NAFLD
Conditions
Keywords
NAFLD, Non-alcoholic Fatty Liver Disease, Obesity, Pediatrics, Children, Losartan, Cozaar
Brief summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease among children and is closely associated with obesity and the metabolic syndrome. NAFLD increases risk of mortality and natural history studies of adults show that NAFLD is an independent risk factor for cardiovascular disease. Pediatric NAFLD is particularly concerning from a public health standpoint, as it represents an early and possibly more aggressive form of the disease. Currently there is no effective treatment for pediatric NAFLD. Losartan is an orally-administered angiotensin II receptor antagonist which is currently on the market to treat high blood pressure. The renin-angiotensin-aldosterone (RAA) system has been shown to be important in many disease states including renal disease, cardiovascular disease, and NAFLD. Angiotensin antagonists are a class of medications that has been proposed as a novel treatment of NAFLD in part because they would treat both the factors increasing cardiovascular (CVD) risks as well as potentially improve steatosis, fibrosis and hepatic inflammation. This study is a randomized, double-blinded, placebo-controlled pilot study to evaluate whether 8 weeks of Losartan will decrease inflammatory markers among children ages 12-19 with a current diagnosis of NAFLD. Efficacy will be assessed by improvement in alanine aminotransferase (ALT) from baseline. Secondary endpoints will include aspartate aminotransferase (AST), cytokeratin 18 levels, and fasting triglyceride levels among others. Safety will be assessed by the recording of adverse events, clinical laboratory parameters, vital signs and physical examinations.
Interventions
DRUGLosartan
Oral tablet to be taken once daily at 0.4mg/kg/day (max 25mg) for one week and then increased to 0.8mg/kg/day (max 50mg) for 7 additional weeks.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Children's Healthcare of Atlanta
Miriam Vos, MD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
11 Years to 19 Years
Healthy volunteers
No
Inclusion criteria
* Body Mass Index (BMI) \> 85th% for age and gender * History of definite or borderline nonalcoholic steatohepatitis (NASH) diagnosed by liver biopsy using NASH Clinical Research Network (CRN) criteria * At least 2 months of attempted lifestyle changes after liver biopsy * Current ALT ≥ 3 times normal (69 U/L for girls, 78 U/L for boys) at enrollment * Glomerular filtration rate (GRF) \> 90 * Weight ≥ 62.5 kg
Exclusion criteria
* Other chronic illness requiring daily medication (except medications for mild mental illness, acid reflux, allergies, stable attention deficit hyperactivity disorder (ADHD), or asthma) * Supplement or anti-oxidant therapy within past 2 weeks * Renal insufficiency * Cirrhosis and liver synthetic dysfunction (International Normalized Ratio ≥ 1.5) * History of hypotension * Diabetes (or fasting glucose \> 125 mg/dL) * Acute illness within past 2 weeks prior to enrollment (fever \> 100.4ºF) * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment) | Baseline (Weeks 0 and 14), Endpoint (Weeks 8 and 22) | The principal objective of this blinded, placebo controlled, crossover pilot study is to evaluate whether 8 weeks of losartan in children with nonalcoholic steatohepatitis (NASH) will decrease inflammation as measured by ALT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Baseline (Week 0 and 14), End of treatment (Week 8 and 22) | For children, a cholesterol level of less than 170 is considered acceptable, 170-199 is borderline high, and 200 and over is high. |
| Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Baseline (Week 0 and 14), End of treatment (Week 8 and 22) | For children aged 10 to 19, triglyceride levels of less than 90 is considered acceptable, 90 to 129 is borderline high, and greater than or equal to 130 and over is high. |
| Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment) | Baseline (Week 0 and 14), End of Treatment (Week 8 and 22) | Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) is an equation which indicates the degree of insulin resistance, where higher scores equate to greater insulin resistance. HOMA-IR is calculated as fasting glucose (mg/dl) × insulin (mU/L)/405. A HOMA-IR value \>2.0 in prepubertal children and \>2.6 in pubertal children, may be considered a warning sign for pediatricians to further investigate insulin resistance. |
| Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment | Baseline, Week 8, Week 14, Week 22 | PAI-1 is an acute-phase protein that is associated with both injury and inflammation, and has been found to be elevated in adolescents with significant hepatic steatosis. The reference range for PAI-1 in fasting adults is 3-72 ng/mL |
| Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Baseline (Week 0 and 14), End of Treatment (Week 8 and 22) | In human studies, losartan has been shown to decrease serum free fatty acids, thus any decrease in this measurement indicates a positive response to losartan. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment | Baseline, Week 8, Week 14, and Week 22 | The normal range for AST in children is 0 - 60 IU/L. AST can respond rapidly to treatment so decreases between Baseline and subsequent measurements indicate positive effects of treatment. |
Countries
United States
Participant flow
Recruitment details
Children were recruited from the patient population of Children's Healthcare of Atlanta and the Emory Children's Center Clinics.
