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    Clinical Trial Results:
    Pharmacokinetics and safety of treatment with paracetamol in children and adults with spinal muscular atrophy and cerebral palsy

    Summary
    EudraCT number
    		 2018-002295-40
    Trial protocol
    		 DK  
    Global end of trial date
    09 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jun 2025
    First version publication date
    21 Jun 2025
    Other versions
    Summary report(s)
    		 Medical journal publication of the results_publication 1
    Medical journal publication of the results_publication 2

    Trial information

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    Trial identification
    Sponsor protocol code
    08-06-2018-paracet
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet, Copenhagen University Hospital
    Sponsor organisation address
    Blegdamsvej 9 , København Ø, Denmark, 2100
    Public contact
    Copenhagen Neuromuscular Center, Rigshospitalet, marie.mostue.naume.01@regionh.dk
    Scientific contact
    Copenhagen Neuromuscular Center, Rigshospitalet, marie.mostue.naume.01@regionh.dk
    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
    09 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to explore pharmacokinetics, pharmacogenetics and safety of treatment with paracetamol in children and adults with spinal muscular atrophy type II (SMA II) and cerebral palsy (CP).
    Protection of trial subjects
    We measured liver biomarkers three times on study day 1 and day 3. If the liver biomarkers were markedly elevated (judged by the treating physician), the paracetamol intake was stopped, and the patient was excluded from the rest of the study. Before inserting venous catheters and blood samples from the children, EMLA cream, a local anaesthetic, was applied to minimise any discomfort. Furthermore, these procedures were performed only by experienced staff.
    Background therapy
    		 -
    Evidence for comparator
    		 As a part of postoperative mild-to-moderate pain treatment and antipyretic treatment, patients with SMA often receive paractamol for several days at same dose levels as healthy subjects without considering the patient's lower muscle mass. Thus, several individual case reports involving children and adults with SMA, limb-girdle muscular dystrophy, Duchenne muscular dystrophy (DMD) and congenital muscular dystrophy with low skeletal muscle mass have reported hepatotoxic side effects of paracetamol administered in therapeutic doses after surgery, infections, or critical illness. In line with this, we have experienced one adult patient with SMA II that developed fatal acute liver failure following abdominal surgery, suspected to be caused by paractamol toxicity (unpublished data). Furthermore, a DMD boy in our clinic recently developed acute liver failure after intake of therapeutic doses of paracetamol during hospitalization (unpublished data). The majority of paracetamol is conjugated to sulfate and glucuronide to form nontoxic metabolites. A small portion undergoes CYP-mediated metabolism, forming the reactive and potentially toxic metabolite N-acetyl-p-benzo-quinone imine (NAPQI). NAPQI is conjugated by glutathione (GSH) to the nontoxic oxidative metabolites cysteine and mercapturic acid. In toxic doses, the usual metabolic pathways are overloaded, and paracetamol is shunted to the oxidative pathway, leading to the depletion of GSH stores. Hepatic cellular injury and necrosis occur as NAPQI accumulates. Glutathione is a tripeptide consisting of glutamate, cysteine, and glycine. However, GSH synthesis depends on glutamine from the skeletal muscle to form glutamate. Thus, patients with SMA may have a lower concentration of GSH compared to healthy due to their altered body composition, i.e., low skeletal muscle mass. This may increase the risk of paracetamol-induced hepatotoxicity in the patients, even when treated with therapeutic doses.
    Actual start date of recruitment
    01 Aug 2018
    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
    Denmark: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    5
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    18
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients of SMA II were eligible for inclusion if genetically verified. The patients with SMA II were in the age group of 6-45 years. We recruited healthy adults from official recruitment sites for healthy controls and Facebook.com. The healthy controls should be in the age group of 18-45 years.

    Pre-assignment
    Screening details
    		 Exclusion criteria were intake of medications (that may interfere with the results and that may affect gastric emptying), failure to obtain consent, or the participant being considered unsuitable by the treating physician.

    Pre-assignment period milestones
    Number of subjects started
    		 24
    Number of subjects completed
    		 24

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Adult participants with the disease, SMA
    Arm description
    		 The adult participants with the disease who received paracetamol, the study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paracetamol
    Investigational medicinal product code
    Other name
    Acetaminophen
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    All participants were treated with an oral liquid formulation of paracetamol in therapeutic doses, 15 mg/kg/dose every six hours, with a maximum of 1 gram x 4 per day, for three consecutive days.

