Clinical Trial Results:
The effects of RNS60 on ALS biomarkers

Clinical trials

Clinical Trial Results: The effects of RNS60 on ALS biomarkers

Clinical Trial Results:
The effects of RNS60 on ALS biomarkers

Trial information

Subject disposition

Baseline characteristics

End points

Adverse events

More information

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Adverse events

Adverse events

More information

More information

Primary: MCP-1 on-treatment period variation

Primary: Cyp-A on-treatment period variation

Primary: Actin-NT on-treatment period variation

Primary: 3-NT on-treatment period variation

Primary: IL-17 on-treatment period variation

Primary: Nfl on-treatment period variation

Primary: FOXP3 mRNA on-treatment period variation

Primary: CD25 mRNA on-treatment period variation

Secondary: MCP-1 off-treatment period variation

Secondary: Cyp-A off-treatment period variation

Secondary: Actin-NT off-treatment period variation

Secondary: 3-NT off-treatment period variation

Secondary: IL-17 off-treatment period variation

Secondary: FOXP3 mRNA off-treatment period variation

Secondary: CD25 mRNA off-treatment period variation

Secondary: FVC% on-treatment and off-treatment variation

Secondary: ALSFRS-R on-treatment and off-treatment variation

Secondary: ALSAQ-40 - physical mobility domain

Secondary: ALSAQ-40 - ADL and independence domain

Secondary: ALSAQ-40 - eating and drinking domain

Secondary: ALSAQ-40 - communication domain

Secondary: ALSAQ-40 - emotional reactions domain

Secondary: Self-sufficiency

Secondary: Survival

Secondary: AE leading to treatment discontinuation

Secondary: Mean number of AE

Primary: MCP-1 on-treatment period variation

Primary: MCP-1 on-treatment period variation

Primary: Cyp-A on-treatment period variation

Primary: Cyp-A on-treatment period variation

Primary: Actin-NT on-treatment period variation

Primary: Actin-NT on-treatment period variation

Primary: 3-NT on-treatment period variation

Primary: 3-NT on-treatment period variation

Primary: IL-17 on-treatment period variation

Primary: IL-17 on-treatment period variation

Primary: Nfl on-treatment period variation

Primary: Nfl on-treatment period variation

Primary: FOXP3 mRNA on-treatment period variation

Primary: FOXP3 mRNA on-treatment period variation

Primary: CD25 mRNA on-treatment period variation

Primary: CD25 mRNA on-treatment period variation

Secondary: MCP-1 off-treatment period variation

Secondary: MCP-1 off-treatment period variation

Secondary: Cyp-A off-treatment period variation

Secondary: Cyp-A off-treatment period variation

Secondary: Actin-NT off-treatment period variation

Secondary: Actin-NT off-treatment period variation

Secondary: 3-NT off-treatment period variation

Secondary: 3-NT off-treatment period variation

Secondary: IL-17 off-treatment period variation

Secondary: IL-17 off-treatment period variation

Secondary: FOXP3 mRNA off-treatment period variation

Secondary: FOXP3 mRNA off-treatment period variation

Secondary: CD25 mRNA off-treatment period variation

Secondary: CD25 mRNA off-treatment period variation

Secondary: FVC% on-treatment and off-treatment variation

Secondary: FVC% on-treatment and off-treatment variation

Secondary: ALSFRS-R on-treatment and off-treatment variation

Secondary: ALSFRS-R on-treatment and off-treatment variation

Secondary: ALSAQ-40 - physical mobility domain

Secondary: ALSAQ-40 - physical mobility domain

Secondary: ALSAQ-40 - ADL and independence domain

Secondary: ALSAQ-40 - ADL and independence domain

Secondary: ALSAQ-40 - eating and drinking domain

Secondary: ALSAQ-40 - eating and drinking domain

Secondary: ALSAQ-40 - communication domain

Secondary: ALSAQ-40 - communication domain

Secondary: ALSAQ-40 - emotional reactions domain

Secondary: ALSAQ-40 - emotional reactions domain

Secondary: Self-sufficiency

Secondary: Self-sufficiency

Secondary: Survival

Secondary: Survival

Secondary: AE leading to treatment discontinuation

Secondary: AE leading to treatment discontinuation

Secondary: Mean number of AE

Secondary: Mean number of AE

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Download PDF

Summary
EudraCT number	2016-002382-62
Trial protocol	IT
Global end of trial date	23 Nov 2020

Results information
Results version number	v1(current)
This version publication date	14 Oct 2022
First version publication date	14 Oct 2022
Other versions

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

Collapse all Expand all

Top of page

Sponsor protocol code

RNS60-ALS

ISRCTN number

US NCT number

NCT03456882

WHO universal trial number (UTN)

Sponsor organisation name

IRCCS Istituto di Ricerche Farmacologiche "Mario Negri"

Sponsor organisation address

Via Mario Negri 2, Milano, Italy, 20156

Public contact

Laboratorio di malattie neurologich, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milano, 0039 0239014605, rns60@marionegri.it

Scientific contact

Laboratorio di malattie neurologich, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milano, 0039 0239014605, rns60@marionegri.it

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

18 Jun 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Nov 2020

Global end of trial reached?

Yes

Global end of trial date

23 Nov 2020

Was the trial ended prematurely?

Main objective of the trial

To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include: 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

Protection of trial subjects

Eligible patients can be included in the study only after proving written the IRB/IEC/REB -approved informed consent, or, if incapable of doing so, after such consent has been provided by a legally acceptable representative. In cases where the patient’s representative gives consent, the patient should be informed about the study to the extent possible given his/her understanding. The physician will obtain a signed informed consent form (ICF) from the subject prior to any procedures. The signed and completed ICF will be accessible in the patient’s records on site. A copy of the signed ICF will be given to each subject. The process of obtaining informed consent should be documented in the patient source documents. Women of child bearing potential should be informed that taking the study treatment may involve unknown risks to the fetus if pregnancy were to occur during the study and agree that in order to participate in the study they must adhere to the contraception requirement for the duration of the study. All AEs and SAEs will be recorded. Subject diaries about AEs and/or concomitant medication will not be copied but will be considered source documents. AE documentation by the investigator will include the date of onset and duration of the AE, as well as the severity and causality of each AE, and the actions taken, including the discontinuation of the experimental drug, where required.

Background therapy

Patients were treated wit 50mg riluzole twice in a day while concomitantly taking active or placebo

Evidence for comparator

Actual start date of recruitment

03 Oct 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 147

Worldwide total number of subjects

147

EEA total number of subjects

147

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)

101

From 65 to 84 years

85 years and over

Top of page

Recruitment details

Trial participants were enrolled at 22 Italian Expert ALS Centers from May 2017 to January 2020. The trial enrolled adults (age: 18-80) with a diagnosis of definite, probable or probable lab-supported ALS according to the revised El Escorial criteria whose symptom onset had occurred 6 to 24 months prior to enrollment.

