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    Clinical Trial Results:
    A Phase IIb double-blind, randomised, placebo-controlled, multi-centre, confirmative three-way cross-over study on cognitive function with two doses of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation.

    Summary
    EudraCT number
    		 2019-000599-40
    Trial protocol
    		 NL   GB   DE   DK  
    Global end of trial date
    24 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2023
    First version publication date
    15 Oct 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    KH176-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04165239
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Khondrion B.V.
    Sponsor organisation address
    Transistorweg 5C, Nijmegen, Netherlands, 6534 AT
    Public contact
    Gerrit Ruiterkamp, Khondrion B.V., +31 612805425, ruiterkamp@khondrion.com
    Scientific contact
    Gerrit Ruiterkamp, Khondrion B.V., +31 612805425, ruiterkamp@khondrion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Nov 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of KH176 during a 4 week treatment period on the attention domain score of cognitive functioning, as assessed by the visual identification test of the Cogstate computerised cognitive testing battery.
    Protection of trial subjects
    1. Monitoring incidence and severity of Treatment Emergent Adverse Events 2. Evaluation of changes in findings of physical examination, vital signs and clinical laboratory results
    Background therapy
    		 None
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Germany: 8
    Worldwide total number of subjects
    27
    EEA total number of subjects
    19
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    27
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Study KH176-202 was conducted at 4 Investigational sites (the Netherlands, Germany, the United Kingdom, and Denmark). 50 unique patients were screened and signed informed consent. A total of 23 unique subjects were screening failures and 27 subjects were randomized over 3 treatment sequences.

    Pre-assignment
    Screening details
    		 Males and females aged 18 years or older with a confirmed m.3243A>G mutation and with clinical signs and disease severity of mitochondrial disease as demonstrated by an NMDAS score of >10, including attentional dysfunction, defined as a Cogstate Identification Test (IDN) score of ≥0.5 standard deviations poorer than healty controls

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The treatment (sequence) that was assigned to the randomization treatment numbers was blinded to the study team. Treatment blind was maintained by the use of identically packaged active and placebo medications, which fully matched visually, and which could not be distinguished by taste, odor or touch either. Treatments remained blinded until the issuing of a final statement confirming that all data had been collected, verified, and stored in a locked database.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 A-B-C
    Arm description
    		 All subjects who received bid oral administration in the randomized sequence: placebo, KH176 50 mg, KH176 100 mg
    Arm type
    		 Randomized sequence

    Investigational medicinal product name
    KH176
    Investigational medicinal product code
    SUB198953
    Other name
    sonlicromanol
    Pharmaceutical forms
    Oral solution in bottle
    Routes of administration
    Oral use
    Dosage and administration details
    KH176 is available as a powder for reconstitution, to be reconstituted with physiologic salt. KH176 50 mg or 100 mg will be provided in 20 mL bottles, which can be used to add the physiological salt (10 mL) and consequently drink the oral liquid. Placebo will be a NaCl salt/bitrex powder, to be reconstituted with physiologic salt solution in 20 mL bottles.

    Arm title
    		 B-C-A
    Arm description
    		 All subjects who received bid oral administration in the randomized sequence: KH176 50 mg, KH176 100 mg, placebo
    Arm type
    		 Randomized sequence

    Investigational medicinal product name
    KH176
    Investigational medicinal product code
    SUB198953
    Other name
    sonlicromanol
    Pharmaceutical forms
    Oral solution in bottle
    Routes of administration
    Oral use
    Dosage and administration details
    KH176 is available as a powder for reconstitution, to be reconstituted with physiologic salt. KH176 50 mg or 100 mg will be provided in 20 mL bottles, which can be used to add the physiological salt (10 mL) and consequently drink the oral liquid. Placebo will be a NaCl salt/bitrex powder, to be reconstituted with physiologic salt solution in 20 mL bottles.

    Arm title
    		 C-A-B
    Arm description
    		 All subjects who received bid oral administration in the randomized sequence: KH176 100 mg, KH176 50 mg, placebo
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    KH176
    Investigational medicinal product code
    SUB198953
    Other name
    sonlicromanol
    Pharmaceutical forms
    Oral solution in bottle
    Routes of administration
    Oral use
    Dosage and administration details
    KH176 is available as a powder for reconstitution, to be reconstituted with physiologic salt. KH176 50 mg or 100 mg will be provided in 20 mL bottles, which can be used to add the physiological salt (10 mL) and consequently drink the oral liquid. Placebo will be a NaCl salt/bitrex powder, to be reconstituted with physiologic salt solution in 20 mL bottles.

