Liver Function After Intravenous Methylprednisolone Administration

NCT03667157 | Completed Phase 4

• 1 other identifier: IVMPLiver
• Study Type: interventional
• Target: 68
• Locations: 0 countries
• Sites: N/A

Brief Summary

Graves' orbitopathy (GO) is a characterized by orbital soft tissue inflammation and oedema associated with glycosaminoglycan deposition and fibrosis. The most frequent cause is Graves' disease. The classification is comprised based on the severity of orbital changes ranging from mild, moderate-to-severe GO and sight-threatening GO, which includes dysthyroid optic neuropathy (DON). Intravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment in the active-phase of moderate-to-severe GO and DON. This therapy is more effective and better tolerated than oral glucocorticoids (GCs). The current recommendation of the European Group of Graves' Orbitopathy (EUGOGO) is that cumulative doses of IVMP should not exceed 8.0g in each treatment course, and pulses should not be given on consecutive or alternate days, except in the case of DON. According to EUGOGO recommendations patients with moderate-to-severe GO are treated with IVMP cumulative dose 4.5g during a 12-week period (for the first 6 weeks 0.5g IVMP per week, for the next 6 weeks 0.25g IVMP per week). According to EUGOGO recommendations patients with DON should receive 3.0g IVMP (1.0g/day for 3 consecutive days) as the basic treatment. This limitation in doses are due to the necessity of the prevention of severe side effects that are rare but may be fatal. One of the most severe adverse events is acute liver injury (ALI), in some cases irreversible and/or fatal. The estimated morbidity and mortality of ALI was found to be 1-4 % and 0.01-0.3%, respectively. Since 2000, there were 5 reported fatal cases. Mechanisms causing an IVMP-induced ALI remains incompletely elucidated. There are some possible hypotheses that may explain the occurrence of ALI. Firstly, GCs can lead to reactivation of autoimmune hepatitis: an immune "rebound phenomenon" following GCs withdrawal. The second mechanism of ALI is reactivation of viral hepatitis. Finally, there is well known direct toxic effect of GCs on hepatocytes, probably dose-dependent. This study was performed to evaluate the influence of two different, routinely used schemes of therapy with IVMP in patients with moderate-to-severe GO (first scheme) and DON (second scheme) on biochemical liver parameters. Patients included into the study were treated according to EUGOGO recommendations with routine doses of IVMP and routine scheme of administration for moderate-to-severe GO and DON. No additional treatment was performed during the study protocol.

Conditions

Graves Disease; Graves Ophthalmopathy; Liver Diseases; Liver Failure; Liver Injury; Liver Dysfunction; Liver Insufficiency; Acute Liver Failure; Acute Liver Injury; Acute Liver Injury, Drug Induced; Methylprednisolone Adverse Reaction; Glucocorticoids Toxicity; Dysthyroid Orbitopathy; Dysthyroid Ophthalmopathy

Keywords

Graves Disease; Graves Ophthalmopathy; Dysthyroid Orbitopathy; Liver Failure; Liver Injury; Acute Liver Failure; Acute Liver Injury; Methylprednisolone; Glucocorticoids; Glucocorticoids Toxicity; Intravenous; Side effects; Adverse effects; Aminotransferase

Outcome Measures

Primary Outcomes (2)

• Influence of IVMP pulses in 12 every week schedule on mean ALT

  Administration of IVMP in 12 every week schedule: 6 weeks 0.5g IVMP per week plus 6 weeks 0.25g IVMP per week. Change of mean value of alanine aminotransferase (ALT) between baseline (before administration of IVMP) and the end of the therapy (after the last pulse of IVMP).

  12 weeks

• Influence of IVMP pulses in 3 consecutive days schedule on mean ALT

  Administration of 3g IVMP (1g in 3 consecutive days). Change of mean value of ALT between baseline (before IVMP) and the end of the therapy (after the last pulse of IVMP).

  3 days

Secondary Outcomes (2)

• Influence of IVMP pulses in 12 every week schedule on prevalence of mild, moderate and severe liver dysfunction.

  12 weeks

• Influence of IVMP pulses in 3 consecutive days schedule on prevalence of mild, moderate and severe liver dysfunction.

  3 days

Study Arms (2)

moderate-to-severe Graves Orbitopathy

ACTIVE COMPARATOR

active, moderate-to-severe Graves Orbitopathy according to EUGOGO.

Drug: every week IVMP therapy

Dysthyroid Orbit Neuropathy

ACTIVE COMPARATOR

Dysthyroid Orbit Neuropathy according to EUGOGO

Drug: very high doses IVMP therapy

Interventions

every week IVMP therapy DRUG

12 pulses of intravenous methylprednisolone (IVMP) in every week schedule (for the first 6 weeks 0.5g IVMP per week, for the next 6 weeks 0.25g IVMP per week; cumulative dose 4.5g) according to EUGOGO recommendations

moderate-to-severe Graves Orbitopathy

very high doses IVMP therapy DRUG

3 pulses of intravenous methylprednisolone (IVMP) (1.0g/day for 3 consecutive days; cumulative dose 3.0g) according to EUGOGO recommendations

Dysthyroid Orbit Neuropathy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• active, moderate-to-severe Graves' orbitopathy or dysthyroid orbit neuropathy
• euthyroidism

You may not qualify if:

• alanine aminotransferase and/or aspartate aminotransferase \>2x upper limit of normal
• active viral hepatitis
• cirrhosis
• present or past medical history of autoimmune hepatitis
• previous glucocorticoids therapy within the last 6 months
• alcohol abuse
• active inflammation
• active neoplastic disease

Sponsors & Collaborators

• Medical University of Warsaw: lead

Related Publications (1)

• Miskiewicz P, Jankowska A, Brodzinska K, Milczarek-Banach J, Ambroziak U. Influence of Methylprednisolone Pulse Therapy on Liver Function in Patients with Graves' Orbitopathy. Int J Endocrinol. 2018 Oct 21;2018:1978590. doi: 10.1155/2018/1978590. eCollection 2018.

  PMID: 30420883 DERIVED

MeSH Terms

Conditions

Graves Disease; Graves Ophthalmopathy; Liver Diseases; Liver Failure; Hepatic Insufficiency; Liver Failure, Acute; Chemical and Drug Induced Liver Injury

Condition Hierarchy (Ancestors)

Exophthalmos; Orbital Diseases; Eye Diseases; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases; Eye Diseases, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Digestive System Diseases; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning

Study Officials

• Piotr Miśkiewicz, MD, PhD

  Medical University of Warsaw

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant professor

Study Record Dates

• First Submitted: September 8, 2018
• First Posted: September 12, 2018
• Study Start: January 1, 2012
• Primary Completion: October 30, 2016
• Study Completion: October 30, 2016
• Last Updated: September 13, 2018

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will share
• Time Frame: The results of the study will be published in 2018-2019