Graves' DiseasePhase 1/2IndigoNCT02373995
Role of the Microbiome in Graves' Orbitopathy
A Phase 1/2 study testing LAB4 in people with Graves' Disease, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.
Trial summary
Graves' orbitopathy (GO), also known as thyroid eye disease, affects approximately 3 million people in Europe with an estimated socioeconomic burden of 6.4 billion euros per annum. GO is a complication of Graves' disease which is an autoimmune disease and the commonest cause of an overactive thyroid gland. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Graves' Disease
- What is being tested?
- LAB4
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteItaly
- Study dates
- Feb 2015to Dec 2016
- Phase
- Phase 1/2
- 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 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Group A: Untreated Graves' hyperthyroidism (or within 4 weeks of initiating ATD treatment)
- definition hyperthyroidism: TSH decreased, FT4 and /or FT3 increased
- definition Graves': diffusely enlarged thyroid gland either by palpation or echograpy, and/or homogeneous thyroid uptake at scintigraphy, or positive TSHRAb
- first episode or recurrence of Graves' hyperthyroidism
- minimal or no eye signs, defined as lid retraction / lid lag but no other signs.
- Planned treatment with antithyroid drugs either titration regimen or block-and-replace regimen for 18 months.
Show all 10Show fewer
- Group B. Untreated Graves' hyperthyroidism (or within 4 weeks of initiating ATD treatment) with overt signs of GO as defined by EUGOGO1
- Mild GO: patients whose features of GO have only a minor impact on daily life insufficient to justify immunosuppressive or surgical treatment. They usually have only one or more of the following: minor lid retraction (<2 mm), mild soft tissue involvement, exophthalmos <3 mm above normal for race and gender, transient or no diplopia, and corneal exposure responsive to lubricants)
- Moderate-to-severe GO: Patients without sight-threatening GO whose eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate-to-severe GO usually have any one or more of the following: lid retraction R2 mm, moderate or severe soft tissue involvement, exophthalmos >3 mm above normal for race and gender, inconstant, or constant diplopia.
- Sight -threatening GO: Patients with dysthyroid optic neuropathy (DON) and/or corneal
Who cannot join
- Previous or planned treatment with 131I or thyroidectomy (A\&B); sight threatening GO requiring decompression (B); drugs interfering with the natural course of GO (A\&B): steroids, immunosuppressants, thiazolidinediones, antibiotics / antifungals / antivirals (both topical and systemic for at least 4 weeks prior to recruitment to the study); acute diarrhea illness (gastroenteritis for at least 4 weeks prior to recruitment to the study); Drugs interfering with thyroid function (A\&B): amiodarone, lithium, iodine supplements; Drug or alcohol abuse (A\&B); no informed consent (A\&B); Age less than 18 (A\&B); Pregnancy (A\&B).
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Investigation of Novel Biomarkers and Definition of the Role of the Microbiome In Graves' Orbitopathy
Graves' orbitopathy (GO), also known as thyroid eye disease, affects approximately 3 million people in Europe with an estimated socioeconomic burden of 6.4 billion euros per annum. GO is a complication of Graves' disease which is an autoimmune disease and the commonest cause of an overactive thyroid gland. The treatment of GO remains unsatisfactory and the majority of patients report long-term impairment of quality of life. The effects of gut derived antigens, from micro-organisms and nutrients, on the autoimmune response will be tested in the animal model by probiotic and "contra-biotic" intervention. In the Indigo interventional trial the investigators will add to the standard anti-thyroid drug treatment (ATD) a specifically designed probiotics (LAB4, Cultech Ltd., West Glamorgan, UK) to assess whether it is possible to modify the microbiome in GD patients and improve their immunological status.
Read the detailed description
Investigation of Novel biomakers and Definition of the role of the microbiome In Graves' Orbitopathy (GO) (INDIGO)
Background Graves' orbitopathy (GO), also known as thyroid eye disease, affects approximately 3 million people in Europe with an estimated socioeconomic burden of 6.4 billion euros per annum. GO is a complication of Graves' disease which is an autoimmune disease and the commonest cause of an overactive thyroid gland. The treatment of GO remains unsatisfactory and the majority of patients report long-term impairment of quality of life. To improve the outcomes of people with GO and thus reduce long-term illness and cost to society, research is needed to address the identification of risk factors, develop a better understanding of the pathophysiology of the disease, devise approaches for early diagnosis during the pre-clinical stage of the disease, and create novel and safe interventions. The effects of gut derived antigens, from micro-organisms and nutrients, on the autoimmune response will be tested in the animal model by probiotic and "contra-biotic" intervention. In the Indigo interventional trial the investigators will add to the standard anti-thyroid drug treatment (ATD) a specifically designed probiotics (LAB4, Cultech Ltd., West Glamorgan, UK) to assess whether it is possible to modify the microbiome in GD patients and improve their immunological status.
