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Clinical Trial Results:
A phase II baseline versus treatment study to determine the efficacy of raltegravir (ISENTRESS) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI

Summary
EudraCT number	2012-004847-61
Trial protocol	GB
Global end of trial date	10 Jun 2015

Results information
Results version number	v1(current)
This version publication date	25 Jun 2016
First version publication date	25 Jun 2016
Other versions
Summary report(s)	INSPIRE end of study report

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

008717QM

ISRCTN number

US NCT number

NCT02104661

WHO universal trial number (UTN)

Sponsor organisation name

Queen Mary University of London

Sponsor organisation address

5 Walden Street, London, United Kingdom, E12EF

Public contact

Prof Gavin Giovannoni, Queen Mary University of London, +44 02078822579, g.giovannoni@qmul.ac.uk

Scientific contact

Prof Gavin Giovannoni, Queen Mary University of London, +44 02078822579, g.giovannoni@qmul.ac.uk

Sponsor organisation name

Queen Mary University of London

Sponsor organisation address

5 Walden Street, London, United Kingdom, E12EF

Public contact

Prof Gavin Giovannoni Neuroscience and Trauma Centre Blizard Institute 4 Newark St London E12AT, Queen Mary University of London Blizard Institute 4 Newark St London E12AT, +44 020 7882 8954, g.giovannoni@qmul.ac.uk

Scientific contact

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

12 Oct 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Sep 2014

Global end of trial reached?

Yes

Global end of trial date

10 Jun 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective is to assess whether treatment with raltegravir in patients with active MS has the effect of reducing the total number or rate of development of new or recurrent Gd-enhanced lesions on brain MRI over the period of treatment, compared to baseline.

Protection of trial subjects

All participants provided written informed consent before any study specific assessments were performed. Participants were given ample time for consideration before consenting to take part. Participants were made aware of their right to withdraw from the study at any time for any reason. The investigator also had the right to withdraw participants from the study. The total time on the study for enrolled participants was six months, which was considered to be an ethically acceptable timeframe for patients who are in the early stages of RRMS as this is the time limit before they meet Association of British Neurologists (ABN) criteria for currently licensed disease modifying treatment.

Background therapy

Not applicable

Evidence for comparator

Not applicable for this open label single arm study

Actual start date of recruitment

01 Feb 2013

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: 31

Worldwide total number of subjects

EEA total number of subjects

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)

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

All participants were recruited at the Clinical Research Centre of the Royal London Hospital and were drawn prevalently from the catchment area of greater London. Participants were also referred to the site by six Patient Identification Centres (PICs). Recruitment into the study started in May 2013. The last patient was screened in June 2014.

Screening details

A total of 31 participants were screened, of these 8 had no evidence of Gd enhancing lesions in their baseline MRI and were screen failed. Of the 23 participants who were recruited into the study 3 were withdrawn prior to starting the treatment phase; one at the request of the participant and the remaining two due to MS relapse.

Number of subjects started

Intermediate milestone: Number of subjects

Observation period: 23

Number of subjects completed

Reason: Number of subjects

No gd-enhancing lesions in MRI: 8

Reason: Number of subjects

MS relapse: 2

Reason: Number of subjects

Consent withdrawn by subject: 1

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Not applicable for this open label single arm trial.

Treatment

Arm description

Single arm open label

Arm type

Experimental

Investigational medicinal product name

Raltegravir

Investigational medicinal product code

Other name

Isentress

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

400mg twice a day administrated as the potassium salt in a film coated tablet

Number of subjects in period 1 ^[1]	Treatment
Started	20
Completed	20

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Of the 31 subjects screened, 20 received treatment.

Baseline characteristics

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Reporting group title

Treatment period

Reporting group description

Reporting group values	Treatment period	Total
Number of subjects	20	20
Age categorical
Patients eligible for the study were between 18-55 years of age. PP mean age baseline 41.62yrs (31.15-52.99); ITT mean age baseline 40.73yrs (31.15-52.99).
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	0	0
From 65-84 years	0	0
85 years and over	0	0
Adults (18-55 years)	20	20
Age continuous
PP Mean age baseline 41.62yrs (31.15-52.99) ITT Mean age baseline 40.73yrs (31.15-52.99)
Units: years
arithmetic mean (standard deviation)	40.73 ( 6.98 )	-
Gender categorical
PP 12 females (75%), 4 males (25%). ITT 14 females (70%), 6 males (30%).
Units: Subjects
Female	14	14
Male	6	6
Height
PP mean height 168.91cm (156.0-180.0) ITT mean height 169.04cm (156.0-183.0) There are only reported height values for n=18.
Units: cm
arithmetic mean (standard deviation)	( )	-
Weight
PP n=14; mean weight 77.9; (51.9-108.3) ITT n=18; mean weight 78.73; (51.9-109.7) Weight was not recorded for 2 subjects.
Units: Kg
arithmetic mean (standard deviation)	( )	-
Baseline EDSS
PP n=16; mean EDSS 2.25; (0.0-3.5) ITT n=20; mean EDSS 2.4; (0.0-4.0)
Units: score
arithmetic mean (standard deviation)	( )	-
Number of relapses in the past year
PP n= 16; mean 1.44; sd= 0.63 (1.0-3.0) ITT n= 20; mean 1.50; sd= 0.61 (0.0-4.0)
Units: number of relapses
arithmetic mean (standard deviation)	( )	-

Subject analysis set title

Per protocol

Subject analysis set type

Per protocol

Subject analysis set description

4 subjects were excluded from per protocol (PP) analysis due to concomitant medications (2 has steroids/immunosuppressants at screening and 2 had proton pump inhibitors during the study). PP 12 females (75%), 4 males (25%). Mean age baseline 41.62yrs (31.15-52.99); mean height 168.91cm (156.0-180.0); mean weight 77.9Kg (51.9-108.3); mean EDSS 2.25 (0.0-3.5); mean no. relapses past year 1.44 (1-3)

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

All 20 subjects who completed the study were includedin the ITT analysis. ITT 14 females (70%), 6 males (30%). Mean age baseline 40.73yrs (31.15-52.99); mean height 169.04cm (156.0-183.0); mean weight 78.73Kg (51.9-109.7); mean EDSS 2.4 (0.0-4.0); mean no. relapses past year 1.5 (1-3)

Subject analysis set title

Flexible per protocol

Subject analysis set type

Per protocol

Subject analysis set description

Flexible PP sample n=18. Two subjects were excluded for all visits, one subject had visits seven and eight excluded, and one subject had just visit eight excluded.

Subject analysis sets values	Per protocol	ITT	Flexible per protocol
Number of subjects	16	20	18
Age categorical
Patients eligible for the study were between 18-55 years of age. PP mean age baseline 41.62yrs (31.15-52.99); ITT mean age baseline 40.73yrs (31.15-52.99).
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)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Adults (18-55 years)	16	20	18
Age continuous
PP Mean age baseline 41.62yrs (31.15-52.99) ITT Mean age baseline 40.73yrs (31.15-52.99)
Units: years
arithmetic mean (standard deviation)	41.62 ( 7.49 )	40.73 ( 6.98 )	( )
Gender categorical
PP 12 females (75%), 4 males (25%). ITT 14 females (70%), 6 males (30%).
Units: Subjects
Female	12	14
Male	4	6
Height
PP mean height 168.91cm (156.0-180.0) ITT mean height 169.04cm (156.0-183.0) There are only reported height values for n=18.
Units: cm
arithmetic mean (standard deviation)	168.91 ( 8 )	169.04 ( 8.61 )	( )
Weight
PP n=14; mean weight 77.9; (51.9-108.3) ITT n=18; mean weight 78.73; (51.9-109.7) Weight was not recorded for 2 subjects.
Units: Kg
arithmetic mean (standard deviation)	77.9 ( 18.45 )	78.73 ( 19.04 )	( )
Baseline EDSS
PP n=16; mean EDSS 2.25; (0.0-3.5) ITT n=20; mean EDSS 2.4; (0.0-4.0)
Units: score
arithmetic mean (standard deviation)	2.25 ( 1 )	2.4 ( 1.03 )	( )
Number of relapses in the past year
PP n= 16; mean 1.44; sd= 0.63 (1.0-3.0) ITT n= 20; mean 1.50; sd= 0.61 (0.0-4.0)
Units: number of relapses
arithmetic mean (standard deviation)	1.44 ( 0.63 )	1.5 ( 0.61 )	( )

End points

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Reporting group title

Treatment

Reporting group description

Single arm open label

Subject analysis set title

Per protocol

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Flexible per protocol

Subject analysis set type

Per protocol

Subject analysis set description

Flexible PP sample n=18. Two subjects were excluded for all visits, one subject had visits seven and eight excluded, and one subject had just visit eight excluded.