Screening details

not applicable

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

This is a randomized, double-blind, placebo-controlled trial. Both subject and physician will be blinded to the treatment assignment.

Are arms mutually exclusive

Yes

active

Arm description

Patients randomly assigned to receive RNS60 administered intravenously (375ml) once a week and inhaled via nebulization (4ml/day) on non-infusion days for 24 weeks, and then followed by a 24-week off-treatment observation period

Arm type

Experimental

Investigational medicinal product name

RNS60

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion, Inhalation solution

Routes of administration

Enteral use , Inhalation use

Dosage and administration details

intravenously (375ml) once a week and inhaled via nebulization (4ml/day) on non-infusion days for 24 weeks

PLACEBO

Arm description

Patients randomly assigned to receive placebo administered intravenously (375ml) once a week and inhaled via nebulization (4ml/day) on non-infusion days for 24 weeks, and then followed by a 24-week off-treatment observation period

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion, Inhalation solution

Routes of administration

Enteral use , Inhalation use

Dosage and administration details

intravenously (375ml) once a week and inhaled via nebulization (4ml/day) on non-infusion days for 24 weeks

Number of subjects in period 1	active	PLACEBO
Started	74	73
Completed	60	50
Not completed	14	23
Adverse event, serious fatal	7	6
Consent withdrawn by subject	5	6
covid-19 infection	-	2
Adverse event, non-fatal	2	3
started prhibited therapy	-	1
disease progression	-	2
Protocol deviation	-	3

Top of page

Reporting group title

active

Reporting group description

Reporting group title

PLACEBO

Reporting group description

Reporting group values	active	PLACEBO	Total
Number of subjects	74	73	147
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	59.3 ± 10.4	56.0 ± 10.0	-
Gender categorical
Units: Subjects
Female	22	26	48
Male	52	47	99
Onset type
Site of onset of the disease
Units: Subjects
Bulbar	11	9	20
Spinal	63	63	126
Missing	0	1	1
El Escorial category
ALS diagnostic category
Units: Subjects
Definite ALS	21	20	41
Probable ALS	46	43	89
Probable laboratory supported ALS	7	10	17
Disease duration
Time between the date of ALS diagnosis and the date of inclusion into the study
Units: Months
arithmetic mean (standard deviation)	15.5 ± 5.8	14.3 ± 5.8	-
Diagnostic delay
Time between the date of onset of ALS symptoms and the date of ALS diagnosis
Units: Months
arithmetic mean (standard deviation)	9.8 ± 5.1	8.8 ± 4.9	-
BMI
Body mass index
Units: Units
arithmetic mean (standard deviation)	25.0 ± 3.3	24.8 ± 4.1	-
FVC%
Forced Vital Capacity percent value
Units: Percent of predicted
arithmetic mean (standard deviation)	102.7 ± 18.2	103.3 ± 16.1	-
ALSFRS-R
ALS functional rating scale - min score 0 corresponding to maximum functional impairment - max score 48 corresponding to no functional impairment
Units: Points
arithmetic mean (standard deviation)	41.6 ± 3.2	41.4 ± 3.6	-
ALSAQ-40 - physical mobility domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the physical mobility domain addresses problems of mobility, for example, falling and difficulties in walking, standing up and going up and down the stairs (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	32.1 ± 21.3	33.2 ± 23.1	-
ALSAQ-40 - ADL and independence domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the ADL (activities of daily living) and independence domain addresses a variety of limitations in ADL, for example, difficulties in washing/dressing oneself, doing tasks around the house, as well as difficulty writing (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	36.8 ± 27.8	32.9 ± 26.1	-
ALSAQ-40 - eating and drinking domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the eating and drinking domain adresses problems eating solid foods, swallowing and drinking liquids (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	14.5 ± 23.9	13.5 ± 23.9	-
ALSAQ-40 - communication domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the communication domain addresses a variety of problems in communicating with others, for example difficulties with speech such as talking slowly, stuttering whilst speaking and feeling self-conscious about speech (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	19.3 ± 25.5	18.6 ± 28.6	-
ALSAQ-40 - emotional reactions domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the emotional reactions domain addresses various emotional problems, for example, feeling lonely, bored, depressed, feeling embarrassed in social situations and feeling worried about future disease progression (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	33.6 ± 18.5	33.1 ± 22.2	-

Subject analysis set title

Intention to Treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

All randomized participants

Subject analysis set title

Per Protocol - active group

Subject analysis set type

Per protocol

Subject analysis set description

Participants randomized to active arm and completing the study without significant protocol deviations

Subject analysis set title

Per Protocol - placebo group

Subject analysis set type

Per protocol

Subject analysis set description

Participants randomized to placebo arm and completing the study without significant protocol deviations

Subject analysis set title

Completers and compliers - active group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants randomized to active arm, completing the 24 weeks of treatment and 24 weeks of follow-up, for a total of 48 weeks in the study, and taking at least 75% of the assigned study medication

Subject analysis set title

Completers and compliers - placebo group

Subject analysis set type

Per protocol

Subject analysis set description

Participants randomized to active arm, completing the 24 weeks of treatment and 24 weeks of follow-up, for a total of 48 weeks in the study, and taking at least 75% of the assigned study medication

