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Clinical Trial Results:
Arimoclomol prospective double blind, randomised, placebo-controlled study in patients diagnosed with Niemann Pick disease type C

Summary
EudraCT number	2015-004438-93
Trial protocol	DK DE IT PL ES GB
Global end of trial date	31 Oct 2024

Results information
Results version number	v1(current)
This version publication date	20 Jul 2025
First version publication date	20 Jul 2025
Other versions

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

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Trial information

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Sponsor protocol code

CT-ORZY-NPC-002

ISRCTN number

US NCT number

NCT02612129

WHO universal trial number (UTN)

Other trial identifiers

IND Number: 124547

Sponsor organisation name

Zevra Denmark A/S

Sponsor organisation address

Nordre Fasanvej 215, Frederiksberg, Denmark, DK-2000

Public contact

Medical Affairs, Zevra Denmark A/S, 1 8882895607, medicalaffairs@zevra.com

Scientific contact

Medical Affairs, Zevra Denmark A/S, 1 8882895607, medicalaffairs@zevra.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001748-PIP01-15

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

24 Apr 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Oct 2024

Global end of trial reached?

Yes

Global end of trial date

31 Oct 2024

Was the trial ended prematurely?

Main objective of the trial

MAIN STUDY: To evaluate therapeutic response to arimoclomol versus placebo, both in addition to best available standard of care, at 12 months. PEDIATRIC SUB-STUDY: To evaluate the safety and tolerability of arimoclomol in patients aged 6 to <24 months at study enrolment, over 36 months. OPEN LABEL EXTENSION: To evaluate the long-term therapeutic response (clinical and biological assessments) at 18, 24, 30, 36, 42, 48, 54 and 60 months (after randomization into the double-blind phase of the trial), and to evaluate the safety of arimoclomol.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted. All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Arimoclomol is administered as an add-on therapy to the patient’s current prescribed best standard of care; each patient’s standard of care may, or may not, include miglustat.

Evidence for comparator

Actual start date of recruitment

14 Jun 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

48 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 6

Country: Number of subjects enrolled

Poland: 9

Country: Number of subjects enrolled

Spain: 3

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

Denmark: 4

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Switzerland: 2

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The main study was conducted at 14 sites and the open label extension study was conducted at 15 sites in the following countries: Denmark, France, Germany, Italy, Poland, Spain, Switzerland, United Kingdom, and United States. The pediatric substudy was conducted at 4 sites in Denmark, Germany, United Kingdom, and United States.

Screening details

The Investigator carried out the screening and enrolment for each patient; eligibility criteria was checked for compliance prior to enrolment. To confirm the selected dose in the main study, participants less than 12 years of age underwent an arimoclomol single-dose PK evaluation before randomization and the start of continuous treatment

Period 1 title

Main Study

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

All participants enrolled into the pediatric substudy received open-label arimoclomol. All participants randomized into the double-blind period were randomized to receive blinded placebo or arimoclomol (with an allocation ratio of 2:1). Both the participants and the investigators were blinded to the treatment assignment and remained blinded throughout the 12-month blinded treatment phase until the final database lock.

Are arms mutually exclusive

Yes

Arimoclomol (12-month Double-blind Phase)

Arm description

Participants received arimoclomol capsules, orally based on participant's body weight, TID for 12 months.

Arm type

Experimental

Investigational medicinal product name

Arimoclomol

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Participants received arimoclomol capsules orally three times a day (TID) for 12 months. The dose was 31-124 mg arimoclomol base TID (equivalent to 50-200 mg arimoclomol citrate TID), based on participant's body weight.

Placebo (12-month Double-blind Phase)

Arm description

Participants received matching placebo to arimoclomol capsules, orally based on participant's body weight, TID for 12 months.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Participants received matching placebo capsules (with regard to weight, appearance, smell, flavor etc.) orally TID for 12 months.

Arimoclomol (36-month pediatric substudy)

Arm description

Participants received arimoclomol orally based on participant's age and body weight, TID for 36 months.

Arm type

Experimental

Investigational medicinal product name

Arimoclomol

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Participants received arimoclomol orally three times a day (TID) for 36 months. The dose was based on participant's age and body weight.

Number of subjects in period 1	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)	Arimoclomol (36-month pediatric substudy)
Started	34	16	5
Completed through 12 months	27	15	4
Completed	27	15	2
Not completed	7	1	3
Adverse event, serious fatal	1	-	-
Consent withdrawn by subject	1	-	-
Safety reasons	3	-	-
IMP stopping criteria met	-	1	1
Informed consent withdrawn by LAR	-	-	2
Early escape	2	-	-

Period 2 title

Open-Label Extension Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Experimental: Arimoclomol

Arm description

Arm type

Experimental

Investigational medicinal product name

Arimoclomol

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 2 ^[1]	Experimental: Arimoclomol
Started	41
Completed	29
Not completed	12
Adverse event, serious fatal	2
Physician decision	2
Safety issues	2
Consent withdrawn by parent/guardian	6

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: A total of 42 participants completed the double-blind phase, 1 of whom withdrew consent before being dosed in the OLE phase. The remaining 41 participants who completed the double-blind phase were enrolled in the OLE phase. The participants in the pediatric substudy were not eligible to enroll into the OLE phase and therefore do not contribute to the number of participants starting the period.

Baseline characteristics

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Reporting group title

Arimoclomol (12-month Double-blind Phase)

Reporting group description

Participants received arimoclomol capsules, orally based on participant's body weight, TID for 12 months.

Reporting group title

Placebo (12-month Double-blind Phase)

Reporting group description

Participants received matching placebo to arimoclomol capsules, orally based on participant's body weight, TID for 12 months.

Reporting group title

Arimoclomol (36-month pediatric substudy)

Reporting group description

Participants received arimoclomol orally based on participant's age and body weight, TID for 36 months.

Reporting group values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)	Arimoclomol (36-month pediatric substudy)	Total
Number of subjects	34	16	5	55
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	5	5
Children (2-11 years)	16	11	0	27
Adolescents (12-17 years)	13	5	0	18
Adults (18-64 years)	5	0	0	5
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Gender categorical
Units: Subjects
Female	17	9	3	29
Male	17	7	2	26

Subject analysis set title

Open-label Arimoclomol (48-month OLE Phase)

Subject analysis set type

Full analysis

Subject analysis set description

Includes all participants who completed the 12-month double-blind, randomized, placebo-controlled phase of the trial, were eligible for and agreed to participate in the OLE, and subsequently received at least 1 dose of open-label arimoclomol.

