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Clinical Trial Results:
A Phase IIb open-label, multi-centre, extension study to explore the long-term safety and efficacy of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation who have completed study KH176-202.

Summary
EudraCT number	2020-000832-23
Trial protocol	NL DK
Global end of trial date	08 Aug 2023

Results information
Results version number	v1(current)
This version publication date	06 Dec 2024
First version publication date	06 Dec 2024
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

KH176-203

ISRCTN number

US NCT number

NCT04604548

WHO universal trial number (UTN)

Sponsor organisation name

Khondrion B.V.

Sponsor organisation address

Transistorweg 5C, Nijmegen, Netherlands, 6534 AT

Public contact

G. Ruiterkamp, M. Sc., Khondrion B.V., +31 612805425, ruiterkamp@khondrion.com

Scientific contact

Jan M.A. Smeitink, MD, PhD, MAE, Khondrion B.V., +31 24 763 5000 Option 1, info@khondrion.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

01 Nov 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Aug 2023

Global end of trial reached?

Yes

Global end of trial date

08 Aug 2023

Was the trial ended prematurely?

Main objective of the trial

To assess the long-term safety of sonlicromanol (KH176) during an 18-months treatment period, including: 1. The tolerability and safety of sonlicromanol 100 mg BID following 18 months of oral administration 2. Electrocardiogram (ECG) intervals, rhythm and morphology

Protection of trial subjects

This study was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The Informed Consent Forms were signed and dated by the patient or the patient’s legally authorized representative before his or her participation in the study. The Data Safety Monitoring Committee (DSMB) safeguarded the interests of the study subjects, assessed the accumulating safety data of the interventions during the study, and reviewed the study’s progress including accruing data of recruitment and data quality.

Background therapy

Use of (multi)vitamins, co-enzyme Q10, Vitamin E, riboflavin and anti-oxidant supplements (including, but not limited to idebenone/EPI-743, mitoQ or alternative names of similar products) is not allowed from 4 weeks prior to the first dosing until follow up, unless stable for at least one month prior to first dosing and remaining stable throughout the study. Any medication negatively influencing mitochondrial functioning (including but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone, and NSAIDs) is prohibited from 4 weeks prior to the first dosing until follow up, unless stable for at least one month prior to first dosing and remaining stable throughout the study. Strong CYP3A4 inhibitors (all ‘conazoles-anti-fungals’, certain HIV antivirals, grapefruit) and Cytochrome P450 3A4 inducers, including certain HIV antivirals, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort, pioglitazone, troglitazone are not allowed from 4 weeks prior to the first dosing until follow up. Any medication known to affect cardiac repolarisation, unless QTc interval at screening is normal during stable treatment for a period of two weeks, or 5 half-lives of the medication and its major metabolite(s), whichever period is the shortest: all anti-psychotics, several anti-depressants: e.g. anti-emetics: domperidone, granisetron, ondansetron.

Evidence for comparator

Not Applicable

Actual start date of recruitment

01 Sep 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 7

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

United Kingdom: 3

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

Study KH176-202 was initially conducted at 4 Investigational sites (the Netherlands, Germany, the United Kingdom, and Denmark). Subjects having fulfilled all inclusion and exclusion criteria and completed the full treatment period of study KH176-202 were enrolled in study KH176-203.

Screening details

18 of 24 subjects who completed Study KH176-202 were screened. 3 subjects were screening failures, 15 subjects were eligible to participate. 11 of the 15 subjects completed the Wk 52 visit, 4 subjects discontinued prior to Wk52: 3 subjects due to withdrawal of consent by subject (2 in the UK and 1 in Germany) and 1 subject due to study terminated.

Period 1 title

Baseline to End of Treatment (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

100 mg BID sonlicromanol

Arm description

Oral administration of sonlicromanol 100 mg BID

Arm type

Experimental

Investigational medicinal product name

sonlicromanol

Investigational medicinal product code

SUB198953

Other name

KH176

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

KH176 is available as a powder for reconstitution, to be reconstituted with tapwater. KH176 50 mg or 100 mg will be provided in 20 mL bottles, which can be used to add the tapwater and consequently drink the oral liquid.

Number of subjects in period 1	100 mg BID sonlicromanol
Started	15
Completed	8
Not completed	7
Consent withdrawn by subject	3
Study Termination by Sponsor	4

Baseline characteristics

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Reporting group title

Baseline to End of Treatment

Reporting group description

Subjects with a genetically confirmed mitochondrial deoxyribonucleic acid (DNA) transfer ribonucleic acid (tRNA)Leu(UUR) m.3243A>G mutation who completed study KH176-202. In the KH176-203 study subjects will be receiving sonlicromanol 100 mg BID or sonlicromanol 50 mg BID (as determined by the investigator based on safety / tolerability considerations) for a period of 18 months , thereby ensuring treatment continuation with sonlicromanol after study KH176-202.

Reporting group values	Baseline to End of Treatment	Total
Number of subjects	15	15
Age categorical
Units: Subjects
Adults (18-64 years)	15	15
From 65-84 years	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	47.9 ( 5.9 )	-
Gender categorical
Units: Subjects
Female	10	10
Male	5	5
Country
Units: Subjects
Netherlands	7	7
Germany	3	3
United Kingdom	3	3
Denmark	2	2
Diagnosis
Units: Subjects
MELAS	2	2
MIDD	12	12
Mixed Phenotype	1	1
Race
Units: Subjects
Black	0	0
American Native Or Alaska Native	0	0
Asian	0	0
Native Hawaiian Or Other Pacific Islander	0	0
White	15	15
Height
Units: Centimeters
arithmetic mean (standard deviation)	168.4 ( 8.6 )	-
Body Mass Index (BMI)
Units: kg/m2
arithmetic mean (standard deviation)	23.12 ( 4.64 )	-
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	65.29 ( 12.21 )	-

End points

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Reporting group title

100 mg BID sonlicromanol

Reporting group description

Oral administration of sonlicromanol 100 mg BID

Subject analysis set title

FAS

Subject analysis set type

Full analysis

Subject analysis set description

The Full-Analysis Set (FAS) consists of all subjects who received study medication in this study and who had at least one on-treatment efficacy assessment after first drug intake.

Primary: Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events (SAEs)

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End point title

Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events (SAEs) ^[1]

End point description

The All-Subjects-Treated/Safety population: includes all subjects who received at least one dose of study medication (sonlicromanol) in this study. A treatment emergent adverse event (TEAE) is defined as an adverse event when the date of onset or when an existing condition increased during the use of the study medication up to 14 days after the last study medication or when an existing condition increased in severity relative to pretreatment state An AE is considered related if the causality to the study medication is classified as either ‘Definite’, ‘Probable’, or ‘Possible’. Otherwise, it will be considered unrelated.

End point type

Primary

End point timeframe

Baseline (Day 1) to end of study (Week 78)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned; only descriptive data were reported for this endpoint.