    Arm title
    		 The children with the disease, SMA
    Arm description
    		 The participants being childrne with the disease who received paracetamol, the study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paracetamol
    Investigational medicinal product code
    Other name
    Acetaminophen
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    All participants were treated with an oral liquid formulation of paracetamol in therapeutic doses, 15 mg/kg/dose every six hours, with a maximum of 1 gram x 4 per day, for three consecutive days.

    Arm title
    		 Healthy controls
    Arm description
    		 The participants being healthy controls receiving paracetamol, the study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paracetamol
    Investigational medicinal product code
    Other name
    Acetaminophen
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    All participants were treated with an oral liquid formulation of paracetamol in therapeutic doses, 15 mg/kg/dose every six hours, with a maximum of 1 gram x 4 per day, for three consecutive days.

    Number of subjects in period 1
    		Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Started
    6
    6
    12
    Completed
    6
    6
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 24 24
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 5 5
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 18 18
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 13 13
    Subject analysis sets

    Subject analysis set title
    Participants with SMA combined
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with the disease SMA combined. This category is used when analysing the frequency of pharmacogenetic polymorphisms in the group.

    Subject analysis set title
    North-western European dataset
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The prevalence of pharmacogenetics variants in healthy controls was assumed to be similar to the North-western European population, which had already been studied in a large sample of 4294 individuals, and thus not investigated in the healthy controls in this study. The pharmacogenetic profiles in the SMA patients were compared to the prevalence of homozygous carriers of the alternative alleles in the specific SNPs found in the North-western European population of 4294 individuals (1). The system will not accept the number of subjects being 4294 since that is not the overall number in the study, 12 is therefore registered. 1. A genome-wide mutational constraint map quantified from variation in 76,156 human genomes | bioRxiv [Internet]. [cited 2023 Jun 13]. Available from: https://www.biorxiv.org/content/10.1101/2022.03.20.485034v2

    Subject analysis sets values
    		 Participants with SMA combined North-western European dataset
    Number of subjects
    12
    12
    Age categorical
    Units: Subjects
        Children (2-11 years)
    5
        Adolescents (12-17 years)
    1
        Adults (18-64 years)
    6
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    5
        Male
    7

    End points

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    End points reporting groups
    Reporting group title
    Adult participants with the disease, SMA
    Reporting group description
    		 The adult participants with the disease who received paracetamol, the study drug.

    Reporting group title
    The children with the disease, SMA
    Reporting group description
    		 The participants being childrne with the disease who received paracetamol, the study drug.

    Reporting group title
    Healthy controls
    Reporting group description
    		 The participants being healthy controls receiving paracetamol, the study drug.

    Subject analysis set title
    Participants with SMA combined
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with the disease SMA combined. This category is used when analysing the frequency of pharmacogenetic polymorphisms in the group.

    Subject analysis set title
    North-western European dataset
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The prevalence of pharmacogenetics variants in healthy controls was assumed to be similar to the North-western European population, which had already been studied in a large sample of 4294 individuals, and thus not investigated in the healthy controls in this study. The pharmacogenetic profiles in the SMA patients were compared to the prevalence of homozygous carriers of the alternative alleles in the specific SNPs found in the North-western European population of 4294 individuals (1). The system will not accept the number of subjects being 4294 since that is not the overall number in the study, 12 is therefore registered. 1. A genome-wide mutational constraint map quantified from variation in 76,156 human genomes | bioRxiv [Internet]. [cited 2023 Jun 13]. Available from: https://www.biorxiv.org/content/10.1101/2022.03.20.485034v2

    Primary: Clearance of paracetamol in the participants

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    End point title
    		 Clearance of paracetamol in the participants
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [1]
    Units: L/h
        median (full range (min-max))
    14.13 (10.53 to 20.7)
    17.05 (9.07 to 26.60)
    21.51 (17.58 to 37.68)
    Notes
    [1] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Clearance of paracetamol 1
    Statistical analysis description
    Comparison of clearance of paracetamol in the adults participants with SMA and the healthy controls
    Comparison groups
    Healthy controls v Adult participants with the disease, SMA
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Statistical analysis title
    		 Clearance of paracetamol 2
    Statistical analysis description
    Comparison of clearance of paracetamol in the children participants and the healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval

    Primary: Volume of distribution of paracetamol in the participants

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    End point title
    		 Volume of distribution of paracetamol in the participants
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    3 days. The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [2]
    Units: L/h
        median (full range (min-max))
    53.02 (32.1 to 56.47)
    41.50 (32.76 to 67.69)
    69.46 (30.90 to 96.50)
    Attachments
    		 Untitled (Filename: Table 2.docx)
    Notes
    [2] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Volume of distribution of paracetamol 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [3] - To investigate if the pharmacokinetics of paracetamol are significantly different in SMA patients compared to people without the disease
    Statistical analysis title
    		 Volume of distribution of paracetamol 2
    Statistical analysis description
    Children with SMA vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [4] - To investigate if the pharmacokinetics of paracetamol are significantly different in SMA patients compared to people without the disease

    Primary: Formation rate of glucuronide

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    End point title
    		 Formation rate of glucuronide
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [5]
    Units: L/h
        median (full range (min-max))
    3.87 (2.02 to 4.32)
    3.61 (1.95 to 6.58)
    7.25 (4.17 to 13.85)
    Attachments
    		 Untitled (Filename: Table 2.docx)
    Notes
    [5] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Formation of glucuronide 1
    Statistical analysis description
    Adults SMA patients compared to healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [6] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease
    Statistical analysis title
    		 Formation of glucuronide 2
    Statistical analysis description
    To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval

    Primary: Elimination rate of glucuronide

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    End point title
    		 Elimination rate of glucuronide
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [7]
    Units: L/h
        median (full range (min-max))
    3.24 (2.63 to 4.42)
    2.75 (2.39 to 4.88)
    6.18 (4.49 to 7.60)
    Attachments
    		 Untitled (Filename: Table 2.docx)
    Notes
    [7] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Elimination rate of glucuronide 1
    Statistical analysis description
    Adults SMA patients vs healty controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [8] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease
    Statistical analysis title
    		 Elimination rate of glucuronide 2
    Statistical analysis description
    SMA children vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [9] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease

    Primary: Formation rate of sulfate

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    End point title
    		 Formation rate of sulfate
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [10]
    Units: L/h
        median (full range (min-max))
    4.70 (2.51 to 6.76)
    4.58 (3.4 to 8.40)
    9.50 (6.66 to 12.52)
    Attachments
    		 Untitled (Filename: Table 2.docx)
    Notes
    [10] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Formation rate of sulfate 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [11] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease
    Statistical analysis title
    		 Formation rate of sulfate 2
    Statistical analysis description
    Children with SMA vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [12] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease

    Primary: Elimination rate of sulfate

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    End point title
    		 Elimination rate of sulfate
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [13]
    Units: L/h
        median (full range (min-max))
    11.62 (9.44 to 15.88)
    9.86 (8.58 to 17.52)
    22.16 (16.12 to 27.30)
    Attachments
    		 Untitled (Filename: Table 2.docx)
    Notes
    [13] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Elimination rate of sulfate 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [14] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease
    Statistical analysis title
    		 Elimination rate of sulfate 2
    Statistical analysis description
    Children with SMA vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [15] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease

    Primary: Formation rate of oxidative metabolites

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    End point title
    		 Formation rate of oxidative metabolites
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [16]
    Units: L/h
        median (full range (min-max))
    0.12 (0.09 to 0.16)
    0.10 (0.09 to 0.17)
    0.22 (0.16 to 0.27)
    Attachments
    		 Untitled (Filename: Table 2.docx)
    Notes
    [16] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Formation rate of oxidative metabolites 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [17] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease
    Statistical analysis title
    		 Formation rate of oxidative metabolites 2
    Statistical analysis description
    Children with SMA vs healthy adults
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [18] - To investigate if the pharmacokinetics of paracetamol is significantly different in SMA patients compared to people without the disease

    Primary: Elimination rate of oxidative metabolites

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    End point title
    		 Elimination rate of oxidative metabolites
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [19]
    Units: L/h
        median (full range (min-max))
    2.52 (1.45 to 4.51)
    1.65 (1.30 to 2.69)
    3.82 (2.43 to 4.95)
    Attachments
    		 Untitled (Filename: Table 2.docx)
    Notes
    [19] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Elimination rate of oxidative metabolies 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [20] - To investigate if the pharmacokinetics of paracetamol are significantly different in SMA patients compared to people without the disease
    Statistical analysis title
    		 Elimination rate of oxidative metabolites
    Statistical analysis description
    Children with SMA vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [21] - To investigate if the pharmacokinetics of paracetamol are significantly different in SMA patients compared to people without the disease