Subject analysis set title

Arimoclomol (36-month pediatric substudy)

Subject analysis set type

Safety analysis

Subject analysis set description

test

Subject analysis set title

Arimoclomol (12-month Double-blind Phase)

Subject analysis set type

Full analysis

Subject analysis set description

Participants received arimoclomol capsules, orally based on participant's body weight, TID for 12 months. Participants formed the Full Analysis Set (FAS), which included participants who were randomized and who received at least one dose of randomized treatment medication (excluding single dose of arimoclomol [patients less than 12 years of age] for the assessment of PK prior to initiation of their randomized treatment).

Subject analysis set title

Placebo (12-month Double-blind Phase)

Subject analysis set type

Full analysis

Subject analysis set description

Participants received matching placebo to arimoclomol capsules, orally based on participant's body weight, TID for 12 months. Participants formed the Full Analysis Set (FAS), which included participants who were randomized and who received at least one dose of randomized treatment medication (excluding single dose of arimoclomol [patients less than 12 years of age] for the assessment of PK prior to initiation of their randomized treatment).

Subject analysis sets values	Open-label Arimoclomol (48-month OLE Phase)	Arimoclomol (36-month pediatric substudy)	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects	41	5	34	16
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	5	0	0
Children (2-11 years)	22	0	16	11
Adolescents (12-17 years)	16	0	13	5
Adults (18-64 years)	3	0	5	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age continuous
Units:
	( )	( )	( )	( )
Gender categorical
Units: Subjects
Female	21	3	17	9
Male	20	2	17	7

End points

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Reporting group title

Arimoclomol (12-month Double-blind Phase)

Reporting group description

Participants received arimoclomol capsules, orally based on participant's body weight, TID for 12 months.

Reporting group title

Placebo (12-month Double-blind Phase)

Reporting group description

Participants received matching placebo to arimoclomol capsules, orally based on participant's body weight, TID for 12 months.

Reporting group title

Arimoclomol (36-month pediatric substudy)

Reporting group description

Participants received arimoclomol orally based on participant's age and body weight, TID for 36 months.

Reporting group title

Experimental: Arimoclomol

Reporting group description

Subject analysis set title

Open-label Arimoclomol (48-month OLE Phase)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Arimoclomol (36-month pediatric substudy)

Subject analysis set type

Safety analysis

Subject analysis set description

test

Subject analysis set title

Arimoclomol (12-month Double-blind Phase)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Placebo (12-month Double-blind Phase)

Subject analysis set type

Full analysis

Subject analysis set description

Primary: 1. Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Score

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End point title

1. Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Score

End point description

NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. The analysis is based on the Full Analysis Set (FAS). Overall Number analyzed is the number of participants evaluated at a specified timepoint.

End point type

Primary

End point timeframe

Baseline to Month 12

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Score on a scale
arithmetic mean (standard deviation)	0.7 ( 1.9 )	2.0 ( 3.0 )

Statistical Analysis 1

Statistical analysis description

A general linear mixed model (GLMM) for repeated measurements was used for the analysis of NPC disease severity assessed based on the 5-domain NPCCSS scores at Month 12. The general linear mixed model analysis for repeated measures was fitted with treatment, miglustat level and visit as fixed effects including treatment-by-visit interaction and baseline score as a covariate.

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0456

Method

GLMM for Repeated Measures

Parameter type

Least Square (LS) Mean Difference

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.76

upper limit

-0.03

Secondary: 2. Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I)

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End point title

2. Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I)

End point description

The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement. Responders were defined as the participants who remained stable or showed improvement at Month 12. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Month 12

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Percentage of responders
number (not applicable)	58.8	56.3

Statistical Analysis 1

Statistical analysis description

Chi-squared Test

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 1

Method

Chi-squared

Confidence interval

Notes
[1] - Participants who discontinued before 12 months have been imputed as non-responders.

Secondary: 3. Percentage of Responders in 5-domain NPCCSS

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End point title

3. Percentage of Responders in 5-domain NPCCSS

End point description

The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. Responders were defined as participants who remained stable or improved compared to baseline. Stable was defined as a participant's total score for the 5 domains being the same at month 12 as at baseline. Improvement was defined as a participant's total score for the 5 domains at month 12 being lower than at baseline. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to Month 12

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Percentage of participants
number (not applicable)	50.0	37.5

Statistical Analysis 1

Statistical analysis description

Fisher's exact test

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.5456

Method

Fisher exact

Confidence interval

Notes
[2] - Participants who discontinued before 12 months have been imputed as non-responders.

Secondary: 4. Time to Worsening

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End point title

4. Time to Worsening

End point description

Time to worsening was defined as the time until the participant reached the predefined minimal clinically important difference (MCID) of 2 points compared to baseline on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. The values reported per group are the 25th percentile Kaplan-Meier estimates and 95% confidence intervals. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to Month 12

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Months
number (confidence interval 95%)	5.2 (2.9 to 12.0)	5.5 (1.0 to 6.5)

Statistical Analysis 1

Statistical analysis description

Log-rank test stratified by miglustat use

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8021

Method

Logrank

Confidence interval

Secondary: 5. Percentage of Participants with Worsening

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End point title

5. Percentage of Participants with Worsening

End point description

Worsening was defined as participants that have reached the predefined MCID of 2 points on their 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. Discontinuation before 6 or 12 months was considered as worsened. Missing scores at 6 or 12 months was also considered as worsened. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Months 6 and 12

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Percentage of participants
number (not applicable)
Worsening at Month 6	35.3	50.0
Worsening at Month 12	44.1	43.8

Statistical Analysis 1

Statistical analysis description

Fisher's Exact Test

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.3662

Method

Fisher exact

Confidence interval

Notes
[3] - Percentage of participants worsening at Month 6

Statistical Analysis 2

Statistical analysis description

Fisher's Exact Test

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 1

Method

Fisher exact

Confidence interval

Notes
[4] - Percentage of participants worsening at Month 12

Secondary: 6. Change from Baseline in 17-domain NPCCSS Apart from Hearing Domains (i.e. Hearing and Auditory Brainstem Response)

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End point title

6. Change from Baseline in 17-domain NPCCSS Apart from Hearing Domains (i.e. Hearing and Auditory Brainstem Response)

End point description

The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify NPC disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major and eight minor domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). The total score is the sum of the score of each of the 17 domains and ranges from 0 to 61, with a high score indicating a more severe clinical impairment. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to 6 and 12 months

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Score on a scale
least squares mean (confidence interval 95%)
Change at Month 6	0.53 (-0.85 to 1.90)	2.22 (0.33 to 4.10)
Change at Month 12	1.20 (-0.40 to 2.79)	2.81 (0.75 to 4.87)

Statistical Analysis 1

Statistical analysis description

Change From Baseline in 17-Domain NPCCSS Apart from Hearing Domains (i.e. Hearing and Auditory Brainstem Response) at Month 6 was analyzed using the Analysis of covariance (ANCOVA) model. ANCOVA model was fitted with treatment, baseline full-scale NPCCSS apart from hearing domains score, and use of miglustat as covariates.

