Graves DiseasePhase 4NCT03667157
Liver Function After Intravenous Methylprednisolone Administration
A Phase 4 study testing every week IVMP therapy and very high doses IVMP therapy in people with Graves Disease and Graves Ophthalmopathy, run by Medical University of Warsaw.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Graves Disease, Graves Ophthalmopathy, Liver Diseases
- What is being tested?
- every week IVMP therapy and very high doses IVMP therapy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 68 participants
- Where
- No sites listed yet
- Study dates
- 1 Jan 2012to 30 Oct 2016
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- active, moderate-to-severe Graves' orbitopathy or dysthyroid orbit neuropathy
- euthyroidism
Who cannot join
- 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
About this study
Official title: Influence of Methylprednisolone Pulse Therapy on Liver Function in Patients With Graves' Orbitopathy
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.
Read the detailed description
Depending on the severity according to EUGOGO recommendations, patients were divided into two groups: the first group with active, moderate-to-severe GO (49 patients) and the second group with DON (19 patients). Moderate-to-severe GO was diagnosed according to EUGOGO recommendations. Diagnosis of DON in patients with GO was based on at least two signs, including (i) deterioration of VA (< 1.0), (ii) loss of colour vision (more than two errors in Ishihara plates), (iii) optic disc swelling, and/or (iv) signs of DON in a magnetic resonance (MR) scan (presence of apical crowding and/or optic nerve stretching).
Laboratory tests were performed before treatment in all patients from both evaluated groups. Serum markers of exposure to hepatitis B (HBV) and hepatitis C (HCV) were checked: hepatitis B surface antigen (HBs-Ag), hepatitis B surface antibody (HBs-Ab), hepatitis B core antibody (HBc-Ab), hepatitis C antibody (HCV-Ab). Serum autoantibodies associated with autoimmune hepatitis including anti-nuclear antibodies (ANA1), anti-smooth muscle antibodies (ASMA), anti-mitochondrial antibodies (AMA) and anti-liver kidney-microsomal antibodies (anti-LKM) were also assessed. Thyroid evaluation included measurement of: thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and serum antithyroid autoantibodies including anti-thyroid peroxidase (aTPO), thyroglobulin antibodies (aTG), thyroid-binding inhibitory immunoglobulin (TBII).
According to EUGOGO recommendations: patients with moderate-to-severe GO were treated with IVMP cumulative dose 4.5g during a 12-week period (for the first 6 weeks 0.5g IVMP per week was administrated and for the next 6 weeks 0.25g IVMP per week) and patients with DON received 3.0g IVMP (1.0g/day for 3 consecutive days).
Liver function parameters for further analysis included alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. These parameters were measured the day before treatment in both groups and the day after administration of IVMP in selected pulses: after 0.5g (1st pulse), after 3.0g (6th pulse) and after 4.5g (12th pulse ) in the group with moderate-to-severe GO; after 3.0g IVMP in the group with DON.
Depending on concentrations of ALT, liver dysfunction was divided into: mild (above the upper limit of normal but less than 100 U/L), moderate (100-300 U/L) and severe (>300 U/L). ALI was defined as an ALT concentration >300 U/L. However, the investigators also evaluated a 4-fold increase of ALT in comparison to the initial values.
Routine laboratory tests and clinical evaluation were performed before every single pulse. Laboratory tests consisted of: ALT, AST, C reactive protein (CRP). In cases of moderate and severe increase in ALT (more than 100U/L) therapy was stopped.
Follow-up was performed in all of the patients and it included evaluation of AST, ALT and total bilirubin between 1-3 months after completion of IVMP therapy.