    Number of subjects in period 1
    		A-B-C B-C-A C-A-B
    Started
    10
    9
    8
    Completed
    9
    7
    8
    Not completed
    1
    2
    0
         Adverse event, non-fatal
    1
    2
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    A-B-C
    Reporting group description
    		 All subjects who received bid oral administration in the randomized sequence: placebo, KH176 50 mg, KH176 100 mg

    Reporting group title
    B-C-A
    Reporting group description
    		 All subjects who received bid oral administration in the randomized sequence: KH176 50 mg, KH176 100 mg, placebo

    Reporting group title
    C-A-B
    Reporting group description
    		 All subjects who received bid oral administration in the randomized sequence: KH176 100 mg, KH176 50 mg, placebo

    Reporting group values
    		 A-B-C B-C-A C-A-B Total
    Number of subjects
    		 10 9 8
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.0 ± 14.1 44.8 ± 10.7 45.0 ± 6.0 -
    Gender categorical
    Units: Subjects
        Female
    		 9 4 7 20
        Male
    		 1 5 1 7
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were administered bid oral administration of placebo

    Subject analysis set title
    50 mg KH176
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were administered bid oral administration 50 mg KH176

    Subject analysis set title
    100 mg KH176
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were administered bid oral administration of 100 mg KH176

    Subject analysis sets values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects
    27
    27
    27
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.0 ± 10.8
    46.0 ± 10.8
    46.0 ± 10.8
    Gender categorical
    Units: Subjects
        Female
    20
    20
    20
        Male
    7
    7
    7

    End points

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    End points reporting groups
    Reporting group title
    A-B-C
    Reporting group description
    		 All subjects who received bid oral administration in the randomized sequence: placebo, KH176 50 mg, KH176 100 mg

    Reporting group title
    B-C-A
    Reporting group description
    		 All subjects who received bid oral administration in the randomized sequence: KH176 50 mg, KH176 100 mg, placebo

    Reporting group title
    C-A-B
    Reporting group description
    		 All subjects who received bid oral administration in the randomized sequence: KH176 100 mg, KH176 50 mg, placebo

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were administered bid oral administration of placebo

    Subject analysis set title
    50 mg KH176
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were administered bid oral administration 50 mg KH176

    Subject analysis set title
    100 mg KH176
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were administered bid oral administration of 100 mg KH176

    Primary: Changes from baseline at Day 28 in the attention domain score of cognitive functioning: Identification Test (IDN)

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    End point title
    		 Changes from baseline at Day 28 in the attention domain score 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
    Primary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: seconds
        least squares mean (standard error)
    0.005498 ± 0.01002
    -0.00084 ± 0.009309
    0.002007 ± 0.009702
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Statistical analysis description
    Superiority analysis using a three-period, three treatment cross-over model comparing change from baseline at Day 28 for all treatments. Period effects are investigated using a mixed model (treatment/period: fixed effects, subject: random effect). Treatment effects of active doses vs. placebo are estimated and 95% confidence intervals are calculated using mixed-modelling results incorporating a multiplicity correction for the prim. efficacy parameter doses comparison with placebo (Dunnet's)
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.00634
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03612
         upper limit
    		 0.02345
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01446
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Statistical analysis description
    Superiority analysis using a three-period, three treatment cross-over model comparing change from baseline at Day 28 for all treatments. Period effects are investigated using a mixed model (treatment/period: fixed effects, subject: random effect). Treatment effects of active doses vs. placebo are estimated and 95% confidence intervals are calculated using mixed-modelling results incorporating a multiplicity correction for the prim. efficacy parameter doses comparison with placebo (Dunnet's)
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.00349
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03467
         upper limit
    		 0.02769
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01514

    Secondary: Changes from baseline at day 28 in the following domains of cognitive functioning: 1. Executive functioning: Groton Maze Learning (GML).

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    End point title
    		 Changes from baseline at day 28 in the following domains of cognitive functioning: 1. Executive functioning: Groton Maze Learning (GML).
    End point description
    Measure of problem solving and reasoning and uses a well-validated maze learning paradigm. The subject is 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 refers to the box array (i.e., 10 × 10). Subjects are required to find the hidden pathway guided by four search rules. These rules are: do not move diagonally, do not move more than one box, do not move back on the pathway, and return to the last correct location after an error. At each step only the most recently selected box is shown. Feedback is given with visual and auditory cues (green check marks and red crosses) to indicate whether the selected box is correct or incorrect. The head of path, or the last correct location, flashes with a green check when two errors are made in succession to indicate to the subject that they must return to this location. There are 21 well-matched alternate pathways
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1(baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: sec
        least squares mean (standard error)
    -3.7912 ± 2.8641
    -2.9229 ± 2.8803
    1.3719 ± 2.8580
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.8682
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.0173
         upper limit
    		 9.7537
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.3143
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.1631
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5638
         upper limit
    		 13.8899
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.2373

    Secondary: Changes from baseline at day 28 in the following domains of cognitive functioning: 2. Working memory: One Back Test (ONB)

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    End point title
    		 Changes from baseline at day 28 in the following domains of cognitive functioning: 2. Working memory: One Back Test (ONB)
    End point description
    The One Back test 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 is asked whether the card displayed in the centre of the screen is the same as the card presented immediately previously. The subject responds by pressing the Yes or No key. Because no card has been presented yet on the first study, a correct first response is always No. The software measures the speed and accuracy of each response.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: sec
        least squares mean (standard error)
    -0.01867 ± 0.01200
    -0.00578 ± 0.01157
    0.000936 ± 0.01181
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.01288
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02334
         upper limit
    		 0.0491
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01759
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.0196
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01703
         upper limit
    		 0.05623
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01779