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	15
Units: (S)AEs
Number of Subjects with any TEAE	13	13
Number of subjects with any related TEAE	8	8
Number of subjects with any severe TEAE	2	2
Number of subjects with any serious TEAE	2	2
Number of subjects with TEAE leading to study disc	0	0
Number of subjects with TEAE leading to death	0	0

No statistical analyses for this end point

Primary: Changes from baseline to End of Treatment (Week 52) in safety laboratory parameters: biochemistry

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End point title

Changes from baseline to End of Treatment (Week 52) in safety laboratory parameters: biochemistry ^[2]

End point description

End point type

Primary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned; only descriptive data were reported for this endpoint.

End point values	100 mg BID sonlicromanol
Number of subjects analysed	15
Units: Percentage
arithmetic mean (standard deviation)
Albumin (g/L)	1.46 ( 6.63 )
Alkaline Phosphatase (ukat/L)	-3.097 ( 9.284 )
Alanine Aminotransferase (ukat/L)	13.652 ( 33.867 )
Amylase (ukat/L)	14.256 ( 47.449 )
Aspartate Aminotransferase (ukat/L)	-2.231 ( 23.799 )
Creatine Kinase (ukat/L)	1.08 ( 42.22 )
Bilirubin (umol/L)	32.03 ( 57.19 )
Calcium Corrected for Albumin (mmol/L)	1.26 ( 4.58 )
Cholesterol (mmol/L)	3.415 ( 8.530 )
Chloride (mmol/L)	0.00 ( 1.93 )
Creatinine (umol/L)	-1.43 ( 8.83 )
C Reactive Protein (mg/L)	-17.21 ( 33.98 )
Gamma Glutamyl Transferase (ukat/L)	3.283 ( 21.057 )
Glucose (mmol/L)	-6.93 ( 24.19 )
Hemoglobin A1C (mmol/mol)	0.26 ( 7.55 )
HDL Cholesterol (mmol/L)	-3.508 ( 27.800 )
Potassium (mmol/L)	-1.527 ( 9.504 )
Lactic Acid (mmol/L)	-2.765 ( 25.622 )
LDL Cholesterol (mmol/L)	0.651 ( 11.137 )
Lipase (ukat/L)	-2.561 ( 24.959 )
Phosphate (mmol/L)	-7.724 ( 23.423 )
Protein (g/L)	-0.14 ( 5.48 )
Sodium (mmol/L)	-0.52 ( 1.51 )
Thyroxine Free (pmol/L)	6.353 ( 9.323 )
Triglycerides (mmol/L)	6.034 ( 29.586 )
Thyrotropin (mIU/L)	48.542 ( 57.525 )
Urate (mmol/L)	-2.4 ( 7.3 )
Urea (mmol/L	-1.306 ( 20.270 )

No statistical analyses for this end point

Primary: Changes from baseline to End of Treatment (Week 52) in safety laboratory parameters: haematology

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End point title

Changes from baseline to End of Treatment (Week 52) in safety laboratory parameters: haematology ^[3]

End point description

End point type

Primary

End point timeframe

Baseline (Day 1) to End of Treatment (week 52)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned; only descriptive data were reported for this endpoint.

End point values	100 mg BID sonlicromanol
Number of subjects analysed	11
Units: Percentage
arithmetic mean (standard deviation)
Basophils (10^9/L)	2.035 ( 40.101 )
Eosinophils (10^9/L)	-7.586 ( 39.332 )
Ery. Mean Corpuscular HGB Concentration (mmol/L)	-1.080 ( 2.875 )
Ery. Mean Corpuscular Hemoglobin (fmol)	0.4164 ( 3.0922 )
Ery. Mean Corpuscular Volume (fL)	1.46 ( 2.16 )
Erythrocytes (10^12/L)	1.738 ( 5.438 )
Hematocrit (fraction of 1)	2.9755 ( 4.5619 )
Hemoglobin (mmol/L)	1.751 ( 4.515 )
Leukocytes (10^9/L)	-4.472 ( 12.752 )
Lymphocytes (10^9/L)	-1.98 ( 17.01 )
Monocytes (10^9/L)	-1.70 ( 16.27 )
Neutrophils (10^9/L)	-1.860 ( 22.953 )
Thrombocytes (10^9/L)	2.4 ( 7.8 )

No statistical analyses for this end point

Primary: Changes from baseline to End of Treatment (Week 52) in ECG parameters

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End point title

Changes from baseline to End of Treatment (Week 52) in ECG parameters ^[4]

End point description

End point type

Primary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned; only descriptive data were reported for this endpoint.

End point values	100 mg BID sonlicromanol
Number of subjects analysed	11
Units: Percentage
arithmetic mean (standard error)
QT Interval Aggregate	0.5 ( 6.3 )
QTc Interval Framingham correction	0.9 ( 2.6 )
QTcB Interval Aggregate	1.0 ( 3.4 )
QTcF Interval Aggregate	0.8 ( 2.6 )
RR Interval Aggregate	-0.2 ( 15.7 )
PR Interval Aggregate	-5.4 ( 7.4 )
ECG Mean Heart Rate	2.3 ( 16.2 )
QRS Duration Aggregate	1.3 ( 6.4 )
QRS Axis	3.8 ( 481.9 )
T Wave Amplitude Single Beat	-5.2 ( 21.2 )
Tpeak-Tend Interval Aggregate	14.4 ( 29.6 )

No statistical analyses for this end point

Primary: Changes from baseline to End of Treatment (Week 52) in Vital signs

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End point title

Changes from baseline to End of Treatment (Week 52) in Vital signs ^[5]

End point description

End point type

Primary

End point timeframe

Baseline (Day 1) to End of Treatment (week 52)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned; only descriptive data were reported for this endpoint.

End point values	100 mg BID sonlicromanol
Number of subjects analysed	11
Units: Percentage
arithmetic mean (standard deviation)
Systolic Blood Pressure (mmHg)	2.25 ( 8.99 )
Diastolic Blood Pressure (mmHg)	-1.16 ( 10.73 )
Heart Rate (beats/min)	-2.08 ( 9.22 )
Weight (kg)	-0.80 ( 2.94 )
Body Mass Index (kg/m2)	-0.80 ( 2.94 )

No statistical analyses for this end point

Primary: Changes from baseline to End of Treatment (Week 52) in Thyroid parameters

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End point title

Changes from baseline to End of Treatment (Week 52) in Thyroid parameters ^[6]

End point description

End point type

Primary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned; only descriptive data were reported for this endpoint.

