Liraglutide in Obesity and Diabetes: Identification of CNS Targets Using fMRI

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01562678
• Collaborator: (none)
• Enrollment: 28
• Location: 1
• Arms: 2
• Duration (Months): 26
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The main purpose of this study is to help us understand the effects of diabetes medication Liraglutide on weight loss and hunger. The investigators have already determined what the highest tolerated dose of Liraglutide is through earlier human research studies. Liraglutide was approved by the FDA in January 2010 for treatment of diabetes.

The investigators will also study the following:

1. The impact of Liraglutide on brain responses to food

2. It's effect on physiological and mental performance

3. If its effect on the brain differs among obese and lean diabetic subjects.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Effects of Liraglutide Administration on Brain Activity; Weight Loss; Hunger	Drug: Liraglutide; Drug: Placebo	Phase 4

Detailed Description

This is a randomized, placebo controlled, cross-over, double-blinded study to assess the effects of liraglutide on brain activation in areas involved in cognitive control and reward during food visualization.

Study participation will span approximately 1.5-2 months. Subjects will learn to self-administer the medication and will have a total of 8 study visits plus one screening visit. The visits will include the following tests/procedures:

1. Vital signs (blood pressure, temperature, heart rate, breathing rate)

2. Height, weight and other body measurements like waist

3. Blood tests

4. Urine pregnancy test (women only)

5. Electrocardiogram (EKG)

6. Medical history

7. Physical exam

8. Body Composition tests

9. Study logs to record food intake and blood sugar

10. functional MRI

We plan to recruit a total of 24 subjects to be treated with placebo and liraglutide. We propose to enroll 12 obese diabetic (type 2) and 12 lean diabetic (type 2) subjects. Equal numbers of men and women will be enrolled and the randomization will block for gender.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: Liraglutide in Obesity and Diabetes: Identification of CNS Targets Using fMRI
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Liraglutide	Drug: Liraglutide; In the experimental arm of this randomized, placebo controlled, cross-over, double-blinded study to assess the effects of liraglutide. Subjects will self-inject Liraglutide once per day for 18 days. Subjects will start the treatment with a dose of 0.6 mg for the first week, then 1.2 mg for the second week and 1.8 mg for 3 days in the third week.; Other Names: victoza
Placebo Comparator: Placebo	Drug: Placebo; In the placebo arm of this randomized, placebo controlled, cross-over, double-blinded study to assess the effects of liraglutide. Subjects will self-inject placebo once per day for 18 days.

Outcome Measures

Primary Outcome Measures

1. Change Between Highly Desirable vs. Less Desirable Food Cues in the Effect Size of Cortical Activation During Food Visualization [18 days of Liraglutide or placebo treatment]

   Effect size (region of interest z-scores, derived from z-maps of the brain) shown below is the difference in parietal cortex activation to highly desirable (high fat or high calorie, e.g. cakes, pies, fries) versus less desirable (low fat or low calorie, e.g. vegetables, fruits) food cues for each treatment condition (liraglutide or placebo) at the end of the treatment period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Subjects will be men and women between the ages of 18 and 65. The following table list inclusion criteria for each group (lean diabetic and obese diabetic). Subjects must meet either HbA1c or fasting plasma glucose (FPG) criteria.

Lean diabetic:

BMI: 18-25 kg/m2 HbA1c: < 8.9% Fasting plasma glucose: <250 mg/dL Other inclusion criteria:

On dietary modification and/or metformin

Obese diabetic:

BMI: >27 kg/m2 HbA1c: < 8.9% Fasting plasma glucose: <250 mg/dL Other inclusion criteria:

On dietary modification and/or metformin

Additionally, women participants must use double barrier methods to prevent pregnancy (diaphragm with intravaginal spermicide, cervical cap, male or female condom with spermicide). If a woman suspects that she has become pregnant at any time or does not use one of the contraceptive methods recommended by the investigator, she must notify the study staff. If a woman becomes pregnant, she will be withdrawn from the study. The study staff will follow the progress of her pregnancy and the birth of her child.