Primary: Total T1 Gd-enhancing lesions in brain MRI scans

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End point title

Total T1 Gd-enhancing lesions in brain MRI scans

End point description

Within-patient average no. new Gd-enh lesions observed on serial T1-weighted brain MRI scans. Counts of new or recurrent Gd-enh lesions appearing on brain T1-weighted MRI. These counts are available at each of visits 2 to 8 in the majority of patients. ITT n=20 ‘flexible’ PP n=18. 2 patients were excluded for all visits, 1 patient had just visits 7 and 8 excluded, and 1 had visit 8 excluded. PP n=16, 4 patients had all their visits excluded. There were missing counts for 1patient at visit 3, 1 at visit 5, and missing counts for 2 at visit 6. Lesion outcomes provide no statistical evidence consistent with an effect of raltegravir. This is not because of lack of power: changes were not only non-significant statistically, but also generally clinically small (including both small reductions and small increases). For the most substantial change, a reduction in persisting T1 Gd lesions in the PP sample, the decrease before intervention was greater than that afterwards

End point type

Primary

End point timeframe

Visit two (enrolment) is excluded from analysis, which covers visits three, four and five "before-", and six, seven and eight "after-" medication was first dispensed.

End point values	Treatment	Per protocol	ITT	Flexible per protocol
Number of subjects analysed	20	16	20	18
Units: Number and ratio of lesions
arithmetic mean (full range (min-max))
Number of T1 gd-enhancing lesions before	8.65 (0 to 32)	7.5 (0 to 32)	8.65 (0 to 32)	7.28 (0 to 32)
Number of T1 Gd-enhancing lesions after	9.05 (0 to 31)	7 (0 to 31)	9.05 (0 to 31)	6.83 (0 to 31)
Number of T1 Gd-enh lesions within patient change	0.12 (-2.67 to 3.33)	-0.18 (-2.67 to 2.33)	0.12 (-2.67 to 3.33)	-0.16 (-2.67 to 2.33)
Ratio of T1 Gd-Enh lesions within patient change	0.88 (0.15 to 3.33)	0.81 (0.15 to 3.33)	0.88 (0.15 to 3.33)	0.83 (0.15 to 3.33)

Mixed effect Poisson regression model

Statistical analysis description

A mixed effect Poisson regression model with before/after indicator, adjusting for the (log) enrolment visit value

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.681 ^[2]

Method

Regression, Linear

Parameter type

Rate ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.29

Notes
[1] - The analyses compare the mean rate after vs before. The potential gradients of change over the three-month before vs after periods were also compared. For all three samples above there was no significant change in the after vs before gradients of monthly lesion accrual: P-values were respectively P=0.659, 0.429 and 0.463 for ITT, flexible PP and PP.
[2] - Est rate ratio after vs before: 1.04 (95% CI .85, 1.29); represents 4% non-significant incr lesions/month in after period, weighted ITT rate ratio 1.03 Simple non-parametric Wilcoxon sign rank test within-patient changes non-significant, P=0.646

Mixed effect Poisson regression model

Statistical analysis description

A mixed effect Poisson regression model with before/after indicator, adjusting for the (log) enrolment visit value

Comparison groups

Treatment v Flexible per protocol

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.714 ^[3]

Method

Regression, Linear

Parameter type

rate ratio

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.22

Notes
[3] - 5% non-significant decrease in rate. This is in close agreement with the summary weighted rate ratio of 0.92. The p-value from the simple non-parametric Wilcoxon sign rank test of changes is non-significant, P=0.183.

Mixed effect Poisson regression model

Statistical analysis description

A mixed effect Poisson regression model with before/after indicator, adjusting for the (log) enrolment visit value

Comparison groups

Treatment v Per protocol

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.577 ^[4]

Method

Regression, Linear

Parameter type

rate ratio

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.2

Notes
[4] - Non-significant 7% decrease. This is similar to the summary weighted rate ratio of 0.92. The p-value from the simple non-parametric Wilcoxon sign rank test of changes is also non-significant, P=0.197.

Primary: Persisting T1 Gd-enhancing brain MRI lesions

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End point title

Persisting T1 Gd-enhancing brain MRI lesions

End point description

End point type

Primary

End point timeframe

Visits 3, 4 and 5 (before) and 6, 7 and 8 (after medication was first dispensed).

End point values	Treatment	Per protocol	ITT
Number of subjects analysed	20	16	20
Units: Change in gradient of rate ratio
arithmetic mean (full range (min-max))
Monthy rate before	1.46 (0 to 7.67)	1.53 (0 to 7.67)	1.46 (0 to 7.67)
Monthly rate after	1.35 (0 to 5.67)	1.19 (0 to 5.67)	1.35 (0 to 5.67)
Within patient change in rate	-0.11 (-2 to 1.67)	-0.34 (-2 to 0.67)	-0.11 (-2 to 1.67)

Poisson regression

Statistical analysis description

A mixed effect Poisson regression model with before/after indicator.

Comparison groups

Treatment v Per protocol

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.16 ^[5]

Method

Regression, Linear

Parameter type

Slope

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

1.1

Notes
[5] - The rate ratio was estimated as 0.78 (95% CI:0.55, 1.10) P=0.160, a non-significant reduction. There was no significant change in gradient in the PP (0.762). In this PP sample the rate of reduction after was slightly lower than that before.

Poisson regression

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.652 ^[6]

Method

Regression, Linear

Parameter type

Slope

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.26

Notes
[6] - The rate ratio was estimated as 0.93 (95% CI .69, 1.26), P=0.652, a slight and non-significant reduction in persisting lesions.

Primary: New T1 Gd enhancing brain MRI lesions

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End point title

New T1 Gd enhancing brain MRI lesions

End point description

Rates in each 3-months period.

End point type

Primary

End point timeframe

Before (visits 3, 4, 5) vs After (visits 6, 7, 8).

End point values	Treatment	Per protocol	ITT
Number of subjects analysed	20	16	20
Units: Monthly rate of new lesions
arithmetic mean (full range (min-max))
Monthly rate before	1.46 (0 to 7.67)	1.53 (0 to 7.67)	1.46 (0 to 7.67)
Monthly rate after	1.35 (0 to 5.67)	1.19 (0 to 5.67)	1.35 (0 to 5.67)
Within patient change in monthly rate	-0.11 (-2 to 1.67)	-0.34 (-2 to 0.67)	-0.11 (-2 to 1.67)

Poisson regression model

Statistical analysis description

A mixed effect Poisson regression model with before/after indicator estimates the rate ratio after vs before as 1.16 (95% CI 0.87, 1.55), P=0.314; this represents a slight and non-significant increase in new lesions per month in the ‘after’ period. The above analyses compare the mean rate after vs before. The gradients of change over the three-month before vs after periods were also compared.

Comparison groups

Treatment v Per protocol

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.456

Method

Regression, Linear

Confidence interval

Notes
[7] - There was no significant change in the after vs before gradients of monthly lesion accrual in the PP (P=0.137).

Poisson regression model

Statistical analysis description

A mixed effect Poisson regression model with before/after indicator estimates the rate ratio after vs before as 1.16 (95% CI 0.87, 1.55), P=0.314; this represents a slight and non-significant increase in new lesions per month in the ‘after’ period. This analysis compares the mean rate after vs before. The gradients of change over the three-month before vs after periods were also compared.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.314 ^[8]

Method

Regression, Linear

Parameter type

Slope

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.55

Notes
[8] - There was no significant change in the after vs before gradients of monthly lesion accrual in the ITT (P=0.562) analysis.

Secondary: New or enlarging T2 weighted lesions on brain MRI

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End point title

New or enlarging T2 weighted lesions on brain MRI

End point description

For T2 lesions (where the only ‘after’ observation is visit 8, so no comparison is possible for the two ‘flexible PP’ patients), only ITT and PP are given. Within-patient ratios averaged on log scale before back transforming, substituting 0.1 for zero counts. Weighted mean ratios pooled on log scale by weighting for lesion counts.

End point type

Secondary

End point timeframe

Counts of new or enlarging T2-weighted lesions at visits five (before) and eight (after).

End point values	Treatment	Per protocol	ITT
Number of subjects analysed	20	16	20
Units: Number and ratio of lesions
arithmetic mean (full range (min-max))
Number of T2 lesions before	4.45 (0 to 17)	3.13 (0 to 9)	4.45 (0 to 17)
Number of T2 lesions after	4.65 (0 to 20)	3.31 (0 to 13)	4.65 (0 to 20)
Within patient T2 lesions count change	0.2 (-4 to 5)	0.19 (-4 to 5)	0.2 (-4 to 5)
Within patient T2 lesions count ratio	1.47 (0.2 to 10)	1.64 (0.2 to 10)	1.47 (0.2 to 10)

Wilcoxon sign rank test

Comparison groups

Treatment v Per protocol

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.462 ^[9]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[9] - Non-significant: Wilcoxon sign rank test of the within-patient changes was P= 0.462 for PP analysis.