End point values	100 mg BID sonlicromanol
Number of subjects analysed	2
Units: Percentage
arithmetic mean (standard deviation)
Left Lob: Anterior - Posterior	0.3 ( 0.1 )
Left Lob: Craniocaudal	1 ( 0 )
Left Lob: Transverse	-0.4 ( 0.1 )
Right Lob: Anterior-Posterior	-0.3 ( 0.1 )
Right Lob: Craniocaudal	1 ( 0 )
Right Lob: Transverse	-0.9 ( 0.3 )

No statistical analyses for this end point

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the attention domain of cognitive functioning: Identification Test (IDN)

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the attention domain of cognitive functioning: Identification Test (IDN)

End point description

Visual Identification Test (IDN) of the Cogstate computerized cognitive testing battery was used to evaluate the effect of KH176 during a 4-week treatment period on the attention domain score of cognitive functioning. Changes from baseline (measured at pre-dose Day 1) to end of treatment (Day 28 of each treatment period) in the attention domain score of cognitive functioning are measured. The Identification Test (IDN) is a measure of visual attention and uses a well-validated choice reaction time paradigm with playing card stimuli. In this test, the playing cards are all either red or black jokers. The subject is asked whether the card displayed in the centre of the screen is red. The subject responds by pressing the Yes key when the joker card is red and No when it is black. The software measures the speed and accuracy of each response

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of treatment Week 52

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
median (standard deviation)	0.2766 ( 0.5552 )	0.2766 ( 0.5552 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Statistical analysis are performed on the change from baseline values at Week 52 using repeated measures analysis of covariance (ANCOVA) model including visit as a fixed effect and baseline value as a covariate.

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.2456

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2023

upper limit

0.6936

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the executive functioning domain of cognitive functioning: Groton Maze Learning (GML).

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the executive functioning domain of cognitive functioning: Groton Maze Learning (GML).

End point description

Executive functioning: GML (number of errors learning the same hidden pathway across the consecutive learning trails [Total Errors], lower is better). The GML test is a measure of problem solving and reasoning and uses a maze learning paradigm. The subject was shown a 10×10 grid of boxes on a computer screen. A 28-step pathway is hidden among these 100 possible locations. Each box represents move locations, and the grid referred to the box array. Subjects were required to find the hidden pathway guided by 4 search rules: do not move diagonally, more than 1 box, move back on the pathway, and return to the last correct location after an error. At each step, only the most recently selected box was shown. Feedback was given with visual and auditory cues. The head of path, or the last correct location, flashed with a green check when 2 errors were made in succession to indicate to the subject that they had to return to this location. There were 21 well-matched alternate pathways available

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	10	10
Units: Z-score
arithmetic mean (standard deviation)	0.1210 ( 0.6361 )	0.1210 ( 0.6361 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.1049

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1432

upper limit

0.362

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: One Back Test (ONB) - speed of performance

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: One Back Test (ONB) - speed of performance

End point description

Working memory: ONB (speed of performance; mean of the log10 transformed reaction times for correct responses [Reaction Time], lower is better) The One Back Test (ONB) is a measure of working memory and uses a well-validated n-back paradigm with playing card stimuli. In this test, the playing cards are identical to those found in a standard deck of 52 playing cards (without the joker cards). The subject was asked whether the card displayed in the center of the screen was the same as the card presented immediately previously. The subject responded by pressing the Yes or No key. The software measured the speed and accuracy of each response.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	0.2383 ( 0.4763 )	0.2383 ( 0.4763 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.2255

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0867

upper limit

0.5376

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: One Back Test (ONB) – accuracy of performance

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: One Back Test (ONB) – accuracy of performance

End point description

Working memory: ONB (accuracy of performance; arcsine square root of proportion corrects [Accuracy], higher is better) The One Back Test (ONB) is a measure of working memory and uses a well-validated n-back paradigm with playing card stimuli. In this test, the playing cards are identical to those found in a standard deck of 52 playing cards (without the joker cards). The subject was asked whether the card displayed in the center of the screen was the same as the card presented immediately previously. The subject responded by pressing the Yes or No key. Because no card had been presented yet on the first study, a correct first response was always No. The software measured the speed and accuracy of each response.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	0.2216 ( 1.3847 )	0.2216 ( 1.3847 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.2858

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5103

upper limit

1.0818

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: Detection Test (DET) – speed of performance

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: Detection Test (DET) – speed of performance

End point description

Psychomotor function: DET (speed of performance; mean of the log10 transformed reaction times for correct responses [Reaction Time], lower is better) The Detection Test (DET) is a measure of psychomotor function and uses a well-validated simple reaction time paradigm with playing card stimuli. In this test, the playing cards all depict the same joker. The subject was asked to press the Yes key as soon as the card in the center of the screen turned face up. The software measured the speed and accuracy of each response.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.0698 ( 1.1579 )	-0.0698 ( 1.1579 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.0636

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5897

upper limit

0.4626

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the visual learning domain of cognitive functioning: Visual learning: One Card Learning Test (OCL)

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the visual learning domain of cognitive functioning: Visual learning: One Card Learning Test (OCL)

End point description

Visual learning: One Card Learning Test (OCL) Test (accuracy of performance; arcsine square root of proportion corrects [Accuracy], higher is better) The One Card Learning (OCL) Test is a measure of visual learning and uses a well-validated pattern separation paradigm with playing card stimuli. In this test, the playing cards are identical to those found in a standard deck of 52 playing cards (without the joker cards). The subject was asked whether the card displayed in the center of the screen was seen previously in this test. The subject responded by pressing the Yes or No key. The software measured the speed and accuracy of each response.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	0.2266 ( 0.9625 )	0.2266 ( 0.9625 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.2286

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3165

upper limit

0.7736

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the verbal learning domain of cognitive functioning: International Shopping List (ISL)

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the verbal learning domain of cognitive functioning: International Shopping List (ISL)

End point description

Verbal learning: ISL (number of correct responses remembering the word list on 3 consecutive trials [Total Correct], higher is better) The International Shopping List Test (ISL) is a measure of verbal learning and uses a well-validated list-learning paradigm. High frequencies, high imagery, and concrete nouns (items from a shopping list) were read to the subject by the test supervisor at the rate of 1 word every 2 seconds. Once all words had been read, the subject was asked to recall as many of the words as he/she could as quickly as possible. The test supervisor used a mouse to mark the words recalled by the subject on the computer screen. When the subject could recall no more words, the same list was read a second time. The test supervisor recorded the words recalled by the subject on this study. This was then repeated a third time. The software measured the number of correct responses as recorded by the test supervisor.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	10	10
Units: Z-score
arithmetic mean (standard deviation)	-0.3582 ( 0.6255 )	-0.3582 ( 0.6255 )

Repeated measures analysis of covariance (ANCOVA)

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.3538

Confidence interval

level

95%

sides

2-sided

lower limit

-0.779

upper limit

0.0715

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Attention Domain Composites of cognitive functioning: DET and IDN

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Attention Domain Composites of cognitive functioning: DET and IDN

End point description

Composite scores will be calculated by taking the equally weighted average of the available z-scores if the required number of z-scores available is met. Only computed if z-scores are available for both tests (DET and IDN).

