Chronic Kidney Diseases
Conditions
Keywords
Chronic Kidney Disease, Intermuscular fat deposition, Glucagon-like peptide-1 agonist, Insulin resistance, Mitochondrial function
Brief summary
Chronic kidney disease (CKD) is a burden of morbidity and mortality. Increased protein breakdown in skeletal muscle (wasting) and ectopic fat deposition are important determinants of poor clinical outcome in patient with CKD. Insulin resistance plays a critical role in skeletal muscle wasting and ectopic fat deposition. Glucagon-like peptide-1 receptor agonists (GLP-1RA) decrease ectopic fat deposition in patients with type 2 diabetes, prediabetes, obese and overweight subjects. The influence of GLP-1RA on ectopic fat deposition in CKD patients in unknown. The investigators' will test the hypothesis that GLP-1RA decreases intermuscular (ectopic) fat deposition in patients with stage 3-4 CKD. The investigators' will do so by addressing the following specific aims: Specific Aim 1: To test the hypothesis that GLP-1RA decreases intermuscular fat deposition in patients with stage 3-4 CKD. Specific Aim 2: To test the hypothesis that GLP-1RA improves skeletal muscle mitochondrial function in patients with stage 3-4 CKD. Specific Aim 3: To test the hypothesis that GLP-1RA improves physical performance in patients with stage 3-4 CKD. Specific Aim 4: To test the safety and feasibility of 12 weeks of dulaglutide 1.5 mg/wk administration as an adjunct therapy to the standard care of patients with stage 3-4 CKD.
Interventions
All participants will undergo a 4-week run-in phase followed by 12 weeks of treatment (dulaglutide 1.5 mg/wk), followed by 4 weeks of follow up after discontinuing the study medication
Sponsors
VA Tennessee Valley Health Care System
Vanderbilt University Medical Center
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with stage 3-4 CKD (eGFR 15-59 ml/min/1/73 m2) 2. Age ≥ 18 years and ≤75 years
Exclusion criteria
1. Patients with type 1 diabetes mellitus 2. Patients with T2D who are on insulin therapy or who started a new antidiabetic medication within 1 month prior to study or who received incretin-based therapy within 3 months prior to study 3. BMI \<25 kg/m2, BMI \>40 kg/m2 4. HbA1c\>8% measured within 1 month prior to study, or a history of hypoglycemic episode within 1 year prior to study, or a history of diabetic ketoacidosis 5. Uncontrolled hypertension (\>200/100 mmHg) despite optimal antihypertensive therapy 6. Arrythmia, heart failure (NYHA class III-IV), valve disease or heart diseases other than coronary artery disease 7. History of major gastrointestinal surgery, inflammatory bowel disease, pancreatitis or cholelithiasis 8. Personal or family history of medullary thyroid cancer, or personal history of Multiple Endocrine Neoplasia (MEN)-2 9. Pregnancy, breast feeding or intention to become pregnant 10. Previous renal transplantation 11. Acute or chronic infectious diseases 12. Cancer or chemotherapy within 3 years prior to study 13. Treatment with systemic corticosteroids within 3 months prior to study 14. Known or suspected allergy to dulaglutide 15. Claustrophobia or other contraindications for magnetic resonance imaging
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Intermuscular Fat Deposition as Assessed by Magnetic Resonance Imaging (MRI). | 16 weeks | Sequential MRI will be performed during the run-in phase, at the beginning and end of the dulaglutide treatment and at the end of the observational follow up period. Intermuscular fat will be calculated as the ratio between intermuscular fat and muscle volumes in the mid-thigh region. Changes in intermuscular fat deposition will be calculated. the reported value is the difference between the end of study and baseline values (end of study minus baseline). A negative value will reflect a decrease in IMAT. |
| Changes in Skeletal Muscle Mitochondrial Function as Assessed by Phosphocreatine Recovery Time Constant by 31P Magnetic Resonance Spectroscopy (31P-MRS). | 16 weeks | Sequential 31P-MRS, a gold standard technique for muscle mitochondrial function assessment, will be performed during the run-in phase, at the beginning and end of the dulaglutide treatment and at the end of the observational follow up period. Changes in phosphocreatine recovery time constant will be assessed. |
| Changes in Physical Performance as Assessed by Systemic Physical Performance Battery Test | 16 weeks | Systemic physical performance battery test will be performed at the beginning and end of the dulaglutide treatment period. Changes will be assessed. The total score that will be reported is calculated by adding scores obtained from Balance test, Gait speed test and Chair stand test scores. The score for the primary outcome will be the difference between baseline and end of study. The SPPB total score ranges from 0 (worst performance) to 12 points (best performance) and categorically evaluates performance in the tests using three or four classes of scores: three classes: 0-6 points (poor performance), 7-9 points (moderate performance), and 10-12 points (good performance); or four classes: 0-3 points (disability/very poor performance), 4-6 points (poor performance), 7-9 points (moderate performance), and 10-12 points (good performance) |
| Safety and Feasibility of Dulaglutide Treatment as Evaluated by Subject Interview, Continuous Glucose Monitoring, Adverse Events (AE), Laboratory Tests, Vital Signs, ECG & Allergic/Hypersensitivity Reactions. | 16 weeks | An AE will be defined as any undesirable medical event occurring to a subject in a clinical trial, whether it is related to the study agent. All adverse events will be graded as follows: 0 = No adverse events or within normal limits; 1 = Mild-did not require treatment; 2 = Moderate resolved with treatment; 3 = Severe-required professional medical attention; 4 = Life-threatening or disabling; 5 = Death. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dulagutide Arm Patient will receive 1.5 mg injections per week for 12 weeks.
