Conditions: Non-alcoholic Fatty Liver Disease (NAFLD) Non-alcoholic Steatohepatitis (NASH)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 93
Healthy volunteers: no

Brief summary:
Does the novel drug decrease liver fat in subjects with NASH or NAFLD as compared to placebo

Detailed description:
We propose to evaluate hepatic fat and hepatic fibrosis using magnetic resonance elastography (MRE) liver (pre vs. post). We will also establish glucose tolerance status by our established labeled oral glucose tolerance test (OGTT) (6,6 ²H2 glucose). Following baseline evaluation subjects with biopsy/MRE proven NASH will be randomized to one of two groups and treated either with active drug (AZ compound) or placebo for 12 weeks (plus or minus 1 week). Subjects with history suggestive of non-alcoholic fatty liver disease (NAFLD) or NASH will be invited to participate. If they meet criteria following initial screening they will be included in the study. OGTT, liver MRE will be repeated. Liver enzymes \[aspartate aminotransferase (AST), alanine aminotransferase (ALT),alkaline phosphatase (ALP)\] as well as other safety tests \[creatine phosphokinase (CPK), thyroid stimulating hormone (TSH), international normalized ratio (INR),total bilirubin\] will be measured before, monthly during therapy and at one month following therapy. Furthermore, we will also do the subgroup analysis in NASH/NAFLD subjects with and without diabetes to see the effect of the drug.

Arms:
arm 1: AZ compound 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg). arm 2: Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).

Interventions: intervention 1: AZ compound intervention 2: Placebo
Intervention descriptions: intervention 1: AZ compound 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg). intervention 2: Placebo 800 mg/day for 12 weeks (plus or minus 1 week) in two divided doses morning (400 mg) and evening (400 mg).

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Study Title: Does inhibition of liver specific 11β-
hydroxysteroid dehydrogenase type 1 enzyme 
lower liver fat in NAFLD or NASH? 
 
 
 
Version Date: 04-08-2019 
  
 
NCT Number: NCT02605616 
 
 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
1 
 
Title:  Does inhibition of liver specific 11β-hydroxysteroid dehydrogenase type 1 enzyme lower 
liver fat in NAFLD or NASH? 
 
Protocol Version date:  4-8-19 Edited by R.Basu,MD 
 
Dr Rita Basu (PI) has relocated to University of Virginia Health System (UVa). The study will be 
conducted at both Mayo Clinic and UVa.We have completed enrollment at Mayo Clinic and are 
currently enrolling at UVA only.  
 
Background and Rationale: 
11β-hydroxysteroid dehydrogenase type 1 enzyme pathway: 
Glucocorticoids are potent regulators of glucose, fat and protein metabolism. Tissue specific 
conversion of cortisone to cortisol via 11β-hydroxysteroid dehydrogenase type 1 enzyme pathway 
(11β-HSD-1) results in high local cortisol concentrations (1). 11β-HSD-1 is present in multiple tissues 
including the liver and adipose tissue with activity being greater in omental than subcutaneous fat (2-
5). The 11β-HSD-1 pathway has attracted considerable attention both as a therapeutic target and a 
potential contributor to the pathogenesis of diabetes, obesity and the so called “metabolic syndrome” 
(1; 6; 7). Our observation that the splanchnic bed of obese humans (8) produces large amounts of 
cortisol with all of it occurring within the liver strongly implies that the resultant high local cortisol 
concentrations within the liver could be important determinants of hepatic insulin action. If so, 
inhibitors of hepatic 11β-HSD-1 could have dramatic effects on hepatic insulin action and could 
become an important new therapy for type 2 diabetes. 
 
 
The role of high circulating intra-hepatic cortisol on modulation of insulin action in humans is an area 
of active investigation. Glucocorticoids induce glucose intolerance in humans in a dose and duration 
dependent manner (9-12) by inducing hepatic and extra hepatic insulin resistance (12-21). However, 
the exact mechanism of this effect was unknown. In vitro studies have reported that glucocorticoids 
increase11β-HSD-1 enzyme activity and mRNA expression in rat liver cells (3; 22). Our laboratory 
has developed a non-invasive technique to measure hepatic cortisone to cortisol conversion in 
humans (23). We have recently reported that liver cortisol production is higher in obese humans (8; 
23; 24) through increased activity of hepatic 11β-HSD-1 enzyme. We also have recently completed a 
series of experiments and concluded that glucocorticoid excess stimulates hepatic cortisone to 
cortisol conversion via 11β-HSD-1 enzyme pathway and is associated with hepatic and extrahepatic 
insulin resistance in nondiabetic humans (25 ; 26). This implies targeting hepatic 11β-HSD-1 enzyme 
could ameliorate steroid induced changes in lipid and glucose metabolism. 
 