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	0.1034 ( 0.7955 )	0.1034 ( 0.7955 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.0951

Confidence interval

level

95%

sides

2-sided

lower limit

-0.312

upper limit

0.5023

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Executive Function Composite of cognitive functioning: ONB (speed), GML

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Executive Function Composite of cognitive functioning: ONB (speed), GML

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	10	10
Units: Z-score
arithmetic mean (standard deviation)	0.1872 ( 0.3994 )	0.1872 ( 0.3994 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.1874

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0291

upper limit

0.4039

Secondary: Changes from baseline (measured at Day 1) to End of Treatment (Week 52) in the Global Composite of cognitive functioning: DET, IDN, OCL, ONB (speed), ISL, GML

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End point title

Changes from baseline (measured at Day 1) to End of Treatment (Week 52) in the Global Composite of cognitive functioning: DET, IDN, OCL, ONB (speed), ISL, GML

End point description

Global Composite Score: DET, IDN, OCL, ONB (speed), ISL, GML. Composite scores will be calculated by taking the equally weighted average of the available z-scores if the required number of z-scores available is met. Only computed if z-scores are available for DET, IDN, OCL, ONB (speed), ISL, GML: only computed if z-scores are available for a minimum of three tests with representation from all three domain composites listed above.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	0.0035 ( 0.4821 )	0.0035 ( 0.4821 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.0176

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2139

upper limit

0.2491

Secondary: Changes from baseline measured at Day 1 to End of Treatment Week 52 of Attentional Performance (TAP): Alertness with alarm median

Top of page

End point title

Changes from baseline measured at Day 1 to End of Treatment Week 52 of Attentional Performance (TAP): Alertness with alarm median

End point description

Test of Attentional Performance (TAP) (Version 2.3.1) is a standardised test to evaluate alertness and mental flexibility. Only the alertness subtest, with reaction time examination under 2 conditions, was used in this study.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	56.6 ( 59.5 )	56.6 ( 59.5 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-53

Confidence interval

level

95%

sides

2-sided

lower limit

-72.6

upper limit

-33.4

Secondary: Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Total score

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End point title

Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Total score

End point description

The Beck Depression Inventory (BDI) is a 21-question multiple-choice self-report inventory, for measuring the severity of depression. It is composed of items relating to symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex. Each answer is scored on a scale value of 0 to 3; higher scores indicate more severe depressive symptoms. The total score can thus range from 0 to 63. The BDI can be divided into subscales, ie, BDI-Affective (BDI-A), BDI-Cognitive (BDI-C), and BDI-Somatic (BDI-S). A BDI total score of more than 10 points was considered as affected. For BDI-A, BDI-C and BDI-S these cut-off values are >0.9, >1.4, and >4 respectively.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-4.5 ( 6.8 )	-4.5 ( 6.8 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-7.5

upper limit

-0.8

Secondary: Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Affective scale

Top of page

End point title

Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Affective scale

End point description

End point type

Secondary

End point timeframe

Baeline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.5 ( 1.8 )	-0.5 ( 1.8 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

0.5

Secondary: Changes from baseline (measured at pre-dose Day 1) to End of Treatment in (Week 52) in the Beck Depression Inventory (BDI): Somatic scale

Top of page

End point title

Changes from baseline (measured at pre-dose Day 1) to End of Treatment in (Week 52) in the Beck Depression Inventory (BDI): Somatic scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-3.2 ( 4.0 )	-3.2 ( 4.0 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Confidence interval

level

95%

Secondary: Changes from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Total score

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End point title

Changes from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Total score

End point description

The Hospital Anxiety and Depression Scale (HADS) is a subject-reported outcome measure and comprises 14 items equally divided over the two subscales anxiety (HADS-A) and depression (HADS-D). HADS-A includes items such as tension, worry, fear, panic, difficulties in relaxing, and restlessness, HADS-D includes items predominantly measuring anhedonia (not experiencing joy). Respondents indicate how they currently feel, rated on a 4-point Likert scale ranging from 0 to 3, with higher scores indicating higher severity. The ratings of the 14 items are summed to yield a total score (0 to 42), or for each subscale separately (0 to 21).

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-1.6 ( 7.1 )	-1.6 ( 7.1 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

1.9

Secondary: Changes from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Anxiety score

Top of page

End point title

Changes from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Anxiety score

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.9 ( 4.1 )	-0.9 ( 4.1 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.7

upper limit

Secondary: Change from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Depression score

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Depression score

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.7 ( 3.8 )	-0.7 ( 3.8 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

1.3

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section 1

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section 1

End point description

Section I, Current function, consists of vision; hearing; speech; swallowing; handwriting; cutting food and handling utensils; dressing; hygiene; exercise; and gait stability. Each item is scored according to the subject (or caregiver) and is not based upon the physician’s judgment. Each question/item in the NMDAS has a possible score from 0 to 5. Each of the first 3 section scores are calculated by simply summing the scores obtained for each question in that section, with a higher score indicating more severe disease. Thus, scores can range from 0 to 50 for Sections I and III, from 0 to 45 for Section II, and from 0 to 145 for Sections I through III.

End point type

Secondary

End point timeframe

Baseline (Day 1) To End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-1.4 ( 2.3 )	-1.4 ( 2.3 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.7

upper limit

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section II

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section II

End point description

Section II, System-specific involvement, is based on both input from the subject and clinical judgment and encompasses psychiatric; migraine headaches; seizures; stroke-like episodes; encephalopathic episodes; gastro-intestinal symptoms, diabetes mellitus; respiratory weakness; cardiovascular system. Each question/item in the NMDAS has a possible score from 0 to 5. Each of the first 3 section scores are calculated by simply summing the scores obtained for each question in that section, with a higher score indicating more severe disease. Thus, scores can range from 0 to 50 for Sections I and III, from 0 to 45 for Section II, and from 0 to 145 for Sections I through III.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.8 ( 1.3 )	-0.8 ( 1.3 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

-0.1

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section III

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section III

End point description

Section III, Current clinical assessment, is entirely based on the clinician’s assessment. It includes visual acuity; ptosis; CPEO; dysphonia/dysarthria; myopathy; cerebellar ataxia; neuropathy; pyramidal; extrapyramidal; cognition (measured by an adult reading test, Symbol Search (SS), and Speed of Comprehension Test [SOCT]). Each question/item in the NMDAS has a possible score from 0 to 5. Each of the first 3 section scores are calculated by simply summing the scores obtained for each question in that section, with a higher score indicating more severe disease. Thus, scores can range from 0 to 50 for Sections I and III, from 0 to 45 for Section II, and from 0 to 145 for Sections I through III.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard error)	0.6 ( 1.4 )	0.6 ( 1.4 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Confidence interval

level

95%

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Physical functioning

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Physical functioning

End point description

Section IV, Quality of Life, is assessed by the subject (or caregiver) using the SF-12. The SF-12 is a standard, extensively validated questionnaire which comes complete with its own administration and scoring manual. There should be no input from the clinician or health professional as this survey assesses the subject’s own opinion of their health status. The SF-12 is the abridged practical version of the SF-36. The instrument contains 8 subscales: physical functioning (2 items), role limitations due to physical problems (2 items), bodily pain (1 item), general health perceptions (1 item), vitality (1 item), social functioning (1 item), role limitations due to emotional problems (2 items) and mental health (2 items). Scores are such that a higher score indicates a better health state. Raw scores for each subscale are transformed to 0 to 100 scale scores.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	5.7 ( 7.9 )	5.7 ( 7.9 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