Wilcoxon sign rank test

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.472 ^[10]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[10] - Non-significant: Wilcoxon sign rank test of the within-patient changes was P=0.472 for ITT analysis.

Secondary: Inflammatory markers

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End point title

Inflammatory markers

End point description

Statistical analysis performed on three inflammatory markers: Interleukin-8 (IL-8), or chemokine (C-X-C motif) ligand 8, CXCL8, is a chemokine produced by macrophages and other cell types. IL-8 secretion is increased by oxidant stress, which thereby cause the recruitment of inflammatory cells and induces a further increase in oxidant stress mediators, making it a key parameter in localized inflammation. Reported in pg/mL Unit. Serum CD163 (a soluble form of the receptor exists in plasma, commonly denoted sCD163. It is generated by ectodomain shedding of the membrane bound receptor. sCD163 is upregulated in a large range of inflammatory diseases). Reported in ng/mL Unit. Human C-reactive protein (HCRP), CRP is used mainly as a marker of inflammation. For HCRP, three measurements above the measureable threshold were assigned values of 10000 ng/ml. The largest measurable HCRP value in the dataset is 9492.25. Reported in ng/mL Unit.

End point type

Secondary

End point timeframe

Changes in mean at visits 3, 4, and 5 (before) and 6, 7, and 8 (after).

End point values	Treatment	ITT
Number of subjects analysed	20	20
Units: Changes in mean after - before
arithmetic mean (standard deviation)
IL-8	0.82 ( 2.12 )	0.82 ( 2.12 )
CD163	18.67 ( 38.18 )	18.67 ( 38.18 )
HCRP	535.82 ( 1244 )	535.82 ( 1244 )

IL-8 One sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1 ^[11]

Method

One sample t-test

Confidence interval

Notes
[11] - Non significant

IL-8 Mixed model

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.47 ^[12]

Method

Mixed models analysis

Confidence interval

Notes
[12] - Non significant

IL-8 Change in gradient

Statistical analysis description

Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.193 ^[13]

Method

Change in gradient

Confidence interval

Notes
[13] - Non significant

CD163 one sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.041 ^[14]

Method

One sample t-test

Confidence interval

Notes
[14] - Significant decline changes to a significant positive gradient. The gradient change is significant in both ITT and PP.

CD163 Mixed model

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.04 ^[15]

Method

Mixed models analysis

Confidence interval

Notes
[15] - Significant decline changes to a significant positive gradient. The gradient change is significant in both ITT and PP.

CD163 Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.018 ^[16]

Method

Change in gradient

Confidence interval

Notes
[16] - Significant.

HCRP one sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.069 ^[17]

Method

One sample t-test

Confidence interval

Notes
[17] - Significant overall increase not credibly attributable to intervention, since the gradient before, though non-significant, is too similar to the gradient after intervention.

HCRP Mixed model

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.04 ^[18]

Method

Mixed models analysis

Confidence interval

Notes
[18] - Significant overall increase not credibly attributable to intervention, since the gradient before, though non-significant, is too similar to the gradient after intervention

HCRP Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.944 ^[19]

Method

Change in gradient

Confidence interval

Notes
[19] - Non significant

Secondary: Retroviral activity

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End point title

Retroviral activity

End point description

To date, there has been no definitive evidence to link HERVs as the cause of immune-mediated disease; however, HERV elements have been found in sera of people with a range of diseases such as type 1 diabetes, rheumatoid arthritis and SLE but not in control populations. The evidence suggesting a postulated link between HERVs and MS has been accumulating. evidence is summarized to demonstrate that HERV-H and HERV-W are epidemiologically linked to patients with relapsing remitting MS. Further evidence was recently published by Perron et al. (4) that also links MS to a HERV which Perron calls multiple sclerosis associated retroviral element (MSRV). Raltegravir effect in relation to MS is not known, it may act by inhibiting HERVs, possibly in a similar mode of action that Raltegravir inhibits HIV replication.

End point type

Secondary

End point timeframe

Changes in mean after - before

End point values	Treatment	ITT
Number of subjects analysed	20	20 ^[20]
Units: Changes in mean after - before/ dim-less
arithmetic mean (standard deviation)
MSRV_a	-0.01 ( 0.06 )	-0.01 ( 0.06 )
MSRV_b	-0.01 ( 0.08 )	-0.01 ( 0.08 )
HERV_c	0 ( 0.09 )	0 ( 0.09 )
HERV_d	0 ( 0.07 )	0 ( 0.07 )
HERV_e	0.01 ( 0.09 )	0.01 ( 0.09 )
HERV_f	0.01 ( 0.04 )	0.01 ( 0.04 )
HERV_W_a	-0.05 ( 0.07 )	-0.05 ( 0.07 )
HERV_H_b	0.03 ( 0.13 )	0.03 ( 0.13 )
HERV_H_c	0.03 ( 0.1 )	0.03 ( 0.1 )
HERV_H_d	0.05 ( 0.14 )	0.05 ( 0.14 )
HERV_W_e	0 ( 0.09 )	0 ( 0.09 )
HERV_W_f	0.02 ( 0.19 )	0.02 ( 0.19 )
PROP_B_g	0.46 ( 1.37 )	0.46 ( 1.37 )
PROP_mon_h	-1.98 ( 4.31 )	-1.98 ( 4.31 )
HERV_W_i	-0.01 ( 0.06 )	-0.01 ( 0.06 )
HERV_H_j	0.12 ( 0.05 )	0.12 ( 0.05 )
HERV_H_k	0.03 ( 0.09 )	0.03 ( 0.09 )
HERV_H_l	0.02 ( 0.14 )	0.02 ( 0.14 )
HERV_W_m	-0.03 ( 0.06 )	-0.03 ( 0.06 )
HERV_W_n	0.04 ( 0.12 )	0.04 ( 0.12 )

Notes
[20] - HERV_W_a; HERV_W_m; HERV_W_n n=18 HERV_H_b; HERV_H_c; HERV_H_k n=17 HERV_W_i n=13 HERV_H_j n=15

One sample t-test MSRV_a

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.551 ^[21]

Method

One sample t-test

Confidence interval

Notes
[21] - Non significant.

One sample t-test MSRV_b

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.484 ^[22]

Method

One sample t-test

Confidence interval

Notes
[22] - Non significant.

One sample t-test HERV_c

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.835 ^[23]

Method

One sample t-test

Confidence interval

Notes
[23] - Non significant.

One sample t-test HERV_d

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.928

Method

One sample t-test

Confidence interval

One sample t-test HERV_e

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.563 ^[24]

Method

One sample t-test

Confidence interval

Notes
[24] - Non significant.

One sample t-test HERV_f

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.408 ^[25]

Method

One sample t-test

Confidence interval

Notes
[25] - Non significant.

One sample t-test HERV_W_a

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.012 ^[26]

Method

One sample t-test

Confidence interval

Notes
[26] - There is a significant drop in mean from before to after; however, there is a negative gradient of decline throughout the trial period. Therefore the after vs before drop cannot reasonably be attributed to the intervention.

One sample t-test HERV_H_b

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.372 ^[27]

Method

One sample t-test

Confidence interval

Notes
[27] - Non significant.

One sample t-test HERV_H_c

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.177 ^[28]

Method

One sample t-test

Confidence interval

Notes
[28] - Non significant.

One sample t-test HERV_H_d

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.113 ^[29]

Method

One sample t-test

Confidence interval

Notes
[29] - Non significant.

One sample t-test HERV_W_e

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.907 ^[30]

Method

One sample t-test

Confidence interval

Notes
[30] - Non significant.

One sample t-test HERV_W_f

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.632 ^[31]

Method

One sample t-test

Confidence interval

Notes
[31] - Non significant.

One sample t-test PROP_B_g

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.148 ^[32]

Method

One sample t-test

Confidence interval

Notes
[32] - Non significant.

One sample t-test PROP_mon_h

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.053

Method

One sample t-test

Confidence interval

One sample t-test HERV_W_i

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.561 ^[33]

Method

One sample t-test

Confidence interval

Notes
[33] - Non significant.

One sample t-test HERV_H_j

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.029 ^[34]

Method

One sample t-test

Confidence interval

Notes
[34] - Non significant.

One sample t-test HERV_H_k

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.266 ^[35]

Method

One sample t-test

Confidence interval

Notes
[35] - Non significant.

One sample t-test HERV_H_l

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.522 ^[36]

Method

One sample t-test

Confidence interval

Notes
[36] - Non significant.

One sample t-test HERV_W_m

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.035 ^[37]

Method

One sample t-test

Confidence interval

Notes
[37] - Non significant.

One sample t-test HERV_W_n

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.158 ^[38]

Method

One sample t-test

Confidence interval

Notes
[38] - Non significant.

Mixed model MSRV_a

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.364 ^[39]

Method

Mixed models analysis

Confidence interval

Notes
[39] - Non significant.

