NAFLD - Nonalcoholic Fatty Liver Disease, NASH - Nonalcoholic Steatohepatitis
Conditions
Keywords
Pediatric, NAFLD - nonalcoholic fatty liver disease, Curcumin, Fatty liver
Brief summary
This is a single-center, randomized, double-blinded, placebo-controlled, parallel treatment groups phase 2a study of curcumin for pediatric nonalcoholic fatty liver disease (NAFLD).
Detailed description
30 subjects ages 8-17y, with biopsy-proven NASH/NAFLD (≤ 730 days prior to registration and a NAFLD Activity Score (NAS) of ≥3) and serum ALT at screening ≥ 50 IU/L at enrollment. Eligible participants will receive curcumin 500 mg, 1.0 g or placebo for 24 weeks, randomized 1:1:1. The primary outcome of the study will determine whether 24 weeks of curcumin supplementation compared to matching placebo improves measures of nonalcoholic fatty liver disease (NAFLD) as determined by relative improvement in serum ALT from baseline. The hypothesis is that curcumin will significantly decrease ALT relative to placebo in children with NAFLD.
Interventions
DRUGphosphatidylcholine-curcumin complex supplement
a dietary curcumin supplement given at two different doses
DRUGPlacebo curcumin capsule
matching placebo to active curcumin capsules
Sponsors
Thorne HealthTech, Inc
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Participants, investigators, clinical staff, and data monitoring committee will not have knowledge of the interventions assigned to individual participants.
Intervention model description
The comparison of two different doses (500mg/qd and 1g/qd) of a phosphatidylcholine-curcumin complex supplement, to matching placebo
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Age 8-17 years at initial screening interview * Histological evidence of NAFLD with or without fibrosis and a NAFLD activity score (NAS) of ≥3, on a liver biopsy obtained no more than 730 days prior to enrollment * Serum ALT at screening ≥ 50 IU/L
Exclusion criteria
* Significant alcohol consumption or inability to reliably quantify alcohol intake * Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, other known hepatotoxins) for more than 2 consecutive weeks in the past year prior to randomization * New treatment with vitamin E or metformin started in the past 90 days or plans to alter the dose or stop over the next the 24 weeks. A stable dose is acceptable. * Prior or planned bariatric surgery * Uncontrolled diabetes (HbA1c 9.5% or higher within 30 days prior to enrollment) * Presence of cirrhosis on liver biopsy * Stage 2 Hypertension or \>140 systolic or \>90 diastolic at screening * Current daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) * Platelet counts below 100,000 /mm3 * Clinical evidence of hepatic decompensation (serum albumin \< 3.2 g/dL, international normalized ratio (INR) \>1.3, direct bilirubin \>1.3 mg/dL, history of esophageal varices, ascites, or hepatic encephalopathy) * Evidence of chronic liver disease other than NAFLD: * Biopsy consistent with histological evidence of autoimmune hepatitis * Serum hepatitis B surface antigen (HBsAg) positive. * Serum hepatitis C antibody (anti-HCV) positive. * Iron/total iron binding capacity (TIBC) ratio (transferrin saturation) \> 45% with histological evidence of iron overload * Alpha-1-antitrypsin (A1AT) phenotype/genotype ZZ or SZ * Wilson's disease * History of biliary diversion * History of kidney disease and/or estimated glomerular filtration rate (eGFR) \< than 60 mL/min/1.73 m2 using Schwartz Bedside GFR Calculator for Children isotope dilution mass spectroscopy (IDMS)-traceable * Known Human Immunodeficiency Virus (HIV) infection * Active, serious medical disease with life expectancy less than 5 years * Active substance abuse including inhaled or injected drugs, in the year prior to screening * Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use effective birth control during the trial, breast feeding * Participation in any clinical/investigational trial within the prior 150 days and during the study. * Any other condition which, in the opinion of the investigator, would impede compliance or hinder completion of the study * Inability to swallow capsules * Known allergy to curcumin or any of its components * Failure of parent or legal guardian to give informed consent or subject to give informed assent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in serum alanine aminotransferase (ALT) from baseline. | 24 weeks | ALT value in U/L |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) compared to baseline | 24 weeks | 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 (mmol/L) x insulin (pmol/L))/22.5. 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 |
| Change in Body-mass Index Z- Score | 24 weeks | Body mass index z-scores is calculated using age, gender, height and weight and calculated using 2000 CDC Growth Charts for norms. |
| Change in serum lipids compared to baseline | 24 weeks | lipid profiles |
| Change in High Sensitivity C-Reactive Protein (hsCRP) compared to baseline | 24 weeks | serum marker of inflammation (mg/L) |
| Change in Pediatric Quality of Life Inventory (PedsQL) Score scores compared to baseline | 24 weeks | Pediatric Quality of Life Inventory (PedsQL) version 4.0 is completed by both the child and parent/caregiver, and is composed of 23 items comprising 4 dimensions: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Scores are transformed on a scale from 0 to 100, with higher scores indicating better health-related quality of life. Physical Health Summary Score =Physical Functioning Scale Score. Psychosocial Health Summary Score = Sum of items over the number of items answered in the Emotional, Social, and School Functioning Scales. |
| Change in Intrahepatic fat content and liver stiffness | 24 weeks | Hepatic fat content and liver stiffness will be measured by CAP and VCTE (Fibroscan®) |
| Change in frequency of adverse events compared to baseline | 24 weeks | Numbers of adverse events reported |
| Relative change in ALT compared to baseline ALT | 24 weeks | ALT value in U/L |
| Proportion of patients achieving normalization of ALT | 24 weeks | ALT value in U/L |
| Change in serum aspartate aminotransferase (AST) | 24 weeks | AST value in U/L |
| Change in serum gamma-glutamyl transpeptidase (GGT) | 24 weeks | GGT value in U/L |
| Change in ALT at 12 weeks compared to baseline ALT | 12 weeks | ALT value in U/L |
| Change in Weight | 24 weeks | kilograms (kg) |
| Change in Waist circumference | 24 weeks | centimeters (cm) |
| Change in Waist to Hip ratio | 24 weeks | ratio of the circumference of the waist to that of the hips. This is calculated as waist measurement divided by hip measurement (W ÷ H). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in interleukin 8 (IL-8) | 24 weeks | cytokine protein involved in the pro-inflammatory and anti-inflammatory response |
| Change in (TNF-a) Tumor Necrosis Factor alpha | 24 weeks | cytokine protein involved in the pro-inflammatory and anti-inflammatory response |
| Change in Plasminogen Activator Inhibitor (PAI-1) | 24 weeks | cytokine protein involved in the pro-inflammatory and anti-inflammatory response |
| Change in adiponectin | 24 weeks | cytokine protein involved in the pro-inflammatory and anti-inflammatory response |
| Change in interleukin 6 (IL-6) | 24 weeks | cytokine protein involved in the pro-inflammatory and anti-inflammatory response |
| Plasma concentrations of curcumin and active metabolites from baseline to 24 weeks. | Day 0 pre-dose and 1, 2, 4, 6, 8 hours post-dose; Day 14; Day 28; Day 84 and Day 168 | Pharmacokinetic analysis |
Outcome results
None listed