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

198

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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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.

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.

Number of subjects started

976 ^[1]

Number of subjects completed

293

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

Reason: Number of subjects

Consent withdrawn by subject: 1

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.

Period 1 title

Main trial (visits at: 0m/3m/6m/9m/12m) (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Trial was open-label. Blood samples sent to the laboratory did not indicate allocated intervention.

Are arms mutually exclusive

Yes

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)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for infusion

Routes of administration

Subcutaneous use

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.

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)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled injector

Routes of administration

Subcutaneous use

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.

Investigational medicinal product name

Insulin Aspart (Novorapid 100 U/ml solution for injection)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled injector

Routes of administration

Subcutaneous use

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.

Investigational medicinal product name

Insulin Detimir. Levemir Cartridge 100 units/ml - Penfill, Levemir Pre-filled Pen 100 units/ml - FlexPen and InnoLet

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled injector

Routes of administration

Subcutaneous use

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.

Number of subjects in period 1	CSII group	MDI group
Started	144	149
Completed	143	144
Not completed	1	5
Personal circumstances	-	1
No longer wished to participate	1	-
Coeliac disease Can't comply with gluten free diet	-	1
Lost to follow-up	-	1
Relocated	-	2

Baseline characteristics

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Reporting group title

CSII group

Reporting group description

Roche CSII Insulin pump. Medtronic and Omnipod could also be used as per clinical judgement.

Reporting group title

MDI group

Reporting group description

Insulin delivered subcutaneously using an insulin pen injection device in accordance with manufacturer instructions for use.

Reporting group values	CSII group	MDI group	Total
Number of subjects	144	149	293
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	8	6	14
Children (2-11 years)	96	102	198
Adolescents (12-17 years)	40	41	81
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	9 ( 4.1 )	9.1 ( 4.1 )	-
Gender categorical
Units: Subjects
Female	71	69	140
Male	73	80	153
Age (strata categories)
Units: Subjects
7mths – <5 yrs	33	32	65
5 – <12 yrs	71	76	147
12-15 yrs	40	41	81
Ethnicity
Units: Subjects
Missing	1	3	4
Asian or Asian British	3	3	6
Black or British Black	0	3	3
British White	124	118	242
Indian	2	2	4
Mixed	4	6	10
Other White	6	8	14
Other	3	2	5
Pakistani	1	4	5
Deprivation score (quintile categories)
Units: Subjects
Missing	7	6	13
1 (<=8.49)	32	40	72
2 (8.5 – 13.79)	23	30	53
3 (13.8 – 21.35)	18	22	40
4 (21.36 – 34.17)	25	18	43
5 (>=34.18)	39	33	72
Thyroid test result
* Test not a requirement of the study protocol.
Units: Subjects
Not done	25	19	44
Missing	7	6	13
Abnormal	6	3	9
Normal	105	118	223
Results unobtainable	1	3	4
Coeliac screen test result
* Test not a requirement of the study protocol.
Units: Subjects
Not done	28	30	58
Missing	14	10	24
Abnormal	3	9	12
Normal	97	97	194
Results unobtainable	2	3	5
Islet Cell Antibodies test result
* Test not a requirement of the study protocol.
Units: Subjects
Not done	39	34	73
Missing	17	17	34
Negative	35	31	66
Positive	39	53	92
Weak positive	13	10	23
Results unobtainable	1	4	5
GAD 65 Antibodies test result
* Test not a requirement of the study protocol.
Units: Subjects
Note done	65	65	130
Missing	13	14	27
Equivocal	4	4	8
Negative	11	16	27
Positive	50	50	100
Results unobtainable	1	0	1
Conmeds prescribed up to baseline
Units: Subjects
Missing	2	0	2
No	102	114	216
Yes	40	35	75
Deprivation score (continuous)
CSII missing = 7 MDI missing = 6 Total missing = 13
Units: IMD
median (inter-quartile range (Q1-Q3))	19.4 (8.9 to 37.9)	14.7 (7.8 to 31.8)	-
BMI SDS
CSII missing = 20 MDI missing = 17 Total missing = 37
Units: SDS
arithmetic mean (standard deviation)	0.2 ( 1.3 )	0.1 ( 1.4 )	-
Height SDS
CSII missing = 20 MDI missing = 17 Total missing = 37
Units: SDS
arithmetic mean (standard deviation)	0.3 ( 1.1 )	0.3 ( 1.1 )	-
Local HbA1c
CSII missing = 22 MDI missing = 27 Total missing = 49
Units: mmol/mol
arithmetic mean (standard deviation)	105.9 ( 24.2 )	103.6 ( 26.3 )	-
Central HbA1c
CSII missing = 80 MDI missing = 78 Total missing = 158 * High levels of missing data for ‘Central HbA1c’ because the central laboratory for sending all blood samples to for measuring HbA1c was only set up part-way through the trial.
Units: mmol/mol
arithmetic mean (standard deviation)	101.2 ( 24.9 )	96.4 ( 24 )	-
HbA1c#
# When available central lab HbA1c measurement taken in preference of local lab HbA1c measurement. CSII missing = 12 MDI missing = 18 Total missing = 30
Units: mmol/mol
arithmetic mean (standard deviation)	104.6 ( 24.4 )	102.6 ( 26.7 )	-
Blood glucose
CSII missing = 3 MDI missing = 3 Total missing = 6
Units: mmol/L
arithmetic mean (standard deviation)	26.8 ( 9.2 )	26.9 ( 10 )	-
Blood pH
CSII missing = 17 MDI missing = 16 Total missing = 33
Units: pH
arithmetic mean (standard deviation)	7.3 ( 0.2 )	7.3 ( 0.1 )	-
Health Utilities Index
CSII Not done (HUI not completed properly) = 7 CSII Not done (HUI not completed at all) = 22 MDI Not done (HUI not completed properly) = 3 MDINot done (HUI not completed at all) = 19 Total Not done (HUI not completed properly) = 10 Total Not done (HUI not completed at all) = 41
Units: HUI
arithmetic mean (standard deviation)	0.9 ( 0.19 )	0.9 ( 0.1 )	-

