Transcript NASH CRN - Ennect Mail

Nonalcoholic Fatty Liver Disease
Stephanie H. Abrams, MD, MS
Assistant Professor of Pediatrics
Baylor College of Medicine
Medical Director-Kamp K’aana
[email protected]
NASH: a typical case

57 year old white female with elevated LFTs in
2008
 No symptoms; history of obesity, type 2
diabetes, hypertension, hyperlipidemia,
depression/anxiety
 Meds: metformin, olmesartan/HCTZ, thyroxine,
alprazolam, metoprolol, sertraline, clonidine,
vitamins
 SH: Occasional alcohol; nonsmoker
 PE: BMI 41 kg/m2
 Lab: ALT 77, AST 81, AP 179, T bili 0.3, gluc 199,
plts 168, INR 1.1
NASH: a typical case

Liver biopsy: NASH, NAS 4,
stage 2 with extensive
periportal fibrosis
Plan: weight loss, exercise
 Follow up at 6 months: "No
symptoms"; "working on wt
loss"
 PE: weight down 3 lbs/6 months

NASH: a typical case

Admitted after no follow up x 2 years







Increased abdominal girth, dyspnea, leg
edema
Wt up 60 lbs in 6 weeks
Minor MVA with confusion
Interim diagnosis: obstructive sleep apnea
PE: Ascites, 3+ leg edema, alert/oriented
Lab: ALT 55, AST 102, Alb 2.6, INR 1.7,
MELD 15, plts 149
CT: nodular liver, splenomegaly,
perisplenic varices, moderate ascites
NASH: a typical case

Abdominal CT:
NASH: a typical case

Summary:
Progression of NASH to cirrhosis
in setting of obesity, DM2, HTN
 Near normal liver enzymes

Prevalence of NAFLD in Adults

NAFLD was present in 46% of all subjects by ultrasound
(n=400)




74% of diabetics
Prevalence higher in men (58.9%)
Most common in Hispanics (58.3%), Caucasians (44.4%),
African Americans (35.1%)
NAFLD patients:
Were more likely to have HTN,
higher BMI, & DM
 Ate more fast food & exercised less


NASH present in 12.2% of all adults



Present in 22.2% of diabetics
Advanced fibrosis in 22.5%
30% of all of those with NAFLD
NASH: 12%
Williams CD, et al. Gastroenterology 2011; 140: 124-131
Prevalence of NAFLD in Children
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Fatty liver was present in 13% of all subjects
Prevalence higher in boys (11.1%) compared
with girls (7.9%)
Prevalence increases with age


17.3% for ages 15-19 years
NASH present in 3% of all children
Schwimmer, et al. Pediatrics 2006
Prevalence of Fatty Liver by
Race/Ethnicity
Percentage
15
10
5
0
Black
White
Asian
Hispanic
•Using a logistic regression model, the odds
ratio for the presence of fatty liver in Hispanics
was 5.0
Schwimmer, et al. Pediatrics 2006
NASH as an indication for transplant
*
*PN = Probable NASH based on risk factors
Brandman et al, AASLD 2011
Primary Diagnoses
for Patients
in 2006
NASH Accounted
for 10.3%
of all Transplanted
Liver Transplantation
at
the Cleveland Clinic in 2006
33.1%
12.8%
10.3%
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www.clevelandclinic.org
Pathogenesis: new ideas