Exclusion Criteria:

1. Uncontrolled diabetes (HbA1c>8.9%, or FPG>250 mg/dL)

2. Women who are breastfeeding, pregnant, or wanting to become pregnant.

3. Women using IUD

4. Any change in the dosage of hormonal contraceptive medications (birth control pills, implanon). Subjects should remain on same medication/ same dose during the time of the entire study.

5. Moderate (creatinine clearance of 30-59 ml/min) and severe renal impairment (creatinine clearance below 30 ml/min) and end-stage renal disease

6. Moderate, or severe hepatic impairment

7. Hypersensitivity to the active substance or any of the excipients in liraglutide

8. History of diabetic ketoacidosis

9. Congestive heart failure

10. Inflammatory conditions like inflammatory bowel disease, Rheumatoid arthritis etc

11. Gastroparesis

12. Pancreatitis

13. Gallstones- as they may cause increased risk of pancreatitis

14. Alcohol consumption- the maximum quantity for men is 140g-210g per week. For women, the range is 84g-140g per week or drinking as consuming no more than two drinks a day for men and one for women. Alcohol can cause increased risk of pancreatitis and hypoglycemia.

15. Untreated thyroid disease like hypothyroidism or hyperthyroidism

16. Subjects taking the following medications: warfarin, steroids (inhaled or systemic due to reduced hypoglycemic effect), and subjects on other hormones (LHRH analogs etc).

17. Subjects on any oral anti-diabetic agent except metformin

18. Personal or family history of MEN II or medullary thyroid cancer

19. Subjects with any type of bioimplant activated by mechanical, electronic, or magnetic means (e.g. cochlear implants, pacemakers, neuron or biostimulators, electronic infusion pumps, etc.)

20. Subjects with any type of metallic implant that could potentially be displaced or damaged during MRI, such as aneurysm clips, metallic skull plates, surgical implants etc. or metal containing tattoos

21. Anxiety and/or claustrophobia

22. Uncontrolled cardiac impairment, circulatory impairment, or inability to perspire (poor thermoregulatory function)

23. Significant sensory or motor impairment

24. Epilepsy, particularly photo-sensitive epilepsy, which may place the individual at a higher risk for adverse events during fMRI scanning with visual stimulation

25. Subjects with neurological problems which may interfere with or complicate testing (e.g. presence of titubation)

26. Body weight above the limitation of the MRI scanning table (330lbs/150 Kg) or body dimensions that could difficult the performance of the scan.

27. Subjects who cannot adhere to the experimental protocol for any reason

28. Anemia with Hgb less than 10

29. Uncontrolled infectious diseases (e.g. HIV, hepatitis, chronic infections etc)

30. Any uncontrolled endocrine condition, e.g Cushing's, Acromegaly, etc

31. Any cancers or lymphoma

32. Eating disorders like anorexia, bulimia

33. Severe hypertriglyceridemia (triglycerides >500 mg/dl)

34. Weight loss surgery or gastrectomy

35. Any changes in medications that affect brain function, e.g. anti-depressants, anti-psychotics, anti-anxiety, anti-seizure medications, antihypertensives etc (subjects should remain on same medication/ same dose during the time of the entire study).

36. Irregular periods, defined as cycle length less than 22 days or more than 40 days.

37. Any change in smoking status.

38. Vegetarians- as food images presented will include numerous non-vegetarian items and thus will not be appealing as high calorie food items.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center

Investigators

• Principal Investigator: Christos Mantzoros, MD, Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mantzoros Lab Website

Publications

None provided.