- Conditions
- Graves Disease, Graves Ophthalmopathy, Liver Diseases, Liver Failure, Liver Injury, Liver Dysfunction
- Being tested
- every week IVMP therapy, very high doses IVMP therapy
- 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
- Medical subject headings
- Graves Disease, Graves Ophthalmopathy, Liver Diseases, Liver Failure, Hepatic Insufficiency, Liver Failure, Acute, Chemical and Drug Induced Liver Injury
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
every week IVMP therapyDrug
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
very high doses IVMP therapyDrug
3 pulses of intravenous methylprednisolone (IVMP) (1.0g/day for 3 consecutive days; cumulative dose 3.0g) according to EUGOGO recommendations
| Study group | Role | What they receive |
|---|---|---|
| moderate-to-severe Graves Orbitopathy | Active comparator | active, moderate-to-severe Graves Orbitopathy according to EUGOGO. Receives: Drug: every week IVMP therapy |
| Dysthyroid Orbit Neuropathy | Active comparator | Dysthyroid Orbit Neuropathy according to EUGOGO Receives: Drug: very high doses IVMP therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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).
Measured: 3 days
Secondary outcomes (2)
Influence of IVMP pulses in 12 every week schedule on prevalence of mild, moderate and severe liver dysfunction.
Administration of IVMP in 12 every week schedule: 6 weeks 0.5g IVMP per week plus 6 weeks 0.25g IVMP per week. Depending on concentrations of ALT, liver dysfunction was divided into: mild (above the upper limit of normal but less than 100 U/L), moderate (100-300 U/L) and severe (>300 U/L). ALI was defined as an ALT concentration >300 U/L. Prevalence of all types of liver dysfunction was count after IVMP treatment.
Measured: 12 weeks
Influence of IVMP pulses in 3 consecutive days schedule on prevalence of mild, moderate and severe liver dysfunction.
Administration of 3g IVMP (1g in 3 consecutive days). Depending on concentrations of ALT, liver dysfunction was divided into: mild (above the upper limit of normal but less than 100 U/L), moderate (100-300 U/L) and severe (>300 U/L). ALI was defined as an ALT concentration >300 U/L. Prevalence of all types of liver dysfunction was count after IVMP treatment.
Measured: 3 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Sep 2018
- Study start1 Jan 2012
- Primary completion30 Oct 2016
- Study completion30 Oct 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Graves DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Supportive care
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 68 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical University of Warsaw
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Piotr Miskiewicz, Medical University of Warsaw
- Investigators
- Piotr Miśkiewicz, MD, PhD, Principal investigator, Medical University of Warsaw
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03667157
- Sponsor's protocol ID
- IVMPLiver
- Status last verified
- Sep 2018
- First submitted
- 8 Sep 2018
- Last updated
- 13 Sep 2018
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The collected data will be shared in a publication.
Publications
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.
PubMed 30420883
Study at a glance
From the registry record, last updated by the sponsor on 13 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Influence of Methylprednisolone Pulse Therapy on Liver Function in Patients With Graves' Orbitopathy
- ClinicalTrials.gov ID
- NCT03667157
- Acronym / sponsor ID
- IVMPLiver
- Conditions
- Graves Disease, Graves Ophthalmopathy, Liver Diseases, Liver Failure, Liver Injury, Liver Dysfunction
- Keywords
- Graves Disease, Graves Ophthalmopathy, Dysthyroid Orbitopathy, Liver Failure, Liver Injury, Acute Liver Failure, Acute Liver Injury, Methylprednisolone
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 68 participants (actual)
- Lead sponsor
- Medical University of WarsawUniversity, hospital or other
- Study start
- 1 Jan 2012 (actual)
- Primary completion
- 30 Oct 2016 (actual)
- Study completion
- 30 Oct 2016 (actual)
- First posted
- 12 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Depending on the severity according to EUGOGO recommendations, patients were divided into two groups: the first group with active, moderate-to-severe GO (49 patients) and the second group with DON (19 patients). Moderate-to-severe GO was diagnosed according to EUGOGO recommendations. Diagnosis of DON in patients with GO was based on at least two signs, including (i) deterioration of VA (< 1.0), (ii) loss of colour vision (more than two errors in Ishihara plates), (iii) optic disc swelling, and/or (iv) signs of DON in a magnetic resonance (MR) scan (presence of apical crowding and/or optic nerve stretching).
