Paracetamol Study in Patients With Low Muscle Mass

NCT03648658 | Recruiting Phase 4 DMC

• 2 other identifiers: 08-06-2018-paracet2018-002295-40
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

To investigate the safety and toxicity related to paracetamol treatment in children and adults with respectively SMA and CP.

Conditions

SMA II; Cerebral Palsy

Outcome Measures

Primary Outcomes (7)

• Clearance paracetamol

  \- Clearance (total, glucuronidation, sulphation, CYP2E1 oxidation and unchanged) of paracetamol in patients with SMA, CP and ICU-admitted patients with either SMA or CP

  Three days

• Clearance paracetamol

  \- Clearance (total paracetamol) of paracetamol in patients with SMA, CP and ICU-admitted patients with either SMA or CP

  Three days

• Clearance paracetamol

  \- Clearance (glucuronidation) of paracetamol in patients with SMA, CP and ICU-admitted patients with either SMA or CP

  Three days

• Clearance paracetamol

  \- Clearance (sulphation) of paracetamol in patients with SMA, CP and ICU-admitted patients with either SMA or CP

  Three days

• Clearance paracetamol

  \- Clearance (CYP2E1 oxidation) of paracetamol in patients with SMA, CP and ICU-admitted patients with either SMA or CP

  Three days

• Clearance paracetamol

  \- Clearance (unchanged paracetamol) of paracetamol in patients with SMA, CP and ICU-admitted patients with either SMA or CP

  Three days

• Volume of distribution of paracetamol

  \- Volume of distribution of paracetamol in patients with SMA, CP and ICU-admitted patients with SMA or CP, in comparison with healthy controls.

  Three days

Secondary Outcomes (2)

• Liver function tests: ALT, AST, LDH, Alkaline Phosphatase, Bilirubin (U/L)

  Three days

• Concentration-time data on liver function and paracetamolparametres

  Three days

Study Arms (1)

Paracetamol 15mg/kg

EXPERIMENTAL

Drug: Paracetamol 120Mg/5mL Oral Suspension

Interventions

Paracetamol 120Mg/5mL Oral Suspension DRUG

The subjects will be treated with paracetamol in therapeutic doses, 15mg/kg/dose every six hour, with a maximum dosage of 1 g x 4 per day, for three consecutive days.

Paracetamol 15mg/kg

Eligibility Criteria

• Age: 6 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• \- Patients: Men, women and children diagnosed with/biochemically verified SMA and CP
• Patients admitted to the ICU: Men, women, children diagnosed with/biochemically verified SMA and CP
• Healthy controls: Need to be healthy, evaluated by the investigator.
• Age:
• Children: 6-18 years
• Adult patients: 18-45 years
• Healthy controls: 18-45 years
• ICU-admitted patients: 6-45 years
• Signed informed consent to participation in the trial

You may not qualify if:

• \- Inability to understand the purpose of the trial or cooperate in the conduction of the experiments.
• o For the children this will concern of course the parents or the guardians of the child.
• Competing conditions at risk for compromising the results of the study.
• Participation in other trials that may interfere with the results.
• Intake of medications that may interfere with the results, evaluated by investigator.
• Pregnancy and breastfeeding.
• BMI \>30\*
• In morbidly obese patients, the median area under the plasma concentration-time curve from 0 to 8 h. (AUC0-8h) of paracetamol is significantly smaller (p = 0.009), while the AUC0-8h ratios of the glucuronide, sulphate and cysteine metabolites to paracetamol are significantly higher (p = 0.043, 0.004 and 0.010, respectively). In this model, paracetamol CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight.

Sponsors & Collaborators

• Mette Cathrine Oerngreen: lead
• Elsass Foundation: collaborator

Study Sites (1)

Copenhagen Neuromuscular Center

Copenhagen, 2200, Denmark

RECRUITING

Related Publications (14)

• Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015 Nov;33(4):831-46. doi: 10.1016/j.ncl.2015.07.004.

  PMID: 26515624 BACKGROUND

• Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, Dan B, Jacobsson B. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl. 2007 Feb;109:8-14.