Mixed model MSRV_b

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.433 ^[40]

Method

Mixed models analysis

Confidence interval

Notes
[40] - Non significant.

Mixed model HERV_c

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.775 ^[41]

Method

Mixed models analysis

Confidence interval

Notes
[41] - Non significant.

Mixed model HERV_d

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.609 ^[42]

Method

Mixed models analysis

Confidence interval

Notes
[42] - Non significant.

Mixed model HERV_e

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.781 ^[43]

Method

Mixed models analysis

Confidence interval

Notes
[43] - Non significant.

Mixed model HERV_f

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.324 ^[44]

Method

Mixed models analysis

Confidence interval

Notes
[44] - Non significant.

Mixed model HERV_W_a

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.008

Method

Mixed models analysis

Confidence interval

Mixed model HERV_H_b

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.307 ^[45]

Method

Mixed models analysis

Confidence interval

Notes
[45] - Non significant.

Mixed model HERV_H_c

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.212 ^[46]

Method

Mixed models analysis

Confidence interval

Notes
[46] - Non significant.

Mixed model HERV_H_d

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.203 ^[47]

Method

Mixed models analysis

Confidence interval

Notes
[47] - Non significant.

Mixed model HERV_W_e

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.235 ^[48]

Method

Change in gradient

Confidence interval

Notes
[48] - Non significant.

Mixed model HERV_W_f

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.627 ^[49]

Method

Mixed models analysis

Confidence interval

Notes
[49] - Non significant.

Mixed model PROP_B_g

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.298 ^[50]

Method

Mixed models analysis

Confidence interval

Notes
[50] - Non significant.

Mixed model PROP_mon_h

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.16 ^[51]

Method

Mixed models analysis

Confidence interval

Notes
[51] - Non significant.

Mixed model HERV_W_i

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.93 ^[52]

Method

Mixed models analysis

Confidence interval

Notes
[52] - Non significant.

Mixed model HERV_H_j

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.008

Method

Mixed models analysis

Confidence interval

Mixed model HERV_H_k

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.642

Method

Mixed models analysis

Confidence interval

Mixed model HERV_H_l

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.807

Method

Mixed models analysis

Confidence interval

Mixed model HERV_W_m

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.005

Method

Mixed models analysis

Confidence interval

Mixed model HERV_W_n

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.259 ^[53]

Method

Mixed models analysis

Confidence interval

Notes
[53] - Non significant.

Change in gradient MSRV_a

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.488 ^[54]

Method

Change in gradient

Confidence interval

Notes
[54] - Non significant.

Change in gradient MSRV_b

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.691 ^[55]

Method

Change in gradient

Confidence interval

Notes
[55] - Non significant.

Change in gradient HERV_c

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.172 ^[56]

Method

Mixed models analysis

Confidence interval

Notes
[56] - Non significant.

Change in gradient HERV_d

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.802 ^[57]

Method

Change in gradient

Confidence interval

Notes
[57] - Non significant.

Change in gradient HERV_e

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.621 ^[58]

Method

Change in gradient

Confidence interval

Notes
[58] - Non significant.

Change in gradient HERV_f

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.533 ^[59]

Method

Change in gradient

Confidence interval

Notes
[59] - Non significant.

Change in gradient HERV_W_a

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.438 ^[60]

Method

Change in gradient

Confidence interval

Notes
[60] - Non significant.

Change in gradient HERV_H_b

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.012 ^[61]

Method

Mixed models analysis

Confidence interval

Notes
[61] - Gradient change significant P=0.012. Gradient before borderline significantly negative. After is significantly positive. Decline in values in period before intervention appears to change significantly after v 5 into an increase in values over time.

Change in gradient HERV_H_c

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.197 ^[62]

Method

Mixed models analysis

Confidence interval

Notes
[62] - Non significant.

Change in gradient HERV_H_d

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[63]

P-value

= 0.01 ^[64]

Method

Mixed models analysis

Confidence interval

Notes
[63] - The change in gradient is consistent with intervention effect. However, interpretation dependent on biological plausibility because of possibility of Type I error.
[64] - Borderline significant negative gradient before changes to significant positive after v 5. Decline in values appears to change significantly after intervention into increase in values over time.

Change in gradient HERV_W_e

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.008 ^[65]

Method

Change in gradient

Confidence interval

Notes
[65] - Significantly negative decline before visit 5 changes to a non-significant positive gradient after; the change in gradients is significant P=0.008.

Change in gradient HERV_W_f

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.195 ^[66]

Method

Change in gradient

Confidence interval

Notes
[66] - Non significant.

Change in gradient PROP_B_g

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.405 ^[67]

Method

Change in gradient

Confidence interval

Notes
[67] - Non significant.

Change in gradient PROP_mon_h

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.072 ^[68]

Method

Change in gradient

Confidence interval

Notes
[68] - Non-significant positive gradient changes to borderline significant negative gradient; change in gradient borderline significant consistent with intervention effect. Interpretation dependent on biological plausibility due to possibility Type 1 error

Change in gradient HERV_W_i

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.552 ^[69]

Method

Change in gradient

Confidence interval

Notes
[69] - Non-significant.

Change in gradient HERV_H_i

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.054 ^[70]

Method

Change in gradient

Confidence interval

Notes
[70] - A non-signifiant negative gradient before intervention changes to a significantly positive gradient after; the change is borderline signififcant P=0.054.

Change in gradient HERV_H_k

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.802 ^[71]

Method

Change in gradient

Confidence interval

Notes
[71] - Non-significant.

Change in gradient HERV_H_l

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.314 ^[72]

Method

Change in gradient

Confidence interval

Notes
[72] - Non-significant.

Change in gradient HERV_W_m

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.178 ^[73]

Method

Change in gradient

Confidence interval

Notes
[73] - Non-significant.

Change in gradient HERV_W_n

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.047 ^[74]

Method

Change in gradient

Confidence interval

Notes
[74] - Non-significant decline before visit 5 becomes a borderline significant increase after; the change in gradient is significant. Biological plausibility important, both for change displayed and for negative correlation with Gd T1 lesions.

Secondary: EDSS Clinical responses (disability data)

Top of page

End point title

EDSS Clinical responses (disability data)

End point description

Expanded Disability Status Scale score at screening between 0-6.0 inclusive for trial eligibility. Disability measures summaries at baseline, before and after.

End point type

Secondary

End point timeframe

EDSS performed at visits 1, 2, 4, 6 and 8. Summaries of disability measured at baseline, before and after.

End point values	Treatment	ITT
Number of subjects analysed	20	20
Units: Within patient change in means
arithmetic mean (standard deviation)
EDSS	0.14 ( 0.45 )	0.14 ( 0.45 )

One-sample t-test

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[75]

P-value

= 0.179

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[75] - One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Mixed model

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[76]

P-value

= 0.13

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[76] - Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Secondary: MSFC Clinical responses (disability data)

Top of page

End point title

MSFC Clinical responses (disability data)

End point description

MSFC (the standardly derived composite score from 9-hole peg test (9HPT), timed walk and PASAT scores); higher scores indicate less disability

End point type

Secondary

End point timeframe

Changes in mean after - before (treatment)

End point values	Treatment	ITT
Number of subjects analysed	20	20
Units: Changes in mean after - before
arithmetic mean (standard deviation)
MSFC	0.23 ( 0.28 )	0.23 ( 0.28 )

One-sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.002 ^[77]

Method

One sample t-test

Confidence interval

Notes
[77] - Both change and change in gradient significant.

Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[78]

Method

Mixed models analysis

Confidence interval

Notes
[78] - Both change and change in gradient significant.

Secondary: 9HPT speed Clinical responses (disability data)

Top of page

End point title

9HPT speed Clinical responses (disability data)

End point description

End point type

Secondary

End point timeframe

Changes in mean after - before

End point values	Treatment	ITT
Number of subjects analysed	20	20
Units: Changes in mean after - before
arithmetic mean (standard deviation)
9HPT	0.003 ( 0.003 )	0.003 ( 0.003 )

One sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[79]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[79] - Highly significant improvement. There are statistically significant improvements in the 9HPT, but the rate of improvement slowed after intervention. This is not consistent with an effect of intervention.

Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[80]

Method

Mixed models analysis

Confidence interval

Notes
[80] - There are statistically significant improvements in the 9HPT, but the rate of improvement slowed after intervention. This is not consistent with an effect of intervention.

Change in gradient

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.217 ^[81]

Method

Mixed models analysis

Confidence interval

Notes
[81] - No significant gradient change. Rate of improvement substantially greater before than after intervention

Secondary: 25 foot walk speed Clinical responses (disability data)

Top of page

End point title

25 foot walk speed Clinical responses (disability data)

End point description

End point type

Secondary

End point timeframe

Changes in mean after - before

End point values	Treatment	ITT
Number of subjects analysed	20	20
Units: Changes in mean after - before
arithmetic mean (standard deviation)
25' walk speed	-0.04 ( 0.47 )	-0.04 ( 0.47 )

One sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.738 ^[82]

Method

One sample t-test

Confidence interval

Notes
[82] - Non significant.