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1546

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1.69

Confidence interval

level

95%

sides

2-sided

lower limit

-4.04

upper limit

0.66

Statistical Analysis 2

Statistical analysis description

Change From Baseline in 17-Domain NPCCSS Apart from Hearing Domains (i.e. Hearing and Auditory Brainstem Response) at Month 12 was analyzed using the ANCOVA model. ANCOVA model was fitted with treatment, baseline full-scale NPCCSS apart from hearing domains score, and use of miglustat as covariates.

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2199

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1.61

Confidence interval

level

95%

sides

2-sided

lower limit

-4.24

upper limit

1.01

Secondary: 7. Change from Baseline in 5-domain NPCCSS Score

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End point title

7. Change from Baseline in 5-domain NPCCSS Score

End point description

The 5-domain NPC Clinical Severity Scale (NPCCSS) focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to 6 months

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Score on a scale
least squares mean (confidence interval 95%)	0.48 (-0.05 to 1.02)	1.60 (0.86 to 2.34)

Statistical Analysis 1

Statistical analysis description

An ANCOVA model was fitted with treatment, baseline 5-domain NPCCSS score, and use of miglustat as covariates.

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0188

Method

ANCOVA

Parameter type

Least Square Mean Difference

Point estimate

-1.11

Confidence interval

level

95%

sides

2-sided

lower limit

-2.03

upper limit

-0.19

Secondary: 8. Changes from Baseline in Each Individual Domain of the NPCCSS

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End point title

8. Changes from Baseline in Each Individual Domain of the NPCCSS

End point description

The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing,) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). A higher score indicates a more severe clinical impairment. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to 6 and 12 Months

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Score on a scale
arithmetic mean (standard deviation)
Ambulation: Baseline	2.5 ( 1.6 )	2.2 ( 1.6 )
Ambulation: Change at Month 6	0.1 ( 0.4 )	0.3 ( 1.0 )
Ambulation: Change at Month 12	0.3 ( 0.5 )	0.3 ( 0.9 )
Speech: Baseline	2.2 ( 1.6 )	1.6 ( 1.2 )
Speech: Change at Month 6	0.1 ( 0.5 )	0.1 ( 0.3 )
Speech: Change at Month 12	-0.2 ( 1.0 )	0.3 ( 0.8 )
Swallow: Baseline	1.9 ( 1.7 )	1.3 ( 1.7 )
Swallow: Change at Month 6	0.1 ( 1.1 )	0.4 ( 1.0 )
Swallow: Change at Month 12	0.1 ( 1.1 )	0.6 ( 1.0 )
Fine Motor Skills: Baseline	2.8 ( 1.8 )	1.9 ( 1.8 )
Fine Motor Skills: Change at Month 6	0.1 ( 0.7 )	0.5 ( 1.1 )
Fine Motor Skills: Change at Month 12	0.2 ( 0.8 )	0.6 ( 1.3 )
Cognition: Baseline	2.8 ( 1.3 )	2.5 ( 1.5 )
Cognition: Change at Month 6	0.2 ( 0.5 )	0.3 ( 0.8 )
Cognition: Change at Month 12	0.3 ( 0.6 )	0.1 ( 0.6 )
Eye Movement: Baseline	2.2 ( 1.2 )	2.1 ( 1.1 )
Eye Movement: Change at Month 6	0.0 ( 0.6 )	-0.1 ( 0.7 )
Eye Movement: Change at Month 12	0.2 ( 0.9 )	-0.1 ( 0.6 )
Memory: Baseline	1.9 ( 1.4 )	1.3 ( 1.5 )
Memory: Change at Month 6	0.1 ( 0.5 )	0.2 ( 1.1 )
Memory: Change at Month 12	0.1 ( 0.5 )	0.3 ( 0.8 )
Seizures: Baseline	1.9 ( 1.9 )	1.3 ( 1.8 )
Seizures: Change at Month 6	-0.1 ( 0.8 )	0.0 ( 1.5 )
Seizures: Change at Month 12	0.3 ( 0.8 )	-0.1 ( 1.7 )
Hearing: Baseline	0.4 ( 1.0 )	0.0 ( 0.0 )
Hearing: Change at Month 6	-0.2 ( 0.8 )	0.0 ( 0.0 )
Hearing: Change at Month 12	0.0 ( 0.0 )	0.3 ( 0.8 )
Auditory Brainstem Response: Baseline	0.2 ( 0.4 )	0.1 ( 0.4 )
Auditory Brainstem Response: Change at Month 6	0.0 ( 0.0 )	0.2 ( 0.4 )
Auditory Brainstem Response: Change at Month 12	0.0 ( 0.0 )	0.0 ( 0.0 )
Behavior: Baseline	0.4 ( 0.6 )	0.4 ( 0.6 )
Behavior: Change at Month 6	0.0 ( 0.5 )	-0.1 ( 0.5 )
Behavior: Change at Month 12	0.1 ( 0.6 )	-0.2 ( 0.4 )
Gelastic Cataplexy: Baseline	0.8 ( 0.9 )	0.4 ( 0.8 )
Gelastic Cataplexy: Change at Month 6	0.1 ( 0.5 )	0.3 ( 0.6 )
Gelastic Cataplexy: Change at Month 12	0.2 ( 0.6 )	0.3 ( 0.6 )
Hyperreflexia: Baseline	1.0 ( 0.7 )	1.1 ( 0.9 )
Hyperreflexia: Change at Month 6	-0.0 ( 0.5 )	0.2 ( 0.6 )
Hyperreflexia: Change at Month 12	0.1 ( 0.7 )	0.1 ( 0.5 )
Incontinence: Baseline	1.0 ( 0.8 )	0.8 ( 0.9 )
Incontinence: Change at Month 6	-0.1 ( 0.4 )	0.1 ( 0.5 )
Incontinence: Change at Month 12	-0.0 ( 0.4 )	0.1 ( 0.9 )
Narcolepsy (NARCO): Baseline	0.1 ( 0.4 )	0.3 ( 0.7 )
Narcolepsy (NARCO): Change at Month 6	0.0 ( 0.4 )	-0.1 ( 0.3 )
Narcolepsy (NARCO): Change at Month 12	-0.1 ( 0.4 )	-0.1 ( 0.3 )
Psychiatric: Baseline	0.1 ( 0.4 )	0.1 ( 0.5 )
Psychiatric: Change at Month 6	-0.0 ( 0.3 )	0.1 ( 0.6 )
Psychiatric: Change at Month 12	0.0 ( 0.3 )	0.0 ( 0.4 )
Respiratory: Baseline	0.1 ( 0.3 )	0.0 ( 0.0 )
Respiratory: Change at Month 6	0.0 ( 0.5 )	0.1 ( 0.3 )
Respiratory: Change at Month 12	0.1 ( 0.5 )	0.2 ( 0.4 )