End points

Top of page

Reporting group title

CSII group

Reporting group description

Roche CSII Insulin pump. Medtronic and Omnipod could also be used as per clinical judgement.

Reporting group title

MDI group

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

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.

Subject analysis set title

Per protocol - MDI

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Primary outcome: HbA1c measured 12 months after randomisation

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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.

End point type

Primary

End point timeframe

Measured 12 months after randomisation.

End point values	CSII group	MDI group	Per protocol - CSII	Per protocol - MDI
Number of subjects analysed	143	142	87	66
Units: mmol/mol
arithmetic mean (standard deviation)
7mths - < 5yrs	63.9 ( 12.1 )	58.4 ( 9.9 )	62.6 ( 13.1 )	56.2 ( 11 )
5yrs - <12yrs	58 ( 11.4 )	59.3 ( 11.4 )	57.9 ( 11.8 )	59.7 ( 10.8 )
12yrs - <16yrs	61.3 ( 13.3 )	54.7 ( 14.7 )	57.6 ( 14.2 )	57.8 ( 16.8 )
Overall	60.3 ( 12.3 )	57.9 ( 12.2 )	59 ( 12.8 )	58.4 ( 13.1 )

Attachments

All tables and figures for outcome

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.

Comparison groups

CSII group v MDI group

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.09 ^[1]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

5.3

Notes
[1] - Not significant.

HbA1c at 12 months - Mixed model analysis (PP)

Statistical analysis description

Comparison groups

Per protocol - CSII v Per protocol - MDI

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.67 ^[2]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

Notes
[2] - Not significant. Confirms the robustness of the ITT analysis result.

Secondary: Secondary outcome 1: Percentage of participants in each group with 12-month HbA1c < 6.5%

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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.

End point type

Secondary

End point timeframe

Measured 12 months after randomisation.

End point values	CSII group	MDI group
Number of subjects analysed	143	142
Units: mmol/mol	22	29

Attachments

Secondary outcome 1

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.

Comparison groups

CSII group v MDI group

Number of subjects included in analysis

285

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.28 ^[3]

Method

Chi-squared

Parameter type

Risk ratio (RR)

Point estimate

0.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

1.25

Notes
[3] - Not significant.

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.

Secondary: Secondary outcome 2: Incidence of severe hypoglycaemia

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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.

End point values	CSII group	MDI group
Number of subjects analysed	144	149
Units: N/A	6	2

Attachments

All tables and figures for outcome

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.

Secondary: Secondary outcome 3: Incidence of diabetic ketoacidosis

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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.