Subject analysis sets values	Intention to Treat	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects	147	25	22	60	50
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	57.7 ± 10.3	±	±	±	±
Gender categorical
Units: Subjects
Female	48
Male	99
Onset type
Site of onset of the disease
Units: Subjects
Bulbar	20
Spinal	63
Missing
El Escorial category
ALS diagnostic category
Units: Subjects
Definite ALS	41
Probable ALS	89
Probable laboratory supported ALS	17
Disease duration
Time between the date of ALS diagnosis and the date of inclusion into the study
Units: Months
arithmetic mean (standard deviation)	14.9 ± 10.3	±	±	±	±
Diagnostic delay
Time between the date of onset of ALS symptoms and the date of ALS diagnosis
Units: Months
arithmetic mean (standard deviation)	9.3 ± 5.0	±	±	±	±
BMI
Body mass index
Units: Units
arithmetic mean (standard deviation)	24.9 ± 3.7	±	±	±	±
FVC%
Forced Vital Capacity percent value
Units: Percent of predicted
arithmetic mean (standard deviation)	103.1 ± 17.1	±	±	±	±
ALSFRS-R
ALS functional rating scale - min score 0 corresponding to maximum functional impairment - max score 48 corresponding to no functional impairment
Units: Points
arithmetic mean (standard deviation)	41.5 ± 3.4	±	±	±	±
ALSAQ-40 - physical mobility domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the physical mobility domain addresses problems of mobility, for example, falling and difficulties in walking, standing up and going up and down the stairs (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	32.7 ± 22.1	±	±	±	±
ALSAQ-40 - ADL and independence domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the ADL (activities of daily living) and independence domain addresses a variety of limitations in ADL, for example, difficulties in washing/dressing oneself, doing tasks around the house, as well as difficulty writing (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	34.9 ± 26.9	±	±	±	±
ALSAQ-40 - eating and drinking domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the eating and drinking domain adresses problems eating solid foods, swallowing and drinking liquids (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	14.0 ± 23.8	±	±	±	±
ALSAQ-40 - communication domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the communication domain addresses a variety of problems in communicating with others, for example difficulties with speech such as talking slowly, stuttering whilst speaking and feeling self-conscious about speech (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	19.0 ± 27.0	±	±	±	±
ALSAQ-40 - emotional reactions domain
ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the emotional reactions domain addresses various emotional problems, for example, feeling lonely, bored, depressed, feeling embarrassed in social situations and feeling worried about future disease progression (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition)
Units: Points
arithmetic mean (standard deviation)	33.4 ± 20.3	±	±	±	±

Top of page

Reporting group title

active

Reporting group description

Reporting group title

PLACEBO

Reporting group description

Subject analysis set title

Intention to Treat

Subject analysis set type

Intention-to-treat

Subject analysis set description

All randomized participants

Subject analysis set title

Per Protocol - active group

Subject analysis set type

Per protocol

Subject analysis set description

Participants randomized to active arm and completing the study without significant protocol deviations

Subject analysis set title

Per Protocol - placebo group

Subject analysis set type

Per protocol

Subject analysis set description

Participants randomized to placebo arm and completing the study without significant protocol deviations

Subject analysis set title

Completers and compliers - active group

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants randomized to active arm, completing the 24 weeks of treatment and 24 weeks of follow-up, for a total of 48 weeks in the study, and taking at least 75% of the assigned study medication

Subject analysis set title

Completers and compliers - placebo group

Subject analysis set type

Per protocol

Subject analysis set description

Participants randomized to active arm, completing the 24 weeks of treatment and 24 weeks of follow-up, for a total of 48 weeks in the study, and taking at least 75% of the assigned study medication

Top of page

End point title

MCP-1 on-treatment period variation

End point description

Mean change of plasma levels of Monocyte Chemoattractant Protein-1 (MCP-1) during the on-treatment period (from baseline to week 24). Measured at weeks 0, 4, 12, 24.

End point type

Primary

End point timeframe

24 weeks (week 0 - week 24)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: pg/ml
least squares mean (standard error)	4.6 ± 1.8	2.2 ± 1.9	6.0 ± 2.8	1.2 ± 3.0	5.0 ± 2.1	3.3 ± 2.4

MCP-1 contrast week 24 (end of treatment)

Statistical analysis description

Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3585 ^[1]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[1] - Global test of treatment*time interaction effect p=0.6346. Null hypothesis: the change over time is not different between groups.

MCP-1 contrast week 24 (end of treatment) - PP

Statistical analysis description

Per Protocol (PP) population. Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

Per Protocol - placebo group v Per Protocol - active group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2508 ^[2]

Method

Repeated measures ANOVA with unstructure

Confidence interval

sides

2-sided

lower limit

upper limit

Notes
[2] - Global test of treatment*time interaction effect p=0.6272. Null hypothesis: the change over time is not different between groups.

MCP-1 contrast week 24 (end of treatment) - CC

Statistical analysis description

Completers and compliers (CC) population. Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5977 ^[3]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[3] - Global test of treatment*time interaction effect p=0.8018. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

Cyp-A on-treatment period variation

End point description

Mean change of blood levels of Cyclophilin A (Cyp-A) during the on-treatment period (from baseline to week 24). Measured at weeks 0, 4, 12, 24.

End point type

Primary

End point timeframe

24 weeks (week 0 - week 24)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Arbitrary units
least squares mean (standard error)	6.6 ± 14.3	6.9 ± 14.4	18.8 ± 25.8	-8.1 ± 28.3	9.0 ± 15.7	7.7 ± 17.1

Cyp-A contrast week 24 (end of treatment)

Statistical analysis description

Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9887 ^[4]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[4] - Global test of treatment*time interaction effect p=0.4388. Null hypothesis: the change over time is not different between groups.

Cyp-A contrast week 24 (end of treatment) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4862 ^[5]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[5] - Global test of treatment*time interaction effect p=0.0.0362. Null hypothesis: the change over time is not different between groups.

Cyp-A contrast week 24 (end of treatment) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.956 ^[6]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[6] - Global test of treatment*time interaction effect p=0.3873. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

Actin-NT on-treatment period variation

End point description

End point type

Primary

End point timeframe

24 weeks (week 0 - week 24)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Arbitrary units
least squares mean (standard error)	9.4 ± 10.0	2.9 ± 10.2	29.5 ± 17.1	14.4 ± 19.2	9.8 ± 11.1	8.1 ± 12.2

Actin-NT contrast week 24 (end of treatment)

Statistical analysis description

Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6533 ^[7]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[7] - Global test of treatment*time interaction effect p=0.9622. Null hypothesis: the change over time is not different between groups.

Actin-NT contrast week 24 (end of treatment) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5529 ^[8]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[8] - Global test of treatment*time interaction effect p=0.7100. Null hypothesis: the change over time is not different between groups.

Actin-NT contrast week 24 (end of treatment) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9178 ^[9]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[9] - Global test of treatment*time interaction effect p=0.7873. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

3-NT on-treatment period variation

End point description

Mean change of blood levels of 3-nitrotyrosine (3-NT) during the on-treatment period (from baseline to week 24). Measured at weeks 0, 4, 12, 24.

End point type

Primary

End point timeframe

24 weeks (week 0 - week 24)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Arbitrary units
least squares mean (standard error)	14.3 ± 13.8	-2.4 ± 14.1	41.3 ± 19.6	13.2 ± 23.4	18.9 ± 13.9	14.2 ± 15.4

3-NT contrast week 24 (end of treatment)

Statistical analysis description

Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3985 ^[10]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[10] - Global test of treatment*time interaction effect p=0.9137. Null hypothesis: the change over time is not different between groups.

3-NT contrast week 24 (end of treatment) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3638 ^[11]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[11] - Global test of treatment*time interaction effect p=0.4919. Null hypothesis: the change over time is not different between groups.