No statistical analyses for this end point

Secondary: 9. Change from Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified "Stampfer Score")

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End point title

9. Change from Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified "Stampfer Score")

End point description

The NPC Clinical Database (NPC-cdb) score aims to reflect the current clinical status of the participant. The NPC-cdb score represents both historical symptoms and a current status. The test consists of ten areas: visceral signs, development, motor function, ocular-motor abnormalities, seizures/cataplexy/narcolepsy, cognitive abilities and memory, behavioral and psychiatric abnormalities, speech, hearing, and abilities in daily life. The current status score is a severity-weighted sum of 72 symptoms considered as disease-relevant at the time of assessment. Each symptom contributes with a score between 1 and 5, the maximum score is 125. An increase in score reflects a reduction in the participant's abilities. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to 6 and 12 Months

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Score on a scale
least squares mean (confidence interval 95%)
Change at Month 6	-0.38 (-3.30 to 2.54)	4.71 (0.49 to 8.93)
Change at Month 12	1.85 (-2.16 to 5.86)	4.88 (-0.63 to 10.39)

Statistical Analysis 1

Statistical analysis description

Change from baseline in the NPC-CDB score (modified "Stampfer Score") at Month 6 was analyzed using the ANCOVA model. ANCOVA model was fitted with treatment, baseline NPC-CDB total score and use of miglustat as covariates.

Comparison groups

Placebo (12-month Double-blind Phase) v Arimoclomol (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0536

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-5.09

Confidence interval

level

95%

sides

2-sided

lower limit

-10.26

upper limit

0.08

Statistical Analysis 2

Statistical analysis description

Change from baseline in the NPC-CDB score (modified "Stampfer Score") at Month 12 was analyzed using the ANCOVA model. ANCOVA model was fitted with treatment, baseline NPC-CDB total score and use of miglustat as covariates.

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3785

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-3.03

Confidence interval

level

95%

sides

2-sided

lower limit

-9.9

upper limit

3.85

Secondary: 10. Percentage of Participants with Change from Baseline in Quality of Life (EQ-5D-Y)

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End point title

10. Percentage of Participants with Change from Baseline in Quality of Life (EQ-5D-Y)

End point description

The EQ-5D-Y descriptive system includes 5 descriptive items: Mobility, self-care, doing usual activities, having pain or discomfort, and feeling anxiety or depressed. Each dimension has 3 levels: No problems, some problems, and a lot of problems. The change in the 5 individual items of the EQ-5D-Y per participant was explored by using the pareto principle at 6 and 12 months to show the number (%) of participants who felt: - Better (better on at least one dimension and no worse in any other dimension), - Worse (worse in at least one dimension, and no better in any other dimension) The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to 6 and 12 months

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	30	15
Units: Percentage of participants
number (not applicable)
Better: Change at Month 6	16.7	26.7
Worse: Change at Month 6	40.0	46.7
Better: Change at Month 12	25.9	40.0
Worse: Change at Month 12	44.4	20.0

Statistical Analysis 1

Statistical analysis description

Percentage of participants with change from baseline at Month 6 in Quality of Life (EQ-5D-Y) being 'Better', analyzed using a Chi-squared Test

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6951

Method

Chi-squared

Confidence interval

Statistical Analysis 2

Statistical analysis description

Percentage of participants with change from baseline at Month 6 in Quality of Life (EQ-5D-Y) being 'Worse', analyzed using a Chi-squared Test

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7542

Method

Chi-squared

Confidence interval

Statistical Analysis 3

Statistical analysis description

Percentage of participants with change from baseline at Month 12 in Quality of Life (EQ-5D-Y) being 'Better', analyzed using a Chi-squared Test

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.488

Method

Chi-squared

Confidence interval

Statistical Analysis 4

Statistical analysis description

Percentage of participants with change from baseline at Month 12 in Quality of Life (EQ-5D-Y) being 'Worse', analyzed using a Chi-squared Test

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1804

Method

Chi-squared

Confidence interval

Secondary: 11. Change from Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score

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End point title

11. Change from Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score

End point description

The SARA included eight items reflecting neurologic manifestations of cerebellar ataxia. The test provides a direct and simple description of motor function in a participant. The test consists of 8 test items: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide. The total score of the 8 items ranges from 0 (normal cerebellar function) to 40 (not able to perform any of the test items). The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to 6 and 12 months

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Score on a scale
least squares mean (confidence interval 95%)
Change at 6 Months	0.79 (-0.16 to 1.75)	0.05 (-1.29 to 1.40)
Change at 12 Months	1.06 (-0.17 to 2.29)	0.78 (-0.90 to 2.47)

Statistical Analysis 1

Statistical analysis description

Change from baseline in the SARA score at Month 6 was measured using an ANCOVA model. ANCOVA model was fitted with treatment, baseline SARA score, and use of miglustat as covariates.

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.371

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.74

Confidence interval

level

95%

sides

2-sided

lower limit

-0.92

upper limit

2.4

Statistical Analysis 2

Statistical analysis description

Change from baseline in the SARA score at Month 12 was measured using an ANCOVA model. ANCOVA model was fitted with treatment, baseline SARA score, and use of miglustat as covariates.

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7899

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-1.82

upper limit

2.37

Secondary: 12. Change from Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT)

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End point title

12. Change from Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT)

End point description

The 9HPT test is a direct and simple measurement of fine motor coordination function, eye/hand coordination, and the ability to follow a simple direction. The 9HPT is a timed test in which nine pegs are inserted and removed from nine holes in the pegboard. Both hands are tested starting with the dominant hand. The time spent in completing the 9 HPT using each hand was recorded. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Baseline to 6 and 12 months

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	34	16
Units: Seconds
least squares mean (confidence interval 95%)
Dominant Hand: Change at 6 months	1.54 (-24.98 to 28.06)	11.88 (-20.88 to 44.64)
Non-dominant Hand: Change at 6 months	0.60 (-27.25 to 28.45)	16.46 (-17.07 to 50.00)
Dominant Hand: Change at 12 months	-3.29 (-15.56 to 8.98)	-6.49 (-20.34 to 7.37)
Non-dominant Hand: Change at 12 months	11.68 (-14.89 to 38.25)	17.59 (-13.24 to 48.42)

Statistical Analysis 1

Statistical analysis description

Dominant Hand: Change From Baseline in the Nine-Hole Peg Test (9HPT) at Month 6 was measured using an ANCOVA model: ANCOVA models were fitted with treatment, baseline dominant/non-dominant hand 9HPT time (secs), and use of miglustat as covariates