    Primary: Unmetabolised paracetamol clearance

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    End point title
    		 Unmetabolised paracetamol clearance
    End point description
    Population pharmacokinetic parameters estimates were obtained using a nonlinear mixed effects model. The structure of the model involves single compartments of paracetamol and its metabolites in plasma. Since paracetamol-cysteine and paracetamol-mercapturic acid were derived from CYP-mediated oxidation, we summed them together into one compartment called oxidative metabolites. The estimated pharmacokinetic parameters in the model were total clearance of paracetamol, formation clearances of each metabolite, unmetabolized clearance of paracetamol, the volume of distribution of paracetamol and its metabolites, renal clearances of each metabolite, and half-life time of paracetamol and each metabolite. Unmetabolized clearance of paracetamol was the estimated paracetamol that the three metabolic pathways could not explain.
    End point type
    Primary
    End point timeframe
    The metabolites were measured every hour for 6 or 8 hours on day 1 and day 3 (last day of trial). The pharmacokinetic parameters are estimated with these numbers.
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [22]
    Units: L/h
        median (full range (min-max))
    6.22 (1.99 to 10.85)
    9.11 (2.72 to 13.01)
    4.56 (1.19 to 14.64)
    Attachments
    		 Untitled (Filename: Table 2.docx)
    Notes
    [22] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Unmetabolised paracetamol clearance 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [23] - To investigate if the pharmacokinetics of paracetamol are significantly different in SMA patients compared to people without the disease
    Statistical analysis title
    		 Unmetabolised paracetamol clearance 2
    Statistical analysis description
    Children with SMA vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [24] - To investigate if the pharmacokinetics of paracetamol are significantly different in SMA patients compared to people without the disease

    Secondary: ALT during paracetamol treatment in the participants

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    End point title
    		 ALT during paracetamol treatment in the participants
    End point description
    Paracetamol parent compound and its metabolite concentrations were measured every hour for six or eight hours after the initial dosing on study days 1 and 3. The participants were at home on day 2 without blood sampling. Liver plasma biomarkers (ALT, aspartate aminotransferase (AST), alkaline phosphatase, INR, lactate dehydrogenase (LDH), bilirubin, miRNA 122, and miRNA 192), kidney plasma biomarkers (creatinine, potassium, sodium, and urea) and creatinine kinase (CK) were collected at three different time points during study days 1 and 2. The endpoint mean is the mean of the ALT measured in the afternoon on day 3.
    End point type
    Secondary
    End point timeframe
    3 days
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [25]
    Units: U/l
        arithmetic mean (standard deviation)
    31.4 ( 34.18 )
    20.6 ( 8.79 )
    26.1 ( 11.84 )
    Notes
    [25] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 Liver biomarker ALT after paracetamol treatment 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Statistical analysis title
    		 Liver biomarker ALT after paracetamol treatment
    Statistical analysis description
    Children with SMA vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Kruskal-wallis
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Secondary: pharmacogenetic screening of SNPs in paracetamol-metabolizing enzymes in SMA participants

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    End point title
    		 pharmacogenetic screening of SNPs in paracetamol-metabolizing enzymes in SMA participants
    End point description
    DNA for investigation of pharmacogenetics was available in our biobank for the SMA patients. The prevalence of pharmacogenetics variants in healthy controls was assumed to be similar to the North-western European population, which had already been studied in a large sample of 4294 individuals, and thus not investigated in the healthy controls in this study. The investigated single-nucleotide polymorphisms (SNPs) were selected after a review of the literature, researching the reported SNPs with possible effects on acetaminophen metabolism. The endpoint is the number of participants being homozygous carriers of the alternative allele in the UGT1A-3 gene and CYP1A. UGT1A is important for the glucuronide pathway, including the SNPs rs10929303 (C/C), rs1042640 (C/C) and rs8330 (C/C). CYP1A2 is important in the oxidation pathway with SNP rs762551 (A/A).
    End point type
    Secondary
    End point timeframe
    one time measurement
    End point values
    		 Participants with SMA combined North-western European dataset
    Number of subjects analysed
    12
    4294
    Units: percentage
        rs10929303
    9
    2662
        rs1042640
    9
    2722
        rs8330
    9
    2559
        rs1902023
    5
    988
        rs762551
    8
    2186
    Statistical analysis title
    		 Pharmacogenetic polymorphisms in the participants
    Statistical analysis description
    The SMA participants vs North-Western European population
    Comparison groups
    Participants with SMA combined v North-western European dataset
    Number of subjects included in analysis
    4306
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 < 0.05
    Method
    		 The two-sample binomial test, Boschloo's
    Parameter type
    		 percentages
    Confidence interval
    Notes
    [26] - The two-sample binomial test, Boschloo's test, was used to compare the percentages of homozygous carriers of the alternative alleles in the investigated SNPs between the patient group and the North-western European population.