• Responsible Party: Christos Mantzoros, Professor of Medicine, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT01562678
• Other Study ID Numbers: 2011P000280
• First Posted: Mar 26, 2012
• Last Update Posted: May 31, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Christos Mantzoros, Professor of Medicine, Beth Israel Deaconess Medical Center: fMRI; Liraglutide; diabetes; GLP-1
• Additional relevant MeSH terms: Diabetes Mellitus; Weight Loss; Liraglutide

Study Results

Participant Flow

Arm/Group Title	Liraglutide First, Then Placebo	Placebo First, Then Liraglutide
Arm/Group Description	14 participants were randomized to receive Liraglutide and then were cross-overed to receive placebo	14 participants were randomized to receive Placebo and then were cross-overed to receive Liraglutide
Period Title: Overall Study
STARTED	14	14
COMPLETED	8	12
NOT COMPLETED	6	2

Baseline Characteristics

Arm/Group Title	Liraglutide First, Then Placebo	Placebo First, Then Liraglutide	Total
Arm/Group Description	14 participants were randomized to receive Liraglutide and then were cross-overed to receive placebo	14 participants were randomized to receive Placebo and then were cross-overed to receive Liraglutide	Total of all reporting groups
Overall Participants	14	14	28
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	14 100%	28 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.5 (10.5)	52.5 (10.5)	52.5 (10.5)
Sex: Female, Male (Count of Participants)
Female	7 50%	5 35.7%	12 42.9%
Male	7 50%	9 64.3%	16 57.1%
Region of Enrollment (participants) [Number]
United States	14 100%	14 100%	28 100%

Outcome Measures

1. Primary Outcome

Title	Change Between Highly Desirable vs. Less Desirable Food Cues in the Effect Size of Cortical Activation During Food Visualization
Description	Effect size (region of interest z-scores, derived from z-maps of the brain) shown below is the difference in parietal cortex activation to highly desirable (high fat or high calorie, e.g. cakes, pies, fries) versus less desirable (low fat or low calorie, e.g. vegetables, fruits) food cues for each treatment condition (liraglutide or placebo) at the end of the treatment period.
Time Frame	18 days of Liraglutide or placebo treatment

Outcome Measure Data

Analysis Population Description

Participants with incomplete MRI scans were excluded from the analysis.

Arm/Group Title	Liraglutide	Placebo
Arm/Group Description	Liraglutide: In the experimental phase of this randomized, placebo-controlled, cross-over, double-blinded study to assess the effects of liraglutide, subjects started the treatment with a dose of 0.6 mg for the first week, then 1.2 mg for the second week and 1.8 mg for 3 days in the third week. This sequence may have occurred for their first phase or second phase (placebo was the other phase).	Placebo: In the placebo phase of this randomized, placebo controlled, cross-over, double-blinded study to assess the effects of liraglutide, subjects will self-inject placebo once per day for 18 days. Participants had this first or second (liraglutide was the other phase).
Measure Participants	18	18
Mean (Standard Error) [z-scores of activation in cortex]	-0.42 (0.27)	0.53 (0.37)

Adverse Events

Time Frame	Throughout the study (4 visits in each phase of liraglutide and placebo).
Adverse Event Reporting Description	There was a systematic assessment of adverse events at each visit (Days 0, 7, 14, and 17) by an MD who asked detailed medical questions and did a physical exam, plus through the use of visual analog scales administered 3 times per day where participants answered on a 10cm line questions such as "How nauseous do you feel right now?"
Arm/Group Title	Liraglutide		Placebo
Arm/Group Description	14 participants were randomized to receive Liraglutide and then were cross-overed to receive placebo and 14 participants were randomized to receive Placebo and then were cross-overed to receive Liraglutide		14 participants were randomized to receive Placebo and then were cross-overed to receive Liraglutide and 14 participants were randomized to receive Liraglutide and then were cross-overed to receive placebo
All Cause Mortality
	Liraglutide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Liraglutide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Liraglutide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/28 (25%)		7/28 (25%)
Gastrointestinal disorders
Nausea	7/28 (25%)	7	7/28 (25%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.