    Secondary: Changes from baseline at Day 28 in the following domains of cognitive functioning: 3. Psychomotor function: Detection Test

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    End point title
    		 Changes from baseline at Day 28 in the following domains of cognitive functioning: 3. Psychomotor function: Detection Test
    End point description
    The Detection Test 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 is asked to press the Yes key as soon as the card in the centre of the screen turns face up. The software measures the speed and accuracy of each response.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    25
    25
    Units: sec
        least squares mean (standard error)
    -0.03608 ± 0.01726
    -0.00515 ± 0.01644
    0.007884 ± 0.01664
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.03093
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02398
         upper limit
    		 0.08584
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02666
    Statistical analysis title
    		 Copy of Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.04397
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01216
         upper limit
    		 0.1001
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02725

    Secondary: Changes from baseline at day 28 in the following domains of cognitive functioning: 4. Visual learning: One Card Learning Test (OCL)

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    End point title
    		 Changes from baseline at day 28 in the following domains of cognitive functioning: 4. Visual learning: One Card Learning Test (OCL)
    End point description
    The One Card Learning 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 is asked whether the card displayed in the centre of the screen was seen previously in this test. The subject responds by pressing the Yes or No key. The software measures the speed and accuracy of each response.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: sec
        least squares mean (standard error)
    -0.00689 ± 0.02298
    0.01383 ± 0.02200
    -0.02481 ± 0.02239
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02072
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03943
         upper limit
    		 0.08086
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0292
    Statistical analysis title
    		 Copy of Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01791
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07905
         upper limit
    		 0.04323
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02969

    Secondary: Changes from baseline at day 28 in the following domains of cognitive functioning: 5. Verbal learning: International Shopping List (ISL)

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    End point title
    		 Changes from baseline at day 28 in the following domains of cognitive functioning: 5. Verbal learning: International Shopping List (ISL)
    End point description
    The International Shopping List test is a measure of verbal learning and uses a well-validated list-learning paradigm. High frequencies, high imagery, concrete nouns (items from a shopping list) are read to the subject by the test supervisor at the rate of one word every two seconds. Once all words have been read, the subject is asked to recall as many of the words as he/she can as quickly as possible. The test supervisor uses a mouse to mark the words recalled by the subject on the computer screen. When the subject can recall no more words, the same list is read a second time. The test supervisor records the words recalled by the subject on this study. This is then repeated a third time. The software measures the number of correct responses as recorded by the test supervisor.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    24
    Units: sec
        least squares mean (standard error)
    1.0274 ± 0.7114
    1.3792 ± 0.6845
    0.5316 ± 0.7061
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.3519
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6695
         upper limit
    		 2.3732
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9814
    Statistical analysis title
    		 Copy of Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.4958
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5657
         upper limit
    		 1.5742
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.005

    Secondary: Changes from baseline at day 28 to end of treatment in Test of Attentional Performance (TAP): Alertness with alarm median

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    End point title
    		 Changes from baseline at day 28 to end of treatment in Test 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
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: sec
        least squares mean (standard error)
    -18.3978 ± 14.6268
    -18.0998 ± 14.0563
    10.6007 ± 14.2719
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.298
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.9794
         upper limit
    		 35.5754
    Variability estimate
    Standard error of the mean
    Dispersion value
    17.1288
    Statistical analysis title
    		 Copy of Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    28.9985
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5757
         upper limit
    		 64.5727
    Variability estimate
    Standard error of the mean
    Dispersion value
    17.2729

    Secondary: Changes from baseline at day 28 in Beck Depression Inventory (BDI): Total score

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    End point title
    		 Changes from baseline at day 28 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 (Kendall 1987). For BDI-A, BDI-C and BDI-S these cut-off values are >0.9, >1.4, and >4 respectively (Beck 2002).
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    23
    26
    25
    Units: units on a scale
        least squares mean (standard error)
    0.3912 ± 1.0322
    -1.0101 ± 0.9857
    -1.9693 ± 0.9770
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (net)
    Point estimate
    -1.4013
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.0581
         upper limit
    		 1.2555
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.29
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (net)
    Point estimate
    -2.3604
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9403
         upper limit
    		 0.2195
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2527

    Secondary: Changes from Baseline at Day 28 in Hospital Anxiety and Depression Scale (HADS): Total score

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    End point title
    		 Changes from Baseline at Day 28 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
    pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    25
    26
    Units: Units on a scale
        least squares mean (standard error)
    0.4455 ± 0.8360
    -0.1603 ± 0.800
    0.7587 ± 0.8102
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.6058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7588
         upper limit
    		 1.5473
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0454
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.3132
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9088
         upper limit
    		 2.5353
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0789