dulaglutide injection: All participants will undergo a 4-week run-in phase followed by 12 weeks of treatment (dulaglutide 1.5 mg/wk), followed by 4 weeks of follow up after discontinuing the study medication | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Dulagutide Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 59 years STANDARD_DEVIATION 8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 0 / 7 | 2 / 7 | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 0 / 7 |
Outcome results
Primary
Changes in Intermuscular Fat Deposition as Assessed by Magnetic Resonance Imaging (MRI).
Sequential MRI will be performed during the run-in phase, at the beginning and end of the dulaglutide treatment and at the end of the observational follow up period. Intermuscular fat will be calculated as the ratio between intermuscular fat and muscle volumes in the mid-thigh region. Changes in intermuscular fat deposition will be calculated. the reported value is the difference between the end of study and baseline values (end of study minus baseline). A negative value will reflect a decrease in IMAT.
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dulagutide Arm | Changes in Intermuscular Fat Deposition as Assessed by Magnetic Resonance Imaging (MRI). | -0.009 fat/muscle ratio | Standard Deviation 0.0526 |
Primary
Changes in Physical Performance as Assessed by Systemic Physical Performance Battery Test
Systemic physical performance battery test will be performed at the beginning and end of the dulaglutide treatment period. Changes will be assessed. The total score that will be reported is calculated by adding scores obtained from Balance test, Gait speed test and Chair stand test scores. The score for the primary outcome will be the difference between baseline and end of study. The SPPB total score ranges from 0 (worst performance) to 12 points (best performance) and categorically evaluates performance in the tests using three or four classes of scores: three classes: 0-6 points (poor performance), 7-9 points (moderate performance), and 10-12 points (good performance); or four classes: 0-3 points (disability/very poor performance), 4-6 points (poor performance), 7-9 points (moderate performance), and 10-12 points (good performance)
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dulagutide Arm | Changes in Physical Performance as Assessed by Systemic Physical Performance Battery Test | 0 score on a scale | Standard Deviation 2.24 |
Primary
Changes in Skeletal Muscle Mitochondrial Function as Assessed by Phosphocreatine Recovery Time Constant by 31P Magnetic Resonance Spectroscopy (31P-MRS).
Sequential 31P-MRS, a gold standard technique for muscle mitochondrial function assessment, will be performed during the run-in phase, at the beginning and end of the dulaglutide treatment and at the end of the observational follow up period. Changes in phosphocreatine recovery time constant will be assessed.
Time frame: 16 weeks
Population: MRS data could not be reported as the required acquisition was not completed. The estimated scan duration exceeded two hours, and there was insufficient time within the reserved scan slot to perform this portion. Additionally, the patients were unable to tolerate the prone position for such an extended period, which ultimately prevented the collection of data necessary for MRS analysis.
Primary
Safety and Feasibility of Dulaglutide Treatment as Evaluated by Subject Interview, Continuous Glucose Monitoring, Adverse Events (AE), Laboratory Tests, Vital Signs, ECG & Allergic/Hypersensitivity Reactions.
An AE will be defined as any undesirable medical event occurring to a subject in a clinical trial, whether it is related to the study agent. All adverse events will be graded as follows: 0 = No adverse events or within normal limits; 1 = Mild-did not require treatment; 2 = Moderate resolved with treatment; 3 = Severe-required professional medical attention; 4 = Life-threatening or disabling; 5 = Death.
Time frame: 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dulagutide Arm | Safety and Feasibility of Dulaglutide Treatment as Evaluated by Subject Interview, Continuous Glucose Monitoring, Adverse Events (AE), Laboratory Tests, Vital Signs, ECG & Allergic/Hypersensitivity Reactions. | 2 Participants |