5.7

Confidence interval

level

95%

sides

2-sided

lower limit

1.8

upper limit

9.5

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Role limitations due to physical problems

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Role limitations due to physical problems

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	9.2 ( 8.0 )	9.2 ( 8.0 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

9.3

Confidence interval

level

95%

sides

2-sided

lower limit

5.6

upper limit

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Bodily pain

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Bodily pain

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1 ) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	6.6 ( 5.8 )	6.6 ( 5.8 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

6.3

Confidence interval

level

95%

sides

2-sided

lower limit

2.2

upper limit

10.5

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: General health perceptions

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: General health perceptions

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	10	10
Units: Z-score
arithmetic mean (standard deviation)	3.8 ( 6.2 )	3.8 ( 6.2 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

6.7

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Vitality

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Vitality

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	7.2 ( 11.7 )	7.2 ( 11.7 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

6.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

11.7

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Social functioning

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Social functioning

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-7.3 ( 7.8 )	-7.3 ( 7.8 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-7.3

Confidence interval

level

95%

sides

2-sided

lower limit

-12

upper limit

-2.7

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: role limitations due to emotional problems

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: role limitations due to emotional problems

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	2.4 ( 9.4 )	2.4 ( 9.4 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

6.9

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Mental health

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Mental health

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	3.6 ( 10.0 )	3.6 ( 10.0 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

8.8

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV (SF-12): Physical Component Score (PCS)

Top of page

End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV (SF-12): Physical Component Score (PCS)

End point description

Section IV, Quality of Life, is assessed using the SF-12. The instrument contains 8 subscales: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems) and mental health. The scoring yields 2 summary measures: Physical Component Summary (PCS) and the Mental Component Summary (MCS); 2 factors have been interpreted as physical and mental components of health status. Three scales (physical functioning, role limitations due to physical restrictions, and bodily pain) correlate with the physical component and contribute most to the scoring of the PCS measure. The mental component correlates with the mental health, role limitations due to emotional issues, and social functioning scales, which contribute most to the scoring of the MCS measure. A higher score indicates a better health state. Raw scores for each subscale are transformed to 0 to 100 scale scores.

End point type

Secondary

End point timeframe

Baseline to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	7.7 ( 5.4 )	7.7 ( 5.4 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

7.8

Confidence interval

level

95%

sides

2-sided

lower limit

5.4

upper limit

10.2

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV (SF-12) Mental Component Score (MCS)

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End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV (SF-12) Mental Component Score (MCS)

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.6 ( 8.0 )	-0.6 ( 8.0 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

3.5

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Short Form 6 Dimension [SF-6D]

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End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Short Form 6 Dimension [SF-6D]

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	0.0 ( 0.1 )	0.0 ( 0.1 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.1

Secondary: Changes from baseline measured at Day 1 to End of Treatment (Week 52) in the Smell Identification Test (UPSIT)

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End point title

Changes from baseline measured at Day 1 to End of Treatment (Week 52) in the Smell Identification Test (UPSIT)

End point description

The 40-item University of Penn Smell Identification Test (UPSIT) is a measurement of the individual's ability to detect odors at a suprathreshold level. The test consists of 4 different 10 page booklets, with a total of 40 questions. On each page, there is a different "scratch and sniff" strip which are embedded with a microencapsulated odorant. There is also a four choice multiple choice question on each page. The scents are released using a pencil. After each scent is released, the subject smells the level and detects the odor from the four choices. There is an answer column on the back of the test booklet, and the test is scored out of 40 items.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	0.7 ( 2.6 )	0.7 ( 2.6 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

3.7

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Cognitive Failure Questionnaire (CFQ): Total score

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End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Cognitive Failure Questionnaire (CFQ): Total score

End point description

The CFQ is a questionnaire to evaluate subjective cognitive functioning. It monitors the occurrence of daily cognitive errors with respect to memory and attention. The questionnaire has 25 items on daily activities related to attention and memory that must be scored on a 5-point scale. CFQ scores can range from 0 to 100. The higher the score, the more cognitive failure is indicated.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-4.6 ( 7.4 )	-4.6 ( 7.4 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-8.4

upper limit

0.7

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) Neuro-Quality-of-Life Fatigue Short Form (NQF-SF) Total score

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End point title

Change from baseline measured at Day 1 to End of Treatment (Week 52) Neuro-Quality-of-Life Fatigue Short Form (NQF-SF) Total score

End point description

The Neuro-QoL (quality in life in neurological disorders) is a measurement system that evaluates and monitors the physical, mental, and social effects experienced by adults and children living with neurological disorders. Each item in the measurement system can be evaluated separately and reference populations are available benchmarking the scores in population in this study at baseline and after treatment. In this study, only the Fatigue Short Form will be applied. The Fatigue Short Form is an 8 item score evaluating the perception of fatigue and its impact in daily life activities. Sensations ranging from tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that decreases one’s capacity for physical, functional, social, and mental activities.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-6.29 ( 5.53 )	-6.29 ( 5.53 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-6

Confidence interval

level

95%

sides

2-sided

lower limit

-9.21

upper limit

-2.8

Secondary: Changes from baseline measured at pre-dose (Day 1) to End of Treatment (week 52) in the Five times Sit-to-Stand Test (5XSTS)

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End point title

Changes from baseline measured at pre-dose (Day 1) to End of Treatment (week 52) in the Five times Sit-to-Stand Test (5XSTS)

End point description

The Five-time Sit-to-Stand (5xSTS) Test is a performance-based measure to assess the body functions needed to accomplish sit-to-stand transitions (e.g., lower limb strength, balance, and trunk control). The 5xSTS measures the amount of time it takes for a patient to sit and stand five times in succession with arms folded across their chest.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-1.21 ( 2.13 )	-1.21 ( 2.13 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-1.26

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

-0.12

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): Total score

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): Total score

End point description

The Mini-Balance Evaluation Systems Test (Mini-BESTest) is a comprehensive, unidimensional, brief 14-item balance scale to measure important aspects of dynamic balance control in adults. The Mini-BESTest contains items covering a broad spectrum of performance tasks, including transitions and anticipatory postural adjustments (anticipatory); postural responses to perturbation (reactive postural); sensory orientation while standing on a compliant or inclined base of support (sensory orientation); and dynamic stability in gait (dynamic gait). Each item is rated on a 3-point ordinal scale (0=severe to 2=normal) with 2 representing no impairment in balance and 0 representing severe impairment of balance.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol
Number of subjects analysed	11
Units: Z-score
arithmetic mean (standard deviation)	0.0873 ( 0.0509 )

No statistical analyses for this end point

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Handgrip Strength HS): Left

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Handgrip Strength HS): Left

End point description

Handgrip strength (HS) is an important clinical outcome measure in assessing upper extremity deficit. Grip strength was measured using a hand-held dynamometer. HS is assessed to quantify impairment level and to evaluate treatment response.