“Two hit” vs lipotoxicity
Liver fat
metabolism:
Insulin
resistance
Diet,
uncontrolled
diabetes
Excess
peripheral
lipolysis
Excess
carbohydrates
Increased
circulating
fatty acids
De novo
lipogenesis
Hepatocellular
free fatty acids
Triglyceride
B Tetri
VLDL
(secreted)
“Two-hit”
hypothesis:
Insulin
resistance
Excess peripheral
lipolysis
Increased
circulating
fatty acids
Diet,
uncontrolled
diabetes
Excess
carbohydrates
De novo
lipogenesis
Hepatocellular
free fatty acids
SER (P450)
ω-oxidation
Peroxisomal
β-oxidation
2
ROS
Mitochondrial
β-oxidation
Triglyceride
1
NASH
B Tetri
Lipid
droplets
(steatosis)
VLDL
(secreted)
ROS = reactive oxygen species
Lipotoxicity
hypothesis:
Insulin
resistance
Excess
peripheral
lipolysis
Excess
carbohydrates
Increased
circulating
fatty acids
De novo
lipogenesis
Hepatocellular
free fatty acids
Lipotoxic
metabolites
•
•
•
•
B Tetri
SER (P450)
ω-oxidation
Peroxisomal
β-oxidation
Mitochondrial
β-oxidation
ER stress
Inflammation
Apoptosis
Necrosis
NASH
Diet,
uncontrolled
diabetes
Triglyceride
Lipid
droplets
(steatosis)
VLDL
(secreted)
Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010
Lipotoxicity
hypothesis:
• Ceramides
• Diacylglycerols
• Lysophosphatidyl choline
• Others
Insulin
resistance
Excess
peripheral
lipolysis
Excess
carbohydrates
Increased
circulating
fatty acids
De novo
lipogenesis
Hepatocellular
free fatty acids
Lipotoxic
metabolites
•
•
•
•
B Tetri
SER (P450)
ω-oxidation
Peroxisomal
β-oxidation
Mitochondrial
β-oxidation
ER stress
Inflammation
Apoptosis
Necrosis
NASH
Diet,
uncontrolled
diabetes
Triglyceride
Lipid
droplets
(steatosis)
VLDL
(secreted)
Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010
Treatment
of NASH
• Weight loss
• Exercise
• TZDs?
Insulin
resistance
Excess peripheral
lipolysis
Divert to muscle
• Exercise
Increased
circulating
fatty acids
•
•
•
Diminish toxicity
• Vitamin E?
ER stress
• Fish oil?
Inflammation • Ursodiol?
Apoptosis
Necrosis
NASH
B Tetri
Excess
carbohydrates
De novo
lipogenesis
Hepatocellular
free fatty acids
Lipotoxic
metabolites
•
Diet,
uncontrolled
diabetes
Lipid
droplets
(steatosis)
• Cut the carbs!
Divert to muscle
• Exercise
SER (P450)
ω-oxidation
Peroxisomal
β-oxidation
Mitochondrial
β-oxidation
Triglyceride
Facilitate storage/secretion
• Betaine?
VLDL
(secreted)
Neuschwander-Tetri BA. Hepatology, 52:774-788, 2010
NASH and the Metabolic
Syndrome
Bad diet
+
Obesity
+
Sedentary
+
Genetic
predisposition
IR
Excess
circulating
NEFA
Increased
liver triglyceride
Steatosis
β-oxidation
Lipotoxic
intermediates
in the liver
NEFA: nonesterified fatty acids, ie, free fatty acids
IR: insulin resistance
PCOS: polycystic ovary syndrome
NASH
NASH and the Metabolic Syndrome
Cancer
PCOS
Hyperinsulinemia β-cell
loss
Bad diet
+
Obesity
+
Sedentary
+
Genetic
predisposition
IR
Excess
circulating
NEFA
Reninangiotensin
activation
Vascular
disease
HTN
CAD/PVD
Hypertriglyceridemia
Hypercholesterolemia
Diabetes
Increased
liver triglyceride
Steatosis
β-oxidation
Lipotoxic
intermediates
in the liver
NASH
Sleep
apnea
NEFA: nonesterified fatty acids, ie, free fatty acids
IR: insulin resistance
PCOS: polycystic ovary syndrome
Treatment of NASH

Lifestyle modification remains the
primary treatment recommendation
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Bariatric surgery
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Neuschwander-Tetri, B. A. Lifestyle modification as the primary
treatment of NASH. Clinics in Liver Disease (2009) 13: 649-665
Harrison, S. A. and Day, C. P. Benefits of lifestyle modification in
NAFLD. Gut (2007) 56: 1760-1769.
Sullivan, S. Implications of diet on nonalcoholic fatty liver disease. Curr
Opin Gastroenterol (2010) 26: 160-164.
Pillai, A. A. and Rinella, M. E. Non-alcoholic fatty liver disease: is
bariatric surgery the answer? Clinics in Liver Disease (2009) 13: 689710.
Drugs
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Ratziu, V. and Zelber-Sagi, S. Pharmacologic therapy of non-alcoholic
steatohepatitis. Clinics in Liver Disease (2009) 13: 667-688.
Trial results
NASH CRN PIVENS trial