End point values	CSII group	MDI group
Number of subjects analysed	144	149
Units: N/A	2	0

Attachments

All tables and figures for outcome

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.

Secondary: Secondary outcome 4: Change in BMI SDS

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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.

End point values	CSII group	MDI group
Number of subjects analysed	122	122
Units: SDS
arithmetic mean (standard deviation)	0.6 ( 0.8 )	0.5 ( 0.8 )

Attachments

All tables and figures for outcome

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

upper limit

0.3

Notes
[8] - Not significant.

Secondary: Secondary outcome 5: Height

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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.

End point values	CSII group	MDI group
Number of subjects analysed	122	122
Units: SDS
arithmetic mean (standard deviation)	-0.1 ( 0.5 )	0 ( 0.4 )

Attachments

All tables and figures for outcome

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

Notes
[9] - Not significant

Secondary: Secondary outcome 6: Insulin requirements

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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.

End point values	CSII group	MDI group
Number of subjects analysed	87	64
Units: Units/kg/day
arithmetic mean (standard deviation)
7mths - < 5yrs	0.7 ( 0.2 )	0.7 ( 0.1 )
5yrs - <12yrs	0.6 ( 0.2 )	0.6 ( 0.3 )
12yrs - <16yrs	0.8 ( 0.2 )	0.5 ( 0.4 )
Overall	0.7 ( 0.2 )	0.6 ( 0.3 )

Attachments

All tables and figures for outcome

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

upper limit

0.2

Notes
[10] - Significant.

Secondary: Secondary outcome 7: Paediatric Quality of Life (PedsQL)

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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.

End point values	CSII group	MDI group
Number of subjects analysed	144	149
Units: 0-100
arithmetic mean (standard deviation)
Children 5-7 years old (12 month follow-up)	72.6 ( 15.5 )	70 ( 15.2 )
Children 8-12 years old (12 month follow-up)	79 ( 12 )	74.4 ( 14.3 )
Children 13-16 years old (12 month follow-up)	73.7 ( 13.8 )	72.4 ( 14.4 )
Parents / carers 2-4 years old (12 month follo	73 ( 12.7 )	67 ( 15.7 )
Parents / carers 5-7 years old (12 month follo	73.1 ( 15.8 )	71 ( 9.3 )
Parents / carers 8-12 years old (12 month foll	73.9 ( 11.9 )	68.2 ( 14.9 )
Parents / carers 13-16 years old (12 month fol	69 ( 14.5 )	67.5 ( 15.7 )

Attachments

All tables and figures for outcome

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.

Parent - Overall QoL at 12m - Mixed model

Statistical analysis description

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.

Secondary: Secondary outcome 8: Cost effectiveness

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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.

End point values	CSII group	MDI group
Number of subjects analysed	144	149
Units: N/A	144	149

Attachments

All tables and figures for outcome

No statistical analyses for this end point

Secondary: Secondary efficacy outcome 9: Partial Remission

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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.

End point values	CSII group	MDI group
Number of subjects analysed	86	64
Units: N/A	21	21

Attachments

All tables and figures for outcome

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

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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 name

MedDRA

Dictionary version

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)