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	2.65 ( 3.45 )	2.65 ( 3.45 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

2.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.24

upper limit

5.44

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Handgrip Stregth Test (HS): Right

Top of page

End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Handgrip Stregth Test (HS): Right

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.14 ( 3.94 )	-0.14 ( 3.94 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-2.79

upper limit

3.07

Secondary: Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Total score

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End point title

Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Total score

End point description

The Short-Form McGill Pain Questionnaire (SF-MPQ) is an easy to administer self-rating scale which has been developed to assess the severity, affective, and evaluative dimensions of pain measuring the different qualities of the subjective pain experience. The main component of the SF-MPQ enables calculation of the pain rating index consisting of 15 pain descriptors. The Pain Rating Index has 2 subscales: the sensory subscale consisting of 11 adjectives describing the sensory qualities of the patient’s pain, and the affective subscale with 4 adjectives describing the affective qualities of the patient’s pain. Both subscales are rated on an intensity scale as 0=none, 1=mild, 2=moderate, or 3=severe. The SF-MPQ also includes the Present Pain Intensity (PPI) index and a visual analog scale (VAS) to record the patient’s PPI, anchored with no pain (0 mm) (0 mm) and worst possible pain (1)

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	10	10
Units: Z-score
arithmetic mean (standard deviation)	-5.7 ( 5.6 )	-5.7 ( 5.6 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-7.9

upper limit

0.4

Secondary: Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Dimension score

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Dimension score

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	8	8
Units: Z-score
arithmetic mean (standard deviation)	-5.1 ( 4.8 )	-5.1 ( 4.8 )

Repeated measures analysis of covariance (ANCOVA)

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

-0.2

Secondary: Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Dimension score

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Dimension score

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.6 ( 2.6 )	-0.6 ( 2.6 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

1.1

Secondary: Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Present Pain Inventory (PPI)

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Present Pain Inventory (PPI)

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-0.9 ( 1.4 )	-0.9 ( 1.4 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

-0.2

Secondary: Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Visual Analogue Scale (VAS)

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment in the Short-Form McGill Pain Questionnaire (SF-MPQ): Visual Analogue Scale (VAS)

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-21.5 ( 13.3 )	-21.5 ( 13.3 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-21

Confidence interval

level

95%

sides

2-sided

lower limit

-32.1

upper limit

-9.9

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Energy/fatigue

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Energy/fatigue

End point description

The RAND SF-36 is a 36-item generic, extensively validated, multidimensional self-reported Health-Related Quality of Life (HRQoL) questionnaire. The SF-36 yields an 8-scale profile of functional health and well-being, physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. This item asks about the general health compared to one year past, and is not included in any of the 8 dimensions. Likert scales and yes/no options are used to assess function and well-being on this 36-item questionnaire. To score the SF-36, scales are standardized with a scoring algorithm to obtain a score ranging from 0 to 100. Higher scores on all subscales represent better health and functioning. The SF-36 also includes a single item that assesses perc

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	18.6 ( 23.5 )	18.6 ( 23.5 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

17.3

Confidence interval

level

95%

sides

2-sided

lower limit

6.2

upper limit

28.5

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Emotional well-being

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Emotional well-being

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	5.8 ( 12.6 )	5.8 ( 12.6 )

Repeated measures analysis of covariance (ANCOVA)

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

5.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

13.8

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: General health

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: General health

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	10	10
Units: Z-score
arithmetic mean (standard deviation)	7.0 ( 8.6 )	7.0 ( 8.6 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

6.9

Confidence interval

level

90%

sides

2-sided

lower limit

0.8

upper limit

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Health change

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Health change

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	27.3 ( 30.5 )	27.3 ( 30.5 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

8.8

upper limit

41.1

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Pain

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Pain

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	18.9 ( 20.0 )	18.9 ( 20.0 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

7.4

upper limit

28.6

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Physical functioning

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Physical functioning

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	11.8 ( 15.2 )	11.8 ( 15.2 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Median difference (net)

Point estimate

11.3

Confidence interval

level

95%

sides

2-sided

lower limit

3.6

upper limit

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Role functioning/emotional

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Role functioning/emotional

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	-6.1 ( 32.7 )	-6.1 ( 32.7 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-9.1

Confidence interval

level

95%

sides

2-sided

lower limit

-30.2

upper limit

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Role functioning/physical

Top of page

End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Role functioning/physical

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	38.6 ( 42.2 )	38.6 ( 42.2 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

36.4

Confidence interval

level

95%

sides

2-sided

lower limit

13.7

upper limit

59.2

Secondary: Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Social functioning

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End point title

Change from baseline at measured at Day 1 to End of Treatment (Week 52) in the RAND SF-36: Social functioning

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	10	10
Units: Z-score
arithmetic mean (standard deviation)	21.1 ( 21.3 )	21.1 ( 21.3 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

20.9

Confidence interval

level

95%

sides

2-sided

lower limit

10.1

upper limit

31.7

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Attention Domain Composites of cognitive functioning: DET, IDN, and ONB (speed):

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Attention Domain Composites of cognitive functioning: DET, IDN, and ONB (speed):

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-scores
arithmetic mean (standard deviation)	0.1484 ( 0.6261 )	0.1484 ( 0.6261 )

Repeated measures analysis of covariance (ANCOVA)

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Median difference (net)

Point estimate

0.1104

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2305

upper limit

0.4514

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Learning/Working Memory Composite of cognitive functioning: OCL and ONB (accuracy)

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Learning/Working Memory Composite of cognitive functioning: OCL and ONB (accuracy)

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-scores
arithmetic mean (standard deviation)	0.2241 ( 0.8794 )	0.2241 ( 0.8794 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.2522

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2989

upper limit

0.8032

Secondary: Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Cognitive scale

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End point title

Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Cognitive scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-scores
arithmetic mean (standard deviation)	-0.7 ( 1.3 )	-0.7 ( 1.3 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

0.4

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Global Composite of cognitive functioning: DET, IDN, OCL, ONB (speed), ISL, GML

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Global Composite of cognitive functioning: DET, IDN, OCL, ONB (speed), ISL, GML

End point description

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Global Composite of cognitive functioning: DET, IDN, OCL, ONB (speed), ISL, GML: Composite scores will be calculated by taking the equally weighted average of the available z-scores if the required number of z-scores available is met. Only computed if z-scores are available for both tests. Only computed if z-scores are available for a minimum of three tests with representation from all three domain composites listed above.