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6195

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-10.34

Confidence interval

level

95%

sides

2-sided

lower limit

-53.01

upper limit

32.33

Statistical Analysis 2

Statistical analysis description

Non-dominant Hand: Change From Baseline in the Nine-Hole Peg Test (9HPT) at Month 6 was measured using an ANCOVA model: ANCOVA models were fitted with treatment, baseline dominant/non-dominant hand 9HPT time (secs), and use of miglustat as covariates

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4693

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-15.87

Confidence interval

level

95%

sides

2-sided

lower limit

-60.73

upper limit

Statistical Analysis 3

Statistical analysis description

Dominant Hand: Change From Baseline in the Nine-Hole Peg Test (9HPT) at Month 12 was measured using an ANCOVA model: ANCOVA models were fitted with treatment, baseline dominant/non-dominant hand 9HPT time (secs), and use of miglustat as covariates

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7283

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-15.71

upper limit

22.12

Statistical Analysis 4

Statistical analysis description

Non-dominant Hand: Change From Baseline in the Nine-Hole Peg Test (9HPT) at Month 12 was measured using an ANCOVA model: ANCOVA models were fitted with treatment, baseline dominant/non-dominant hand 9HPT time (secs), and use of miglustat as covariates

Comparison groups

Arimoclomol (12-month Double-blind Phase) v Placebo (12-month Double-blind Phase)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7708

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-5.91

Confidence interval

level

95%

sides

2-sided

lower limit

-47.54

upper limit

35.72

Secondary: 13. Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)

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End point title

13. Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)

End point description

The CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment. A rating of 1 is considered normal, or with the least severe symptoms, a rating of 7 is extremely ill, or the worst symptoms. Scores thus range from 1-7 with lower scores indicating less severe disease. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Months 6 and 12

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	29	15
Units: Percentage of participants
number (not applicable)
Month 6: Normal, not ill at all	0	0
Month 6: Borderline ill	10.3	14.3
Month 6: Mildly ill	27.6	28.6
Month 6: Moderately ill	10.3	35.7
Month 6: Markedly ill	31.0	0
Month 6: Severely ill	20.7	14.3
Month 6: Most extremely ill participants	0	7.1
Month 12: Normal, not ill at all	0	0
Month 12: Borderline ill	7.4	6.7
Month 12: Mildly ill	29.6	26.7
Month 12: Moderately ill	11.1	33.3
Month 12: Markedly ill	29.6	6.7
Month 12: Severely ill	22.2	26.7
Month 12: Most extremely ill participants	0	0

No statistical analyses for this end point

Secondary: 14. Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)

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End point title

14. Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)

End point description

The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement. The analysis is based on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Months 6 and 12

End point values	Arimoclomol (12-month Double-blind Phase)	Placebo (12-month Double-blind Phase)
Number of subjects analysed	29	15
Units: Percentage of participants
number (not applicable)
Month 6: Very Much Improved	3.4	0
Month 6: Much Improved	0	0
Month 6: Minimally Improved	24.1	25.0
Month 6: No Change	37.9	25.0
Month 6: Minimally Worse	27.6	33.3
Month 6: Much Worse	6.9	16.7
Month 6: Very Much Worse	0	0
Month 12: Very Much Improved	0	0
Month 12: Much Improved	3.7	6.7
Month 12: Minimally Improved	18.5	33.3
Month 12: No Change	51.9	20.0
Month 12: Minimally Worse	14.8	13.3
Month 12: Much Worse	7.4	26.7
Month 12: Very Much Worse	3.7	0

No statistical analyses for this end point

Other pre-specified: 15. Change from OLE Baseline in 5 Domain NPCSS score

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End point title

15. Change from OLE Baseline in 5 Domain NPCSS score

End point description

NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5 domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment.

End point type

Other pre-specified

End point timeframe

OLE Baseline to Month 60

End point values	Open-label Arimoclomol (48-month OLE Phase)
Number of subjects analysed	41
Units: Score on a scale
arithmetic mean (standard deviation)
OLE Baseline	12.3 ( 7.8 )
Change from OLE Baseline to Month 18	0.9 ( 1.8 )
Change from OLE Baseline to Month 24	1.1 ( 2.8 )
Change from OLE Baseline to Month 30	1.4 ( 3.1 )
Change from OLE Baseline to Month 36	2.2 ( 4.0 )
Change from OLE Baseline to Month 42	2.0 ( 4.1 )
Change from OLE Baseline to Month 48	2.2 ( 4.3 )
Change from OLE Baseline to Month 54	2.3 ( 4.0 )
Change from OLE Baseline to Month 60	3.2 ( 4.8 )
Change from OLE Baseline to Final OLE visit	2.9 ( 4.7 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

In the period following the single dose of arimoclomol (single PK dose), from first to last dose of blinded study drug (12-month Double-Blind Phase) and from first to last dose of open-label study drug (48-month OLE Phase, 36-month pediatric substudy)

Adverse event reporting additional description

AEs are reported separately for the single dose period where participants received a single dose of arimoclomol, for the 12-month continuous dose period where participants received blinded treatment (arimoclomol or placebo), and for the 48-month OLE period/36-month pediatric substudy where participants received open-label arimoclomol.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Arimoclomol Single PK Dose

Reporting group description

Participants less than 12 years received a single oral dose of arimoclomol capsule, based on participant's body weight, on Day 1.

Reporting group title

Arimoclomol (12-month Double-Blind Phase)

Reporting group description

Participants received arimoclomol capsules, orally based on participant's body weight, TID for 12 months.

Reporting group title

Placebo (12-month Double-blind Phase)

Reporting group description

Participants received matching placebo to arimoclomol capsules, orally based on participant's body weight, TID for 12 months.

Reporting group title

Open-label Arimoclomol (48-month OLE Phase)

Reporting group description

All participants who completed the 12-month double-blind, randomized, placebo-controlled phase of the trial, were eligible for and agreed to participate in the OLE, and subsequently received at least 1 dose of open-label arimoclomol.

Reporting group title

Open-label Arimoclomol (36-month pediatric substudy)

Reporting group description

Participants received open-label arimoclomol, orally based on participant's age and body weight, TID for 36 months.