    Secondary: Changes from baseline at day 28 in the NMDAS score: Section I

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    End point title
    		 Changes from baseline at day 28 in the NMDAS score: Section I
    End point description
    The Newcastle Mitochondrial Disease Scale for Adults (NMDAS) is a semi-quantitative clinical rating scale designed specifically for all forms of mitochondrial disease. The rating scale encompasses all aspects of mitochondrial disease by exploring several domains: • Section I, Current function, consists of vision; hearing; speech; swallowing; handwriting; cutting food and handling utensils; dressing; hygiene; exercise; gait stability. • Section II, System-specific involvement, (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. • Section III, Current clinical assessment, is based on the clinician’s assessment. It includes visual acuity; ptosis; chronic progressive external ophthalmoplegia; dysphonia/dysarthria; myopathy; cerebellar ataxia; neuropathy; pyramidal; extrapyramidal; cognition
    End point type
    Secondary
    End point timeframe
    Pre dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: Units
        least squares mean (standard error)
    -0.5221 ± 0.2459
    -0.2196 ± 0.2303
    0.1093 ± 0.2365
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    50 mg KH176 v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.3025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3375
         upper limit
    		 0.9424
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3107
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.6314
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02402
         upper limit
    		 1.2868
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3182

    Secondary: Number of headache days

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    End point title
    		 Number of headache days
    End point description
    Subjects report the number of headache days, intensity and duration, and on the use of medication to relieve headache in a diary.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: number
        arithmetic mean (standard deviation)
    6.4 ± 6.6
    5.5 ± 5.5
    4.9 ± 5.2
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 0.5kHz

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    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 0.5kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA was assessed according to international standards (air conduction measurements at 0.25, 0.50, 1, 2, 3, 4, 6, and 8 kHz; bone conduction measurements at octave intervals at 0.5, 1, 2 and 4 kHz).
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1(baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    21
    Units: kHz
        arithmetic mean (standard deviation)
    -0.23 ± 5.63
    1.48 ± 4.89
    0.33 ± 5.10
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Smell Identification Test (UPSIT)

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    End point title
    		 Changes from baseline at Day 28 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
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: Units
        least squares mean (standard error)
    1.1974 ± 0.6150
    -0.1836 ± 0.5889
    0.2700 ± 0.5928
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.381
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1773
         upper limit
    		 0.4153
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8722
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.9274
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7141
         upper limit
    		 0.8593
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8675

    Secondary: Changes from baseline at day 28 in the Cognitive Failure Questionnaire (CFQ): Total score

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    End point title
    		 Changes from baseline at day 28 in the Cognitive Failure Questionnaire (CFQ): Total score
    End point description
    The Cognitive Failure Questionnaire 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 have to be scored on a 5 point scale. The outcome is an overall score over all items and 4 subscales (distraction, distraction in different social environments, names and words, orientation).
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    23
    26
    25
    Units: Units on a scale
        least squares mean (standard error)
    1.0328 ± 1.6203
    -2.5723 ± 1.5259
    -4.5131 ± 1.5474
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.6051
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.9481
         upper limit
    		 0.738
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1087
    Statistical analysis title
    		 Copy of Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.5459
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.893
         upper limit
    		 -1.1988
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1107

    Secondary: Changes from baseline at day 28 in the Quality of Life in neurological disorders Short Form (Neuro-QoL-SF): Total Score

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    End point title
    		 Changes from baseline at day 28 in the Quality of Life in neurological disorders Short Form (Neuro-QoL-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. The Fatigue Short Form is an 8-item self-assessment questionnaire on paper.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: Units on a scale
        least squares mean (standard error)
    -0.4203 ± 0.9988
    -1.7517 ± 0.9701
    -2.2450 ± 0.9721
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    50 mg KH176 v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.3314
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8001
         upper limit
    		 1.1374
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1987
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.824
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2513
         upper limit
    		 0.6019
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1782

    Secondary: Changes from baseline at day 28 to end of treatment in Test of Attentional Performance (TAP): Alertness without alarm

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    End point title
    		 Changes from baseline at day 28 to end of treatment in Test of Attentional Performance (TAP): Alertness without alarm
    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
    Pre dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: sec
        arithmetic mean (standard deviation)
    -10.8555 ± 12.8006
    -7.7724 ± 12.4769
    1.0216 ± 12.4431
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.1367
         upper limit
    		 30.3028
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.2164
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    11.877
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.8221
         upper limit
    		 38.5762
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.9636

    Secondary: Changes from baseline at day 28 in Beck Depression Inventory (BDI): Affective score

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    End point title
    		 Changes from baseline at day 28 in Beck Depression Inventory (BDI): Affective 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.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    23
    26
    25
    Units: Units on a scale
        least squares mean (standard error)
    0.05778 ± 0.3756
    0.05148 ± 0.3490
    -0.1463 ± 0.3539
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.00631
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8937
         upper limit
    		 0.8811
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4309
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.2041
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.0885
         upper limit
    		 0.6803
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4294

    Secondary: Changes from baseline at day 28 in Beck Depression Inventory: Cognitive score