Pioglitazone vs Vitamin E vs
Placebo in adults
Excluded diabetics, cirrhotics
PIVENS Study Design
Randomization
Eligibility assessed by local pathologist
(1:1:1)
Wk 0
Month -6
Liver
biopsy
End of treatment
Liver Biopsy
Wk 96
Vitamin E (rrr α-tocopherol) 800 IU/day
Week
120
end of
study
placebo
Pioglitazone (30 mg/day)
N Engl J Med (2010) 362: 1675-1685
PIVENS
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Primary endpoint:

Decrease in NAS by 2 or more points, with

at least a 1 point drop in ballooning, and

no worsening of fibrosis
2 Primary comparisons:

Vitamin E vs placebo

Pioglitazone vs placebo
Significance set at p< 0.025
Secondary endpoints:

changes in individual histologic features

resolution of steatohepatitis

changes in anthropometrics, insulin resistance, quality of
life

adverse events
N Engl J Med (2010) 362: 1675-1685
Proportion of subjects (%)
Vitamin E alone met the pre-specified primary endpoint
50
40
P< 0.001
P< 0.04
36/84
NNT=4.4
26/80
NNT= 6.6
30
20
16/83
10
0
Vit E
placebo
treatment groups
Pio
proportion of subjects (%)
Both vitamin E and pioglitazone increased the proportion of
subjects with resolution of NASH
100
80
P< 0.0008
P< 0.01
60
40
44/84
40/80
23/83
20
0
Vitamin E
placebo
study groups
pioglitazone
Liver enzymes
-10
-20
-30
-40
Change (U/L)
0
ALT
0
24
48
72
96
Weeks
Placebo
Vitamin E
Pioglitazone
Change in body weight
0
2.5
-2.5
Change (kg)
5
WEIGHT
0
24
48
72
96
Weeks
Placebo
Vitamin E
Pioglitazone
Who should we treat with vitamin E?


Should we look for low vitamin E levels?
Does reduction in the ALT mean the patient is
responding?
Who should we treat with vitamin E?
• Responders didn’t
have low initial vitamin
E levels
Vit E treated
• The increase in
vitamin E did not
correlate with
response
• Non-compliance did
not explain nonresponse
Loomba et al, AASLD 2010
Who should we treat with vitamin E?
• Responders didn’t
have low initial vitamin
E levels
• The increase in
vitamin E did not
correlate with
response
Vit E treated
Placebo
• Non-compliance did
not explain nonresponse
Loomba et al, AASLD 2010
Who should we treat with vitamin E?
Non-responders
P = 0.005
Responders
• ALT dropped a bit
more in responders
than placebo
• ALT dropped in both
responders and nonresponders
Loomba et al, AASLD 2010
PIVENS trial summary

Vitamin E helped in about half the
patients
Non-cirrhotic, non-diabetic
 Natural vitamin E, 800 IU/day
 We don’t know why it works
 We can’t predict who will respond
or who is responding


Pioglitazone helped a bit less that
half the patients
NASH CRN TONIC trial
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
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Treatment of NAFLD in Children = TONIC
NASH Clinical Research Network study
Hypothesis: metformin and vitamin E are
superior to placebo for the treatment of
NAFLD
Lavine et al, JAMA (2011) 305: 1659
TONIC trial

Multicenter, double masked, double placebo,
randomized
Metformin 500 mg bid + vitamin E placebo
or
Vitamin E (natural form) 400 IU bid + metformin
placebo
or
Both placebos bid



Treatment duration: 2 years
A priori endpoint: change in ALT
Secondary endpoint: histology
Lavine et al, JAMA (2011) 305: 1659
ALT
TONIC: changes in primary
endpoint (ALT)
Metformin
Placebo
Vitamin E
Lavine et al, JAMA (2011) 305: 1659
ALT
TONIC: changes in primary
endpoint (ALT)
Metformin
No significant
differences
Placebo
Vitamin E
Lavine et al, JAMA (2011) 305: 1659
% with resolution
TONIC results: Liver biopsy
changes
Vitamin E increased resolution of NASH
(from initial definite or borderline NASH)
P = 0.006
N.S.
Lavine et al, JAMA (2011) 305: 1659
TONIC trial summary