Mixed model analysis

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.669 ^[83]

Method

Mixed models analysis

Confidence interval

Notes
[83] - Non significant.

Change in gradient

Statistical analysis description

Change in gradient’: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.908 ^[84]

Method

change in gradient

Confidence interval

Notes
[84] - Non significant

Secondary: PASAT Clinical responses (disability data)

Top of page

End point title

PASAT Clinical responses (disability data)

End point description

End point type

Secondary

End point timeframe

Changes in mean after - before

End point values	Treatment	ITT
Number of subjects analysed	20	20
Units: Changes in mean after - before
arithmetic mean (standard deviation)
PASAT	4.66 ( 5.21 )	4.66 ( 5.21 )

One sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.001 ^[85]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[85] - Highly significant improvement, but rate of improvement substantially greater before than after intervention

Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[86]

Method

Mixed models analysis

Confidence interval

Notes
[86] - Highly significant improvement, but rate of improvement substantially greater before than after intervention.

Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.004 ^[87]

Method

Change in gradient

Parameter type

Slope

Confidence interval

sides

2-sided

lower limit

upper limit

Notes
[87] - There is a significant gradient change, but rate of improvement substantially greater before than after intervention

Secondary: Quality of life measures

Top of page

End point title

Quality of life measures

End point description

Quality of life measures: patient reported outcomes (PROs) including 3 questionnaires: Health Status Questionnaire (SF-36), Multiple Sclerosis Impact Scale (MSIS-29), Multiple Sclerosis Walking Scale (MSWS-12) and 2 Visual Analogue Scales (VAS): Patient Fatigue Assessment (PFA) and Patient Pain Assessment (PPA). The SF-36 generates 8 subscale scores for Physical Functional Scale (PF), Role-Physical Scale (RP), Bodily Pain Scale (BP), General Health scale (GH), Vitality Scale (VT), Social Functioning Scale (SF), Role Emotional Scale (RE) and Mental Health Scale (MH). Higher scores indicate better health/quality of life on all eight SF-36 measures, and worse health/quality of life on the last four measures.

End point type

Secondary

End point timeframe

Quality of life measures baseline, before and after summeries. Patient reported outcomes completed at visits 2 (baseline), 3, 4 and 5 (before) and 6, 7 and 8 (after).

End point values	Treatment	ITT
Number of subjects analysed	20	20
Units: Change after - before
arithmetic mean (standard deviation)
SF36 PF Before	72.63 ( 23.37 )	72.63 ( 23.37 )
Sf36 PF After	71.71 ( 26.04 )	71.71 ( 26.04 )
SF36 RP Before	59.06 ( 39.66 )	59.06 ( 39.66 )
Sf36 RP After	49.58 ( 38.47 )	49.58 ( 38.47 )
Sf36 BP Before	72.22 ( 19.59 )	72.22 ( 19.59 )
SF36 BP After	66.8 ( 22.63 )	66.8 ( 22.63 )
SF36 GH Before	50.86 ( 15.02 )	50.86 ( 15.02 )
SF36 GH After	46.18 ( 16.86 )	46.18 ( 16.86 )
SF36 VT Before	42.98 ( 21.53 )	42.98 ( 21.53 )
SF36 VT After	48.04 ( 22.21 )	48.04 ( 22.21 )
SF36 Sf After	77.92 ( 16.06 )	77.92 ( 16.06 )
SF36 RE Before	71.92 ( 33.39 )	71.92 ( 33.39 )
SF36 RE After	63.3 ( 38.35 )	63.3 ( 38.35 )
SF36 MH Before	65.85 ( 12.77 )	65.85 ( 12.77 )
SF36 MH After	71.57 ( 11.05 )	71.57 ( 11.05 )
PFA Before	40.02 ( 24.36 )	40.02 ( 24.36 )
PFA After	38.51 ( 26.35 )	38.51 ( 26.35 )
PPA Before	22.8 ( 19.46 )	22.8 ( 19.46 )
PPA After	27.96 ( 21.46 )	27.96 ( 21.46 )
MSIS Before	52.16 ( 17.4 )	52.16 ( 17.4 )
MSIS After	50.06 ( 13.95 )	50.06 ( 13.95 )
MSWS-12 Before	20.87 ( 9.61 )	20.87 ( 9.61 )
MSWS-12 After	20.52 ( 9.76 )	20.52 ( 9.76 )

SF36 PF One sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.713 ^[88]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[88] - Non significant

SF36 PF Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.685 ^[89]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[89] - Non significant

SF36 PF Change in gradient

Statistical analysis description

Change in gradient: this uses the linear mixed model, using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[90]

P-value

= 0.063 ^[91]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[90] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[91] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 RP One sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.198 ^[92]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[92] - Non significant.

SF36 RP Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[93]

P-value

= 0.034 ^[94]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[93] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[94] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 RP Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.873 ^[95]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[95] - Non significant.

SF36 BP One sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.14 ^[96]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[96] - Non significant

SF36 BP Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[97]

P-value

= 0.024 ^[98]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[97] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[98] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 BP Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[99]

P-value

= 0.026 ^[100]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[99] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[100] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 GH One sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[101]

P-value

= 0.019 ^[102]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[101] - Because of the subjective nature of these measures compared to the disability data, they are susceptible to placebo effects, in particular, a positive response both to being in a trial and to receiving an unblinded intervention. Therefore, an improvement, in the period after intervention, though consistent with an effect of the drug administered at intervention, cannot credibly be attributed to the drug.
[102] - Significant improvements in well-being/slowing of deterioration after compared to before intervention. Although consistent with effect of raltegravir, this is most credibly attributable to placebo effect of patients receiving unblinded intervention.

SF36 GH Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[103]

P-value

= 0.001 ^[104]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[103] - Because of the subjective nature of these measures compared to the disability data, they are susceptible to placebo effects, in particular, a positive response both to being in a trial and to receiving an unblinded intervention. Therefore, an improvement, in the period after intervention, though consistent with an effect of the drug administered at intervention, cannot credibly be attributed to the drug.
[104] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 GH Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[105]

P-value

= 0.022 ^[106]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[105] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[106] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 VT One sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.14 ^[107]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[107] - Non significant.

SF36 VT Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[108]

P-value

= 0.011 ^[109]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[108] - Because of the subjective nature of these measures compared to the disability data, they are susceptible to placebo effects, in particular, a positive response both to being in a trial and to receiving an unblinded intervention. Therefore, an improvement, in the period after intervention, though consistent with an effect of the drug administered at intervention, cannot credibly be attributed to the drug.
[109] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 VT Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[110]

P-value

= 0.004 ^[111]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[110] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[111] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 SF One sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.567 ^[112]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[112] - Non significant.

SF36 SF Mixed model

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.414 ^[113]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[113] - Non significant.

SF36 SF Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[114]

P-value

= 0.039 ^[115]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[114] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[115] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

SF36 RE One sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.252 ^[116]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[116] - Non significant.

SF36 RE Mixed model

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.096 ^[117]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[117] - Non significant.

SF36 RE Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.768 ^[118]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[118] - Non significant.

PFA One sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.665 ^[119]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[119] - Non significant.

PFA Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.683 ^[120]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[120] - Non significant.

PFA Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[121]

P-value

= 0.057 ^[122]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[121] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[122] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

PPA One sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.17 ^[123]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[123] - Non significant.

PPA Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.144 ^[124]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[124] - Non significant.

PPA Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[125]

P-value

= 0.01 ^[126]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[125] - Because of subjective nature these measures are susceptible to placebo effects, in particular, a positive response to being in a trial and receiving an unblinded intervention. Improvement after intervention cannot credibly be attibuted to the drug.
[126] - Statistically significant improvements in the period after compared to before intervention. Although consistent with an effect of raltegravir, this is most credibly attributable to the placebo effect of patients receiving an unblinded intervention.

MSIS One sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.477 ^[127]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[127] - Non significant.

MSIS Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.22 ^[128]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[128] - Non significant.

MSIS Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.196 ^[129]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[129] - Non significant.

MSWS One sample t-test

Statistical analysis description

One-sample t-test’: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.817 ^[130]

Method

One sample t-test

Parameter type

Mean difference (net)

Confidence interval

Notes
[130] - Non significant.

MSWS Mixed model

Statistical analysis description

Mixed model’: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.772 ^[131]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Confidence interval

Notes
[131] - Non significant.

MSWS Change in gradient

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.12 ^[132]

Method

Change in gradient

Parameter type

Slope

Confidence interval

Notes
[132] - Non significant.