Laboratory tests were performed before treatment in all patients from both evaluated groups. Serum markers of exposure to hepatitis B (HBV) and hepatitis C (HCV) were checked: hepatitis B surface antigen (HBs-Ag), hepatitis B surface antibody (HBs-Ab), hepatitis B core antibody (HBc-Ab), hepatitis C antibody (HCV-Ab). Serum autoantibodies associated with autoimmune hepatitis including anti-nuclear antibodies (ANA1), anti-smooth muscle antibodies (ASMA), anti-mitochondrial antibodies (AMA) and anti-liver kidney-microsomal antibodies (anti-LKM) were also assessed. Thyroid evaluation included measurement of: thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and serum antithyroid autoantibodies including anti-thyroid peroxidase (aTPO), thyroglobulin antibodies (aTG), thyroid-binding inhibitory immunoglobulin (TBII).
According to EUGOGO recommendations: patients with moderate-to-severe GO were treated with IVMP cumulative dose 4.5g during a 12-week period (for the first 6 weeks 0.5g IVMP per week was administrated and for the next 6 weeks 0.25g IVMP per week) and patients with DON received 3.0g IVMP (1.0g/day for 3 consecutive days).
Liver function parameters for further analysis included alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. These parameters were measured the day before treatment in both groups and the day after administration of IVMP in selected pulses: after 0.5g (1st pulse), after 3.0g (6th pulse) and after 4.5g (12th pulse ) in the group with moderate-to-severe GO; after 3.0g IVMP in the group with DON.
Depending on concentrations of ALT, liver dysfunction was divided into: mild (above the upper limit of normal but less than 100 U/L), moderate (100-300 U/L) and severe (>300 U/L). ALI was defined as an ALT concentration >300 U/L. However, the investigators also evaluated a 4-fold increase of ALT in comparison to the initial values.
Routine laboratory tests and clinical evaluation were performed before every single pulse. Laboratory tests consisted of: ALT, AST, C reactive protein (CRP). In cases of moderate and severe increase in ALT (more than 100U/L) therapy was stopped.
Follow-up was performed in all of the patients and it included evaluation of AST, ALT and total bilirubin between 1-3 months after completion of IVMP therapy.
Study design
- Primary purpose
- Supportive care
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| moderate-to-severe Graves Orbitopathy | Active comparator | Drug: every week IVMP therapyactive, moderate-to-severe Graves Orbitopathy according to EUGOGO. |
| Dysthyroid Orbit Neuropathy | Active comparator | Drug: very high doses IVMP therapyDysthyroid Orbit Neuropathy according to EUGOGO |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- active, moderate-to-severe Graves' orbitopathy or dysthyroid orbit neuropathy
- euthyroidism
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| every week IVMP therapy12 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 | Drug | moderate-to-severe Graves Orbitopathy |
| very high doses IVMP therapy3 pulses of intravenous methylprednisolone (IVMP) (1.0g/day for 3 consecutive days; cumulative dose 3.0g) according to EUGOGO recommendations | Drug | Dysthyroid Orbit Neuropathy |
Primary outcome
Influence of IVMP pulses in 12 every week schedule on mean ALT
Time frame: 12 weeks
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).
Influence of IVMP pulses in 3 consecutive days schedule on mean ALT
Time frame: 3 days
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).
2 secondary outcomes
Influence of IVMP pulses in 12 every week schedule on prevalence of mild, moderate and severe liver dysfunction.
Time frame: 12 weeks
Influence of IVMP pulses in 3 consecutive days schedule on prevalence of mild, moderate and severe liver dysfunction.
Time frame: 3 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2018.
- Derived from this study: PubMed 30420883Miskiewicz 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.
- Individual participant dataSharing planned: Yes. The collected data will be shared in a publication.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Piotr Miśkiewicz, MD, PhD principal investigator
Medical University of Warsaw
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing every week IVMP therapy and very high doses IVMP therapy in people with Graves Disease and Graves Ophthalmopathy, run by Medical University of Warsaw.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Influence of IVMP pulses in 12 every week schedule on mean ALT (time frame: 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03667157, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2018.