Vitamin E helped about half the children
Primary endpoint of ALT change not met
(placebo improved)
 Biopsies did improve
 800 IU of natural vitamin E daily


Metformin did not help
Lavine et al, JAMA (2011) 305: 1659
Treatment of NASH 2011

Focus on preventing adipose IR and
associated systemic lipotoxicity


Doing this treats NASH and comorbidities
Lifestyle modification


Exercise: Goal of 30-45 minutes aerobic daily
Weight loss
gradual and sustained
 bariatric surgery an option


Healthy eating
portion control
 avoid sugar sweetened beverages
 no trans-fats

Treatment of NASH 2011

Drugs

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
Vitamin E?
Thiazolidinediones? (pioglitazone, rosiglitazone)
Statins?
Metformin-no benefit of improving hepatic insulin
sensitivity
Not effective: ursodiol, betaine
Benefit of controlling co-morbidities on NASH?


Recognize and treat obstructive sleep apnea
Treating hyperlipidemia, improving glycemic
control: no effect on liver
Future directions

Incretin mimetics?

Naturally occurring: GIP, GLP-1
 Made
by enteroendocrine L-cells
 Responsible for 70% of post-prandial
insulin secretion
 Delays gastric emptying, increases
satiety
 Peripheral effects?
Analogue: exenetide
 Inhibit breakdown by inhibiting

FXR agonist for NASH



FXR = “Farnesoid X receptor” = ligand
activated nuclear receptor
Bile acids are the major natural ligands
Increased bile acids  decreased synthesis,
increased export
FXR agonist for NASH
Cholesterol
Gut
BA
BA
BA
BA = Bile
acids
FXR agonist for NASH
Cholesterol
Gut
Exporters
(MDRs, BSEP)
TGR5
Bile acid receptor
BA + FXR
BA
BA
Hepatic and
peripheral
effects
FGF19
synthesis by
enterocytes
FXR
BA
BA = Bile acids
FGF=Fibroblast
growth factor
FXR =
Farnesoid X
Regulation of gene
expression by FXR
Neuschwander-Tetri, B. A. Curr Gastroenterol Rep (2012) 14: 55-62
FXR agonist for NASH
High affinity FXR ligand
Research options at SLU

NASH Clinical Research Network studies

NASH CRN treatment trials
 FLINT
(FXR Ligand in the Treatment of NASH)
 Enrolling now!

“Database” observational study, seeking:
 Ideally
patients suspected of having NAFLD but not
yet biopsied
 Can enroll with a biopsy < 3 months old
 Annual visits with free lab tests until 2014
[email protected]
Pathogenesis of NASH: A Two “Hit” Hypothesis
OBESITY
Dyslipidemia
Type 2 Diabetes
FFAs
Hyperinsulinemia
Insulin sensitivity
Leptin sensitivity
Adiponectin effect
FAT STORAGE
FIBROSIS
HSCs
activation
Festi, et al. Ob Rev. 2004; 5: 27- 42
TNFa
IKKb
Endotoxin
Leptin
LPO end products
TNFa
ATP
NF-kb
IL-6
1st Hit
FFAs
Lipid Peroxidation
ROS
Scavengers
Inflammation
Necrosis
Apoptosis
2nd Hit
Normal
Environment
Steatosis
Steatosis genes
Steatohepatitis
Oxidative Stress,
cytokine, &
endotoxin
related genes
Genes
Fibrosis
&
cirrhosis
Fibrosis genes
Day CP. Liver International 2006
Environmental Factors

Alcohol intake





Low is protective
Dietary factors
Low antioxidant
vitamins
 saturated fat





Obesity *
Food intake
Lack of exercise
Type II DM*
Small bowel
bacterial overgrowth
Sleep apnea
syndrome
*Have a genetic component
Wilfred de Alwis, NM & CP Day Seminars Liv ds. 2007
Hypothesis

Both pioglitazone and vitamin E are
superior to placebo for the treatment
of NASH.
NASH CRN
Specific Aim