3-NT contrast week 24 (end of treatment) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8194 ^[12]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[12] - Global test of treatment*time interaction effect p=0.5052. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

IL-17 on-treatment period variation

End point description

Mean change of plasma levels of Interleukin-17 (IL-17) during the on-treatment period (from baseline to week 24). Measured at weeks 0, 4, 12, 24.

End point type

Primary

End point timeframe

24 weeks (week 0 - week 24)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: log(pg/ml*10^5)
least squares mean (standard error)	0.12 ± 0.15	0.39 ± 0.15	0.04 ± 0.18	0.50 ± 0.19	0.09 ± 0.17	0.56 ± 0.19

IL-17 contrast week 24 (end of treatment)

Statistical analysis description

Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2209 ^[13]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[13] - Global test of treatment*time interaction effect p=0.2543. Null hypothesis: the change over time is not different between groups.

IL-17 contrast week 24 (end of treatment) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0839 ^[14]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[14] - Global test of treatment*time interaction effect p=0.1072. Null hypothesis: the change over time is not different between groups.

IL-17 contrast week 24 (end of treatment) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0701 ^[15]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[15] - Global test of treatment*time interaction effect p=0.0653. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

Nfl on-treatment period variation

End point description

Mean change of plasma levels of Neurofilament Light chain (NfL) during the on-treatment period (from baseline to week 24). Measured at weeks 0, 4, 24.

End point type

Primary

End point timeframe

24 weeks (week 0 - week 24)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: pg/ml
least squares mean (standard error)	2.7 ± 2.6	5.6 ± 2.7	3.6 ± 3.2	2.0 ± 3.5	5.1 ± 2.5	6.4 ± 2.7

Nfl contrast week 24 (end of treatment)

Statistical analysis description

Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4239 ^[16]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[16] - Global test of treatment*time interaction effect p=0.2738. Null hypothesis: the change over time is not different between groups.

Nfl contrast week 24 (end of treatment) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7357 ^[17]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[17] - Global test of treatment*time interaction effect p=0.2388. Null hypothesis: the change over time is not different between groups.

Nfl contrast week 24 (end of treatment) - CC

Statistical analysis description

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.719 ^[18]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[18] - Global test of treatment*time interaction effect p=0.2880. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

FOXP3 mRNA on-treatment period variation

End point description

Mean change of quantity of regulatory T cells (measured via FOXP3 mRNA) during the on-treatment period (from baseline to week 24). Measured at weeks 0, 4, 12, 24.

End point type

Primary

End point timeframe

24 weeks (week 0 - week 24)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: (Fold change 2ΔCT)*10^3
least squares mean (standard error)	-0.14 ± 0.18	-0.20 ± 0.18	-0.21 ± 0.27	0.15 ± 0.28	-0.11 ± 0.21	-0.17 ± 0.22

FOXP3 mRNA contrast week 24 (end of treatment)

Statistical analysis description

Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8133 ^[19]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[19] - Global test of treatment*time interaction effect p=0.1707. Null hypothesis: the change over time is not different between groups.

FOXP3 mRNA contrast week 24 (end of treat) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3558 ^[20]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[20] - Global test of treatment*time interaction effect p=0.8414. Null hypothesis: the change over time is not different between groups.

FOXP3 mRNA contrast week 24 (end of treat) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8508 ^[21]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[21] - Global test of treatment*time interaction effect p=0.3676. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

CD25 mRNA on-treatment period variation

End point description

Mean change of quantity of regulatory T cells (measured via CD25 mRNA) during the on-treatment period (from baseline to week 24). Measured at weeks 0, 4, 12, 24.

End point type

Primary

End point timeframe

24 weeks (week 0 - week 24)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: log((Fold change 2ΔCT)*10^3)
least squares mean (standard error)	-0.01 ± 0.08	-0.10 ± 0.09	-0.02 ± 0.18	0.03 ± 0.19	-0.01 ± 0.09	-0.02 ± 0.10

CD25 mRNA contrast week 24 (end of treatment)

Statistical analysis description

Contrast between treatment groups of the differences (week 24 - baseline) within treatment groups. Null hypothesis: the change from baseline to week 24 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4401 ^[22]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[22] - Global test of treatment*time interaction effect p=0.5239. Null hypothesis: the change over time is not different between groups.

CD25 mRNA contrast week 24 (end of treat) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8409 ^[23]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[23] - Global test of treatment*time interaction effect p=0.9882. Null hypothesis: the change over time is not different between groups.

CD25 mRNA contrast week 24 (end of treat) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9319 ^[24]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[24] - Global test of treatment*time interaction effect p=0.6591. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

MCP-1 off-treatment period variation

End point description

Mean change of plasma levels of Monocyte Chemoattractant Protein-1 (MCP-1) during the off-treatment follow-up period (from week 24 to week 48)

End point type

Secondary

End point timeframe

24 weeks (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: pg/ml
least squares mean (standard error)	1.1 ± 2.6	-0.2 ± 3.8	0.4 ± 3.8	7.3 ± 4.0	0.8 ± 2.8	0.7 ± 3.0

MCP-1 contrast week 48 (end of study)

Statistical analysis description

Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9563 ^[25]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[25] - Global test of treatment*time interaction effect p=0.6346. Null hypothesis: the change over time is not different between groups.

MCP-1 contrast week 48 (end of study) - PP

Statistical analysis description

Per Protocol (PP) population. Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2124 ^[26]

Method

Repeated measures ANOVA with unstructure

Confidence interval

sides

2-sided

lower limit

upper limit

Notes
[26] - Global test of treatment*time interaction effect p=0.6272. Null hypothesis: the change over time is not different between groups.

MCP-1 contrast week 48 (end of study) - CC

Statistical analysis description

Completers and compliers (CC) population. Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9767 ^[27]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[27] - Global test of treatment*time interaction effect p=0.8018. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

Cyp-A off-treatment period variation

End point description

Mean change of blood levels of Cyclophilin A (Cyp-A) during the off-treatment follow-up period (from week 24 to week 48)

End point type

Secondary

End point timeframe

24 weeks (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Arbitrary units
least squares mean (standard error)	16.0 ± 16.4	-12.5 ± 16.7	36.0 ± 24.8	-22.9 ± 26.7	17.1 ± 16.6	-16.8 ± 17.4

Cyp-A contrast week 48 (end of study)

Statistical analysis description

Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

PLACEBO v active

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2253 ^[28]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[28] - Global test of treatment*time interaction effect p=0.4388. Null hypothesis: the change over time is not different between groups.

Cyp-A contrast week 48 (end of study) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1127 ^[29]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[29] - Global test of treatment*time interaction effect p=0.0362. Null hypothesis: the change over time is not different between groups.