  PMID: 17370477 BACKGROUND

• Ceelie I, James LP, Gijsen V, Mathot RA, Ito S, Tesselaar CD, Tibboel D, Koren G, de Wildt SN. Acute liver failure after recommended doses of acetaminophen in patients with myopathies. Crit Care Med. 2011 Apr;39(4):678-82. doi: 10.1097/CCM.0b013e318206cc8f.

  PMID: 21242792 BACKGROUND

• Hynson JL, South M. Childhood hepatotoxicity with paracetamol doses less than 150 mg/kg per day. Med J Aust. 1999 Nov 1;171(9):497. doi: 10.5694/j.1326-5377.1999.tb123758.x. No abstract available.

  PMID: 10615345 BACKGROUND

• Orngreen MC, Zacho M, Hebert A, Laub M, Vissing J. Patients with severe muscle wasting are prone to develop hypoglycemia during fasting. Neurology. 2003 Oct 14;61(7):997-1000. doi: 10.1212/01.wnl.0000086813.59722.72.

  PMID: 14557579 BACKGROUND

• Sen, C. K. Glutathione: A key role in skeletal muscle metabolism. in Oxidative Stress in Skeletal Muscle 127-139 (Birkhäuser, Basel, 1998). doi:10.1007/978-3-0348-8958-2_8

  BACKGROUND

• Hammarqvist F, Luo JL, Cotgreave IA, Andersson K, Wernerman J. Skeletal muscle glutathione is depleted in critically ill patients. Crit Care Med. 1997 Jan;25(1):78-84. doi: 10.1097/00003246-199701000-00016.

  PMID: 8989180 BACKGROUND

• McClain CJ, Price S, Barve S, Devalarja R, Shedlofsky S. Acetaminophen hepatotoxicity: An update. Curr Gastroenterol Rep. 1999 Feb-Mar;1(1):42-9. doi: 10.1007/s11894-999-0086-3.

  PMID: 10980926 BACKGROUND

• Caparrotta TM, Antoine DJ, Dear JW. Are some people at increased risk of paracetamol-induced liver injury? A critical review of the literature. Eur J Clin Pharmacol. 2018 Feb;74(2):147-160. doi: 10.1007/s00228-017-2356-6. Epub 2017 Oct 24.

  PMID: 29067481 BACKGROUND

• Pearce B, Grant IS. Acute liver failure following therapeutic paracetamol administration in patients with muscular dystrophies. Anaesthesia. 2008 Jan;63(1):89-91. doi: 10.1111/j.1365-2044.2007.05340.x.

  PMID: 18086077 BACKGROUND

• Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982 Mar-Apr;7(2):93-107. doi: 10.2165/00003088-198207020-00001.

  PMID: 7039926 BACKGROUND

• Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol. 1980 Oct;10 Suppl 2(Suppl 2):291S-298S. doi: 10.1111/j.1365-2125.1980.tb01812.x.

  PMID: 7002186 BACKGROUND

• van Rongen A, Valitalo PAJ, Peeters MYM, Boerma D, Huisman FW, van Ramshorst B, van Dongen EPA, van den Anker JN, Knibbe CAJ. Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen. Clin Pharmacokinet. 2016 Jul;55(7):833-847. doi: 10.1007/s40262-015-0357-0.

  PMID: 26818482 BACKGROUND

• Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):87-93. doi: 10.1001/jama.296.1.87.

  PMID: 16820551 BACKGROUND

MeSH Terms

Conditions

Spinal Muscular Atrophies of Childhood; Cerebral Palsy

Interventions

Acetaminophen; Suspensions

Condition Hierarchy (Ancestors)

Muscular Atrophy, Spinal; Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Motor Neuron Disease; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Brain Damage, Chronic; Brain Diseases

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Colloids; Complex Mixtures; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Mette Cathrine Ørngreen, MD, DMSc

  MD

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mette Cathrine Ørngreen, MD, DMSc

CONTACT

+45 35 45 76 14; mette.cathrine.oerngreen.01@regionh.dk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 8, 2018
• First Posted: August 27, 2018
• Study Start: February 18, 2019
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: February 22, 2024

Record last verified: 2024-02

Locations

DK (1)