To perform a prospective multicenter,
double-masked, double-placebo,
randomized clinical trial of
pioglitazone (30 mg/day) or vitamin E
(rrr α tocopherol 800 IU/day) versus
placebo
 pioglitazone provided by Takeda
under a CRADA
 vitamin E provided by Pharmavite
under a clinical trials agreement
NASH CRN
Inclusion and exclusion criteria

Inclusion criteria:



Alcohol consumption <
20 gm/day for women
and 30 gm/day for men
Biopsy proven
steatohepatitis within last
6 months
NAFLD activity score:


≥ 5 with definite or
probable steatohepatitis
=4 + definite
steatohepatitis agreed
by 2/3 pathologists

Exclusion criteria:





Diabetes mellitus
Cirrhosis
Prior bariatric surgery
Any drug therapy for
NASH between biopsy
and randomization
Presence of other liver
diseases
NASH CRN
Study Design
Randomization
Eligibility assessed by local pathologist
(1:1:1)
Wk 0
Month -6
Liver
biopsy
End of treatment
Liver Biopsy
Wk 96
Vitamin E (rrr α-tocopherol) 800 IU/day
Week 120
end of
study
placebo
Pioglitazone (30 mg/day)
NASH CRN
Plan of Analysis
(all histologic analyses on blinded central review of deeper cuts of baseline liver
biopsy & end of treatment biopsy)




Primary endpoint:
 Decrease in NAS by 2 or more points, with
 at least a 1 point drop in ballooning, and
 no worsening of fibrosis
2 Primary comparisons of proportion of subjects who met endpoint:
 Vitamin E vs placebo
 Pioglitazone vs placebo
Significance set at p< 0.025
Secondary endpoints:
 changes in individual histologic features
 resolution of steatohepatitis
 changes in anthropometrics, insulin resistance, quality of life
 adverse events
NASH CRN
Baseline Characteristics
Means or %s
Age (yrs)
Female (%)
Caucasian (%)
BMI (Kg/m2)
Waist circumference (cm)
AST (IU/L)
ALT (IU/L)
AP (IU/L)
Bilirubin (mg/dl)
Triglycerides (mg/dl)
IR (HOMA-IR)
Vitamin E
N= 83
Placebo
N= 84
Pioglitazone
N= 80
46.6
61
66
34
107
59
86
77
0.7
166
5.2
45.4
58
81
35
109
55
81
82
0.7
165
5.5
47
59
74
34
108
54
82
86
0.7
162
5.0
NASH CRN
Baseline histology
blinded central review of
deeper cuts of baseline liver biopsy
Vitamin E
Mean or %
Placebo
Mean or %
Pioglitazone
Mean or %
Steatosis grade
Inflammation grade
Ballooning grade
Fibrosis stage
NAFLD activity score (NAS)
1.9
1.8
1.3
1.5
5.1
1.9
1.6
1.3
1.6
4.8
2
1.8
1.1
1.4
5
% without ballooning on central
review of deeper cuts of
baseline biopsy
18
17
27
NASH CRN
Proportion of subjects (%)
Primary Outcome –Vitamin E alone
met the pre-specified primary endpoint
50
40
P< 0.001
P< 0.04
36/84
NNT=4.4
26/80
NNT= 6.6
30
20
16/83
10
0
Vit E
placebo
Pio
treatment groups
NASH CRN
Both Vitamin E and Pioglitazone improve steatosis
proportion of subjects (%)
worsened
improved
Improvement in severity of steatosis grade
Vit E vs placebo: p< 0.0001
Pio vs placebo: p< 0.0001
80
P< 0.001
P<0.0001
60
40
Δ grade
0.8
Δ grade
0.7
Δ grade
0.1
20
0
-20
Vit E
placebo
pioglitazone
-40
NASH CRN
proportion of subjects (%)
worsened
improved
Both Vitamin E and Pioglitazone improve
lobular inflammation
80
p< 0.01
p< 0.001
60
40
Δ grade
0.6
20
Δ grade
0.7
Δ grade
0.2
0
-20
Vit E
pioglitazone
placebo
-40
-60
Improvement in severity of inflammation:
Vitamin E vs placebo: p< 0.008
Pioglitazone vs placebo: p< 0.0009
NASH CRN
proportion of subjects (%)
worsened
improved
Both Vitamin E and Pioglitazone
improve the severity of ballooning and
the proportion of subjects whose
ballooning improves
80
60
40
P<0.02
Δ grade
0.5
20
-40
-60
Δ grade
0.4
Δ grade
0.2
0
-20
P<0.02
Vit E
pioglitazone
placebo
Improvement in severity (grade) of ballooning:
Vit E vs placebo: p< 0.01
Pioglitazone vs placebo: 0.03
NASH CRN
proportion of subjects (%)
Both vitamin E and pioglitazone
increased the proportion of subjects with
resolution of NASH
100
80
P< 0.0008
P< 0.01
60
40
44/84
20
40/80
23/83
0
Vitamin E
placebo
pioglitazone
study groups
NASH CRN
Mutually exclusive categorization of
reasons for not meeting primary outcome
Vit E
N=48/84
Placebo
N=67/83
Pio
N=53/80
No follow up biopsy
4
11
10
Worsening of fibrosis score
15
16
12
Failure to improve NAS ≥ 2
22
35
20
Failure to meet primary
outcome due to ballooning
score=0 at baseline
7
5
11
Categories
NASH CRN
proportion of subjects (%)
worsened
improved
Neither Vitamin E nor Pioglitazone improved
fibrosis scores or proportion of subjects with
improved fibrosis
60
40
20
n.s.
Δ grade
0.3
n.s.
Δ grade
0.1
Δ grade
0.4
0
-20
Vitamin E
placebo
pioglitazone
-40
-60
Improvement in severity of fibrosis scores:
Vit E vs placebo: p= 0.19 (n.s.)
Pioglitazone vs placebo: p=0.1 (n.s.)
NASH CRN
Liver enzymes
-10
-20
-30
-40
Change (U/L)
0
ALT
0
24
48
72
96
Weeks
Placebo
Vitamin E
Pioglitazone
NASH CRN
Insulin resistance
-1
0
1
HOMA-IR
0
48
96
Weeks
Placebo
Vitamin E
Pioglitazone
NASH CRN
Change in body weight
-2.5
0
2.5
5
WEIGHT
0
24
48
72
96
Weeks
Placebo
Vitamin E
Pioglitazone
NASH CRN
Adverse events
Adverse event
Vitamin E
Placebo
Pioglitazone
Total SAE
Drug-related SAE
Deaths
7
0
1
10
0
0
2
0
0
ALT > 500 IU/l
Bili > 3 mg/dl
0
1
0
0
0
2
CVD events
New onset T2DM
Bone fractures
Bone ΔT > -1
12
4
3
0
12
0
5
0
10
0
3
1
NASH CRN
Summary -1