    Secondary: miRNA 122 during paracetamol treatment

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    End point title
    		 miRNA 122 during paracetamol treatment
    End point description
    Liver plasma biomarkers (ALT, aspartate aminotransferase (AST), alkaline phosphatase, INR, lactate dehydrogenase (LDH), bilirubin, miRNA 122, and miRNA 192), kidney plasma bi-omarkers (creatinine, potassium, sodium, and urea) and creatinine kinase (CK) were collected at three different time points during study days 1 and 2. The miRNA results are registered from the afternoon day 3.
    End point type
    Secondary
    End point timeframe
    3 days
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [27]
    Units: Relative expression
        arithmetic mean (standard deviation)
    2.0 ( 1.8 )
    1.6 ( 1.4 )
    1.5 ( 1.2 )
    Attachments
    		 miRNA change
    Notes
    [27] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 miRNA 122 during paracetamol treatment 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Statistical analysis title
    		 MiRNA 122 during paracetamol treatment 2
    Statistical analysis description
    Children with SMA vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Secondary: miRNA 192 during paracetamol treatment

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    End point title
    		 miRNA 192 during paracetamol treatment
    End point description
    Liver plasma biomarkers (ALT, aspartate aminotransferase (AST), alkaline phosphatase, INR, lactate dehydrogenase (LDH), bilirubin, miRNA 122, and miRNA 192), kidney plasma bi-omarkers (creatinine, potassium, sodium, and urea) and creatinine kinase (CK) were collected at three different time points during study days 1 and 2. Registered results from the afternoon on day 3
    End point type
    Secondary
    End point timeframe
    3 days
    End point values
    		 Adult participants with the disease, SMA The children with the disease, SMA Healthy controls
    Number of subjects analysed
    6
    6
    11 [28]
    Units: relative expression
        arithmetic mean (standard deviation)
    1.3 ( 1.5 )
    1.3 ( 0.7 )
    1.2 ( 0.8 )
    Attachments
    		 miRNA change
    Notes
    [28] - One was excluded from the analyses due to high levels of paracetamol in background sample
    Statistical analysis title
    		 miRNA 192 during paracetamol treatment 1
    Statistical analysis description
    Adults with SMA vs healthy controls
    Comparison groups
    Adult participants with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Statistical analysis title
    		 miRNA 192 during paracetamol treatment 2
    Statistical analysis description
    Children with SMA vs healthy controls
    Comparison groups
    The children with the disease, SMA v Healthy controls
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 days
    Adverse event reporting additional description
    The treatment of paracetamol was stopped if the ALT and/or AST were elevated compared to the baseline sample during the study days judged by the investigator on a patient-by-patient basis or if any other adverse events occurred. All participants completed a journal during the study period to report and monitor compliance and side effects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Adult participants with SMA
    Reporting group description
    		 -

    Reporting group title
    Children with SMA
    Reporting group description
    		 The participants being children with SMA

    Reporting group title
    Healthy controls
    Reporting group description
    		 Participants being healthy controls

    Serious adverse events
    		 Adult participants with SMA Children with SMA Healthy controls
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Adult participants with SMA Children with SMA Healthy controls
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 6 (66.67%)
    3 / 6 (50.00%)
    8 / 11 (72.73%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    4 / 11 (36.36%)
         occurrences all number
    3
    2
    4
    Abdominal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    4 / 11 (36.36%)
         occurrences all number
    2
    0
    4
    Poor appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38052667
    http://www.ncbi.nlm.nih.gov/pubmed/40040359
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