Cyp-A contrast week 48 (end of study) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1612 ^[30]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[30] - Global test of treatment*time interaction effect p=0.3873. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

Actin-NT off-treatment period variation

End point description

Mean change of blood levels of Tyrosine Nitrated-Actin (Actin-NT) during the off-treatment follow-up period (from week 24 to week 48)

End point type

Secondary

End point timeframe

24 weeks (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Arbitrary units
least squares mean (standard error)	-4.8 ± 11.0	2.9 ± 11.2	-0.6 ± 17.5	-6.7 ± 18.5	-6.7 ± 11.4	-0.2 ± 12.2

Actin-NT contrast week 48 (end of study)

Statistical analysis description

Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6263 ^[31]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[31] - Global test of treatment*time interaction effect p=0.9622. Null hypothesis: the change over time is not different between groups.

Actin-NT contrast week 48 (end of study) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8134 ^[32]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[32] - Global test of treatment*time interaction effect p=0.7100. Null hypothesis: the change over time is not different between groups.

Actin-NT contrast week 48 (end of study) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6985 ^[33]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[33] - Global test of treatment*time interaction effect p=0.7873. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

3-NT off-treatment period variation

End point description

Mean change of blood levels of 3-nitrotyrosine (3-NT) during the off-treatment follow-up period (from week 24 to week 48)

End point type

Secondary

End point timeframe

24 weeks (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Arbitrary units
least squares mean (standard error)	-26.3 ± 14.6	-7.3 ± 15.1	-30.9 ± 25.9	-18.7 ± 29.3	-29.4 ± 15.6	-17.7 ± 17.1

3-NT contrast week 48 (end of study)

Statistical analysis description

Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3671 ^[34]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[34] - Global test of treatment*time interaction effect p=0.9137. Null hypothesis: the change over time is not different between groups.

3-NT contrast week 48 (end of study) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7573 ^[35]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[35] - Global test of treatment*time interaction effect p=0.4919. Null hypothesis: the change over time is not different between groups.

3-NT contrast week 48 (end of study) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.613 ^[36]

Method

Repeated measures ANOVA with unstructure

Confidence interval

sides

2-sided

lower limit

upper limit

Notes
[36] - Global test of treatment*time interaction effect p=0.5052. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

IL-17 off-treatment period variation

End point description

Mean change of plasma levels of Interleukin-17 (IL-17) during the off-treatment follow-up period (from week 24 to week 48)

End point type

Secondary

End point timeframe

24 weeks (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: log(pg/ml*10^5)
least squares mean (standard error)	-0.15 ± 0.15	-0.11 ± 0.16	-0.22 ± 0.28	0.004 ± 0.31	-0.16 ± 0.15	-0.10 ± 0.17

IL-17 contrast week 48 (end of study)

Statistical analysis description

Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.854 ^[37]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[37] - Global test of treatment*time interaction effect p=0.2543. Null hypothesis: the change over time is not different between groups.

IL-17 contrast week 48 (end of study) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5921 ^[38]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[38] - Global test of treatment*time interaction effect p=0.1072. Null hypothesis: the change over time is not different between groups.

IL-17 contrast week 48 (end of study) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8215 ^[39]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[39] - Global test of treatment*time interaction effect p=0.0701. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

FOXP3 mRNA off-treatment period variation

End point description

Mean change of quantity of regulatory T cells (measured via FOXP3 mRNA) during the off-treatment follow-up period (from week 24 to week 48)

End point type

Secondary

End point timeframe

24 weeks (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: (Fold change 2ΔCT)*10^3
least squares mean (standard error)	-0.55 ± 0.22	-0.15 ± 0.23	-0.53 ± 0.35	-0.64 ± 0.36	-0.49 ± 0.24	-0.16 ± 0.25

FOXP3 mRNA contrast week 48 (end of study)

Statistical analysis description

Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2161 ^[40]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[40] - Global test of treatment*time interaction effect p=0.1708. Null hypothesis: the change over time is not different between groups.

FOXP3 mRNA contrast week 48 (end of study) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8327 ^[41]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[41] - Global test of treatment*time interaction effect p=0.8414. Null hypothesis: the change over time is not different between groups.

FOXP3 mRNA contrast week 48 (end of study) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3478 ^[42]

Method

Repeated measures ANOVA with unstructure

Confidence interval

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.35

Notes
[42] - Global test of treatment*time interaction effect p=0.3676. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

CD25 mRNA off-treatment period variation

End point description

Mean change of quantity of regulatory T cells (measured via CD25 mRNA) during the off-treatment follow-up period (from week 24 to week 48)

End point type

Secondary

End point timeframe

24 weeks (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: log((Fold change 2ΔCT)*10^3)
least squares mean (standard error)	0.21 ± 0.11	0.11 ± 0.11	0.13 ± 0.18	-0.01 ± 0.19	0.20 ± 0.12	0.08 ± 0.12

CD25 mRNA contrast week 48 (end of study)

Statistical analysis description

Contrast between treatment groups of the differences (week 48 - week 24) within treatment groups. Null hypothesis: the change from week 24 to week 48 is not different between treatment groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4962 ^[43]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[43] - Global test of treatment*time interaction effect p=0.5239. Null hypothesis: the change over time is not different between groups.

CD25 mRNA contrast week 48 (end of study) - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6115 ^[44]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[44] - Global test of treatment*time interaction effect p=0.9882. Null hypothesis: the change over time is not different between groups.

CD25 mRNA contrast week 48 (end of study) - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.49 ^[45]

Method

Repeated measures ANOVA with unstructure

Confidence interval

Notes
[45] - Global test of treatment*time interaction effect p=0.6591. Null hypothesis: the change over time is not different between groups.

Top of page

End point title

FVC% on-treatment and off-treatment variation

End point description

The mean change of Forced Vital Capacity percent value (FVC%) over the on-treatment period and the off-treatment follow-up period. Measured at weeks 0, 4, 12, 24, 36, 48.