Vitamin E (800 IU/day), but not pioglitazone
(30 mg/day), was superior to placebo for
histological improvement as defined in
the primary outcome measure
Both vitamin E and pioglitazone
significantly improved:
 Steatohepatitis
 Steatosis grade
 Inflammation grade
 NAFLD activity score
Neither drug improved fibrosis scores
significantly
NASH CRN
Summary -2


Pioglitazone improved insulin sensitivity, but
was associated with weight gain
There were no study drug related SAEs
NASH CRN
Conclusions




Vitamin E is superior to placebo for the
treatment of active NASH in nondiabetic adult
patients.
Pioglitazone did not meet the primary
outcome for histological improvement, but
significantly improved other key histological
features of NASH.
Neither drug improved fibrosis
Both agents were relatively safe over the 96
week study, although pioglitazone was
associated with weight gain
NASH CRN
Treatment Of Nonalcoholic
steatohepatitis In Children
(TONIC)
The NIDDK Clinical Research Network
(NASH CRN)
Hypothesis

Both metformin and vitamin E are superior to
placebo for the treatment of NAFLD
NASH CRN
Specific Aim

To perform a multicenter, double-masked,
double-placebo, randomized clinical trial of
metformin (500mg BID) or vitamin E (RRR-atocopherol 400 IU BID) versus placebo for
the treatment of NAFLD


Over-encapsulated generic metformin/placebo
Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Inclusion and exclusion criteria

Inclusion criteria:






Boys & girls 8-17yo
Biopsy proven NAFLD
within 6 mos
ALT>60 U/L at
randomization and 112mos prior
Able to swallow pills
Informed consent/assent
Complete screening in
112 days

Exclusion criteria:








Diabetes mellitus
Cirrhosis
Prior bariatric surgery
Significant alcohol
ALT>400
Presence of other liver
diseases
Pregnancy/nursing
Any drug tx for NASH in
the 3mos prior to
randomization
NASH CRN
Hypothesis

Both metformin and vitamin E are superior to
placebo for the treatment of NAFLD
NASH CRN
NASH CRN
Specific Aim

To perform a multicenter, double-masked,
double-placebo, randomized clinical trial of
metformin (500mg BID) or vitamin E (RRR-atocopherol 400 IU BID) versus placebo for
the treatment of NAFLD


Over-encapsulated generic metformin/placebo
Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Primary Outcome-neither treatment met
criterion for sustained ALT reduction
NASH CRN
Specific Aim

To perform a multicenter, double-masked,
double-placebo, randomized clinical trial of
metformin (500mg BID) or vitamin E (RRR-atocopherol 400 IU BID) versus placebo for
the treatment of NAFLD


Over-encapsulated generic metformin/placebo
Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Vitamin E increased resolution of NASH
(from initial definite or borderline NASH)
NASH CRN
Neither Vitamin E nor Metformin Improved Fibrosis Score

To perform a multicenter, double-masked,
double-placebo, randomized clinical trial of
metformin (500mg BID) or vitamin E (RRR-atocopherol 400 IU BID) versus placebo for
the treatment of NAFLD


Over-encapsulated generic metformin/placebo
Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Specific Aim

To perform a multicenter, double-masked,
double-placebo, randomized clinical trial of
metformin (500mg BID) or vitamin E (RRR-atocopherol 400 IU BID) versus placebo for
the treatment of NAFLD


Over-encapsulated generic metformin/placebo
Vitamin E/placebo provided by Pharmavite under
a Clinical Trials Agreement (CRADA)
NASH CRN
Final Conclusions




NAFLD is the most common chronic liver
disease in the world & threatens our organ
allocation system
Vitamin E, Pioglitazone, & Metformin do not
improve fibrosis in NAFLD
Vitamin E improves ballooning and NAS
scores in adults & children
Behavior modification & treatment of
underlying obesity is imperative
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Demographics & physical characteristics (n=39)
Parameters
Mean
Gender
25 females
14 males
Ethnicity
15 Whites
12 Hispanics
11 Blacks
1 Asian
Age (y)
11.9 ± 1.39*
Weight (kg)
88.8 ± 18.6
Height (cm)
159.8 ± 7.3
BMI (kg/m2)
34.6 ± 6.1
FFM (kg)
49.8 ± 9.3
FM (kg)
39.1 ± 13.0
FM (%)
43.2 ± 7.4
Wt z-score
2.65 ± 0.60
BMI z-score
2.38 ± 0.31
Wt percentile
98.8 ± 1.9
BMI percentile
98.9 ± 0.9
Changes in anthropometric & body composition post camp
3
FFM
(kg)
Post Camp - Pre Camp
2
1
0
Wt
(kg)
BMI
2
(kg/m )
Fat
(kg)
BMI
z-score
P<0.01
Fat
(%)
P<0.01
-1
-2
P<0.01
-3
-4
-5
-6
P<0.01
P<0.01
P<0.01
Changes in IWQOL scores post camp
Post Camp - Pre Camp
20
P<0.01
15
10
P<0.02
P<0.01
P<0.03
5
P=0.60
0
Physical
Comfort
-5
Body
Esteem
Social
Life
Family
Relations
Total
Score
Post Camp - Pre Camp
0.5
0.0
-0.5
-3.0
1.0
P=0.51
In
Pr ter
ob pe
le rso
m n
s al
In
ef
fe
ct
iv
en
es
s
An
he
do
ni
a
N
Se ega
lf tiv
Es e
te
em
To
ta
lS
co
re
N
M ega
oo ti
d ve
Changes in CDI scores post camp
P=0.77
P=0.07
-1.0
P<0.05
P=0.10
-1.5
-2.0
-2.5
P=0.94
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