Primary objective:
To modify the microbiome in GD patients to reduce pathogenic species and enrich its commensal, symbiotic components.
Secondary objective:
To decrease the anti-TSHr antibody titer and the concentration of IgG and IgA in GD patients.
Experimental design The investigators are interested in inducing potential modifications of the gut microbioma and in obtaining a reduction of the anti-THSr antibody titer and of the total IgG and IgA concentrations, so as to prevent relapse and development or progression of eye disease. In particular, the expected, beneficial modification of the gut microbioma relates to a reduction at the end of treatment of at least 5% of the Firmicutes:Bacteroides ratio and 30% of the anti-TSHr antibody titer and of total IgG and IgA concentrations.
Patients with a diagnosis of Graves' disease with or without OB will be randomized to receive either ATD plus LAB4 or ATD plus placebo for 6 months. LAB4 consists of 4 strains:
Lactobacillus acidophilus CUL21 (NCIMB 30156) Lactobacillus acidophilus CUL60 (NCIMB 30157) Bifidobacterium bifidum CUL20 (NCIMB 30153) Bifidobacterium animalis subsp. lactis CUL34 (NCIMB 30172) and will be administered orally, twice a day during meals, for 6 months. Samples of blood (for serum and DNA)and, tears (Schirmer strips), nasal swabs and faeces will be collected at the first visit, before any treatment or within 4 weeks of anti-thyroid drug (ATD) therapy commenced by community physician. The same samples will be collected on the first occasion that euthyroidism has been restored on the usual block/replace or titration regimen used locally. The same samples will also be collected 6 months after cessation of treatment or at the point of relapse if that is sooner .
High through-put analysis of microRNA (miRNA) in serum and proteomic analyses of tears and serum will be used to search for biomarkers predictive of eye disease progression . In addition, antibody responses will be analyzed to identify if microbial or food derived antigens are involved in triggering disease or associated with GO progression . Moreover, 16S RNA gene sequencing will serve to characterize the patients microbiomes to assess whether this information can be used to develop diagnostics for individuals at risk of GD and then of developing GO .
- Conditions
- Graves' Disease
- Being tested
- LAB4
- Keywords
- Graves, Orbithopaty, euthyroidism, microbiome
- Medical subject headings
- Graves Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LAB4Biological
Additional treatment with the specific LAB4 probiotic preparation
| Study group | Role | What they receive |
|---|---|---|
| LAB4 | Active comparator | In addition to conventional Anti Thyroid Drug (ATD), LAB4 probiotic preparation will be administered at the 2 cps x 2/die dosing with food for 6 months. It is key to properly store LAB4 at 8°C. Receives: Biological: LAB4 |
| Placebo | Placebo comparator | In addition to conventional Anti Thyroid Drug (ATD) a LAB4 placebo preparation will be administered at the 2 cps x 2/die dosing with food for 6 months. It is key to properly store placebo at 8°C. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Microbiome modification (beneficial modification of the gut microbioma relates to a reduction at the end of treatment of at least 5% of the Firmicutes:Bacteroides ratio and 30% of the anti-TSHr antibody titer and of total IgG and IgA concentrations)
modification the microbiome in GD patients to reduce pathogenic species and enrich its commensal, symbiotic components. The proportion (%) of each species will be assessed and recorded.
Measured: 6 months
Secondary outcomes (1)
Improvement immunological status (antibody responses will be analyzed to identify if microbial or food derived antigens are involved in triggering disease or associated with GO progression)
To decrease the anti-TSHr antibody titer and the concentration of IgG and IgA in patients with Graves' disease. The concentration of each parameter will be assessed in mg/dl and recorded.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Feb 2015 (estimated)
- Study startFeb 2015
- Primary completionJul 2015 (estimated)
- Study completionDec 2016 (estimated)
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.