Serious adverse events	Arimoclomol Single PK Dose	Arimoclomol (12-month Double-Blind Phase)	Placebo (12-month Double-blind Phase)	Open-label Arimoclomol (48-month OLE Phase)	Open-label Arimoclomol (36-month pediatric substudy)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 28 (7.14%)	5 / 34 (14.71%)	6 / 16 (37.50%)	15 / 41 (36.59%)	2 / 5 (40.00%)
number of deaths (all causes)	0	1	0	2	0
number of deaths resulting from adverse events	0	1	0	2	0
Surgical and medical procedures
Complete oral rehabilitation
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Complication associated with device
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory Distress
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Chronic respiratory failure
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillar hypertrophy
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung consolidation
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device leakage
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Aspiration Bronchial
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Craniocerebral Injury
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardio-respiratory Arrest
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	2 / 16 (12.50%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epileptic Encephalopathy
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 28 (3.57%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dystonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lethargy
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Proteinuria
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Foot Deformity
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Lower Respiratory Tract Infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Pneumonia
subjects affected / exposed	1 / 28 (3.57%)	0 / 34 (0.00%)	2 / 16 (12.50%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Tract Infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypophagia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Feeding intolerance
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Arimoclomol Single PK Dose	Arimoclomol (12-month Double-Blind Phase)	Placebo (12-month Double-blind Phase)	Open-label Arimoclomol (48-month OLE Phase)	Open-label Arimoclomol (36-month pediatric substudy)
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 28 (14.29%)	30 / 34 (88.24%)	13 / 16 (81.25%)	38 / 41 (92.68%)	5 / 5 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma of liver
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Vascular disorders
Haematoma
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	1	0	3	0
Haemorrhage
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Surgical and medical procedures
Gastrostomy
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 28 (3.57%)	6 / 34 (17.65%)	3 / 16 (18.75%)	4 / 41 (9.76%)	1 / 5 (20.00%)
occurrences all number	1	15	4	9	9
Medical device site reaction
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Fatigue
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	2	0	2	0
Malaise
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Abasia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Gait disturbance
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	1	0	1	1
Influenza like illness
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Local swelling
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Medical device site haemorrhage
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Medical device site ulcer
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Oedema peripheral
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	1
Unevaluable event
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Asthenia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Medical Device Site Dermatitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Peripheral Swelling
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Secretion Discharge
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Disease progression
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	2
Temperature regulation disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Immune system disorders
Renal abscess
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Seasonal allergy
subjects affected / exposed	0 / 28 (0.00%)	3 / 34 (8.82%)	1 / 16 (6.25%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	4	1	1	0
Drug Hypersensitivity
subjects affected / exposed	1 / 28 (3.57%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	0	0	0
Food Allergy
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	1	0	0	1
Social circumstances
Convalescent
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Perineal rash
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Premenstrual Syndrome
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Menstruation irregular
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	1 / 16 (6.25%)	7 / 41 (17.07%)	2 / 5 (40.00%)
occurrences all number	0	2	1	9	8
Epistaxis
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	1 / 16 (6.25%)	6 / 41 (14.63%)	0 / 5 (0.00%)
occurrences all number	0	6	1	8	0
Oropharyngeal pain
subjects affected / exposed	0 / 28 (0.00%)	3 / 34 (8.82%)	1 / 16 (6.25%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	3	1	4	0
Asthma
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	1 / 5 (20.00%)
occurrences all number	0	0	0	3	1
Interstitial lung disease
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	1	0	2	0
Aspiration
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Bronchial hyperreactivity
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Increased upper airway secretion
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Lung disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Pneumonia aspiration
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Respiratory tract inflammation
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Bronchospasm
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Dysphonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Nasal Congestion
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	0	0
Productive Cough
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	2	0	0	1
Psychiatric disorders
Sleep disorder
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	2 / 41 (4.88%)	1 / 5 (20.00%)
occurrences all number	0	1	0	3	1
Anxiety
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Attention deficit/hyperactivity disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Illusion
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Initial insomnia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Insomnia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Aggression
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	0	0
Agitation
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Hallucination, auditory
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Hallucination, visual
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Investigations
Weight decreased
subjects affected / exposed	0 / 28 (0.00%)	5 / 34 (14.71%)	0 / 16 (0.00%)	6 / 41 (14.63%)	0 / 5 (0.00%)
occurrences all number	0	6	0	8	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	3 / 41 (7.32%)	2 / 5 (40.00%)
occurrences all number	0	0	0	3	3
Alanine aminotransferase increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	3 / 5 (60.00%)
occurrences all number	0	0	0	2	3
Blood triglycerides increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Blood creatine increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Blood creatinine increased
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Blood magnesium increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Eosinophil count increased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Gastric pH decreased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Platelet count decreased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Vitamin D decreased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Body Temperature Abnormal
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Body Temperature Increased
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	11	0	0	1
C-reactive Protein Increased
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Blood iron decreased
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Ultrasound liver abnormal
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	1 / 16 (6.25%)	4 / 41 (9.76%)	0 / 5 (0.00%)
occurrences all number	0	1	1	4	0
Laceration
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	1	0	5	0
Expired product administered
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Fall
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	2	0	2	0
Stoma site hypergranulation
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Eye contusion
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Eye injury
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Joint dislocation
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Lip injury
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Procedural pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	1	0	1	1
Traumatic haemorrhage
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Eschar
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Head Injury
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Injury
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Ligament Sprain
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Tooth Injury
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Congenital, familial and genetic disorders
Phimosis
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	2 / 16 (12.50%)	7 / 41 (17.07%)	0 / 5 (0.00%)
occurrences all number	0	1	2	8	0
Seizure
subjects affected / exposed	0 / 28 (0.00%)	3 / 34 (8.82%)	1 / 16 (6.25%)	6 / 41 (14.63%)	0 / 5 (0.00%)
occurrences all number	0	3	1	11	0
Headache
subjects affected / exposed	0 / 28 (0.00%)	3 / 34 (8.82%)	1 / 16 (6.25%)	4 / 41 (9.76%)	0 / 5 (0.00%)
occurrences all number	0	11	7	15	0
Cataplexy
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Dystonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Lethargy
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	2	0	3	0
Tremor
subjects affected / exposed	0 / 28 (0.00%)	3 / 34 (8.82%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	3	0	2	0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	4	0
Dizziness
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Quadriparesis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Ageusia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Balance disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Coordination abnormal
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Disturbance in attention
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Drooling
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Dysmetria
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Hypertonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Hypotonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Motor dysfunction
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Muscle spasticity
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Neurological decompensation
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Partial seizures
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Quadriplegia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Somnolence