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    End point title
    		 Changes from baseline at day 28 in Beck Depression Inventory: Cognitive 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 (Kendall 1987). For BDI-A, BDI-C and BDI-S these cut-off values are >0.9, >1.4, and >4 respectively (Beck 2002).
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    23
    26
    25
    Units: Units on a scale
        least squares mean (standard error)
    0.3031 ± 0.3647
    -0.1733 ± 0.3561
    -0.2147 ± 0.3447
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.4764
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5136
         upper limit
    		 0.5608
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5036
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.5178
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4978
         upper limit
    		 0.4622
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4758

    Secondary: Changes from Baseline at Day 28 in Hospital Anxiety and Depression Scale (HADS): A-score

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    End point title
    		 Changes from Baseline at Day 28 in Hospital Anxiety and Depression Scale (HADS): A-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
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: Units on a scale
        least squares mean (standard error)
    0.4172 ± 0.4499
    0.1361 ± 0.4273
    0.4344 ± 0.4348
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.2811
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4067
         upper limit
    		 0.8445
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5465
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.01722
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1372
         upper limit
    		 1.1716
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5605

    Secondary: Changes from Baseline at Day 28 in Hospital Anxiety and Depression Scale (HADS): D-score

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    End point title
    		 Changes from Baseline at Day 28 in Hospital Anxiety and Depression Scale (HADS): D-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
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: Units on a scale
        least squares mean (standard error)
    0.2829 ± 0.5080
    -0.3325 ± 0.4913
    0.09058 ± 0.4974
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.6153
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.0039
         upper limit
    		 0.7732
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6742
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.1923
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6208
         upper limit
    		 1.2363
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6936

    Secondary: Changes from Baseline at Day 28 in NMDAS: Section II

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    End point title
    		 Changes from Baseline at Day 28 in NMDAS: Section II
    End point description
    The Newcastle Mitochondrial Disease Scale for Adults (NMDAS) is a semi-quantitative clinical rating scale designed specifically for all forms of mitochondrial disease. The rating scale encompasses all aspects of mitochondrial disease by exploring several domains: • Section I, Current function, consists of vision; hearing; speech; swallowing; handwriting; cutting food and handling utensils; dressing; hygiene; exercise; gait stability. • Section II, System-specific involvement, (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. • Section III, Current clinical assessment, is based on the clinician’s assessment. It includes visual acuity; ptosis; chronic progressive external ophthalmoplegia; dysphonia/dysarthria; myopathy; cerebellar ataxia; neuropathy; pyramidal; extrapyramidal; cognition
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: Units
        least squares mean (standard error)
    0.03490 ± 0.2349
    -0.3924 ± 0.2375
    -0.1116 ± 0.2345
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    50 mg KH176 v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.4273
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1525
         upper limit
    		 0.2979
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3521
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.1465
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8538
         upper limit
    		 0.5609
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3435

    Secondary: Changes from Baseline at Day 28 in NMDAS: Section III

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    End point title
    		 Changes from Baseline at Day 28 in NMDAS: Section III
    End point description
    The Newcastle Mitochondrial Disease Scale for Adults (NMDAS) is a semi-quantitative clinical rating scale designed specifically for all forms of mitochondrial disease. The rating scale encompasses all aspects of mitochondrial disease by exploring several domains: • Section I, Current function, consists of vision; hearing; speech; swallowing; handwriting; cutting food and handling utensils; dressing; hygiene; exercise; gait stability. • Section II, System-specific involvement, (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. • Section III, Current clinical assessment, is based on the clinician’s assessment. It includes visual acuity; ptosis; chronic progressive external ophthalmoplegia; dysphonia/dysarthria; myopathy; cerebellar ataxia; neuropathy; pyramidal; extrapyramidal; cognition
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: Units
        least squares mean (standard error)
    -0.7284 ± 0.4649
    -1.0848 ± 0.4357
    -0.07640 ± 0.4653
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.3564
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4533
         upper limit
    		 0.7404
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5326
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.652
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4902
         upper limit
    		 1.7941
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5546

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 0.25 kHz

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    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 0.25 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    21
    Units: kHz
        arithmetic mean (standard deviation)
    -0.09 ± 7.55
    2.39 ± 6.27
    1.38 ± 7.47
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 1 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 1 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype. P
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    21
    Units: kHz
        arithmetic mean (standard deviation)
    -0.50 ± 4.00
    0.61 ± 3.50
    1.48 ± 5.19
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 2kHz