Secondary: EBV copy number in saliva

Top of page

End point title

EBV copy number in saliva

End point description

Epstein–Barr virus (EBV), also called human herpesvirus 4 (HHV-4), infection is associated with with a higher risk of certain autoimmune diseases, such as Multiple Sclerosis. In particular, people who have had glandular fever, the symptomatic EBV infection , have a higher risk to develop MS. EBV may be found in the saliva of someone who has had glandular fever for several months after their symptoms pass, and most people may continue to have the virus in their saliva on and off for years. Studies of dynamics of virus shedding in healthy carriers demonstrate that EBV shedding into saliva is constant.

End point type

Secondary

End point timeframe

Changes in mean after - before.

End point values	Treatment	ITT
Number of subjects analysed	20	13
Units: Copies/microlitre
arithmetic mean (standard deviation)
EBV	-16.3 ( 46.02 )	-16.3 ( 46.02 )

EBV one sample t-test

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.226 ^[133]

Method

One sample t-test

Confidence interval

Notes
[133] - Non significant.

EBV Mixed model

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 2 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.616 ^[134]

Method

Mixed models analysis

Confidence interval

Notes
[134] - Non significant.

EBV change in gradient

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[135]

P-value

= 0.219 ^[136]

Method

Change in gradient

Confidence interval

Notes
[135] - Change in gradient: this uses the linear mixed model, again using all of a patient’s measurements over the seven visits, to determine if the gradient of change after is significantly different from the gradient of change before. Note that the p-value refers to the change in gradients, not to either of the two gradients, which may or may not be significant (ie significantly different from zero).
[136] - Non significant.

Secondary: Laboratory safety data

Top of page

End point title

Laboratory safety data

End point description

Laboratory safety outcomes. Assessments collected at screening were used to determe study eligibility only. Safety assessments were collected at all visits. Severity of abnormal results was evaluated by the investigator as mild, moderate or severe. Lab findings which the investigator felt were clinically significant based on the Laboratory Guidelines were recorded as adverse events. The relationship of the adverse event to the administration of the study drug was also determined by the investigator.

End point type

Secondary

End point timeframe

Changes in after - before (treatment).

End point values	Treatment	ITT
Number of subjects analysed	20	20
Units: After - before changes in mean
arithmetic mean (standard deviation)
Adjusted calcium serum	0.02 ( 0.05 )	0.02 ( 0.05 )
ALT	1.12 ( 8.75 )	1.12 ( 8.75 )
AST	1.24 ( 4.83 )	1.24 ( 4.83 )
Basophil count	0 ( 0.02 )	0 ( 0.02 )
Chloride serum	-0.75 ( 1.65 )	-0.75 ( 1.65 )
Cholesterol HDL ratio serum	0.04 ( 0.21 )	0.04 ( 0.21 )
Cholesterol serum	0.28 ( 0.38 )	0.28 ( 0.38 )
Creatinine serum	2.08 ( 5.91 )	2.08 ( 5.91 )
Eosinophil count	0 ( 0.06 )	0 ( 0.06 )
Estimated GFR	-3 ( 9.77 )	-3 ( 9.77 )
GGT	-0.5 ( 8.18 )	-0.5 ( 8.18 )
Glucose plasma	-0.18 ( 0.47 )	-0.18 ( 0.47 )
Haemoglobin	-0.13 ( 0.56 )	-0.13 ( 0.56 )
HDL cholesterol serum	0.05 ( 0.16 )	0.05 ( 0.16 )
LDL Cholesterol serum	0.17 ( 0.32 )	0.17 ( 0.32 )
Lymphocyte count	0.05 ( 0.31 )	0.05 ( 0.31 )
Monocyte count	0 ( 0.11 )	0 ( 0.11 )
Neutrophil count	0.15 ( 0.61 )	0.15 ( 0.61 )
Platelet count	6.86 ( 13.92 )	6.86 ( 13.92 )
Potassium serum	0.05 ( 0.15 )	0.05 ( 0.15 )
Sodium serum	0.14 ( 1.57 )	0.14 ( 1.57 )
Total bilirubin serum	0.18 ( 1.5 )	0.18 ( 1.5 )
Triglicerides serum	0.08 ( 0.29 )	0.08 ( 0.29 )
Urea serum	0.24 ( 0.78 )	0.24 ( 0.78 )
White blood count	0.22 ( 0.71 )	0.22 ( 0.71 )

One sample t-test Adjusted Calcium serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.025 ^[137]

Method

One sample t-test

Confidence interval

Notes
[137] - There was a significant increase after vs before, 0.02 (P=0.025). However, there was no significant change in gradient P=0.406

One sample t-test ALT

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.575 ^[138]

Method

One sample t-test

Confidence interval

Notes
[138] - Non significant.

One sample t-test AST

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.266 ^[139]

Method

One sample t-test

Confidence interval

Notes
[139] - Non significant.

One sample t-test basophil count

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.883 ^[140]

Method

One sample t-test

Confidence interval

Notes
[140] - Non significant.

One sample t-test chloride serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.055 ^[141]

Method

One sample t-test

Confidence interval

Notes
[141] - Borderline significant drop, -0.75 (P=0.055). However, there was no significant change in gradient, P=0.194.

One sample t-test Cholesterol HDL ratio serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.369 ^[142]

Method

One sample t-test

Confidence interval

Notes
[142] - Non significant.

One sample t-test Cholesterol serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.004 ^[143]

Method

One sample t-test

Confidence interval

Notes
[143] - There was a significant increase P=0.004. However, there was no significant change in gradient P=0.437. Faster increase before than after.

One sample t-test Creatinine serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.132 ^[144]

Method

One sample t-test

Confidence interval

Notes
[144] - Non significant.

One sample t-test Eosinophil count

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.855 ^[145]

Method

One sample t-test

Confidence interval

Notes
[145] - Non significant.

One sample t-test Estimated GFR

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.186 ^[146]

Method

One sample t-test

Confidence interval

Notes
[146] - Non significant.

One sample t-test GGT

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.789 ^[147]

Method

One sample t-test

Confidence interval

Notes
[147] - Non significant.

One sample t-test Glucose plasma

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.108 ^[148]

Method

One sample t-test

Confidence interval

Notes
[148] - Non significant.

One sample t-test Haemoglobin

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.308 ^[149]

Method

One sample t-test

Confidence interval

Notes
[149] - Non significant.

One sample t-test HDL Cholesterol serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.174 ^[150]

Method

One sample t-test

Confidence interval

Notes
[150] - Non significant.

One sample t-test LDL Cholesterol serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.027 ^[151]

Method

One sample t-test

Confidence interval

Notes
[151] - There was a significant increase, but no significant change in gradient P=0.432.

One sample t-test Lymphocyte count

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.465 ^[152]

Method

One sample t-test

Confidence interval

Notes
[152] - Non significant.

One sample t-test Monocyte count

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.958 ^[153]

Method

One sample t-test

Confidence interval

Notes
[153] - Non significant.

One sample t-test Neutrophil count

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.291 ^[154]

Method

One sample t-test

Confidence interval

Notes
[154] - Non significant.

One sample t-test Platelet count

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.04 ^[155]

Method

One sample t-test

Confidence interval

Notes
[155] - There was asignificant increase P=0.040. However, there was no significant change in gradient P=0.352.

One sample t-test Potassium serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.161 ^[156]

Method

One sample t-test

Confidence interval

Notes
[156] - There was asignificant increase P=0.040. However, there was no significant change in gradient P=0.352.

One sample t-test Sodium serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.692 ^[157]

Method

One sample t-test

Confidence interval

Notes
[157] - Non significant.

One sample t-test Total bilirubin serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.591 ^[158]

Method

One sample t-test

Confidence interval

Notes
[158] - Non significant.

One sample t-test Triglicerides serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.225 ^[159]

Method

One sample t-test

Confidence interval

Notes
[159] - Non significant.

One sample t-test Urea serum

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.183 ^[160]

Method

One sample t-test

Confidence interval

Notes
[160] - Non significant.

One sample t-test White blood count

Statistical analysis description

One-sample t-test: this uses one datapoint per patient, the within-patient change in means, testing whether the mean of these changes is significant.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.184 ^[161]

Method

One sample t-test

Confidence interval

Notes
[161] - Non significant.

Mixed model Adjusted calcium serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.027 ^[162]

Method

Mixed models analysis

Confidence interval

Notes
[162] - There was a significant increase after vs before. However, there was no significant change in gradient.

Mixed model ALT

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.643 ^[163]

Method

Mixed models analysis

Confidence interval

Notes
[163] - Non significant.

Mixed model AST

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.265 ^[164]

Method

Mixed models analysis

Confidence interval

Notes
[164] - Non significant.

Mixed model Basophil count

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.954 ^[165]

Method

Mixed models analysis

Confidence interval

Notes
[165] - Non significant.