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Percentage of predicted
least squares mean (standard error)
Slope on-treatment period (change per week from ba	-0.46 ± 0.11	-0.87 ± 0.10	-0.27 ± 0.1	-0.38 ± 0.1	-0.36 ± 0.1	-0.53 ± 0.1
Slope off-treatment follow-up period (change per w	-0.45 ± 0.11	-0.54 ± 0.13	-0.44 ± 0.2	-0.45 ± 0.2	-0.47 ± 0.1	-0.52 ± 0.1

FVC% slope week 0 week 24

Statistical analysis description

Contrast of the slopes during the on-treatment period (change per week, from baseline to week 24) between treatment groups. Null hypothesis: the rate of change from baseline to week 24 is not different between groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0101

Method

Mixed models analysis

Confidence interval

FVC% slope week 24 week 48

Statistical analysis description

Contrast of the slopes during the off-treatment follow-up period (change per week, from week 24 to week 48) between treatment groups. Null hypothesis: the rate of change from week 24 to week 48 is not different between groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5924

Method

Mixed models analysis

Confidence interval

FVC% slope week 0 week 24 - PP

Statistical analysis description

Per Protocol (PP) population. Contrast of the slopes during the on-treatment period (change per week, from baseline to week 24) between treatment groups. Null hypothesis: the rate of change from baseline to week 24 is not different between groups.

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5153

Method

Mixed models analysis

Confidence interval

FVC% slope week 24 week 48 - PP

Statistical analysis description

Per Protocol (PP) population. Contrast of the slopes during the off-treatment follow-up period (change per week, from week 24 to week 48) between treatment groups. Null hypothesis: the rate of change from week 24 to week 48 is not different between groups.

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9536

Method

Mixed models analysis

Confidence interval

FVC% slope week 0 week 24 - CC

Statistical analysis description

Completers and compliers (CC) population. Contrast of the slopes during the on-treatment period (change per week, from baseline to week 24) between treatment groups. Null hypothesis: the rate of change from baseline to week 24 is not different between groups.

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2522

Method

Mixed models analysis

Confidence interval

FVC% slope week 24 week 48 - CC

Statistical analysis description

Completers and compliers (CC) population. Contrast of the slopes during the off-treatment follow-up period (change per week, from week 24 to week 48) between treatment groups. Null hypothesis: the rate of change from week 24 to week 48 is not different between groups.

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8008

Method

Mixed models analysis

Confidence interval

Top of page

End point title

ALSFRS-R on-treatment and off-treatment variation

End point description

The mean change of ALS functional rating scale (min score 0 corresponding to maximum functional impairment - max score 48 corresponding to no functional impairment) over the on-treatment period and the off-treatment follow-up period. Measured at weeks 0, 4, 12, 24, 36, 48.

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Points
least squares mean (standard error)
Slope on-treatment period (change per week from ba	-0.26 ± 0.03	-0.28 ± 0.03	-0.17 ± 0.03	-0.17 ± 0.04	-0.21 ± 0.03	-0.19 ± 0.03
Slope off-treatment follow-up period (change per w	-0.26 ± 0.03	-0.24 ± 0.03	-0.21 ± 0.03	-0.19 ± 0.03	-0.24 ± 0.03	-0.21 ± 0.03

ALSFRS-R slope week 0 week 24

Statistical analysis description

Comparison groups

PLACEBO v active

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5725

Method

Mixed models analysis

Confidence interval

ALSFRS-R slope week 24 week 48

Statistical analysis description

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5728

Method

Mixed models analysis

Confidence interval

ALSFRS-R slope week 0 week 24 - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9439

Method

Mixed models analysis

Confidence interval

ALSFRS-R slope week 24 week 48 - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6729

Method

Mixed models analysis

Confidence interval

ALSFRS-R slope week 0 week 24 - CC

Statistical analysis description

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5952

Method

Mixed models analysis

Confidence interval

ALSFRS-R slope week 24 week 48 - CC

Statistical analysis description

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4275

Method

Mixed models analysis

Confidence interval

Top of page

End point title

ALSAQ-40 - physical mobility domain

End point description

The mean change of ALSAQ-40 physical mobility domain over the on-treatment period and the off-treatment follow-up period. Measured at weeks 0, 24, 48. The ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the physical mobility domain addresses problems of mobility, for example, falling and difficulties in walking, standing up and going up and down the stairs (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition).

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Points
least squares mean (standard error)
Slope (change per week from baseline to week 48)	0.45 ± 0.10	0.58 ± 0.10	0.35 ± 0.1	0.51 ± 0.1	0.40 ± 0.1	0.53 ± 0.1

ALSAQ-40 physical mobility slopes

Statistical analysis description

Contrast of the slopes during the on-treatment and off-treatment follow-up period (change per week, from baseline to week 48) between treatment groups. Null hypothesis: the rate of change from baseline to week 48 is not different between groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1503

Method

Mixed models analysis

Confidence interval

ALSAQ-40 physical mobility slopes - PP

Statistical analysis description

Per Protocol (PP) population. Contrast of the slopes during the on-treatment and off-treatment follow-up period (change per week, from baseline to week 48) between treatment groups. Null hypothesis: the rate of change from baseline to week 48 is not different between groups.

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2351

Method

Mixed models analysis

Confidence interval

ALSAQ-40 physical mobility slopes - CC

Statistical analysis description

Completers and compliers (CC) population. Contrast of the slopes during the on-treatment and off-treatment follow-up period (change per week, from baseline to week 48) between treatment groups. Null hypothesis: the rate of change from baseline to week 48 is not different between groups.

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1638

Method

Mixed models analysis

Confidence interval

Top of page

End point title

ALSAQ-40 - ADL and independence domain

End point description

The mean change of ALSAQ-40 ADL and independence domain over the on-treatment period and the off-treatment follow-up period. Measured at weeks 0, 24, 48. ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the ADL (activities of daily living) and independence domain addresses a variety of limitations in ADL, for example, difficulties in washing/dressing oneself, doing tasks around the house, as well as difficulty writing (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition).

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Points
least squares mean (standard error)
Slope (change per week from baseline to week 48)	0.47 ± 0.06	0.59 ± 0.10	0.33 ± 0.1	0.56 ± 0.1	0.44 ± 0.1	0.51 ± 0.1

ALSAQ-40 ADL and independence slopes

Statistical analysis description

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1556

Method

Mixed models analysis

Confidence interval

ALSAQ-40 ADL and independence slopes - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0755

Method

Mixed models analysis

Confidence interval

ALSAQ-40 ADL and independence slopes - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4045

Method

Mixed models analysis

Confidence interval

Top of page

End point title

ALSAQ-40 - eating and drinking domain

End point description

The mean change of ALSAQ-40 eating and drinking over the on-treatment period and the off-treatment follow-up period. Measured at weeks 0, 24, 48. ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the eating and drinking domain adresses problems eating solid foods, swallowing and drinking liquids (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition).