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    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 2kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    21
    Units: kHz
        arithmetic mean (standard deviation)
    0.41 ± 4.75
    0.48 ± 3.23
    -0.24 ± 4.90
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 3 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 3 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    21
    Units: kHz
        arithmetic mean (standard deviation)
    -1.59 ± 3.19
    -0.87 ± 4.80
    -0.25 ± 3.35
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 4 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 4 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    21
    Units: kHz
        arithmetic mean (standard deviation)
    -0.05 ± 5.15
    1.48 ± 5.59
    0.05 ± 6.01
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 6 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 6 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    22
    21
    Units: kHz
        arithmetic mean (standard deviation)
    -0.43 ± 9.35
    -0.77 ± 11.24
    0.57 ± 8.63
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 8kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Air Conduction at 8kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    22
    21
    Units: kHz
        arithmetic mean (standard deviation)
    5.81 ± 21.94
    -3.14 ± 13.46
    3.62 ± 21.60
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Right Ear Air Conduction at 0.5 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Right Ear Air Conduction at 0.5 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    23
    24
    22
    Units: kHz
        arithmetic mean (standard deviation)
    -0.13 ± 4.16
    0.58 ± 3.37
    1.59 ± 3.80
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Right Ear Air Conduction at 1 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Right Ear Air Conduction at 1 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    21
    Units: kHz
        arithmetic mean (standard deviation)
    -0.86 ± 4.14
    -0.22 ± 3.91
    -1.05 ± 3.25
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Right Ear Air Conduction at 2 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Right Ear Air Conduction at 2 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    23
    23
    22
    Units: kHz
        arithmetic mean (standard deviation)
    -1.09 ± 3.16
    0.65 ± 2.72
    1.55 ± 6.41
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Right Ear Air Conduction: 3 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Right Ear Air Conduction: 3 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    23
    24
    21
    Units: Khz
        arithmetic mean (standard deviation)
    -1.22 ± 4.37
    -0.58 ± 4.11
    -0.33 ± 4.89
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Conduction: 4 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Conduction: 4 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    21
    Units: KhZ
        arithmetic mean (standard deviation)
    -0.45 ± 2.84
    0.39 ± 4.54
    -0.57 ± 4.11
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Conduction: 6 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Conduction: 6 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    22
    21
    Units: kHz
        arithmetic mean (standard deviation)
    -0.33 ± 7.42
    -6.91 ± 20.65
    2.05 ± 10.78
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Conduction: 8 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Conduction: 8 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    22
    20
    Units: kHz
        arithmetic mean (standard deviation)
    -3.52 ± 8.44
    -3.64 ± 9.70
    4.60 ± 11.91
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Left Ear Bone Conduction: 1 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Left Ear Bone Conduction: 1 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    22
    23
    20
    Units: kHz
        arithmetic mean (standard deviation)
    -0.23 ± 3.29
    -2.43 ± 15.61
    0.70 ± 4.64
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Left Ear Bone Conduction: 2 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Left Ear Bone Conduction: 2 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    21
    20
    Units: kHz
        arithmetic mean (standard deviation)
    0.05 ± 4.10
    0.48 ± 3.33
    0.05 ± 5.21
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Bone Conduction at 0.5 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at day 28 in the Pure Tone Audiometry (PTA): Left Ear Bone Conduction at 0.5 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    23
    20
    Units: kHz
        arithmetic mean (standard deviation)
    -1.05 ± 4.46
    -2.87 ± 13.98
    -1.30 ± 6.42
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Left Ear Bone Conduction: 4 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Left Ear Bone Conduction: 4 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    21
    20
    Units: kHz
        arithmetic mean (standard deviation)
    -0.62 ± 5.37
    1.05 ± 6.16
    -0.85 ± 5.74
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Bone Conduction: 0.5 kHz

    		 Close Top of page
    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Bone Conduction: 0.5 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    22
    20
    Units: kHz
        arithmetic mean (standard deviation)
    -0.33 ± 4.75
    -4.23 ± 13.27
    -0.15 ± 5.89
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Bone Conduction: 1 kHz

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    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Bone Conduction: 1 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    23
    21
    Units: kHz
        arithmetic mean (standard deviation)
    0.33 ± 3.18
    -3.91 ± 14.84
    -1.19 ± 3.98
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Bone Conduction: 2 kHz

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    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Bone Conduction: 2 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    21
    21
    20
    Units: kHz
        arithmetic mean (standard deviation)
    -1.95 ± 4.38
    1.10 ± 3.78
    1.80 ± 6.74
    No statistical analyses for this end point

    Secondary: Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Bone Conduction: 4 kHz

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    End point title
    		 Changes from baseline at Day 28 in the Pure Tone Audiometry (PTA): Right Ear Bone Conduction: 4 kHz
    End point description
    To identify individual hearing threshold levels and changes due to treatment, PTA will be assessed according to international standards. Hearing loss is a common sign in mitochondrial spectrum disorders, especially in the MIDD phenotype.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    20
    21
    20
    Units: kHz
        arithmetic mean (standard deviation)
    -2.70 ± 5.99
    1.24 ± 6.17
    -0.15 ± 4.85
    No statistical analyses for this end point

    Secondary: Changes from baseline at day 28 in the Cognitive Failure Questionnaire (CFQ): Sub Total score

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    End point title
    		 Changes from baseline at day 28 in the Cognitive Failure Questionnaire (CFQ): Sub Total score
    End point description
    The Cognitive Failure Questionnaire 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 have to be scored on a 5 point scale. The outcome is an overall score over all items and 4 subscales (distraction, distraction in different social environments, names and words, orientation).
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    16
    19
    18
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.38 ± 1.71
    -0.68 ± 1.70
    -0.50 ± 2.50
    No statistical analyses for this end point

    Secondary: Changes from Baseline at Day 28 in NMDAS: Total score (Sections I-III)