Pre-assignment details
Of the 16 individuals who signed the consent form, 4 were found to be ineligible to participate during screening process, resulting in 12 participants who began the study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Losartan Followed by Placebo Recipients of treatment with losartan for 8 weeks followed by 8 weeks of treatment with a placebo. | 5 |
| Placebo Followed by Losartan Recipients of treatment with a placebo for 8 weeks followed by 8 weeks of treatment with losartan. | 7 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Losartan Followed by Placebo | Placebo Followed by Losartan | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 6 Participants | 11 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 5 participants | 7 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 5 |
| other Total, other adverse events | 9 / 9 | 5 / 5 |
| serious Total, serious adverse events | 0 / 9 | 0 / 5 |
Outcome results
Primary
Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment)
The principal objective of this blinded, placebo controlled, crossover pilot study is to evaluate whether 8 weeks of losartan in children with nonalcoholic steatohepatitis (NASH) will decrease inflammation as measured by ALT.
Time frame: Baseline (Weeks 0 and 14), Endpoint (Weeks 8 and 22)
Population: In this blinded, crossover treatment, study participants received losartan or a placebo for 8 weeks, then completed a 6 week washout period before crossing over to the other treatment for 8 weeks. The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment) | ALT at Baseline (weeks 0 and 14) | 136.44 U/L | Standard Deviation 80.06 |
| Losartan | Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment) | ALT at End of Treatment (weeks 8 and 22) | 112.78 U/L | Standard Deviation 69.64 |
| Placebo | Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment) | ALT at Baseline (weeks 0 and 14) | 117.40 U/L | Standard Deviation 56.42 |
| Placebo | Change in Alanine Aminotransferase (ALT) From Baseline to End of Treatment (8 Weeks of Treatment) | ALT at End of Treatment (weeks 8 and 22) | 89.40 U/L | Standard Deviation 35.26 |
Secondary
Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment)
For children, a cholesterol level of less than 170 is considered acceptable, 170-199 is borderline high, and 200 and over is high.
Time frame: Baseline (Week 0 and 14), End of treatment (Week 8 and 22)
Population: The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. One additional participant in each treatment group is missing the end of treatment cholesterol level measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Cholesterol at baseline (week 0 or 14) | 137.67 mg/dL | Standard Deviation 28.81 |
| Losartan | Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Cholesterol at end of treatment (week 8 and/or 22) | 132.38 mg/dL | Standard Deviation 23.84 |
| Placebo | Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Cholesterol at end of treatment (week 8 and/or 22) | 144.00 mg/dL | Standard Deviation 13.47 |
| Placebo | Change in Cholesterol Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Cholesterol at baseline (week 0 or 14) | 152.80 mg/dL | Standard Deviation 18.79 |
Secondary
Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment)
In human studies, losartan has been shown to decrease serum free fatty acids, thus any decrease in this measurement indicates a positive response to losartan.
Time frame: Baseline (Week 0 and 14), End of Treatment (Week 8 and 22)
Population: The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. One participant is missing the endpoint measurement for free fatty acid levels, following the 8 week losartan treatment phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Fatty acid at Baseline (week 0 and 14) | 0.38 mEq/L | Standard Deviation 0.17 |
| Losartan | Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Fatty acid at end of treatment (week 8 and 22) | 0.45 mEq/L | Standard Deviation 0.11 |
| Placebo | Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Fatty acid at Baseline (week 0 and 14) | 0.41 mEq/L | Standard Deviation 0.12 |
| Placebo | Change in Fatty Acid Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Fatty acid at end of treatment (week 8 and 22) | 0.38 mEq/L | Standard Deviation 0.12 |
Secondary
Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment)
For children aged 10 to 19, triglyceride levels of less than 90 is considered acceptable, 90 to 129 is borderline high, and greater than or equal to 130 and over is high.
