Trial Outcomes & Findings for Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC) (NCT NCT00063635)

NCT ID: NCT00063635

Last Updated: 2012-09-27

Results Overview

The primary outcome was sustained reduction in ALT level, defined as 50% or less of the baseline level or 40 IU/L or less at each visit from 48 to 96 weeks of treatment.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 173 participants
• Primary outcome timeframe: baseline and 96 weeks
• Results posted on: 2012-09-27

Participant Flow

Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States.

Participant milestones

Measure	Metformin Metformin, 500 mg, twice daily	Vitamin E Vitamin E, 400 IU, twice daily	Placebo Matching placebo
Overall Study STARTED	57	58	58
Overall Study COMPLETED	51	50	49
Overall Study NOT COMPLETED	6	8	9

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC)

Baseline characteristics by cohort

Measure	Metformin n=57 Participants Metformin, 500 mg, twice daily	Vitamin E n=58 Participants Vitamin E, 400 IU, twice daily	Placebo n=58 Participants Matching placebo	Total n=173 Participants Total of all reporting groups
Age Continuous	13.1 years STANDARD_DEVIATION 2.4 • n=5 Participants	13.4 years STANDARD_DEVIATION 2.3 • n=7 Participants	12.9 years STANDARD_DEVIATION 2.6 • n=5 Participants	13.1 years STANDARD_DEVIATION 2.4 • n=4 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	11 Participants n=7 Participants	12 Participants n=5 Participants	33 Participants n=4 Participants
Sex: Female, Male Male	47 Participants n=5 Participants	47 Participants n=7 Participants	46 Participants n=5 Participants	140 Participants n=4 Participants
Region of Enrollment United States	57 participants n=5 Participants	58 participants n=7 Participants	58 participants n=5 Participants	173 participants n=4 Participants
NAFLD activity score	4.5 scores on a scale STANDARD_DEVIATION 1.2 • n=5 Participants	4.8 scores on a scale STANDARD_DEVIATION 1.6 • n=7 Participants	4.6 scores on a scale STANDARD_DEVIATION 1.3 • n=5 Participants	4.6 scores on a scale STANDARD_DEVIATION 1.4 • n=4 Participants

PRIMARY outcome

Timeframe: baseline and 96 weeks

Population: All enrolled patients were included in analysis of the primary outcome, sustained reduction in ALT level. Patients missing a 96-week ALT measurement were imputed as not achieving a sustained reduction.

The primary outcome was sustained reduction in ALT level, defined as 50% or less of the baseline level or 40 IU/L or less at each visit from 48 to 96 weeks of treatment.

Outcome measures

Measure	Metformin n=57 Participants Metformin, 500 mg, twice daily	Vitamin E n=58 Participants Vitamin E, 400 IU, twice daily	Placebo n=58 Participants Matching placebo
Number of Participants With Sustained Reduction in Alanine Aminotransferase (ALT) to Either 50% of Baseline Value or < 40 IU/L	9 participants Interval 7.0 to 28.0	15 participants Interval 15.0 to 39.0	10 participants Interval 9.0 to 29.0

SECONDARY outcome

Timeframe: baseline and 96 weeks

Outcome measures

Measure	Metformin n=51 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=49 Participants Matching placebo
Change in Serum Aspartate Aminotransferase (AST)	-21.5 IU/L Interval -34.6 to -8.4	-22.8 IU/L Interval -33.3 to -12.3	-20.4 IU/L Interval -32.7 to -8.0

SECONDARY outcome

Timeframe: baseline and 96 weeks

Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.

Histological activity was assessed using the NAFLD activity score on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure include steatosis (0-3), lobular inflammation (0-3), and hepatocellular ballooning (0-2).

Outcome measures

Measure	Metformin n=50 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=47 Participants Matching placebo
Change in Nonalcoholic Fatty Liver Disease (NAFLD) Score (Histologic Feature Scores Determined by Standardized Scoring of Liver Biopsies) From Baseline at 96 Weeks of Treatment	-1.1 units on a scale Interval -1.7 to -0.5	-1.8 units on a scale Interval -2.4 to -1.2	-0.7 units on a scale Interval -1.3 to -0.2

SECONDARY outcome

Timeframe: baseline and 96 weeks

Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.

Fibrosis is assessed on a scale of 0 to 4 with higher scores indicating more severe fibrosis. This secondary outcome measure is the number of participants that experienced a decrease in fibrosis score at 96 weeks compared to baseline, which indicates improvement in fibrosis.

Outcome measures

Measure	Metformin n=50 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=47 Participants Matching placebo
Number of Participants With Improvement in Liver Fibrosis Score	22 participants	18 participants	19 participants

SECONDARY outcome

Timeframe: baseline and 96 weeks

Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.

Steatosis is assessed on a scale of 0 to 3 with higher scores indicating more severe steatosis. This secondary outcome measure is the number of participants that experienced a decrease in steatosis score at 96 weeks compared to baseline, which indicates improvement in steatosis.

Outcome measures

Measure	Metformin n=50 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=47 Participants Matching placebo
Number of Participants With Improvement in Steatosis Score	26 participants	27 participants	19 participants

SECONDARY outcome

Timeframe: baseline and 96 weeks

Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.