- More trials run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoThe sponsor's other registered studies.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Cultech Ltd, Universität Duisburg-Essen, School of Medicine and School of Biosciences, Cardiff University, Cardiff, UK, IDRA Laboratory, Parco Tecnologico Padano s.r.l, Lodi, Italy
- Responsible party
- Sponsor
- Investigators
- Mario Salvi, MD, Principal investigator, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02373995
- Sponsor's protocol ID
- Indigo
- Acronym
- Indigo
- Status last verified
- Feb 2015
- First submitted
- 29 Jan 2015
- Last updated
- 27 Feb 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marino M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM; European Group on Graves' Orbitopathy (EUGOGO). Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008 Mar;158(3):273-85. doi: 10.1530/EJE-07-0666. No abstract available.
PubMed 18299459
Study at a glance
From the registry record, last updated by the sponsor on 27 Feb 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigation of Novel Biomarkers and Definition of the Role of the Microbiome In Graves' Orbitopathy
- ClinicalTrials.gov ID
- NCT02373995
- Acronym / sponsor ID
- Indigo / Indigo
- Conditions
- Graves' Disease
- Keywords
- Graves, Orbithopaty, euthyroidism, microbiome
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoUniversity, hospital or other
- Collaborators
- Cultech Ltd, Universität Duisburg-Essen, School of Medicine and School of Biosciences, Cardiff University, Cardiff, UK, IDRA Laboratory, Parco Tecnologico Padano s.r.l, Lodi, Italy
- Study start
- Feb 2015
- Primary completion
- Jul 2015 (estimated)
- Study completion
- Dec 2016 (estimated)
- First posted
- 27 Feb 2015 (estimated)
- 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), also known as thyroid eye disease, affects approximately 3 million people in Europe with an estimated socioeconomic burden of 6.4 billion euros per annum. GO is a complication of Graves' disease which is an autoimmune disease and the commonest cause of an overactive thyroid gland. The treatment of GO remains unsatisfactory and the majority of patients report long-term impairment of quality of life. The effects of gut derived antigens, from micro-organisms and nutrients, on the autoimmune response will be tested in the animal model by probiotic and "contra-biotic" intervention. In the Indigo interventional trial the investigators will add to the standard anti-thyroid drug treatment (ATD) a specifically designed probiotics (LAB4, Cultech Ltd., West Glamorgan, UK) to assess whether it is possible to modify the microbiome in GD patients and improve their immunological status.
Detailed description
Investigation of Novel biomakers and Definition of the role of the microbiome In Graves' Orbitopathy (GO) (INDIGO)
Background Graves' orbitopathy (GO), also known as thyroid eye disease, affects approximately 3 million people in Europe with an estimated socioeconomic burden of 6.4 billion euros per annum. GO is a complication of Graves' disease which is an autoimmune disease and the commonest cause of an overactive thyroid gland. The treatment of GO remains unsatisfactory and the majority of patients report long-term impairment of quality of life. To improve the outcomes of people with GO and thus reduce long-term illness and cost to society, research is needed to address the identification of risk factors, develop a better understanding of the pathophysiology of the disease, devise approaches for early diagnosis during the pre-clinical stage of the disease, and create novel and safe interventions. The effects of gut derived antigens, from micro-organisms and nutrients, on the autoimmune response will be tested in the animal model by probiotic and "contra-biotic" intervention. In the Indigo interventional trial the investigators will add to the standard anti-thyroid drug treatment (ATD) a specifically designed probiotics (LAB4, Cultech Ltd., West Glamorgan, UK) to assess whether it is possible to modify the microbiome in GD patients and improve their immunological status.
Primary objective:
To modify the microbiome in GD patients to reduce pathogenic species and enrich its commensal, symbiotic components.
Secondary objective:
To decrease the anti-TSHr antibody titer and the concentration of IgG and IgA in GD patients.
Experimental design The investigators are interested in inducing potential modifications of the gut microbioma and in obtaining a reduction of the anti-THSr antibody titer and of the total IgG and IgA concentrations, so as to prevent relapse and development or progression of eye disease. In particular, the expected, beneficial modification of the gut microbioma relates to a reduction at the end of treatment of at least 5% of the Firmicutes:Bacteroides ratio and 30% of the anti-TSHr antibody titer and of total IgG and IgA concentrations.
Patients with a diagnosis of Graves' disease with or without OB will be randomized to receive either ATD plus LAB4 or ATD plus placebo for 6 months. LAB4 consists of 4 strains:
Lactobacillus acidophilus CUL21 (NCIMB 30156) Lactobacillus acidophilus CUL60 (NCIMB 30157) Bifidobacterium bifidum CUL20 (NCIMB 30153) Bifidobacterium animalis subsp. lactis CUL34 (NCIMB 30172) and will be administered orally, twice a day during meals, for 6 months. Samples of blood (for serum and DNA)and, tears (Schirmer strips), nasal swabs and faeces will be collected at the first visit, before any treatment or within 4 weeks of anti-thyroid drug (ATD) therapy commenced by community physician. The same samples will be collected on the first occasion that euthyroidism has been restored on the usual block/replace or titration regimen used locally. The same samples will also be collected 6 months after cessation of treatment or at the point of relapse if that is sooner .
High through-put analysis of microRNA (miRNA) in serum and proteomic analyses of tears and serum will be used to search for biomarkers predictive of eye disease progression . In addition, antibody responses will be analyzed to identify if microbial or food derived antigens are involved in triggering disease or associated with GO progression . Moreover, 16S RNA gene sequencing will serve to characterize the patients microbiomes to assess whether this information can be used to develop diagnostics for individuals at risk of GD and then of developing GO .
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| LAB4 | Active comparator | Biological: LAB4In addition to conventional Anti Thyroid Drug (ATD), LAB4 probiotic preparation will be administered at the 2 cps x 2/die dosing with food for 6 months. It is key to properly store LAB4 at 8°C. |
| Placebo | Placebo comparator | –In addition to conventional Anti Thyroid Drug (ATD) a LAB4 placebo preparation will be administered at the 2 cps x 2/die dosing with food for 6 months. It is key to properly store placebo at 8°C. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Group A: Untreated Graves' hyperthyroidism (or within 4 weeks of initiating ATD treatment)
- definition hyperthyroidism: TSH decreased, FT4 and /or FT3 increased
- definition Graves': diffusely enlarged thyroid gland either by palpation or echograpy, and/or homogeneous thyroid uptake at scintigraphy, or positive TSHRAb
- first episode or recurrence of Graves' hyperthyroidism
- minimal or no eye signs, defined as lid retraction / lid lag but no other signs.
Key exclusion criteria (1 listed)
- Previous or planned treatment with 131I or thyroidectomy (A\&B); sight threatening GO requiring decompression (B); drugs interfering with the natural course of GO (A\&B): steroids, immunosuppressants, thiazolidinediones, antibiotics / antifungals / antivirals (both topical and systemic for at least 4 weeks prior to recruitment to the study); acute diarrhea illness (gastroenteritis for at least 4 weeks prior to recruitment to the study); Drugs interfering with thyroid function (A\&B): amiodarone, lithium, iodine supplements; Drug or alcohol abuse (A\&B); no informed consent (A\&B); Age less than 18 (A\&B); Pregnancy (A\&B).
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 |
|---|---|---|
| LAB4Additional treatment with the specific LAB4 probiotic preparation | Biological | LAB4 |
Primary outcome
Microbiome modification (beneficial modification of the gut microbioma relates to a reduction at the end of treatment of at least 5% of the Firmicutes:Bacteroides ratio and 30% of the anti-TSHr antibody titer and of total IgG and IgA concentrations)
Time frame: 6 months
modification the microbiome in GD patients to reduce pathogenic species and enrich its commensal, symbiotic components. The proportion (%) of each species will be assessed and recorded.
1 secondary outcome
Improvement immunological status (antibody responses will be analyzed to identify if microbial or food derived antigens are involved in triggering disease or associated with GO progression)
Time frame: 6 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Feb 2015.
- Results publication: PubMed 18299459Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marino M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM; European Group on Graves' Orbitopathy (EUGOGO). Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008 Mar;158(3):273-85. doi: 10.1530/EJE-07-0666. No abstract available.
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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.
Mario Salvi, MD principal investigator
IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing LAB4 in people with Graves' Disease, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.
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 10 inclusion and 1 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: status not confirmed, as of the sponsor's last update on 27 Feb 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Mario Salvi, MD (+393487362498, mario@mariosalvinet.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Microbiome modification (beneficial modification of the gut microbioma relates to a reduction at the end of treatment of at least 5% of the Firmicutes:Bacteroides ratio and 30% of the anti-TSHr antibody titer and of total IgG and IgA concentrations) (time frame: 6 months). 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 NCT02373995, 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 27 Feb 2015.