Serious adverse events	CSII group	MDI group
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 144 (6.25%)	7 / 149 (4.70%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Investigations
Blood glucose increased
subjects affected / exposed	1 / 144 (0.69%)	1 / 149 (0.67%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood ketone body
subjects affected / exposed	1 / 144 (0.69%)	1 / 149 (0.67%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Drug administration error
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Social circumstances
Social problem
subjects affected / exposed	0 / 144 (0.00%)	1 / 149 (0.67%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Treatment noncompliance
subjects affected / exposed	0 / 144 (0.00%)	1 / 149 (0.67%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 144 (0.00%)	1 / 149 (0.67%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Eating disorder
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Administration site infection
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear infection
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 144 (1.39%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 144 (1.39%)	2 / 149 (1.34%)
occurrences causally related to treatment / all	3 / 3	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	2 / 144 (1.39%)	1 / 149 (0.67%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	CSII group	MDI group
Total subjects affected by non serious adverse events
subjects affected / exposed	28 / 144 (19.44%)	8 / 149 (5.37%)
Investigations
Blood glucose increased
subjects affected / exposed	3 / 144 (2.08%)	0 / 149 (0.00%)
occurrences all number	7	0
Injury, poisoning and procedural complications
Drug administration error
subjects affected / exposed	1 / 144 (0.69%)	2 / 149 (1.34%)
occurrences all number	1	2
General disorders and administration site conditions
Catheter site pain
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences all number	2	0
Device failure
subjects affected / exposed	5 / 144 (3.47%)	1 / 149 (0.67%)
occurrences all number	8	1
Device issue
subjects affected / exposed	2 / 144 (1.39%)	0 / 149 (0.00%)
occurrences all number	2	0
Implant site bruising
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences all number	1	0
Injection site pain
subjects affected / exposed	0 / 144 (0.00%)	2 / 149 (1.34%)
occurrences all number	0	2
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Skin reaction
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences all number	1	0
Infections and infestations
Administration site infection
subjects affected / exposed	7 / 144 (4.86%)	0 / 149 (0.00%)
occurrences all number	7	0
Penile infection
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences all number	1	0
Scrotal infection
subjects affected / exposed	1 / 144 (0.69%)	0 / 149 (0.00%)
occurrences all number	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 144 (0.00%)	1 / 149 (0.67%)
occurrences all number	0	1
Hyperglycaemia
subjects affected / exposed	7 / 144 (4.86%)	1 / 149 (0.67%)
occurrences all number	7	1
Hypoglycaemia
subjects affected / exposed	7 / 144 (4.86%)	3 / 149 (2.01%)
occurrences all number	7	3

More information

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Were there any global substantial amendments to the protocol? Yes

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.

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.

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

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 %

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

N/A

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Clinical trials

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).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary outcome: HbA1c measured 12 months after randomisation

Primary: Primary outcome: HbA1c measured 12 months after randomisation

Secondary: Secondary outcome 1: Percentage of participants in each group with 12-month HbA1c < 6.5%

Secondary: Secondary outcome 1: Percentage of participants in each group with 12-month HbA1c < 6.5%

Secondary: Secondary outcome 2: Incidence of severe hypoglycaemia

Secondary: Secondary outcome 2: Incidence of severe hypoglycaemia

Secondary: Secondary outcome 3: Incidence of diabetic ketoacidosis

Secondary: Secondary outcome 3: Incidence of diabetic ketoacidosis

Secondary: Secondary outcome 4: Change in BMI SDS

Secondary: Secondary outcome 4: Change in BMI SDS

Secondary: Secondary outcome 5: Height

Secondary: Secondary outcome 5: Height

Secondary: Secondary outcome 6: Insulin requirements

Secondary: Secondary outcome 6: Insulin requirements

Secondary: Secondary outcome 7: Paediatric Quality of Life (PedsQL)

Secondary: Secondary outcome 7: Paediatric Quality of Life (PedsQL)

Secondary: Secondary outcome 8: Cost effectiveness

Secondary: Secondary outcome 8: Cost effectiveness

Secondary: Secondary efficacy outcome 9: Partial Remission

Secondary: Secondary efficacy outcome 9: Partial Remission

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Outside EU/EEA

Clinical trials

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).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary outcome: HbA1c measured 12 months after randomisation

Primary: Primary outcome: HbA1c measured 12 months after randomisation

Secondary: Secondary outcome 1: Percentage of participants in each group with 12-month HbA1c < 6.5%

Secondary: Secondary outcome 1: Percentage of participants in each group with 12-month HbA1c < 6.5%

Secondary: Secondary outcome 2: Incidence of severe hypoglycaemia

Secondary: Secondary outcome 2: Incidence of severe hypoglycaemia

Secondary: Secondary outcome 3: Incidence of diabetic ketoacidosis

Secondary: Secondary outcome 3: Incidence of diabetic ketoacidosis

Secondary: Secondary outcome 4: Change in BMI SDS

Secondary: Secondary outcome 4: Change in BMI SDS

Secondary: Secondary outcome 5: Height

Secondary: Secondary outcome 5: Height

Secondary: Secondary outcome 6: Insulin requirements

Secondary: Secondary outcome 6: Insulin requirements

Secondary: Secondary outcome 7: Paediatric Quality of Life (PedsQL)

Secondary: Secondary outcome 7: Paediatric Quality of Life (PedsQL)

Secondary: Secondary outcome 8: Cost effectiveness

Secondary: Secondary outcome 8: Cost effectiveness

Secondary: Secondary efficacy outcome 9: Partial Remission

Secondary: Secondary efficacy outcome 9: Partial Remission

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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).