Curcumin for Pediatric Nonalcoholic Fatty Liver Disease

Curcumin for Pediatric Nonalcoholic Fatty Liver Disease: A Pilot Randomized Controlled Trial

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).

Study Overview

• Status: Withdrawn
• Conditions: NASH - Nonalcoholic Steatohepatitis; NAFLD - Nonalcoholic Fatty Liver Disease
• Intervention / Treatment: Drug: phosphatidylcholine-curcumin complex supplement; Drug: Placebo curcumin capsule

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.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Curcumin 500mg capsules; Dose will be 500mg daily phosphatidylcholine-curcumin complex supplement, orally for 24 weeks	Drug: phosphatidylcholine-curcumin complex supplement; a dietary curcumin supplement given at two different doses; Other Names: Meriva®
Active Comparator: Curcumin 1000mg capsules; Dose will be1g daily of phosphatidylcholine-curcumin complex supplement, orally for 24 weeks	Drug: phosphatidylcholine-curcumin complex supplement; a dietary curcumin supplement given at two different doses; Other Names: Meriva®
Placebo Comparator: Placebo curcumin capsules; Dose will be matching placebo capsules daily, orally for 24 weeks	Drug: Placebo curcumin capsule; matching placebo to active curcumin capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in serum alanine aminotransferase (ALT) from baseline.	ALT value in U/L	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative change in ALT compared to baseline ALT	ALT value in U/L	24 weeks
Proportion of patients achieving normalization of ALT	ALT value in U/L	24 weeks
Change in serum aspartate aminotransferase (AST)	AST value in U/L	24 weeks
Change in serum gamma-glutamyl transpeptidase (GGT)	GGT value in U/L	24 weeks
Change in ALT at 12 weeks compared to baseline ALT	ALT value in U/L	12 weeks
Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) compared to baseline	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	24 weeks
Change in Weight	kilograms (kg)	24 weeks
Change in Waist circumference	centimeters (cm)	24 weeks
Change in Waist to Hip ratio	ratio of the circumference of the waist to that of the hips. This is calculated as waist measurement divided by hip measurement (W ÷ H).	24 weeks
Change in Body-mass Index Z- Score	Body mass index z-scores is calculated using age, gender, height and weight and calculated using 2000 CDC Growth Charts for norms.	24 weeks
Change in serum lipids compared to baseline	lipid profiles	24 weeks
Change in High Sensitivity C-Reactive Protein (hsCRP) compared to baseline	serum marker of inflammation (mg/L)	24 weeks
Change in Pediatric Quality of Life Inventory (PedsQL) Score scores compared to baseline	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.	24 weeks
Change in Intrahepatic fat content and liver stiffness	Hepatic fat content and liver stiffness will be measured by CAP and VCTE (Fibroscan®)	24 weeks
Change in frequency of adverse events compared to baseline	Numbers of adverse events reported	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentrations of curcumin and active metabolites from baseline to 24 weeks.	Pharmacokinetic analysis	Day 0 pre-dose and 1, 2, 4, 6, 8 hours post-dose; Day 14; Day 28; Day 84 and Day 168
Change in interleukin 6 (IL-6)	cytokine protein involved in the pro-inflammatory and anti-inflammatory response	24 weeks
Change in interleukin 8 (IL-8)	cytokine protein involved in the pro-inflammatory and anti-inflammatory response	24 weeks
Change in (TNF-a) Tumor Necrosis Factor alpha	cytokine protein involved in the pro-inflammatory and anti-inflammatory response	24 weeks
Change in Plasminogen Activator Inhibitor (PAI-1)	cytokine protein involved in the pro-inflammatory and anti-inflammatory response	24 weeks
Change in adiponectin	cytokine protein involved in the pro-inflammatory and anti-inflammatory response	24 weeks

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Thorne Research Inc.
• Investigators: Principal Investigator: Joel E Lavine, MD, PhD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2019
• Primary Completion (Actual): April 22, 2020
• Study Completion (Actual): April 22, 2020

Study Registration Dates

• First Submitted: September 23, 2019
• First Submitted That Met QC Criteria: September 27, 2019
• First Posted (Actual): September 30, 2019

Study Record Updates

• Last Update Posted (Actual): September 27, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Pediatric; Curcumin; Fatty liver; NAFLD - nonalcoholic fatty liver disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Curcumin
• Other Study ID Numbers: AAAS6731

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No