Insulin ResistancePhase 2NCT02457897
Thyroid Hormone to Induce Non-Insulin Mediated Glucose Disposal in People With Insulin Receptor Mutations
A Phase 2 study testing Liothyronine in people with Insulin Resistance and Diabetes Mellitus, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.
Trial summary
Background: Insulin receptor mutation causes high blood sugars and sometimes diabetes complications. Researchers want to see if thyroid hormone helps. Objectives: To see if thyroid hormone treatment changes how the body handles sugar in people with insulin receptor mutation and improves blood sugar in people with… Read more about this study
- Who is it for?
- Ages 12 to 65 years
- Conditions the study is for
- Insulin Resistance, Diabetes Mellitus, Abnormal Glucose Metabolism
- What is being tested?
- Liothyronine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Apr 2015to 18 Sep 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 12 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 1. Mutation of the insulin receptor (either recessive or dominant negative). If mutation status is not known prior to enrollment, subjects will undergo genotyping at enrollment. In the unanticipated event that a patient does not have a mutation of the insulin receptor, he or she will not complete the study and his or her data will not be included in the analysis.
Who cannot join
- Changes in doses of diabetes medications (including metformin, insulin, sulfonylureas, thiazolidinediones, leptin, GLP-1 agonists, DPP4 inhibitors, etc.) in the preceding 10 weeks.
- Any medical condition or medication that will increase risk to the subject (e.g. ischemic or structural heart disease, congestive heart failure, uncontrolled hypertension, or arrhythmia) or that will interfere with interpretation of study data.
- Disorders that would lead to erratic gastrointestinal absorption or loss of thyroid hormone from the gut (severe diarrhea, celiac disease, use of bile acid sequestrants, excessive consumption of soybean products).
- Any form of endogenous hyperthyroidism or hypothyroidism at baseline.
- Current or recent (past 8 weeks) use of thyroid hormone or anti-thyroid drugs.
- Extreme disorders of thyroid hormone binding to thyroid binding globulin (excess or deficiency) or protein loss (nephrotic range proteinuria) that would lead to difficulties achieving a consistent thyroid hormone level for study.
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- Known presence of a rare clinical disorder that leads to thyroid hormone insensitivity (known T3 receptor mutations, selenocysteine insertion sequence-binding protein 2 (SBP2) abnormalities, monocarboxylate transporter defects).
- Current use of beta blockers
- Pregnancy or breast feeding
- Any EKG abnormality that could increase risk of T3 treatment (resting sinus tachycardia (age adjusted norms), atrial fibrillation, myocardial ischemia, left or right ventricular excitation block, left ventricular hypertrophy or extrasystoles)
- Known allergy or hypersensitivity to any form of thyroid hormone
- Known adrenal insufficiency
- Dependence on oral anticoagulant medications (adults only)
- Use of tricyclic anti-depressants, as transient cardiac arrhythmias have been observed with the concomitant use of thyroid hormone.
- Use of cholestyramine.
- History of clinically significant osteoporosis per investigator judgment (e.g. previous fragility fracture)
- 6 MONTHS STUDY:
- Patients must meet all inclusion and exclusion criteria for the short-term study, plus have poorly controlled diabetes, defined as a hemoglobin A1c greater than or equal to 7%.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Thyroid Hormone to Induce Non-Insulin Mediated Glucose Disposal in Patients With Insulin Receptor Mutations
Background:
- Insulin receptor mutation causes high blood sugars and sometimes diabetes complications. Researchers want to see if thyroid hormone helps.
Read more
Objectives:
- To see if thyroid hormone treatment changes how the body handles sugar in people with insulin receptor mutation and improves blood sugar in people with diabetes.
Eligibility:
- People ages 12 65 with an insulin receptor mutation.
Design:
- Study part 1:19-day clinic stay. Participants will be monitored for 4 days. Then for 15 days they will take a thyroid hormone pill 3 times a day. Participants will have:
- Blood tests.
- Heart rate and skin temperature monitored.
- All their food provided.
- Two 5-hour sessions in a special room. They will wear special clothes and sometimes sit still.
- Two small tubes inserted in veins. One will deliver tiny amounts of sugar and fat with a non-radioactive tracer. Participants will also drink water with a tracer. The other tube will collect blood.
- A sweet drink. Participants may have finger stick blood sugar tests.
- Glucose-monitoring device inserted into body fat for two 24-hour periods.
- Adults may have samples of fat and muscle taken.
- Heart ultrasound.
- PET-CT scan in a machine. An intravenous catheter will be placed in an arm vein. A small amount of radioactive substance will be injected.
- DEXA scan of body fat and bone density.
- Participants with poorly controlled diabetes will then take thyroid hormone at home for 6 months. They will have blood drawn and sent to the study team monthly.
- After about 3 months, they will have an overnight visit. After 6 months, they will have a 4-day visit.
Read the detailed description
Background
Patients with mutations of the insulin receptor have extreme insulin resistance. This frequently results in diabetes in childhood that is extremely difficult to manage with conventional diabetes therapies, including insulin at doses 10-50 fold higher than usual. Poorly controlled diabetes, in turn, leads to microvascular complications (e.g. blindness) and early death. Hyperthyroidism, whether endogenous (e.g. Graves' disease) or exogenous, increases energy expenditure, activates brown adipose tissue, and enhances skeletal muscle perfusion, leading to enhanced glucose disposal. In a single patient with mutation of the insulin receptor and poorly controlled diabetes despite maximal therapy, iatrogenic mild hyperthyroidism for treatment of thyroid cancer resulted in normalization of glycemic control, suggesting that thyroid hormone treatment could have therapeutic benefit in this rare disease.
Aim
The purpose of this study is to determine if treatment with thyroid hormone will increase glucose disposal in patients with mutations of the insulin receptor, and thereby improve glycemic control. The hypotheses to be tested are:
- Thyroid hormone will increase whole-body glucose disposal in patients with insulin receptor mutations.
- This increased glucose disposal will be mediated via increased glucose uptake in brow adipose tissue (BAT) and muscle.
- Increases in glucose disposal will result in improved glycemic control.
Methods
This study is a non-randomized pre-post design, conducted in two sequential parts. Part 1 is a short-term (2 week) proof-of-principle study to test whether thyroid hormone will increase glucose disposal in patients with insulin receptor mutations (with or without diabetes), and the mechanisms by which increased glucose disposal occurs. Part 2 is a longer term (6 month) therapeutic study to test whether thyroid hormone will result in improved glycemic control in diabetic patients with insulin receptor mutations.
- Being tested
- Liothyronine
- Keywords
- Brown Adipose Tissue, Liothyronine, Insulin Receptors
- Medical subject headings
- Insulin Resistance, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LiothyronineDrug
Oral supplement given every 8 hours
| Study group | Role | What they receive |
|---|---|---|
| Patients with insulin receptor mutation | Experimental | Not described Receives: Drug: Liothyronine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Total Body Glucose Disposal in the Fasting State
Measured: 2 weeks
Hemoglobin A1C
Measured: 6 months
Secondary outcomes (2)
Muscle Glucose Uptake
Measured: 2 weeks
Muscle Glucose Uptake
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 posted29 May 2015 (estimated)
- Study start17 Apr 2015
- Primary completion18 Sep 2018
- Study completion18 Sep 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Insulin ResistanceStudies of the same condition, open and under way.
- More trials run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)The 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Rebecca J Brown, M.D., Principal investigator, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02457897
- Sponsor's protocol ID
- 150119
- Other IDs
- 15-DK-0119
- Status last verified
- 18 Sep 2018
- First submitted
- 22 Apr 2015
- Last updated
- 5 Dec 2019
- Results posted
- Yes, on ClinicalTrials.gov
Publications
Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976 Apr 1;294(14):739-45. doi: 10.1056/NEJM197604012941401.
PubMed 176581Skarulis MC, Celi FS, Mueller E, Zemskova M, Malek R, Hugendubler L, Cochran C, Solomon J, Chen C, Gorden P. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab. 2010 Jan;95(1):256-62. doi: 10.1210/jc.2009-0543. Epub 2009 Nov 6.
PubMed 19897683Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore). 2004 Jul;83(4):209-222. doi: 10.1097/01.md.0000133625.73570.54.
PubMed 15232309Sekizkardes H, Chung ST, Chacko S, Haymond MW, Startzell M, Walter M, Walter PJ, Lightbourne M, Brown RJ. Free fatty acid processing diverges in human pathologic insulin resistance conditions. J Clin Invest. 2020 Jul 1;130(7):3592-3602. doi: 10.1172/JCI135431.
PubMed 32191645Kushchayeva YS, Startzell M, Cochran E, Auh S, Sekizkardes H, Soldin SJ, Kushchayev SV, Dieckmann W, Skarulis M, Abdul Sater Z, Brychta RJ, Cypess AM, Lin TC, Lightbourne M, Millo C, Brown RJ. Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations. J Clin Endocrinol Metab. 2020 Mar 1;105(3):e158-71. doi: 10.1210/clinem/dgz079.
PubMed 31588494
Study at a glance
From the registry record, last updated by the sponsor on 5 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Thyroid Hormone to Induce Non-Insulin Mediated Glucose Disposal in Patients With Insulin Receptor Mutations
- ClinicalTrials.gov ID
- NCT02457897
- Acronym / sponsor ID
- 150119
- Keywords
- Brown Adipose Tissue, Liothyronine, Insulin Receptors
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 7 participants (actual)
- Lead sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)US National Institutes of Health
- Study start
- 17 Apr 2015
- Primary completion
- 18 Sep 2018 (actual)
- Study completion
- 18 Sep 2018 (actual)
- First posted
- 29 May 2015 (estimated)
- Results
- Posted 5 Dec 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Insulin receptor mutation causes high blood sugars and sometimes diabetes complications. Researchers want to see if thyroid hormone helps.
Objectives:
- To see if thyroid hormone treatment changes how the body handles sugar in people with insulin receptor mutation and improves blood sugar in people with diabetes.
Eligibility:
- People ages 12 65 with an insulin receptor mutation.
Design:
- Study part 1:19-day clinic stay. Participants will be monitored for 4 days. Then for 15 days they will take a thyroid hormone pill 3 times a day. Participants will have:
- Blood tests.
- Heart rate and skin temperature monitored.
- All their food provided.
- Two 5-hour sessions in a special room. They will wear special clothes and sometimes sit still.
- Two small tubes inserted in veins. One will deliver tiny amounts of sugar and fat with a non-radioactive tracer. Participants will also drink water with a tracer. The other tube will collect blood.
- A sweet drink. Participants may have finger stick blood sugar tests.
- Glucose-monitoring device inserted into body fat for two 24-hour periods.
- Adults may have samples of fat and muscle taken.
- Heart ultrasound.
- PET-CT scan in a machine. An intravenous catheter will be placed in an arm vein. A small amount of radioactive substance will be injected.
- DEXA scan of body fat and bone density.
- Participants with poorly controlled diabetes will then take thyroid hormone at home for 6 months. They will have blood drawn and sent to the study team monthly.
- After about 3 months, they will have an overnight visit. After 6 months, they will have a 4-day visit.
Detailed description
Background
Patients with mutations of the insulin receptor have extreme insulin resistance. This frequently results in diabetes in childhood that is extremely difficult to manage with conventional diabetes therapies, including insulin at doses 10-50 fold higher than usual. Poorly controlled diabetes, in turn, leads to microvascular complications (e.g. blindness) and early death. Hyperthyroidism, whether endogenous (e.g. Graves' disease) or exogenous, increases energy expenditure, activates brown adipose tissue, and enhances skeletal muscle perfusion, leading to enhanced glucose disposal. In a single patient with mutation of the insulin receptor and poorly controlled diabetes despite maximal therapy, iatrogenic mild hyperthyroidism for treatment of thyroid cancer resulted in normalization of glycemic control, suggesting that thyroid hormone treatment could have therapeutic benefit in this rare disease.
Aim
The purpose of this study is to determine if treatment with thyroid hormone will increase glucose disposal in patients with mutations of the insulin receptor, and thereby improve glycemic control. The hypotheses to be tested are:
- Thyroid hormone will increase whole-body glucose disposal in patients with insulin receptor mutations.
- This increased glucose disposal will be mediated via increased glucose uptake in brow adipose tissue (BAT) and muscle.
- Increases in glucose disposal will result in improved glycemic control.
Methods
This study is a non-randomized pre-post design, conducted in two sequential parts. Part 1 is a short-term (2 week) proof-of-principle study to test whether thyroid hormone will increase glucose disposal in patients with insulin receptor mutations (with or without diabetes), and the mechanisms by which increased glucose disposal occurs. Part 2 is a longer term (6 month) therapeutic study to test whether thyroid hormone will result in improved glycemic control in diabetic patients with insulin receptor mutations.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with insulin receptor mutation | Experimental | Drug: Liothyronine |
Who may qualify
- Ages
- 12 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- 1. Mutation of the insulin receptor (either recessive or dominant negative). If mutation status is not known prior to enrollment, subjects will undergo genotyping at enrollment. In the unanticipated event that a patient does not have a mutation of the insulin receptor, he or she will not complete the study and his or her data will not be included in the analysis.
Key exclusion criteria (18 listed)
- Changes in doses of diabetes medications (including metformin, insulin, sulfonylureas, thiazolidinediones, leptin, GLP-1 agonists, DPP4 inhibitors, etc.) in the preceding 10 weeks.
- Any medical condition or medication that will increase risk to the subject (e.g. ischemic or structural heart disease, congestive heart failure, uncontrolled hypertension, or arrhythmia) or that will interfere with interpretation of study data.
- Disorders that would lead to erratic gastrointestinal absorption or loss of thyroid hormone from the gut (severe diarrhea, celiac disease, use of bile acid sequestrants, excessive consumption of soybean products).
- Any form of endogenous hyperthyroidism or hypothyroidism at baseline.
- Current or recent (past 8 weeks) use of thyroid hormone or anti-thyroid drugs.
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 |
|---|---|---|
| LiothyronineOral supplement given every 8 hours | Drug | Patients with insulin receptor mutation |
Primary outcome
Total Body Glucose Disposal in the Fasting State
Time frame: 2 weeks
Hemoglobin A1C
Time frame: 6 months
2 secondary outcomes
Muscle Glucose Uptake
Time frame: 2 weeks
Muscle Glucose Uptake
Time frame: 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Dec 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 176581Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976 Apr 1;294(14):739-45. doi: 10.1056/NEJM197604012941401.
- Background: PubMed 19897683Skarulis MC, Celi FS, Mueller E, Zemskova M, Malek R, Hugendubler L, Cochran C, Solomon J, Chen C, Gorden P. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab. 2010 Jan;95(1):256-62. doi: 10.1210/jc.2009-0543. Epub 2009 Nov 6.
- Background: PubMed 15232309Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, Gorden P. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore). 2004 Jul;83(4):209-222. doi: 10.1097/01.md.0000133625.73570.54.
- Derived from this study: PubMed 32191645Sekizkardes H, Chung ST, Chacko S, Haymond MW, Startzell M, Walter M, Walter PJ, Lightbourne M, Brown RJ. Free fatty acid processing diverges in human pathologic insulin resistance conditions. J Clin Invest. 2020 Jul 1;130(7):3592-3602. doi: 10.1172/JCI135431.
- Derived from this study: PubMed 31588494Kushchayeva YS, Startzell M, Cochran E, Auh S, Sekizkardes H, Soldin SJ, Kushchayev SV, Dieckmann W, Skarulis M, Abdul Sater Z, Brychta RJ, Cypess AM, Lin TC, Lightbourne M, Millo C, Brown RJ. Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations. J Clin Endocrinol Metab. 2020 Mar 1;105(3):e158-71. doi: 10.1210/clinem/dgz079.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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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.
Rebecca J Brown, M.D. principal investigator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Liothyronine in people with Insulin Resistance and Diabetes Mellitus, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.
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 1 inclusion and 18 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 5 Dec 2019. 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 United States. 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. 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 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?
Yes. Results are posted in the registry (first posted 5 Dec 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Total Body Glucose Disposal in the Fasting State (time frame: 2 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 NCT02457897, which also lists 5 linked publications.
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 5 Dec 2019.