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    End point title
    		 Changes from Baseline at Day 28 in NMDAS: Total score (Sections I-III)
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28) of each treatment period
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    24
    26
    25
    Units: Units
        least squares mean (standard error)
    -1.5529 ± 0.6261
    -1.4324 ± 0.5844
    0.1638 ± 0.6060
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (net)
    Point estimate
    0.1204
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4223
         upper limit
    		 1.6632
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7491
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (net)
    Point estimate
    1.7167
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1515
         upper limit
    		 3.2818
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.76

    Secondary: Changes from baseline at day 28 in Beck Depression Inventory (BDI): Somatic score

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    End point title
    		 Changes from baseline at day 28 in Beck Depression Inventory (BDI): Somatic score
    End point description
    End point type
    Secondary
    End point timeframe
    pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    23
    26
    25
    Units: Units
        least squares mean (standard error)
    -0.4626 ± 0.5705
    -0.8977 ± 0.5494
    -1.2662 ± 0.5463
    Statistical analysis title
    		 Mixed models Treatment diff between B-A
    Comparison groups
    Placebo v 50 mg KH176
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.4351
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9651
         upper limit
    		 1.0949
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7429
    Statistical analysis title
    		 Mixed models Treatment diff between C-A
    Comparison groups
    Placebo v 100 mg KH176
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.8036
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3112
         upper limit
    		 0.704
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.732

    Secondary: Average duration of headaches

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    End point title
    		 Average duration of headaches
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 (baseline) to end of treatment (Day 28 of each treatment period)
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    18
    19
    17
    Units: Hours
        arithmetic mean (standard deviation)
    6.59 ± 5.53
    5.92 ± 3.01
    4.62 ± 2.41
    No statistical analyses for this end point

    Secondary: Intensity of the headaches

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    End point title
    		 Intensity of the headaches
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Placebo 50 mg KH176 100 mg KH176
    Number of subjects analysed
    18
    19
    17
    Units: Units
        arithmetic mean (standard deviation)
    4.49 ± 1.74
    4.58 ± 1.53
    4.18 ± 1.71
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (collected during total study period (all Treatment Periods including FU; AEs were collected from First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    A: Placebo
    Reporting group description
    		 Subjects receiving bid oral administration placebo

    Reporting group title
    B: 50 mg KH176 bid
    Reporting group description
    		 -

    Reporting group title
    C: 100 mg KH176 bid
    Reporting group description
    		 -