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Points
least squares mean (standard error)
Slope (change per week from baseline to week 48)	0.19 ± 0.10	0.38 ± 0.10	0.07 ± 0.1	0.36 ± 0.1	0.13 ± 0.1	0.32 ± 0.1

ALSAQ-40 eating and drinking slopes

Statistical analysis description

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0319

Method

Mixed models analysis

Confidence interval

ALSAQ-40 eating and drinking slopes - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.016

Method

Mixed models analysis

Confidence interval

ALSAQ-40 eating and drinking slopes - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0315

Method

Mixed models analysis

Confidence interval

Top of page

End point title

ALSAQ-40 - communication domain

End point description

The mean change of ALSAQ-40 communication domain over the on-treatment period and the off-treatment follow-up period. Measured at weeks 0, 24, 48. ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the communication domain addresses a variety of problems in communicating with others, for example difficulties with speech such as talking slowly, stuttering whilst speaking and feeling self-conscious about speech (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition).

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Points
least squares mean (standard error)
Slope (change per week from baseline to week 48)	0.29 ± 0.10	0.33 ± 0.10	0.22 ± 0.1	0.26 ± 0.1	0.23 ± 0.1	0.22 ± 0.1

ALSAQ-40 communication slopes

Statistical analysis description

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6419

Method

Mixed models analysis

Confidence interval

ALSAQ-40 communication slopes - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7173

Method

Mixed models analysis

Confidence interval

ALSAQ-40 communication slopes - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.977

Method

Mixed models analysis

Confidence interval

Top of page

End point title

ALSAQ-40 - emotional reactions domain

End point description

The mean change of ALSAQ-40 emotional reactions domain over the on-treatment period and the off-treatment follow-up period. Measured at weeks 0, 24, 48. ALS Assessment Questionnaire, a 40-item questionnaire measuring health status and health related quality of life in ALS patients - the emotional reactions domain addresses various emotional problems, for example, feeling lonely, bored, depressed, feeling embarrassed in social situations and feeling worried about future disease progression (min score =0 corresponding to the better condition - max score =100 corresponding to the worse condition).

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Points
least squares mean (standard error)
Slope (change per week from baseline to week 48)	0.18 ± 0.10	0.25 ± 0.10	0.10 ± 0.1	0.37 ± 0.1	0.14 ± 0.1	0.19 ± 0.1

ALSAQ-40 emotional reactions slopes

Statistical analysis description

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3951

Method

Mixed models analysis

Confidence interval

ALSAQ-40 emotional reactions slopes - PP

Statistical analysis description

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0353

Method

Mixed models analysis

Confidence interval

ALSAQ-40 emotional reactions slopes - CC

Statistical analysis description

Comparison groups

Completers and compliers - active group v Completers and compliers - placebo group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.482

Method

Mixed models analysis

Confidence interval

Top of page

End point title

Self-sufficiency

End point description

The cumulative number of participants losing self-sufficiency at 4, 12, 24, 36 and 48 weeks in the two treatment arms. Self-sufficiency was defined as a score of 3 or higher in the 3 items ALSFRS-R: swallowing, cutting food and handling utensils, walking. ALSFRS-R is the ALS functional rating scale (min score 0 corresponding to maximum functional impairment - max score 48 corresponding to no functional impairment). This scale is made of 12 items, each with scores ranging from 0 to 4.

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	73 ^[46]	71 ^[47]	25	22	60	50
Units: Participants
Week 4	28	27	9	10	21	17
Week 12	51	44	16	14	39	28
Week 24	61	55	20	15	49	36
Week 36	64	60	23	18	52	41
Weekk 48	66	65	24	19	54	45

Notes
[46] - 1 participant excluded because not self-sufficient at baseline
[47] - 2 participants excluded because not self-sufficient at baseline

Self-sufficiency Kaplan-Meier

Statistical analysis description

Kaplan-Meier curves for the probability of remaining self-sufficient at 4, 12, 24, 36 and 48 weeks in the two treatment arms. Null hypothesis: the survival curves describing the probability of remaining self-sufficent over the on-treatment and the off-treatment follow-up period are not different between groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4527

Method

Logrank

Confidence interval

Self-sufficiency Kaplan-Meier - PP

Statistical analysis description

Per Protocol (PP) population. Kaplan-Meier curves for the probability of remaining self-sufficient at 4, 12, 24, 36 and 48 weeks in the two treatment arms. Null hypothesis: the survival curves describing the probability of remaining self-sufficent over the on-treatment and the off-treatment follow-up period are not different between groups.

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5554

Method

Logrank

Confidence interval

Self-sufficiency Kaplan-Meier - CC

Statistical analysis description

Completers and compliers (CC) population. Kaplan-Meier curves for the probability of remaining self-sufficient at 4, 12, 24, 36 and 48 weeks in the two treatment arms. Null hypothesis: the survival curves describing the probability of remaining self-sufficent over the on-treatment and the off-treatment follow-up period are not different between groups.

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3791

Method

Logrank

Confidence interval

Top of page

End point title

Survival

End point description

The cumulative number of deaths at 4, 12, 24, 36 and 48 weeks in the two treatment arms.

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Participants
Week 4	0	0	0	0	0	0
Week 12	0	1	0	0	0	0
Week 24	0	1	0	0	0	0
Week 36	3	1	0	0	0	0
Week 48	7	6	0	0	0	0

Survival Kaplan-Meier analysis

Statistical analysis description

The cumulative survival probability at 4, 12, 24, 36 and 48 weeks in the two treatment arms. Null hypothesis: the survival curves over the on-treatment and the off-treatment follow-up period are not different between groups.

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9212

Method

Logrank

Confidence interval

Top of page

End point title

AE leading to treatment discontinuation

End point description

The total number of subjects in the two treatment arms experiencing at least one adverse event (AE) leading to treatment discontinuation at 4, 12 and 24 weeks

End point type

Secondary

End point timeframe

24 weeks on-treatment period

AE treatment discontinuation 4 weeks

Statistical analysis description

Null hypothesis: the percentage of patients experiencing at least one adverse event leading to treatment discontinuation within 4 weeks is not different between groups

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9598

Method

Fisher exact

Confidence interval

AE treatment discontinuation 12 weeks

Statistical analysis description

Null hypothesis: the percentage of patients experiencing at least one adverse event leading to treatment discontinuation within 12 weeks is not different between groups

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.939

Method

Fisher exact

Confidence interval

AE treatment discontinuation 24 weeks

Statistical analysis description

Null hypothesis: the percentage of patients experiencing at least one adverse event leading to treatment discontinuation within 24 weeks is not different between groups