Mixed model Chloride serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.032 ^[166]

Method

Mixed models analysis

Confidence interval

Notes
[166] - Borderline significant drop. However, there was no significant change in gradient

Mixed model Cholesterol HDL ratio serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.441 ^[167]

Method

Mixed models analysis

Confidence interval

Notes
[167] - Borderline significant drop.

Mixed model Cholesterol serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0 ^[168]

Method

Mixed models analysis

Confidence interval

Notes
[168] - There was a significant increase. However, there was no significant change in gradient.

Mixed model Creatinine serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.097 ^[169]

Method

Mixed models analysis

Confidence interval

Notes
[169] - Non significant.

Mixed model Eosinophil count

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.711 ^[170]

Method

Mixed models analysis

Confidence interval

Notes
[170] - Non significant.

Mixed model Estimated GFR

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.153 ^[171]

Method

Mixed models analysis

Confidence interval

Notes
[171] - Non significant.

Mixed model GGT

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.794 ^[172]

Method

Mixed models analysis

Confidence interval

Notes
[172] - Non significant.

Mixed model Glucose Plasma

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.196 ^[173]

Method

Mixed models analysis

Confidence interval

Notes
[173] - Non significant.

Mixed model Haemoglobin

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.168 ^[174]

Method

Mixed models analysis

Confidence interval

Notes
[174] - Non significant.

Mixed model HDL cholesterol serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.101 ^[175]

Method

Mixed models analysis

Confidence interval

Notes
[175] - Non significant.

Mixed model LDL cholesterol serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.018 ^[176]

Method

Mixed models analysis

Confidence interval

Notes
[176] - There was a significant increase. However, there was no significant change in gradient.

Mixed model Lymphocyte count

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.304 ^[177]

Method

Mixed models analysis

Confidence interval

Notes
[177] - Non significant.

Mixed model Monocyte count

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.789 ^[178]

Method

Mixed models analysis

Confidence interval

Notes
[178] - Non significant.

Mixed model Neutrophil count

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.244 ^[179]

Method

Mixed models analysis

Confidence interval

Notes
[179] - Non significant.

Mixed model Platelet count

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.013 ^[180]

Method

Mixed models analysis

Confidence interval

Notes
[180] - There was a significant increase. However, there was no significant change in gradient.

Mixed model Potassium serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.143 ^[181]

Method

Mixed models analysis

Confidence interval

Notes
[181] - Non significant.

Mixed model Sodium serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.732 ^[182]

Method

Mixed models analysis

Confidence interval

Notes
[182] - Non significant.

Mixed model Total bilirubin serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.57 ^[183]

Method

Mixed models analysis

Confidence interval

Notes
[183] - Non significant.

Mixed model Triglicerides serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.133 ^[184]

Method

Mixed models analysis

Confidence interval

Notes
[184] - Non significant.

Mixed model Urea serum

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.107 ^[185]

Method

Mixed models analysis

Confidence interval

Notes
[185] - Non significant.

Mixed model White blood count

Statistical analysis description

Mixed model: this compares the change in means in a potentially more powerful analysis using a linear mixed model which uses all of a patient’s values, from visit 1 to visit 8.

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.154 ^[186]

Method

Mixed models analysis

Confidence interval

Notes
[186] - Non significant.

Change in gradient Adjusted calcium serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[187]

P-value

= 0.406 ^[188]

Method

Change in gradient

Confidence interval

Notes
[187] - Gradients reported are estimated rates of change in test units per month.
[188] - No significant chnge gradient SE z P-value 95% Conf. Int before -.0000267 .005385 -0.00 0.996 -.0105811 .0105277 after .0077586 .0053828 1.44 0.149 -.0027916 .0183087

Change in gradient ALT

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[189]

P-value

= 0.179 ^[190]

Method

Change in gradient

Confidence interval

Notes
[189] - Gradients reported are estimated rates of change in test units per month
[190] - No signif change gradient SE z P-value 95% Conf. Int before -.0000267 .005385 -0.00 0.996 -.0105811 .0105277 after .0077586 .0053828 1.44 0.149 -.0027916 0183087

Change in gradient AST

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.385 ^[191]

Method

Change in gradient

Confidence interval

Notes
[191] - Non significant.

Change in gradient Basophil count

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.779 ^[192]

Method

Change in gradient

Confidence interval

Notes
[192] - Non significant.

Change in gradient Chloride serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.194 ^[193]

Method

Change in gradient

Confidence interval

Notes
[193] - No signif change gradient SE z P-value 95% Conf. Int before .1363255 .2036459 0.67 0.503 -.2628131 .5354641 after -.3119152 .1915487 -1.63 0.103 -.6873437 .0635134

Change in gradient Chlolesterol HDL ratio serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.928 ^[194]

Method

Change in gradient

Confidence interval

Notes
[194] - Non significant.

Change in gradient Chlolesterol serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[195]

P-value

= 0.437 ^[196]

Method

Change in gradient

Confidence interval

Notes
[195] - Gradients reported are estimated rates of change in test units per month.
[196] - No signif change gradient SE z P-value 95% Conf. Int before .0826927 .043773 1.89 0.059 -.0031008 .1684862 after .0258226 .040227 0.64 0.521 -.0530208 .1046661

Change in gradient Creatinine serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[197]

P-value

= 0.769 ^[198]

Method

Change in gradient

Confidence interval

Notes
[197] - Gradients reported are estimated rates of change in test units per month.
[198] - There was no significant change in gradient.

Change in gradient Eosinophil count

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.768 ^[199]

Method

Change in gradient

Confidence interval

Notes
[199] - There was no significant change in gradient.

Change in gradient Estimated GFR

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.874 ^[200]

Method

Change in gradient

Confidence interval

Notes
[200] - There was no significant change in gradient.

Change in gradient Estimated GGT

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.345 ^[201]

Method

Change in gradient

Confidence interval

Notes
[201] - There was no significant change in gradient.

Change in gradient Estimated Glucose plasma

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.072 ^[202]

Method

Change in gradient

Confidence interval

Notes
[202] - There was a borderline significant gradient change P=0.072, from a non-significant increase before to a significant decline after.

Change in gradient Haemoglobin

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.558 ^[203]

Method

Change in gradient

Confidence interval

Notes
[203] - There was no significant change in gradient.

Change in gradient HDL Cholesterol serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.843 ^[204]

Method

Change in gradient

Confidence interval

Notes
[204] - There was no significant change in gradient.

Change in gradient LDL Cholesterol serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.432 ^[205]

Method

Change in gradient

Confidence interval

Notes
[205] - There was no significant change in gradient.

Change in gradient Lymphocyte count

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.775 ^[206]

Method

Change in gradient

Confidence interval

Notes
[206] - There was no significant change in gradient.

Change in gradient Monocyte count

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.089 ^[207]

Method

Change in gradient

Confidence interval

Notes
[207] - There was no significant change in gradient.

Change in gradient Neutrophil count

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.899 ^[208]

Method

Change in gradient

Confidence interval

Notes
[208] - There was no significant change in gradient.

Change in gradient Platelet count

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[209]

P-value

= 0.352 ^[210]

Method

Change in gradient

Confidence interval

Notes
[209] - Gradients reported are estimated rates of change in test units per month.
[210] - No signif change gradient SE z P-value 95% Conf. Int before -.274596 1.820794 -0.15 0.880 -3.843288 3.294096 after 2.592704 1.709353 1.52 0.129 -.7575659 5.942974

Change in gradient Potassium serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.221 ^[211]

Method

Change in gradient

Confidence interval

Notes
[211] - There was no significant change in gradient

Change in gradient Sodium serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.445 ^[212]

Method

Change in gradient

Confidence interval

Notes
[212] - There was no significant change in gradient

Change in gradient total bilirubin serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.123 ^[213]

Method

Change in gradient

Confidence interval

Notes
[213] - There was no significant change in gradient

Change in gradient Triglicerides serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.767 ^[214]

Method

Change in gradient

Confidence interval

Notes
[214] - There was no significant change in gradient

Change in gradient Urea serum

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.197 ^[215]

Method

Change in gradient

Confidence interval

Notes
[215] - There was no significant change in gradient

Change in gradient White blood count

Statistical analysis description

Comparison groups

Treatment v ITT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.674 ^[216]

Method

Change in gradient

Confidence interval

Notes
[216] - There was no significant change in gradient

Secondary: Adverse events

Top of page

End point title

Adverse events

End point description

End point type

Secondary

End point timeframe

After - before (treatment) changes

End point values	Treatment	Per protocol	ITT
Number of subjects analysed	20	16	20
Units: Number of visits with adverse events
arithmetic mean (standard deviation)
Number of visits with AEs before intervention	2.35 ( 0.75 )	2.31 ( 0.79 )	2.35 ( 0.75 )
Number of visits with AEs after intervention	2.3 ( 0.73 )	2.31 ( 0.79 )	2.3 ( 0.73 )
Adverse events	-0.05 ( 1.28 )	0 ( 1.37 )	-0.05 ( 1.28 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Reporting of adverse events from screening

Adverse event reporting additional description

Adverse events were recorded for all subjects screened (n=31) and include events for patients who did not receive IMP.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Non-serious adverse events

Reporting group description

Adverse events were recorded from screening (n=31) and include subjects who did not receive IMP.