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Speech disorder
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Syncope
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Tonic convulsion
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Aphasia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Cognitive Disorder
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Memory Impairment
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Migraine
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Paraesthesia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	0	0
Peroneal Nerve Palsy
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Petit Mal Epilepsy
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	1	0	3	0
Splenomegaly
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Anaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Eosinophilia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Ear and labyrinth disorders
Excessive cerumen production
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Deafness Neurosensory
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Deafness Unilateral
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Ear Pain
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	1	0	1
Middle ear effusion
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Tympanic membrane perforation
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Eye disorders
Corneal epithelium defect
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Corneal opacity
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Dry eye
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Saccadic eye movement
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Pupils Unequal
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Diplopia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 28 (0.00%)	7 / 34 (20.59%)	2 / 16 (12.50%)	10 / 41 (24.39%)	3 / 5 (60.00%)
occurrences all number	0	23	3	27	4
Vomiting
subjects affected / exposed	0 / 28 (0.00%)	8 / 34 (23.53%)	4 / 16 (25.00%)	5 / 41 (12.20%)	2 / 5 (40.00%)
occurrences all number	0	26	5	7	6
Constipation
subjects affected / exposed	0 / 28 (0.00%)	7 / 34 (20.59%)	3 / 16 (18.75%)	5 / 41 (12.20%)	2 / 5 (40.00%)
occurrences all number	0	14	3	6	3
Dysphagia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Abdominal distension
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	1	0	1	1
Anal fissure
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Anal haemorrhage
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Gastrointestinal disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	1 / 16 (6.25%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	1	1	1	1
Inflammatory bowel disease
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Inguinal hernia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Nausea
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	1	1	0
Salivary hypersecretion
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	1 / 16 (6.25%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	1	1	0
Abdominal Pain Upper
subjects affected / exposed	1 / 28 (3.57%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	0	0	0
Abdominal Discomfort
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Aphthous Ulcer
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	2	0	0	0
Dental Caries
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Lip Dry
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Mouth Cyst
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Odynophagia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Tongue ulceration
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	3
Anorectal disorder
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Hepatic Lesion
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Hepatomegaly
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	5 / 41 (12.20%)	0 / 5 (0.00%)
occurrences all number	0	0	1	5	0
Acne
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	1	0	3	0
Dry skin
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Decubitus ulcer
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Acanthosis nigricans
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Alopecia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Angiokeratoma
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Blister
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Dermatitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Dermatitis allergic
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Dermatitis diaper
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	1
Rash
subjects affected / exposed	1 / 28 (3.57%)	1 / 34 (2.94%)	1 / 16 (6.25%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	1	1	1	1	1
Seborrhoeic dermatitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	1
Skin lesion
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Umbilical discharge
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Angioedema
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Dandruff
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Henoch-Schonlein Purpura
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Urticaria
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	1	0	0	1
Renal and urinary disorders
Urinary incontinence
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Oliguria
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Endocrine disorders
Precocious puberty
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	1 / 16 (6.25%)	2 / 41 (4.88%)	1 / 5 (20.00%)
occurrences all number	0	1	2	2	1
Back pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	3	0
Pain in extremity
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	1 / 16 (6.25%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	2	1	2	0
Muscle atrophy
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Muscular weakness
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Myalgia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Scoliosis
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Coccydynia
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	4 / 16 (25.00%)	8 / 41 (19.51%)	1 / 5 (20.00%)
occurrences all number	0	2	4	18	6
Corona virus infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	8 / 41 (19.51%)	0 / 5 (0.00%)
occurrences all number	0	0	0	8	0
Bronchitis
subjects affected / exposed	0 / 28 (0.00%)	4 / 34 (11.76%)	2 / 16 (12.50%)	7 / 41 (17.07%)	0 / 5 (0.00%)
occurrences all number	0	5	2	7	0
Rhinitis
subjects affected / exposed	0 / 28 (0.00%)	5 / 34 (14.71%)	2 / 16 (12.50%)	5 / 41 (12.20%)	0 / 5 (0.00%)
occurrences all number	0	8	5	14	0
Influenza
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	1 / 16 (6.25%)	4 / 41 (9.76%)	0 / 5 (0.00%)
occurrences all number	0	1	1	6	0
Gastroenteritis
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	2 / 16 (12.50%)	4 / 41 (9.76%)	1 / 5 (20.00%)
occurrences all number	0	2	3	4	1
Conjunctivitis
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	1 / 16 (6.25%)	2 / 41 (4.88%)	1 / 5 (20.00%)
occurrences all number	0	1	2	7	1
Lower respiratory tract infection
subjects affected / exposed	0 / 28 (0.00%)	3 / 34 (8.82%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	4	0	4	0
Eye infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	2 / 16 (12.50%)	2 / 41 (4.88%)	1 / 5 (20.00%)
occurrences all number	0	0	2	3	1
Gastroenteritis viral
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	0	1	3	0
Urinary tract infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	1 / 5 (20.00%)
occurrences all number	0	0	0	3	1
Fungal infection
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	2 / 41 (4.88%)	1 / 5 (20.00%)
occurrences all number	0	3	0	2	1
Hordeolum
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	0	1	2	0
Tonsillitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	2 / 41 (4.88%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Ear infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	2 / 16 (12.50%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	2	4	0
Febrile infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Fungal skin infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Haemophilus infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Infected bite
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Oral fungal infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	1	1	0
Otitis media
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	1
Pharyngitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Pneumonia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	2
Respiratory tract infection
subjects affected / exposed	0 / 28 (0.00%)	3 / 34 (8.82%)	1 / 16 (6.25%)	1 / 41 (2.44%)	1 / 5 (20.00%)
occurrences all number	0	6	2	1	1
Sinusitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Staphylococcal infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Tracheitis
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Varicella
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Hand-foot-and-mouth Disease
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	1	0	1
Localised Infection
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Medical Device Site Infection
subjects affected / exposed	0 / 28 (0.00%)	2 / 34 (5.88%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	5	0	0	0
Onychomycosis
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Oral Candidiasis
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Skin Candida
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Viral Infection
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	1	0	0
Viral Upper Respiratory Tract Infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Vulvovaginal Mycotic Infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Wound infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	1 / 16 (6.25%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 28 (3.57%)	6 / 34 (17.65%)	1 / 16 (6.25%)	9 / 41 (21.95%)	2 / 5 (40.00%)
occurrences all number	1	8	1	17	5
Candida infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Furuncle
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Postoperative wound infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Stoma site infection
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	0 / 41 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Metabolism and nutrition disorders
Iron deficiency
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	2	0	3	0
Vitamin D deficiency
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	3 / 41 (7.32%)	0 / 5 (0.00%)
occurrences all number	0	1	0	3	0
Dehydration
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Folate deficiency
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Hypercholesterolaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Hypokalaemia
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Malnutrition
subjects affected / exposed	0 / 28 (0.00%)	0 / 34 (0.00%)	0 / 16 (0.00%)	1 / 41 (2.44%)	0 / 5 (0.00%)
occurrences all number	0	0	0	1	0
Decreased appetite
subjects affected / exposed	0 / 28 (0.00%)	3 / 34 (8.82%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	4	0	0	0
Refeeding syndrome
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Vitamin C deficiency
subjects affected / exposed	0 / 28 (0.00%)	1 / 34 (2.94%)	0 / 16 (0.00%)	0 / 41 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