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3442

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Top of page

End point title

Mean number of AE

End point description

The mean number of AEs per treatment arm at 4, 12, 24 and 48 weeks

End point type

Secondary

End point timeframe

24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

End point values	active	PLACEBO	Per Protocol - active group	Per Protocol - placebo group	Completers and compliers - active group	Completers and compliers - placebo group
Number of subjects analysed	74	73	25	22	60	50
Units: Number of AE
arithmetic mean (standard deviation)
Week 4	0.4 ± 0.8	0.5 ± 1.1	0.5 ± 0.8	0.4 ± 0.7	0.5 ± 0.8	0.4 ± 1.0
Week 12	1.0 ± 1.6	1.2 ± 2.4	1.0 ± 1.1	0.9 ± 1.3	1.0 ± 1.3	0.9 ± 1.4
Week 24	1.7 ± 2.6	2.0 ± 3.6	1.9 ± 2.1	1.5 ± 1.7	1.6 ± 2.0	1.6 ± 2.4
Week 48	1.9 ± 2.8	2.1 ± 3.6	2.2 ± 2.8	1.8 ± 2.0	1.8 ± 2.4	1.8 ± 2.5

Mean AE treatment discontinuation 4 weeks

Statistical analysis description

Null hypothesis: the number of adverse events occurred within 4 weeks is not different between groups

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8738

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 12 weeks

Statistical analysis description

Null hypothesis: the number of adverse events occurred within 12 weeks is not different between groups

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7556

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 24 weeks

Statistical analysis description

Null hypothesis: the number of adverse events occurred within 24 weeks is not different between groups

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6477

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 48 weeks

Statistical analysis description

Null hypothesis: the number of adverse events occurred within 48 weeks is not different between groups

Comparison groups

active v PLACEBO

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6048

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 4 weeks - PP

Statistical analysis description

Per Protocol (PP) population. Null hypothesis: the number of adverse events occurred within 4 weeks is not different between groups

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3744

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 12 weeks - PP

Statistical analysis description

Per Protocol (PP) population. Null hypothesis: the number of adverse events occurred within 12 weeks is not different between groups

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.572

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 24 weeks - PP

Statistical analysis description

Per Protocol (PP) population. Null hypothesis: the number of adverse events occurred within 24 weeks is not different between groups

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9477

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 48 weeks - PP

Statistical analysis description

Per Protocol (PP) population. Null hypothesis: the number of adverse events occurred within 48 weeks is not different between groups

Comparison groups

Per Protocol - active group v Per Protocol - placebo group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9652

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 4 weeks - CC

Statistical analysis description

Per Protocol (PP) population. Null hypothesis: the number of adverse events occurred within 4 weeks is not different between groups

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5933

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 12 weeks - CC

Statistical analysis description

Completers and compliers (CC) population. Null hypothesis: the number of adverse events occurred within 12 weeks is not different between groups

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7438

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 24 weeks - CC

Statistical analysis description

Completers and compliers (CC) population. Null hypothesis: the number of adverse events occurred within 24 weeks is not different between groups

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9132

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Mean AE treatment discontinuation 48 weeks - CC

Statistical analysis description

Completers and compliers (CC) population. Null hypothesis: the number of adverse events occurred within 48 weeks is not different between groups

Comparison groups

Completers and compliers - placebo group v Completers and compliers - active group

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7659

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Top of page

Timeframe for reporting adverse events

24 weeks on-treatment period + 24 weeks off-treatment follow-up period

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

active

Reporting group description

Reporting group title

PLACEBO

Reporting group description

Serious adverse events	active	PLACEBO
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 74 (6.76%)	5 / 73 (6.85%)
number of deaths (all causes)	7	6
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 74 (1.35%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	0 / 74 (0.00%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 74 (1.35%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
HEART ATTACK
subjects affected / exposed	1 / 74 (1.35%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 74 (1.35%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis
subjects affected / exposed	0 / 74 (0.00%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction
subjects affected / exposed	0 / 74 (0.00%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumopathy
subjects affected / exposed	0 / 74 (0.00%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 74 (1.35%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory infection
subjects affected / exposed	1 / 74 (1.35%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 74 (0.00%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	active	PLACEBO
Total subjects affected by non serious adverse events
subjects affected / exposed	44 / 74 (59.46%)	48 / 73 (65.75%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	5 / 74 (6.76%)	4 / 73 (5.48%)
occurrences all number	6	5
Fracture
subjects affected / exposed	2 / 74 (2.70%)	5 / 73 (6.85%)
occurrences all number	2	6
Haematoma
subjects affected / exposed	3 / 74 (4.05%)	1 / 73 (1.37%)
occurrences all number	4	1
Vascular disorders
Hypertension
subjects affected / exposed	3 / 74 (4.05%)	4 / 73 (5.48%)
occurrences all number	4	4
Nervous system disorders
Headache
subjects affected / exposed	7 / 74 (9.46%)	7 / 73 (9.59%)
occurrences all number	7	11
General disorders and administration site conditions
Chills
subjects affected / exposed	4 / 74 (5.41%)	1 / 73 (1.37%)
occurrences all number	4	1
Flu
subjects affected / exposed	8 / 74 (10.81%)	6 / 73 (8.22%)
occurrences all number	11	11
Malaise
subjects affected / exposed	3 / 74 (4.05%)	2 / 73 (2.74%)
occurrences all number	6	4
Temperature
subjects affected / exposed	3 / 74 (4.05%)	6 / 73 (8.22%)
occurrences all number	4	7
Gastrointestinal disorders
Abdominal colic
subjects affected / exposed	1 / 74 (1.35%)	2 / 73 (2.74%)
occurrences all number	8	2
Achalasia event
subjects affected / exposed	1 / 74 (1.35%)	0 / 73 (0.00%)
occurrences all number	5	0
Diarrhoea
subjects affected / exposed	2 / 74 (2.70%)	1 / 73 (1.37%)
occurrences all number	4	1
Nausea
subjects affected / exposed	1 / 74 (1.35%)	2 / 73 (2.74%)
occurrences all number	1	4
Respiratory, thoracic and mediastinal disorders
Bronchitis
subjects affected / exposed	3 / 74 (4.05%)	0 / 73 (0.00%)
occurrences all number	4	0
Nasal congestion
subjects affected / exposed	2 / 74 (2.70%)	3 / 73 (4.11%)
occurrences all number	2	4
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	4 / 74 (5.41%)	3 / 73 (4.11%)
occurrences all number	8	4
Musculoskeletal and connective tissue disorders
Joint pain
subjects affected / exposed	6 / 74 (8.11%)	1 / 73 (1.37%)
occurrences all number	7	1
Lumbosciatalgia
subjects affected / exposed	0 / 74 (0.00%)	2 / 73 (2.74%)
occurrences all number	0	5

Top of page

Were there any global substantial amendments to the protocol? No

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 reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

End point values

Per Protocol - active group

Per Protocol - placebo group

Completers and compliers - active group

Completers and compliers - placebo group

Number of subjects analysed

Units: Participants