End point type

Secondary

End point timeframe

Baseline 9Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	11	11
Units: Z-score
arithmetic mean (standard deviation)	0.0035 ( 0.4821 )	0.0035 ( 0.4821 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.0176

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2139

upper limit

0.2491

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): anticipatory

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): anticipatory

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	9	9
Units: Z-score
arithmetic mean (standard deviation)	0.1111 ( 0.1863 )	0.1111 ( 0.1863 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.0975

Confidence interval

level

95%

sides

2-sided

lower limit

-0.011

upper limit

0.2059

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): dynamic gait

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): dynamic gait

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	9	9
Units: Z-score
arithmetic mean (standard deviation)	0.09 ( 0.13 )	0.09 ( 0.13 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.16

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): reactive postural

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): reactive postural

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	9	9
Units: Z-score
arithmetic mean (standard deviation)	0.1296 ( 0.2324 )	0.1296 ( 0.2324 )

Mixed models Treatment diff between B-A

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.124

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.249

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): sensory orientation

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End point title

Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Mini-Balance Evaluation Systems Test (MiniBESTest): sensory orientation

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1) to End of Treatment (Week 52)

End point values	100 mg BID sonlicromanol	FAS
Number of subjects analysed	9	9
Units: Z-score
arithmetic mean (standard deviation)	0.0185 ( 0.1547 )	0.0185 ( 0.1547 )

Repeated measures analysis of covariance (ANCOVA)

Statistical analysis description

Comparison groups

100 mg BID sonlicromanol v FAS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.0223

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0584

upper limit

0.103

Adverse events

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Timeframe for reporting adverse events

Treatment Emergent Adverse Events are being reported from Day 1 of study treatment up to and including Follow up; AEs are considered treatment emergent when the date of onset is during the use of the study drug up to 14 days after the last study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

100 mg sonlicromanol (KH176) bid

Reporting group description

Serious adverse events	100 mg sonlicromanol (KH176) bid
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 15 (13.33%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Surgical and medical procedures
Bladder calculus removal
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Internal limiting membrane peeling
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Medical procedure
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Transurethral prostatectomy
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Eye disorders
Retinal detachment
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Endocrine disorders
Adrenocortical insufficiency acute
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

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

Non-serious adverse events	100 mg sonlicromanol (KH176) bid
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 15 (86.67%)
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Hypertension
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Surgical and medical procedures
Bladder calculus removal
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Cochlea implant
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Internal limiting membrane peeling
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Medical procedure
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Transurethral prostatectomy
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
General disorders and administration site conditions
Facial pain
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Oedema peripheral
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Pyrexia
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Swelling
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Vaccination site discomfort
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Menstruation irregular
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Oropharyngeal pain
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Rhinorrhoea
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Psychiatric disorders
Depression
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Insomnia
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Blood glucose fluctuation
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	3
Electrocardiogram T wave inversion
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Epicondylitis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Eye injury
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Fall
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Foot fracture
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Ligament sprain
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Palate injury
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Skin injury
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Wound
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Congenital, familial and genetic disorders
Talipes
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Nervous system disorders
Dizziness postural
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Dysaesthesia
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Migraine
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Multiple sclerosis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Ear pain
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Eustachian tube disorder
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Hypoacusis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Vertigo
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Vertigo positional
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Eye disorders
Retinal degeneration
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Retinal detachment
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	3
Vomiting
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	3
Abdominal pain
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Constipation
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Nausea
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Abdominal discomfort
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Abdominal distension
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Dry mouth
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Dyspepsia
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Tooth ache
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Pigmentation disorder
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Pruritus
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Rash
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Rash maculo-papular
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Urge incontinence
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Endocrine disorders
Adrenocortical insufficiency acute
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Muscle spasms
subjects affected / exposed	4 / 15 (26.67%)
occurrences all number	4
Myalgia
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	3
Back pain
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Joint range of motion decreased
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Muscle fatigue
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Musculoskeletal chest pain
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Neck pain
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Infections and infestations
COVID-19
subjects affected / exposed	8 / 15 (53.33%)
occurrences all number	8
Influenza
subjects affected / exposed	4 / 15 (26.67%)
occurrences all number	4
Upper respiratory tract infection
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	3
Nasopharyngitis
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Bronchitis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Eye infection
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Gastrointestinal infection
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Otitis media
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Post viral fatigue syndrome
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Sinusitis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Metabolism and nutrition disorders
folate
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Hyperglycaemia
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

27 May 2021

Protocol version 2.0 Ger/UK, issued on 27 May 2021: • Section 1.5.2 ‘Study design’ (and synopsis): added text replacing previous text “Primary safety data and secondary efficacy (endpoint) data will be monitored and reviewed every three months by an independent Data Safety Monitoring Board (DSMB) to evaluate potential risks and benefits. The DSMB will provide recommendations to the Sponsor regarding the study conduct.” • Inclusion criterion #3 has been adapted by adding the following excerpt: ‘…with evidence of potential benefit in at least one treatment period in the KH176-202 study.’ • Section 1.5.2. ‘Study design’: text on data review has been replaced by “Primary safety data and secondary efficacy (endpoint) data will be monitored and reviewed every three months by an independent Data Safety Monitoring Board (DSMB) to evaluate potential risks and benefits. Based on the observed benefit/risk the DSMB will provide recommendations regarding future trial conduct to the Sponsor.” • Section 1.5.5. ‘Benefit/risk’: added text “Safety and efficacy data (and consequently Benefit/Risk) will be monitored and reviewed every three months by an independent Data Safety Monitoring Board (DSMB). The DSMB will review and assess the safety and efficacy data as described in section 6.5. and will provide recommendations regarding the study based on the observed benefit-to-risk balance. In view of the safety precautions taken and the periodic review of the accruing benefit/risk information throughout the study by the DSMB, the potential benefits of participating in this trial are considered to outweigh the risks, and therefore the benefit-risk of the trial is considered to be positive.” • Section 3.1. ‘Overview’: revised/added text “Primary safety data and secondary efficacy (endpoint) data will be monitored and reviewed every three months by an independent Data Safety Monitoring Board (DSMB) to evaluate potential risks and benefits (see section 6.5).”

26 Nov 2021

Protocol version 2.0 NL, issued on 26 November 2021: • Section 1.5.2 ‘Study design’ (and synopsis): updated to include “Primary safety data and secondary efficacy (endpoint) data will be monitored and reviewed periodically, and/or on request of the Sponsor or regulatory authorities by an independent Data Safety Monitoring Board (DSMB) to evaluate potential risks and benefits. DSMB meetings in which the accumulating safety and efficacy data will be reviewed are organized at three monthly intervals, the timing of the first DSMB meeting depending on recruitment rate and accruing data, eg, when data collected in the first treatment period (week 13) are available for a subset of subjects. When the DSMB requests to receive urgent safety information, AE listings and of Medical Monitoring Reports (MMR) will be submitted. The DSMB will provide recommendations to the Sponsor regarding the study conduct. If during the study any severe Serious Adverse Events (SAEs) and Serious Unexpected Suspected Adverse Reaction (SUSARs) are reported, the DSMB will be informed immediately.”