30 Aug 2016

Protocol version 4.0: Specification of “end of trial” at 36 months (based on regulatory feedback). The secondary objectives and the corresponding endpoints were updated to include the evaluation of therapeutic response and safety at 36 months. CGI-S and CGI-I added as secondary endpoints as requested by the FDA.

11 May 2017

Protocol version 5.0: Biomarker endpoints updated: 7-ketocholesterol removed from the assessments due to stability problems with the analyte. Glycosphingolipids and sphingoid bases added as endpoints. Sample size updated to include up to 52 randomised patients.

13 Mar 2018

Protocol version 6.0: Change of primary endpoint to the 5-domain NPCCSS instead of the full scale NPCCSS upon recommendation from the FDA. This was done in order to reduce the variability and thereby increase the robustness of the primary endpoint analysis. The selection of domains was based upon the clinical importance as verified by research conducted by Orphazyme in collaboration with therapeutic area experts, patients, and families. Secondary endpoints ranked to specify “key secondary endpoints” and "other secondary endpoints” to indicate the level of importance. The following key secondary endpoints included: responder analyses (on CGI-I score and 5-domain NPCCSS) and time to worsening (defined as the time until the patient reaches the predefined MCT of 2 points on the 5- domain NPCCSS) added as key secondary endpoints based on regulatory feedback. For the FDA submission, CGI-score was to be considered a coprimary endpoint. The original primary endpoint, change in full scale NPCCSS (apart from hearing domains) at 12 months, changed to be a key secondary endpoint. Additional secondary endpoints added: - Change in 5-domain NPCCSS score at 6, 18, 24, 30, and 36 months;- Change in full scale NPCCSS score apart from hearing domains (i.e. Hearing and Auditory Brainstem Response) at 6, 18, 24, 30, and 36 months;- Responder analyses for CGI-I and NPCCSS, respectively, at 6, 18, 24, 30, and 36 months;- Proportion of patients worsening at 18, 24, 30, and 36 months. Clarification that the exploratory endpoint for NPC disease progression rate is based on NPCCSS apart from hearing domains. Definition of baseline clarified to be the latest assessment prior to randomisation. Interim analysis included, planned to be performed once approximately 50% of the ongoing patients had received 6 months of open-label treatment with arimoclomol. Clarification of analysis set definitions

12 Jul 2018

Protocol version 7.0: Changes implemented which were only relevant for the open-label extension phase: Collection of a PK sample was added at Visit 8 (after 12 months of open-label treatment). It was clarified that the DSMB was only to review safety data during the double-blind phase of the trial.

09 Jul 2019

Protocol version 8.0: Addition of the Lyso-SM-509 biomarker. Additional changes which were only relevant for the open-label extension phase: Since a marketing authorization had not been obtained and efficacy and/or safety of arimoclomol did not require trial termination, the original 2-year OLE phase of the trial was extended with 2 years to a total duration of 60 months for the full trial (12 months double-blind and 48 months OLE). Accordingly, 4 additional visits (Visits 10, 11, 12, and 13 at Months 36, 42, 48, and 54 in the full trial) were added throughout the protocol, and end of the OLE phase (at Month 60 in the full trial) was changed to Visit 14. Furthermore, the corresponding timepoints were added to the secondary objectives and endpoints. • Based upon the observations from the double-blind part of the trial, it was found relevant to continue analyzing the levels of unesterified cholesterol, HSP70, and GSLs in the OLE phase. In addition, lyso-SM-509, a promising new biomarker for NPC, was added as a potential marker of the disease progression. The analysis of NPC-1 active protein was omitted.

09 Jun 2020

Protocol version 9.0: The period of using contraception after last dose of IMP was extended for female patients from 1 to 3 weeks to cover 5 half-lives of the arimoclomol metabolites. The CRO for the trial was changed from Orion Clinical Services to Worldwide Clinical Trials, and the vendor for the statistical analyses was changed from Orion Clinical Services to Larix A/S.

25 Sep 2020

Protocol version 10.0: It was added that dose adjustment due to increased serum creatinine could be temporary and that subsequent dose increase had to be discussed with the medical monitor (or delegate).• Safety and tolerability were deleted as primary endpoint. This had been included as primary endpoint by mistake when adding the pediatric sub-study to the protocol. The primary objective of the pediatric sub-study is safety and tolerability; however, the pediatric sub-study has no primary endpoint.• Clarification in wording regarding AE/SAE reporting procedures was made. The names of data management vendors were removed to avoid later amendments due to changes in vendors.

21 Jun 2022

The name of the sponsor was changed from Orphazyme A/S to KemPharm Denmark A/S (taking over from Orphazyme A/S on 01-Jun-2022) throughout the protocol

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

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Clinical trials

Clinical Trial Results: Arimoclomol prospective double blind, randomised, placebo-controlled study in patients diagnosed with Niemann Pick disease type C

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1. Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Score

Primary: 1. Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Score

Secondary: 2. Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I)

Secondary: 2. Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I)

Secondary: 3. Percentage of Responders in 5-domain NPCCSS

Secondary: 3. Percentage of Responders in 5-domain NPCCSS

Secondary: 4. Time to Worsening

Secondary: 4. Time to Worsening

Secondary: 5. Percentage of Participants with Worsening

Secondary: 5. Percentage of Participants with Worsening

Secondary: 6. Change from Baseline in 17-domain NPCCSS Apart from Hearing Domains (i.e. Hearing and Auditory Brainstem Response)

Secondary: 6. Change from Baseline in 17-domain NPCCSS Apart from Hearing Domains (i.e. Hearing and Auditory Brainstem Response)

Secondary: 7. Change from Baseline in 5-domain NPCCSS Score

Secondary: 7. Change from Baseline in 5-domain NPCCSS Score

Secondary: 8. Changes from Baseline in Each Individual Domain of the NPCCSS

Secondary: 8. Changes from Baseline in Each Individual Domain of the NPCCSS

Secondary: 9. Change from Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified "Stampfer Score")

Secondary: 9. Change from Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified "Stampfer Score")

Secondary: 10. Percentage of Participants with Change from Baseline in Quality of Life (EQ-5D-Y)

Secondary: 10. Percentage of Participants with Change from Baseline in Quality of Life (EQ-5D-Y)

Secondary: 11. Change from Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score

Secondary: 11. Change from Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score

Secondary: 12. Change from Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT)

Secondary: 12. Change from Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT)

Secondary: 13. Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)

Secondary: 13. Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)

Secondary: 14. Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)

Secondary: 14. Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)

Other pre-specified: 15. Change from OLE Baseline in 5 Domain NPCSS score

Other pre-specified: 15. Change from OLE Baseline in 5 Domain NPCSS score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Arimoclomol prospective double blind, randomised, placebo-controlled study in patients diagnosed with Niemann Pick disease type C