    Serious adverse events
    		 A: Placebo B: 50 mg KH176 bid C: 100 mg KH176 bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 A: Placebo B: 50 mg KH176 bid C: 100 mg KH176 bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 25 (60.00%)
    14 / 27 (51.85%)
    26 / 26 (100.00%)
    General disorders and administration site conditions
    Medical device site reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 27 (11.11%)
    3 / 26 (11.54%)
         occurrences all number
    3
    3
    3
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 27 (3.70%)
    2 / 26 (7.69%)
         occurrences all number
    2
    1
    2
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Exercise tolerance decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Gait disturbance
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Intermenstrual bleeding
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Poor quality sleep
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Investigations
    Blood pressure increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Electrocardiogram T wave amplitude decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Glomerular filtration rate decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    SARS-CoV-2 test positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Weight decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Injury, poisoning and procedural complications
    Arthropod sting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Eye contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Limb injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Skin laceration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Sunburn
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitations
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    2
    Tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Memory impairment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    1
    Disturbance in attention
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Neuralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Paraesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Altered state of consciousness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Balance disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Lethargy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    External ear inflammation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoacusis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Vertigo
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Eye pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid ptosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Eyelids pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 27 (3.70%)
    2 / 26 (7.69%)
         occurrences all number
    2
    1
    2
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    3 / 26 (11.54%)
         occurrences all number
    0
    1
    3
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    2
    Abdominal distension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Gastritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Irritable bowel syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Regurgitation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Toothache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    COVID-19
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Oral herpes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Post-acute COVID-19 syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Eczema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Hyperhidrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Neurodermatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Skin irritation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Skin reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    1
    3
    1
    lower res
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperkalaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2019
    Protocol version 1.1 (NL only): Section 1.4 ‘KH176’: updated to include a summary of the results of the assessment of the phototoxicity potential of KH176 (by determining the UV-Vis spectrum for KH176 and its metabolite KH183 in methanol. The assessment showed that KH183 is not considered photoreactive.
    23 Jan 2020
    Protocol version 2.0 (GER, UK): • Thyroid sonography included as safety assessment preceding the first Treatment Period and at Follow Up visit Requested by German Ethics Committee. • Inclusion criteria #11: More stringent contraceptive measures for male and female subjects Requested by German (Bundesinstitut für Arzneimittel und Medizinprodukte [BfArM]) and United Kingdom (MHRA) Health Authorities. • Exclusion criteria #2: Specification of prior treatment with an Investigational Product Requested by German Health Authority (BfArM). • Exclusion criteria #5: Addition of threshold values for blood pressure, and renal and hepatic laboratory parameters. Requested by German Health Authority (BfArM). • Exclusion criteria #15: Specification of prior and concomitant use of disallowed medications and supplements Requested by German Health Authority (BfArM) and Dutch Ethics Committee. • Pregnancy test included as Follow Up visit assessment Requested by German Health Authority (BfArM). • Section 1.4 ‘KH176’: Assessment of and guidance on phototoxicity potential included. Requested by United Kingdom Health Authority (MHRA). • Section 1.5.4 ‘KH176 Dose Justification’: Specification of the concomitant use of CYP3A4 and PGP inhibitors. Requested by German Health Authority (BfArM). • Section 4.3.5 ‘Premature Termination or Suspension of Study’: Specification of criteria for (premature) termination or suspension of study Requested by German Health Authority (BfArM). • Section 4.5.3 ‘Emergency Procedure for Unblinding’: Procedure updated to remove requirement of sponsor contact Requested by United Kingdom Health Authority (MHRA). • Section 6.3.7.2 ‘Clinical Chemistry’: Addition of lipase to clinical chemistry panel Requested by German Health Authority (BfArM).
    04 Mar 2020
    Protocol version 2.0 (Local amendment: NL only): • Inclusion criterion #11: More stringent contraceptive measures for male and female subjects. Requested by German (BfArM) and United Kingdom (MHRA) Health Authorities. • Exclusion criterion #2: Specification of prior treatment with an Investigational Product. Requested by German Health Authority (BfArM). • Exclusion criterion #5: Addition of threshold values for blood pressure, and renal and hepatic laboratory parameters. Requested by German Health Authority (BfArM). • Exclusion criterion #15: Specification of prior and concomitant use of disallowed medications and supplements. Requested by German Health Authority (BfArM) and Dutch Ethics Committee. • Schedule of Assessments: Pregnancy test included as Follow Up visit assessment. Requested by German Health Authority (BfArM). • Section 1.5.4 ‘KH176 Dose Justification’: Specification of the concomitant use of CYP3A4 and PGP inhibitors. Requested by German Health Authority (BfArM). • Section 4.3.5 ‘Premature Termination or Suspension of the Study’: Specification of criteria for (premature) termination or suspension of study. Requested by German Health Authority (BfArM). • Section 6.3.7.2 ‘Clinical Chemistry’: Addition of lipase to clinical chemistry panel Requested by German Health Authority (BfArM).
    15 Oct 2020
    Protocol version 3.0 (Local amendment NL): Protocol version 3.0 (UK, Ger), issued 15 October 2020: • Exclusion criterion #4: Adapted: Further specification of exclusion criterion.• Exclusion criterion #6: Addition of gender specific QTc exclusion thresholds. Normal values for QTc differ between males and females. • Additional exclusion criterion #15: KH176 is an antagonist of the NMDA1A/2B receptor and for other NMDA (1A/2B) antagonists dissociative effects (leading to abuse potential) and other CNS AEs were reported. Therefore, subjects with a history of abuse potential are excluded and subjects will be cautioned against driving or working in situations where alertness and adequate motor coordination are important when they notice adverse CNS effects. • Exclusion criterion #16e: Adapted; subjects using drugs known to prolong QTc interval who have a normal QTc value will not be excluded. If despite use of potentially QTcprolonging drugs patients have a normal QTc interval, there is no increased risk for torsades de pointes. Also, synergism of two potentially QT-prolonging drugs is not expected: currently, there are no data available suggesting the possibility of a more pronounced QTc prolongation by KH176 if the patient is taking any medication expected to affect cardiac repolarization. • Section 1.4 ‘KH176’: o Summary of additional data from receptor binding assay on NMDAR (1A/2B) blocker/antagonism: in a recent receptor binding assay, KH176 was found to be a NMDAR (1A/2B) blocker/antagonist with an half-maximal inhibitory concentration (IC50) of 7.4 uM. o Summary of additional data on anti-inflammatory properties of KH183, and (the absence of) NMDAR (1A/2B) blocker/antagonism of KH183. o Additional text to further clarify occurrence of (TE)AEs. o Additional text further clarifying the reported dissociative TEAEs. o Additional explanation/specification of ‘cardiac electrophysiology’.
    19 Mar 2021
    Protocol version 5.0 (Ger, UK): • Additional site in Denmark: Dr John Vissing, Rigshospitalet, University of Copenhagen. • Section 3.2.3 ‘Treatment periods’: Visit window increased for D28 (treatment periods 1 to 3): +/- 1 day. • Inclusion criterion #11: additional details and more stringent contraceptive measures with regards to hormonal contraception, vasectomy and sexual abstinence. Requested by German Health Authority (BfArM) for the KHENEREXT study and according to the Clinical Trials Facilitation Group recommendations. • Section 4.3.1 ‘Discontinuation of Study Medication’: Clarification of the discontinuation criteria for the case of abnormal ECG and in case a pregnancy is diagnosed (subjects must be discontinued). Requested by German Health Authority (BfArM) for the KHENEREXT study. • Section 4.3.4 ‘End of Study Definition’: Clarification of the end of study definition as Last Patient Last Visit. Requested by German Health Authority (BfArM) for the KHENEREXT study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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