26 Nov 2021

Protocol version 3.0 Ger/UK/DK, issued on 26 November 2021: • Section 1.5.2 ‘Study design’ (and synopsis): updated to include “Primary safety data and secondary efficacy (endpoint) data will be monitored and reviewed periodically, and/or on request of the Sponsor or regulatory authorities by an independent Data Safety Monitoring Board (DSMB) to evaluate potential risks and benefits. DSMB meetings in which the accumulating safety and efficacy data will be reviewed are organized at three monthly intervals, the timing of the first DSMB meeting depending on recruitment rate and accruing data, eg, when data collected in the first treatment period (week 13) are available for a subset of subjects. When the DSMB requests to receive urgent safety information, AE listings and of Medical Monitoring Reports (MMR) will be submitted. The DSMB will provide recommendations to the Sponsor regarding the study conduct. If during the study any severe Serious Adverse Events (SAEs) and Serious Unexpected Suspected Adverse Reaction (SUSARs) are reported, the DSMB will be informed immediately.”

06 Sep 2022

Protocol version 4.0 Ger/UK/DK, issued on 06 September 2022: · General change throughout the document: Extension of treatment period of 12 months to 18 months. · Sponsor will not initiate a (generic) compassionate use program; however, each study participant who has experienced benefit from the study medication application will be offered access to the study medication via an individual ‘Named Patient Supply’ application by the principal investigator.

21 Sep 2022

Protocol version 3.0 NL, issued on 21 September 2022: · General change throughout the document: Extension of treatment period of 12 months to 18 months. For this purpose, 2 additional study visits have been added and an additional objective has been added: “To assess the longer-term safety and efficacy of sonlicromanol during an additional 6-months treatment period for a total study treatment duration of 18-months by measuring the same safety and efficacy parameters as the primary and secondary objectives in the12-months study”. · Each study participant who has experienced benefit from the study medication application will be offered access to the study medication via an individual ‘Named Patient Supply’ application by the principal investigator.

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: A Phase IIb open-label, multi-centre, extension study to explore the long-term safety and efficacy of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation who have completed study KH176-202.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events (SAEs)

Primary: Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events (SAEs)

Primary: Changes from baseline to End of Treatment (Week 52) in safety laboratory parameters: biochemistry

Primary: Changes from baseline to End of Treatment (Week 52) in safety laboratory parameters: biochemistry

Primary: Changes from baseline to End of Treatment (Week 52) in safety laboratory parameters: haematology

Primary: Changes from baseline to End of Treatment (Week 52) in safety laboratory parameters: haematology

Primary: Changes from baseline to End of Treatment (Week 52) in ECG parameters

Primary: Changes from baseline to End of Treatment (Week 52) in ECG parameters

Primary: Changes from baseline to End of Treatment (Week 52) in Vital signs

Primary: Changes from baseline to End of Treatment (Week 52) in Vital signs

Primary: Changes from baseline to End of Treatment (Week 52) in Thyroid parameters

Primary: Changes from baseline to End of Treatment (Week 52) in Thyroid parameters

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the attention domain of cognitive functioning: Identification Test (IDN)

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the attention domain of cognitive functioning: Identification Test (IDN)

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the executive functioning domain of cognitive functioning: Groton Maze Learning (GML).

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the executive functioning domain of cognitive functioning: Groton Maze Learning (GML).

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: One Back Test (ONB) - speed of performance

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: One Back Test (ONB) - speed of performance

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: One Back Test (ONB) – accuracy of performance

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: One Back Test (ONB) – accuracy of performance

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: Detection Test (DET) – speed of performance

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the working memory domain of cognitive functioning: Detection Test (DET) – speed of performance

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the visual learning domain of cognitive functioning: Visual learning: One Card Learning Test (OCL)

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the visual learning domain of cognitive functioning: Visual learning: One Card Learning Test (OCL)

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the verbal learning domain of cognitive functioning: International Shopping List (ISL)

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the verbal learning domain of cognitive functioning: International Shopping List (ISL)

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Attention Domain Composites of cognitive functioning: DET and IDN

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Attention Domain Composites of cognitive functioning: DET and IDN

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Executive Function Composite of cognitive functioning: ONB (speed), GML

Secondary: Changes from baseline (measured at Day 1) at End of Treatment (Week 52) in the Executive Function Composite of cognitive functioning: ONB (speed), GML

Secondary: Changes from baseline (measured at Day 1) to End of Treatment (Week 52) in the Global Composite of cognitive functioning: DET, IDN, OCL, ONB (speed), ISL, GML

Secondary: Changes from baseline (measured at Day 1) to End of Treatment (Week 52) in the Global Composite of cognitive functioning: DET, IDN, OCL, ONB (speed), ISL, GML

Secondary: Changes from baseline measured at Day 1 to End of Treatment Week 52 of Attentional Performance (TAP): Alertness with alarm median

Secondary: Changes from baseline measured at Day 1 to End of Treatment Week 52 of Attentional Performance (TAP): Alertness with alarm median

Secondary: Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Total score

Secondary: Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Total score

Secondary: Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Affective scale

Secondary: Changes from baseline at measured at Day 1 to End of Treatment in Beck Depression Inventory (BDI): Affective scale

Secondary: Changes from baseline (measured at pre-dose Day 1) to End of Treatment in (Week 52) in the Beck Depression Inventory (BDI): Somatic scale

Secondary: Changes from baseline (measured at pre-dose Day 1) to End of Treatment in (Week 52) in the Beck Depression Inventory (BDI): Somatic scale

Secondary: Changes from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Total score

Secondary: Changes from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Total score

Secondary: Changes from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Anxiety score

Secondary: Changes from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Anxiety score

Secondary: Change from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Depression score

Secondary: Change from baseline measured at Day 1 to End of Treatment in Hospital Anxiety and Depression Scale (HADS): Depression score

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section 1

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section 1

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section II

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section II

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section III

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section III

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Physical functioning

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Physical functioning

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Role limitations due to physical problems

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Role limitations due to physical problems

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Bodily pain

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Bodily pain

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: General health perceptions

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: General health perceptions

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Vitality

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Vitality

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Social functioning

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Social functioning

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: role limitations due to emotional problems

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: role limitations due to emotional problems

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Mental health

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV: Mental health

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV (SF-12): Physical Component Score (PCS)

Secondary: Change from baseline measured at Day 1 to End of Treatment (Week 52) in the Newcastle Mitochondrial Disease Adult Scale (NMDAS): Section IV (SF-12): Physical Component Score (PCS)

Clinical Trial Results:
A Phase IIb open-label, multi-centre, extension study to explore the long-term safety and efficacy of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation who have completed study KH176-202.