Curcumin for Pediatric Nonalcoholic Fatty Liver Disease

Phase 2

Withdrawn

• Conditions: NASH - Nonalcoholic Steatohepatitis; NAFLD - Nonalcoholic Fatty Liver Disease
• Interventions: Drug: phosphatidylcholine-curcumin complex supplement; Drug: Placebo curcumin capsule

• Registration Number: NCT04109742
• Lead Sponsor: Columbia University

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.

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study First Submitted: 2019-09-23
• Study First Submitted QC: 2019-09-27
• Study First Posted: 2019-09-30
• Study Start: 2019-12-09
• Primary Completion: 2020-04-22
• Study Completion: 2020-04-22
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-21
• Last Update Posted: 2021-09-27

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Curcumin 1000mg capsules	phosphatidylcholine-curcumin complex supplement	Dose will be1g daily of phosphatidylcholine-curcumin complex supplement, orally for 24 weeks
Curcumin 500mg capsules	phosphatidylcholine-curcumin complex supplement	Dose will be 500mg daily phosphatidylcholine-curcumin complex supplement, orally for 24 weeks
Placebo curcumin capsules	Placebo curcumin capsule	Dose will be matching placebo capsules daily, orally for 24 weeks

Primary Outcome Measures

Name	Time	Method
Change in serum alanine aminotransferase (ALT) from baseline.	24 weeks	ALT value in U/L

Secondary Outcome Measures

Name	Time	Method
Relative change in ALT compared to baseline ALT	24 weeks	ALT value in U/L
Change in serum aspartate aminotransferase (AST)	24 weeks	AST value in U/L
Change in ALT at 12 weeks compared to baseline ALT	12 weeks	ALT value in U/L
Change in Waist circumference	24 weeks	centimeters (cm)
Change in serum gamma-glutamyl transpeptidase (GGT)	24 weeks	GGT value in U/L
Change in Weight	24 weeks	kilograms (kg)
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.
Proportion of patients achieving normalization of ALT	24 weeks	ALT value in U/L
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 High Sensitivity C-Reactive Protein (hsCRP) compared to baseline	24 weeks	serum marker of inflammation (mg/L)
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).
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
Change in serum lipids compared to baseline	24 weeks	lipid profiles