Serious adverse events	Non-serious adverse events
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 20 (5.00%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Nervous system disorders
MS relapse
Additional description: MS relapse which required hospitalisation for administration of IV methylprednisolone. Normal practise would not have been to admit to hospital. However the patient had no care at home and could not care for self at home.
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Non-serious adverse events
Total subjects affected by non serious adverse events
subjects affected / exposed	20 / 20 (100.00%)
General disorders and administration site conditions
Headache
subjects affected / exposed	10 / 20 (50.00%)
occurrences all number	12
Liver function test abnormal
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Liver function test increased
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Dizziness
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Fall
subjects affected / exposed	5 / 20 (25.00%)
occurrences all number	5
Insomnia
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
poor sleep
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Nausea
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Swelling in left arm
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Stomach pain
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Loss of libido
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Pyrexia
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Dysphonia
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Problems concentrating
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Stiff neck
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Fainting
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Vivid dreams
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Tiredness
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Night sweats
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Dry mouth
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Weight loss diet
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Lack of motivation
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Low blood pressure asymptomatic
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Chest pain
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Choking on liquids
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Flushing to face
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Strange sensation when swallowing
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Swelling in fingers
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Swelling feeling in fingers
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Immune system disorders
Adenopathies
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Itchy eyes
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Allergic skin rash worsening
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Hayfever congestion
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Hayfever worsening
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Reproductive system and breast disorders
Menopause onset
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Erectile dysfunction
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Pelvic mass
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Wheeze
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Psychiatric disorders
Depression
subjects affected / exposed	4 / 20 (20.00%)
occurrences all number	4
Depression worsening
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Low mood
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Anxiety
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Panic attack increased
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Emotional instability
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Injury, poisoning and procedural complications
Haematoma
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Bruised knee (due to fall)
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Broken toenail
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Cut knee
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Twisted knee
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Hurt wrist
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Cardiac disorders
Hypertension
subjects affected / exposed	4 / 20 (20.00%)
occurrences all number	7
Tachycardia
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	2
Hypertension worsening
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Arrhythmia
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Nervous system disorders
Multiple sclerosis relapse
alternative assessment type: Non-systematic
subjects affected / exposed	9 / 20 (45.00%)
occurrences all number	9
Multiple sclerosis sensory relapse
alternative assessment type: Non-systematic
subjects affected / exposed	5 / 20 (25.00%)
occurrences all number	6
Sensory disturbance
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Fatigue
subjects affected / exposed	4 / 20 (20.00%)
occurrences all number	4
Fatigue increased
subjects affected / exposed	4 / 20 (20.00%)
occurrences all number	4
Migraine
subjects affected / exposed	4 / 20 (20.00%)
occurrences all number	4
Dysaesthesia worsening
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Nystagmus
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Neuropathic pain
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Tremor in hands
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Numbness - loss of sensation
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Tremor in arm worsened
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Subjective worsening of leg weakness
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Neurological signs worsening
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Back pain (burning sensation)
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Blood and lymphatic system disorders
Dyslipidemia
subjects affected / exposed	10 / 20 (50.00%)
occurrences all number	17
Mycrocytic Anemia
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Hypoglycaemia
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Normocytic anaemia
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Eye disorders
Visual fatigue
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Decreased vision
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Stye
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Gastrointestinal disorders
Gastroenteritis
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Defective gastro-ileal valve
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Bloated abdomen (during antibiotics)
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Skin and subcutaneous tissue disorders
Itching
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	3
Eczema
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Fungal infection
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Fungal infection worsening
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Dry skin
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Petechial purpura
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Naevus
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Scar from mole removal
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Rash on face
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Mole on toe
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Allergic rash worsening
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Renal and urinary disorders
Bladder dysfunction
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	4
Dysuria
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Bladder problems worsening
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Musculoskeletal and connective tissue disorders
Pain
subjects affected / exposed	14 / 20 (70.00%)
occurrences all number	17
Pain worsening
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Carpal tunnel syndrome
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Cramps in legs
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Infections and infestations
Common cold
subjects affected / exposed	14 / 20 (70.00%)
occurrences all number	21
Urinary tract infection
subjects affected / exposed	6 / 20 (30.00%)
occurrences all number	8
Sore throat
subjects affected / exposed	5 / 20 (25.00%)
occurrences all number	5
Cough
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Sinusitis
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Tooth infection
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Chest infection
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Upper respiratory tract infection
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

23 May 2013

Approved documents: • Protocol Version 5.0 • PIS/ICF Version 6.0 • Questionnaires Version 2.0 • Website Advertising Text Version 1.0 • Additional IMP Label 1. Updates to Patient Questionnaires The following questionnaires remain in the study and patients will be asked to complete these at visits 2-8. 1. Health Status Questionnaire (SF-36) 2. Multiple Sclerosis Impact Scale (MSIS-29) 3. Multiple Sclerosis Walking Scale (MSWS-12v2) The following assessments replace patient assessments of pain and fatigue. 1. Patient Fatigue Assessment – Visual Analogue Scale 2. Patient Pain Assessment – Visual Analogue Scale 2. Reduction of EDSS Frequency Frequency of EDSS assessments was reduced (every 2 months)as it was deemed unnecessary by the Chief Investigator to have this number of EDSS in the study. 3. Use of an Additional Pharmacy Label Additional IMP label to be attached to the study IMP. 4. Pregnancy Tests before MRI Clarification on pregnancy tests to be performed prior to MRI scans (standard of care but this information was not clearly outlined in the Protocol and Patient Information Sheet). 5. Advertising Materials In order to advertise the study on the websites of patient support groups such as the MS Society and Shift MS to aid recruitment.

11 Nov 2014

Approved document: Protocol Version 6.0 Summary of changes made to the protocol: 1. End of Trial Definition The end of study definition was revised from ‘Last Patient Last Visit’ to ‘Last Patient Last Visit plus six months’. 2. Criteria for Premature Withdrawal Both protocol sections 3.4 and sections 5.8 of the protocol indicated the reasons for premature withdrawal from this study. However, section 3.4 did not include all reasons as given in protocol section 5.8. Section 3.4 was updated with the reason, which was previously present in protocol section 5.8 but missing in protocol section 3.4 : Severe or disabling MS relapse needing IVMP and admission to hospital during the 3 months on treatment phase of the study.

13 Apr 2015

Clarifications were made to the following sections of the protocol post last patient last visit: 1. Inclusion/Exclusion criteria section 3.3 2. Criteria for Premature Withdrawal section 3.4 3. Prior and concomitant therapies section 4.8 The amendment was approved by the MHRA but rejected by the ethics committee. Therefore it was felt appropriate to withdraw the amendment. MHRA were notified of this on 08/06/15.

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.

None

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Clinical trials

Clinical Trial Results: A phase II baseline versus treatment study to determine the efficacy of raltegravir (ISENTRESS) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Total T1 Gd-enhancing lesions in brain MRI scans

Primary: Total T1 Gd-enhancing lesions in brain MRI scans

Primary: Persisting T1 Gd-enhancing brain MRI lesions

Primary: Persisting T1 Gd-enhancing brain MRI lesions

Primary: New T1 Gd enhancing brain MRI lesions

Primary: New T1 Gd enhancing brain MRI lesions

Secondary: New or enlarging T2 weighted lesions on brain MRI

Secondary: New or enlarging T2 weighted lesions on brain MRI

Secondary: Inflammatory markers

Secondary: Inflammatory markers

Secondary: Retroviral activity

Secondary: Retroviral activity

Secondary: EDSS Clinical responses (disability data)

Secondary: EDSS Clinical responses (disability data)

Secondary: MSFC Clinical responses (disability data)

Secondary: MSFC Clinical responses (disability data)

Secondary: 9HPT speed Clinical responses (disability data)

Secondary: 9HPT speed Clinical responses (disability data)

Secondary: 25 foot walk speed Clinical responses (disability data)

Secondary: 25 foot walk speed Clinical responses (disability data)

Secondary: PASAT Clinical responses (disability data)

Secondary: PASAT Clinical responses (disability data)

Secondary: Quality of life measures

Secondary: Quality of life measures

Secondary: EBV copy number in saliva

Secondary: EBV copy number in saliva

Secondary: Laboratory safety data

Secondary: Laboratory safety data

Secondary: Adverse events

Secondary: Adverse events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase II baseline versus treatment study to determine the efficacy of raltegravir (ISENTRESS) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI