Type 2 DiabetesPhase 4NCT02344186
Effects of Liraglutide on ER Stress in Obese Patients With Type 2 Diabetes
A Phase 4 study testing Liraglutide in people with Type 2 Diabetes, run by Temple University at 1 site in United States.
Trial summary
The main objective of the study will be to test the hypothesis that treatment with Liraglutide will decrease ER stress and adipose tissue in obese patients with type 2 diabetes. Experimental Approach: The investigators will use a prospective, single blind, placebo controlled study design to study 12 obese patients… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Type 2 Diabetes
- What is being tested?
- Liraglutide
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- May 2014to 31 Dec 2023
- 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 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with established type 2 diabetes, BMI 27-35, Age - 18-75 years, HbA1c 7-10%, patients treated with exercise, diet, metformin and/or alpha glucosidase inhibitors (all up to ½ of their maximal dose) or pioglitazone (up to 30 mg/d), ability to provide informed consent before any trial-related activities.
Who cannot join
- Patients with pancreatitis or a history of pancreatitis, patients with HbA1c < 7% or > 10%, type 2 diabetic patients treated with insulin, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP1) agonists or corticosteroids, patients with hypoglycemia unawareness and with impaired liver functions (≥ 2.5 times the upper normal limit), known or suspected allergy against liraglutide or contraindications to liraglutide (as specified in the product prescribing information), pregnancies, breastfeeding or intention of becoming pregnant or not using adequate contraceptive measures, patients with a personal or family history of medullary thyroid cancer and patients with Multiple Endocrine Neoplasia type 2.
Trial locations and contacts
1 site in 1 country.
United States1 site
Temple University Hospital
Philadelphia, Pennsylvania, 19140
About this study
Official title: Effects of Liraglutide on Endoplasmic (ER) Stress in Obese Patients With Type 2 Diabetes
The main objective of the study will be to test the hypothesis that treatment with Liraglutide will decrease ER stress and adipose tissue in obese patients with type 2 diabetes. Experimental Approach: The investigators will use a prospective, single blind, placebo controlled study design to study 12 obese patients with type 2 diabetes mellitus (T2DM). 6 patients will first receive Liraglutide for 24 weeks followed by placebo for 12 weeks. The other 6 patients will first receive placebo for 12 weeks followed by Liraglutide for 24 weeks.
Measurements: The investigators will determine glycemic control (with HbA1c), body composition (bioelectric impedance analysis), insulin sensitivity (with hyperinsulinemic-euglycemic clamps), insulin secretion (with oral glucose tolerance testing), energy balance (calories in vs. calories out), plasma lipid levels and obtain subcutaneous fat biopsies to determine ER stress response markers before and after placebo and before and after Liraglutide treatment.
Read the detailed description
This will be a prospective, single-blind, placebo-controlled study with a crossover design.
Visit Procedures: After a 1 month run-in period during which there will be no changes in medications, physical activity or diet, patients will be randomly divided into 2 groups of 6 patients each. Subjects have a 50:50 chance of being randomized to either group 1 or group 2.
In Group 1, (n=6), liraglutide will be started first with 0.6 mg/d for 1 week, then increased to 1.2 mg/d from week 2 to week 12, followed by 1.8 mg/d from week 12 to week 24. Group 1 patients will then be switched from liraglutide to placebo injections for another 12 weeks. For subjects in Group 1 the placebo period (weeks 24 to 36 will be the washout period.
Group 2 patients (n=6) will be started with placebo for 12 weeks and then switched to liraglutide for the next 24 weeks (0.6 mg/d for 1 week, 1.2 mg/d for 11 weeks and 1.8 mg/d for 12 weeks).
Assessment of Efficacy
Outpatient visits:
During the entire study, all patients (Groups 1 and 2) will perform home glucose monitoring 7 times/day (pre and ~ 2 h post breakfast, lunch and dinner and bedtime) and will be seen at Temple University Hospital as outpatients at 4 week intervals.
One week before the first, second or third and final inpatient visit, patients will undergo a 75, gram 2-hour oral glucose tolerance test.
Inpatient visits:
All patients (Groups 1 and 2) will be studied in our Clinical Research Center (CRC) at Temple University Hospital in the morning after an overnight fast, at the end of the run-in period (Week 0 ) and again at Weeks 12, 24 and 36. All study patients will be admitted to the CRC the evening before their study and discharged in the afternoon of the following day.
During the inpatient visits, the following procedures will be performed.
- At baseline and again at weeks 12 and 36, subcutaneous fat biopsies will be obtained from the lateral aspect of one thigh by a surgeon as described (8) for determination of ER stress markers. In brief, the skin will be cleaned with betadine and anesthetized with 1% lidocaine without epinephrine in a field block pattern (at 2 X 3 in). (We have found that injection of lidocaine too close to the biopsy site interfered with the measurement of acetyl-CoA). After an incision (~ 1 in.) will be made through the skin, ~ 300 mg of fat will be mobilized and excised. The fat will be dropped immediately into isopentane, kept at its freezing point (-160°C) by liquid nitrogen. The frozen fat will be stored at -70°. To screen for changes in unfolded protein response (UPR) genes, we will first perform an UPR PCR microarray (SA Biosciences, Frederick, MD) using pooled fat biopsy extracts. This array profiles expression of 84 key genes recognizing and responding to misfolded protein accumulation in the ER. Significant changes (> 1.5 fold comparing post vs. pre drug biopsies) will then be confirmed by real time reverse transcription (RT)-PCR of the UPR messenger RNAs (mRNAs). Thus, mRNAs of the identified UPR markers (for instance, GRP78, X-box-binding-protein 1 (XBP-1), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), protein disulfide isomerase (PDI), calreticulin, calnexin) will be measured by real time RT-PCR in triplicate and normalized against 18s and β-actin mRNAs and will be expressed as arbitrary units. The respective proteins will be analyzed by Western blots.
- Glycemic control will be assessed by
- measurement of HbA1c
- patients home glucose monitoring records
- Determination of insulin resistance will be determined (with euglycemic-hyperinsulinemic clamping with use of stable isotopes for determination of peripheral (GRd) and hepatic (GRa) insulin action as described (18).
- . Determination of energy balance, which will be calculated as change in fat mass (by bioelectric impedance analysis) plus total energy expenditure (determined with indirect calorimetry and the doubly labeled water method) (17).
- Postabsorptive blood samples will be obtained for determination of plasma lipids (total cholesterol, LDL, HDL and triglycerides).
- Assessment of changes in insulin secretion will be determined with Oral Glucose Tolerance Testing.
- Conditions
- Type 2 Diabetes
- Being tested
- Liraglutide
- Keywords
- diabetes, ER stress, glucagon-like peptide-1 analogs
- Medical subject headings
- Diabetes Mellitus, Type 2, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LiraglutideDrug
Also called Victoza
Crossover design - 24 weeks on active drug and 12 weeks daily placebo
| Study group | Role | What they receive |
|---|---|---|
| Liraglutide | Experimental | Liraglutide will be started first with 0.6 mg/d for 1 week, then increased to 1.2 mg/d from week 2 to week 12, followed by 1.8 mg/d from week 12 to week 24. Receives: Drug: Liraglutide |
| Placebo | Placebo comparator | Subjects will receive placebo for 12 weeks. Receives: Drug: Liraglutide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes in unfolded protein response markers
Changes in unfolded protein response markers in adipose tissue biopsy samples. Specifically, the investigators will determine changes in mRNA (by RT-PCR) and protein (by Western blots) levels of the following ER stress markers: GRP78, ATF4, XBP-1s, PDI, calreticulin and calnexin.
Measured: baseline, 6 months, 9 months
Secondary outcomes (6)
Insulin sensitivity
Changes in insulin resistance will be determined by measuring changes in total body glucose uptake and in plasma free fatty acid (FFA) levels during euglycemic-hyperinsulinemic clamping.
Measured: baseline, 3 months, 6 months and 9 months
Glucose control
Glucose control will be assessed by monthly A1c determinations.
Measured: baseline, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months
Energy expenditure
Changes in energy expenditure will be assessed by indirect calorimetry
Measured: baseline, 3 months, 6 months, 9 months
Body weight
Patients will be weighed monthly
Measured: baseline, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months
Body composition
Body composition will be determined using bioelectrical impedance.
Measured: baseline, 3 months, 6 months and 9 months
Beta cell function
Subjects will undergo an oral glucose tolerance tests(OGTT) to assess beta cell function.
Measured: baseline, 6 months, 9 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2015 (estimated)
- Study startMay 2014
- Primary completion31 Dec 2022 (estimated)
- Study completion31 Dec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Type 2 DiabetesStudies 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
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Temple University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ajaykumar D Rao, MD, Principal investigator, Temple University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02344186
- Sponsor's protocol ID
- 21440
- Status last verified
- Jul 2022
- First submitted
- 14 Jan 2015
- Last updated
- 29 Jul 2022
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Liraglutide on Endoplasmic (ER) Stress in Obese Patients With Type 2 Diabetes
- ClinicalTrials.gov ID
- NCT02344186
- Acronym / sponsor ID
- 21440
- Conditions
- Type 2 Diabetes
- Keywords
- diabetes, ER stress, glucagon-like peptide-1 analogs
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- Temple UniversityUniversity, hospital or other
- Study start
- May 2014
- Primary completion
- 31 Dec 2022 (estimated)
- Study completion
- 31 Dec 2023 (estimated)
- First posted
- 22 Jan 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.
The main objective of the study will be to test the hypothesis that treatment with Liraglutide will decrease ER stress and adipose tissue in obese patients with type 2 diabetes. Experimental Approach: The investigators will use a prospective, single blind, placebo controlled study design to study 12 obese patients with type 2 diabetes mellitus (T2DM). 6 patients will first receive Liraglutide for 24 weeks followed by placebo for 12 weeks. The other 6 patients will first receive placebo for 12 weeks followed by Liraglutide for 24 weeks.
Measurements: The investigators will determine glycemic control (with HbA1c), body composition (bioelectric impedance analysis), insulin sensitivity (with hyperinsulinemic-euglycemic clamps), insulin secretion (with oral glucose tolerance testing), energy balance (calories in vs. calories out), plasma lipid levels and obtain subcutaneous fat biopsies to determine ER stress response markers before and after placebo and before and after Liraglutide treatment.
Detailed description
This will be a prospective, single-blind, placebo-controlled study with a crossover design.
Visit Procedures: After a 1 month run-in period during which there will be no changes in medications, physical activity or diet, patients will be randomly divided into 2 groups of 6 patients each. Subjects have a 50:50 chance of being randomized to either group 1 or group 2.
In Group 1, (n=6), liraglutide will be started first with 0.6 mg/d for 1 week, then increased to 1.2 mg/d from week 2 to week 12, followed by 1.8 mg/d from week 12 to week 24. Group 1 patients will then be switched from liraglutide to placebo injections for another 12 weeks. For subjects in Group 1 the placebo period (weeks 24 to 36 will be the washout period.
Group 2 patients (n=6) will be started with placebo for 12 weeks and then switched to liraglutide for the next 24 weeks (0.6 mg/d for 1 week, 1.2 mg/d for 11 weeks and 1.8 mg/d for 12 weeks).
Assessment of Efficacy
Outpatient visits:
During the entire study, all patients (Groups 1 and 2) will perform home glucose monitoring 7 times/day (pre and ~ 2 h post breakfast, lunch and dinner and bedtime) and will be seen at Temple University Hospital as outpatients at 4 week intervals.
One week before the first, second or third and final inpatient visit, patients will undergo a 75, gram 2-hour oral glucose tolerance test.
Inpatient visits:
All patients (Groups 1 and 2) will be studied in our Clinical Research Center (CRC) at Temple University Hospital in the morning after an overnight fast, at the end of the run-in period (Week 0 ) and again at Weeks 12, 24 and 36. All study patients will be admitted to the CRC the evening before their study and discharged in the afternoon of the following day.
During the inpatient visits, the following procedures will be performed.
- At baseline and again at weeks 12 and 36, subcutaneous fat biopsies will be obtained from the lateral aspect of one thigh by a surgeon as described (8) for determination of ER stress markers. In brief, the skin will be cleaned with betadine and anesthetized with 1% lidocaine without epinephrine in a field block pattern (at 2 X 3 in). (We have found that injection of lidocaine too close to the biopsy site interfered with the measurement of acetyl-CoA). After an incision (~ 1 in.) will be made through the skin, ~ 300 mg of fat will be mobilized and excised. The fat will be dropped immediately into isopentane, kept at its freezing point (-160°C) by liquid nitrogen. The frozen fat will be stored at -70°. To screen for changes in unfolded protein response (UPR) genes, we will first perform an UPR PCR microarray (SA Biosciences, Frederick, MD) using pooled fat biopsy extracts. This array profiles expression of 84 key genes recognizing and responding to misfolded protein accumulation in the ER. Significant changes (> 1.5 fold comparing post vs. pre drug biopsies) will then be confirmed by real time reverse transcription (RT)-PCR of the UPR messenger RNAs (mRNAs). Thus, mRNAs of the identified UPR markers (for instance, GRP78, X-box-binding-protein 1 (XBP-1), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), protein disulfide isomerase (PDI), calreticulin, calnexin) will be measured by real time RT-PCR in triplicate and normalized against 18s and β-actin mRNAs and will be expressed as arbitrary units. The respective proteins will be analyzed by Western blots.
- Glycemic control will be assessed by
- measurement of HbA1c
- patients home glucose monitoring records
- Determination of insulin resistance will be determined (with euglycemic-hyperinsulinemic clamping with use of stable isotopes for determination of peripheral (GRd) and hepatic (GRa) insulin action as described (18).
- . Determination of energy balance, which will be calculated as change in fat mass (by bioelectric impedance analysis) plus total energy expenditure (determined with indirect calorimetry and the doubly labeled water method) (17).
- Postabsorptive blood samples will be obtained for determination of plasma lipids (total cholesterol, LDL, HDL and triglycerides).
- Assessment of changes in insulin secretion will be determined with Oral Glucose Tolerance Testing.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Liraglutide | Experimental | Drug: LiraglutideLiraglutide will be started first with 0.6 mg/d for 1 week, then increased to 1.2 mg/d from week 2 to week 12, followed by 1.8 mg/d from week 12 to week 24. |
| Placebo | Placebo comparator | Drug: LiraglutideSubjects will receive placebo for 12 weeks. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Patients with established type 2 diabetes, BMI 27-35, Age - 18-75 years, HbA1c 7-10%, patients treated with exercise, diet, metformin and/or alpha glucosidase inhibitors (all up to ½ of their maximal dose) or pioglitazone (up to 30 mg/d), ability to provide informed consent before any trial-related activities.
Key exclusion criteria (1 listed)
- Patients with pancreatitis or a history of pancreatitis, patients with HbA1c < 7% or > 10%, type 2 diabetic patients treated with insulin, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP1) agonists or corticosteroids, patients with hypoglycemia unawareness and with impaired liver functions (≥ 2.5 times the upper normal limit), known or suspected allergy against liraglutide or contraindications to liraglutide (as specified in the product prescribing information), pregnancies, breastfeeding or intention of becoming pregnant or not using adequate contraceptive measures, patients with a personal or family history of medullary thyroid cancer and patients with Multiple Endocrine Neoplasia type 2.
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 |
|---|---|---|
| LiraglutideAlso: VictozaCrossover design - 24 weeks on active drug and 12 weeks daily placebo | Drug | Liraglutide, Placebo |
Primary outcome
Changes in unfolded protein response markers
Time frame: baseline, 6 months, 9 months
Changes in unfolded protein response markers in adipose tissue biopsy samples. Specifically, the investigators will determine changes in mRNA (by RT-PCR) and protein (by Western blots) levels of the following ER stress markers: GRP78, ATF4, XBP-1s, PDI, calreticulin and calnexin.
6 secondary outcomes
Insulin sensitivity
Time frame: baseline, 3 months, 6 months and 9 months
Glucose control
Time frame: baseline, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months
Energy expenditure
Time frame: baseline, 3 months, 6 months, 9 months
Body weight
Time frame: baseline, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months
Body composition
Time frame: baseline, 3 months, 6 months and 9 months
Beta cell function
Time frame: baseline, 6 months, 9 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2022.
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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.
Ajaykumar D Rao, MD principal investigator
Temple University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Liraglutide in people with Type 2 Diabetes, run by Temple University 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 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 29 Jul 2022. 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. 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 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?
Results are not available in the source record.
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?
Changes in unfolded protein response markers (time frame: baseline, 6 months, 9 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 29 Jul 2022.