Time frame: Baseline (Week 0 and 14), End of treatment (Week 8 and 22)
Population: The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. One participant is missing data for the endpoint measurement of triglyceride levels, following 8 weeks of losartan treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Triglyceride at end of treatment (week 8 or 22) | 65.75 mg/dL | Standard Deviation 25.34 |
| Losartan | Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Triglyceride at baseline (week 0 or 14) | 97.11 mg/dL | Standard Deviation 50.27 |
| Placebo | Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Triglyceride at end of treatment (week 8 or 22) | 80.40 mg/dL | Standard Deviation 16.59 |
| Placebo | Change in Triglyceride Levels From Baseline to End of Treatment (8 Weeks of Treatment) | Triglyceride at baseline (week 0 or 14) | 69.60 mg/dL | Standard Deviation 11.87 |
Secondary
Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment)
Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) is an equation which indicates the degree of insulin resistance, where higher scores equate to greater insulin resistance. HOMA-IR is calculated as fasting glucose (mg/dl) × insulin (mU/L)/405. A HOMA-IR value \>2.0 in prepubertal children and \>2.6 in pubertal children, may be considered a warning sign for pediatricians to further investigate insulin resistance.
Time frame: Baseline (Week 0 and 14), End of Treatment (Week 8 and 22)
Population: The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. An additional participant is missing HOMA-IR data from the placebo phase of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment) | HOMA-IR at Baseline (week 0 or 14) | 20.12 units on a scale | Standard Deviation 11.31 |
| Losartan | Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment) | HOMA-IR at end of treatment (week 8 or 22) | 9.35 units on a scale | Standard Deviation 4.81 |
| Placebo | Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment) | HOMA-IR at end of treatment (week 8 or 22) | 11.67 units on a scale | Standard Deviation 4.42 |
| Placebo | Changes in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) Between Baseline and End of Treatment (8 Weeks of Treatment) | HOMA-IR at Baseline (week 0 or 14) | 6.59 units on a scale | Standard Deviation 2.91 |
Secondary
Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment
PAI-1 is an acute-phase protein that is associated with both injury and inflammation, and has been found to be elevated in adolescents with significant hepatic steatosis. The reference range for PAI-1 in fasting adults is 3-72 ng/mL
Time frame: Baseline, Week 8, Week 14, Week 22
Population: The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment. One additional participant is missing PAI-1 data from the placebo phase of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment | PAI-1 at Baseline (week 0 or 14) | 5.25 ng/mL | Standard Deviation 1.55 |
| Losartan | Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment | PAI-1 at end of treatment (week 8 or 22) | 5.04 ng/mL | Standard Deviation 2.5 |
| Placebo | Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment | PAI-1 at Baseline (week 0 or 14) | 6.39 ng/mL | Standard Deviation 2.57 |
| Placebo | Changes in Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations Between Baseline and End of Treatment | PAI-1 at end of treatment (week 8 or 22) | 6.58 ng/mL | Standard Deviation 4.01 |
Other Pre-specified
Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment
The normal range for AST in children is 0 - 60 IU/L. AST can respond rapidly to treatment so decreases between Baseline and subsequent measurements indicate positive effects of treatment.
Time frame: Baseline, Week 8, Week 14, and Week 22
Population: In this blinded, crossover treatment, study participants received losartan or a placebo for 8 weeks, then completed a 6 week washout period before crossing over to the other treatment for 8 weeks. The placebo results for four participants in the losartan followed by placebo arm were not usable due to carry over effects from the active treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losartan | Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment | AST at Baseline (week 0 or 14) | 66.89 IU/L | Standard Deviation 28.01 |
| Losartan | Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment | AST from Baseline to Week 22 | 54.22 IU/L | Standard Deviation 21.52 |
| Placebo | Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment | AST at Baseline (week 0 or 14) | 51.60 IU/L | Standard Deviation 18.05 |
| Placebo | Change in Aspartate Aminotransferase (AST) From Baseline to End of Treatment | AST from Baseline to Week 22 | 37.80 IU/L | Standard Deviation 10.71 |