Lobular inflammation is assessed on a scale of 0 to 3 with higher scores indicating more severe lobular inflammation. This secondary outcome measure is the number of participants that experienced a decrease in lobular inflammation score at 96 weeks compared to baseline, which indicates improvement in lobular inflammation.

Outcome measures

Measure	Metformin n=50 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=47 Participants Matching placebo
Number of Participants With Improvement in Lobular Inflammation Score	23 participants	22 participants	20 participants

SECONDARY outcome

Timeframe: baseline and 96 weeks

Population: Number of participants analyzed reflects the number of participants with baseline and 96 week liver biopsies.

Ballooning is assessed on a scale of 0 to 2 with higher scores indicating more severe ballooning. This secondary outcome measure is the number of participants that experienced a decrease in ballooning score at 96 weeks compared to baseline, which indicates improvement in ballooning.

Outcome measures

Measure	Metformin n=50 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=47 Participants Matching placebo
Number of Participants With Improvement in Ballooning Degradation Score	22 participants	22 participants	10 participants

SECONDARY outcome

Timeframe: baseline and 96 weeks

Outcome measures

Measure	Metformin n=51 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=49 Participants Matching placebo
Change in Body Mass Index	1.3 kg/m-squared Interval 0.6 to 2.0	2.1 kg/m-squared Interval 1.2 to 3.0	1.9 kg/m-squared Interval 1.1 to 2.7

SECONDARY outcome

Timeframe: baseline and 96 weeks

Change in alpha-Tocopherol

Outcome measures

Measure	Metformin n=51 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=49 Participants Matching placebo
Change in Serum Vitamin E Levels	-0.5 mg/L Interval -1.1 to 0.2	9.4 mg/L Interval 6.2 to 12.6	-0.9 mg/L Interval -2.1 to 0.4

SECONDARY outcome

Timeframe: baseline and 96 weeks

Change in self-reported QOL physical health Pediatric Quality of Life Inventory (version 4.0) scores were recorded to range from 0 to 100 with increasing scores indicating better quality of life.

Outcome measures

Measure	Metformin n=51 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=49 Participants Matching placebo
Change in Quality of Life (QOL) Scores- Physical Health	5.4 units on a scale Interval 0.8 to 10.0	7.6 units on a scale Interval 2.7 to 12.5	5.4 units on a scale Interval -0.7 to 11.5

SECONDARY outcome

Timeframe: baseline and 96 weeks

Change in self-reported QOL physical health Pediatric Quality of Life Inventory (version 4.0) scores were recorded to range from 0 to 100 with increasing scores indicating better quality of life.

Outcome measures

Measure	Metformin n=51 Participants Metformin, 500 mg, twice daily	Vitamin E n=50 Participants Vitamin E, 400 IU, twice daily	Placebo n=47 Participants Matching placebo
Change in QOL- Psychosocial Health	4.0 units on a scale Interval -0.4 to 8.4	6.0 units on a scale Interval 1.4 to 10.6	5.6 units on a scale Interval 0.0 to 11.2

Adverse Events

Metformin

Serious events: 7 serious events

Other events: 17 other events

Deaths: 0 deaths

Vitamin E

Serious events: 6 serious events

Other events: 17 other events

Deaths: 0 deaths

Placebo

Serious events: 14 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Measure	Metformin n=57 participants at risk Metformin, 500 mg, twice daily	Vitamin E n=58 participants at risk Vitamin E, 400 IU, twice daily	Placebo n=58 participants at risk Matching placebo
Respiratory, thoracic and mediastinal disorders Airway constriction/bronchospasm	0.00% 0/57	1.7% 1/58	1.7% 1/58
Gastrointestinal disorders Appendicitis	1.8% 1/57	0.00% 0/58	1.7% 1/58
Gastrointestinal disorders Cholecystitis	0.00% 0/57	0.00% 0/58	1.7% 1/58
General disorders Constipation	1.8% 1/57	0.00% 0/58	0.00% 0/58
Endocrine disorders Diabetes	0.00% 0/57	0.00% 0/58	1.7% 1/58
Endocrine disorders Elevated serum glucose	1.8% 1/57	1.7% 1/58	0.00% 0/58
Hepatobiliary disorders Hepatobiliary/pancreas	0.00% 0/57	0.00% 0/58	8.6% 5/58
Hepatobiliary disorders Hepatotoxicity	3.5% 2/57	1.7% 1/58	0.00% 0/58
General disorders Pain	1.8% 1/57	0.00% 0/58	1.7% 1/58
Cardiac disorders Syncope	0.00% 0/57	1.7% 1/58	1.7% 1/58
General disorders	0.00% 0/57	0.00% 0/58	1.7% 1/58
General disorders Depression	1.8% 1/57	1.7% 1/58	3.4% 2/58
General disorders Suicide	0.00% 0/57	1.7% 1/58	0.00% 0/58

Other adverse events

Measure	Metformin n=57 participants at risk Metformin, 500 mg, twice daily	Vitamin E n=58 participants at risk Vitamin E, 400 IU, twice daily	Placebo n=58 participants at risk Matching placebo
General disorders Unspecified- Mild	17.5% 10/57	17.2% 10/58	10.3% 6/58
General disorders Unspecified- Moderate	12.3% 7/57	12.1% 7/58	20.7% 12/58

Additional Information

Joel E. Lavine, MD, PhD

Columbia University Medical Center

Email: jl3553@columbia.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place