That the liver is an important regulator of the diabetogenic effects induced by GC use is borne by the 
fact that liver selective GC receptor antagonists have been shown to reduce fasting glucose and 
improve hepatic insulin action during a hyperinsulinemic euglycemic clamp (27). A recent clinical trial 
has shown that 11-HSD inhibition for 12 weeks can reduce liver fat (~14%), and total body weight 
without any effects on insulin induced suppression of glucose production (28). However, to our 
knowledge liver specific inhibitors of 11-HSD have not been rigorously tested in the manner we 
currently propose. 
 
Hepatic fat: 
 
Under physiologic conditions, the liver is exposed to free fatty acids (FFA) derived from food and 
adipose tissue depots. These FFA are taken up by hepatocytes, where they undergo esterification to 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
2 
 
form triglycerides (TG) that are ultimately stored in vacuoles or released to the bloodstream as very-
low-density lipoproteins (VLDL). When equilibrium is disrupted, uptake and/or de novo synthesis of 
FFA is increased relative to fatty acid oxidation; if the rate of TG production is greater than that of 
VLDL synthesis and secretion, TGs accumulate in macrovacuoles within the hepatocyte (29) (termed 
hepatic steatosis). Clinically, hepatic steatosis is defined as macrovesicular fat accumulation in ≥ 5% 
of hepatocytes (30). NASH (non-alcoholic steatohepatitis) is an advanced form of fatty liver disease 
associated with inflammation and fibrosis. Liver enzymes (AST and ALT) are likely to be elevated in 
more than 90% of cases of NASH. In patients with NAFLD (non-alcoholic fatty liver disease), 
approximately 30% with isolated steatosis will progress to NASH. Of those with NASH, approximately 
20% will develop cirrhosis, and of those with cirrhosis, 30–40% will decompensate and succumb to 
liver-related death over a 10-year period (31).  
 
Currently, the favored technique for estimating the liver fat fraction (LFF) is quantitative magnetic 
resonance (MR) imaging (32). MR imaging in general ignores the multispectral nature of hepatic TG 
that can be used to distinguish between saturated fat, monounsaturated fatty acid (MUFA), and 
polyunsaturated fatty acid (PUFA). MR spectroscopy (MRS) of liver fat has been performed, and 
although it suffers from sampling error due to the small voxel size relative to liver size, the wealth of 
spectral information obtained can be used to determine the composition and quantity of hepatic fatty 
acids. Previous MRS studies of the liver (32-37) have used manual fitting techniques that are time 
intensive and operator biased (38-43). LC Model is a semi-automated, widely available MRS fitting 
program that can quantify up to 10 different fat resonances in the liver (38). We have developed a 
reliable, reproducible method for acquiring liver spectra on a 3T MRI scanner to calculate liver fat 
composition. This method was evaluated with 6 nondiabetic subjects scanned during 2 separate 
sessions, 10 days apart. In each session, 4 separate liver fat measurements were taken (8 
scans/subject). Spectra were preprocessed (phased, averaged) and then analyzed using LC Model 
software. Quantified spectral data were combined into 4 liver fat indices: total fatty acids (TFA), 
polyunsaturated fatty acid index (PUFAI), total unsaturated fatty acids (TUFA), and the standard fat 
water ratio (FWR), similar to the LFF. Calculations were performed to evaluate intraclass correlation 
coefficient (ICC) for each index and variability within the cohort (ie, intrascan, interscan, inter-session, 
intersubject). The FWR varied from 0.02 to 0.26, indicating a wide range of liver fat in this healthy 
cohort (normal was defined as FWR0.05).  Liver fat index ICCs for intrascan, interscan, and 
intersession reliability ranged from 0.92 (PUFAI interscan) to 0.99 (FWR intrascan and interscan), 
indicating that our method is highly reproducible. Variance components models (SAS PROC 
NESTED) showed that the majority of variance in the indices resulted from differences between 
subjects (FWR=98%, TFA=90%, TUFA=96%, PUFAI=89%). TFA had a small intersession variance 
(4%), whereas TFA and PUFAI had small scanner-related variance (6% and 9%, respectively). The 
remaining variance components were negligible (39). Mayo Clinic is implementing this scanning 
method for patients being evaluated for liver fat. We recently concluded a nutritional intervention trial 
in which this method was used to measure hepatic fat in subjects with IFG (impaired fasting glucose) 
(40; 41).  
 
Magnetic resonance elastography (MRE) is a non-invasive MRI based technique that measures 
tissue stiffness (42). The widely applied clinical MRE technique was developed at the Mayo Clinic and 
is available at more than 300 centers worldwide. MRE provides a new quantitative parameter "tissue 
stiffness" useful for tissue characterization and differentiation and found useful in the detection and 
staging of liver fibrosis with high technical success and excellent accuracy (43-47) . Liver stiffness is 
affected by the presence of inflammation and fibrosis. MRE by way of measuring elevated liver 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
3 
 
stiffness can differentiate nonalcoholic steatohepatitis  characterized by inflammation and or fibrosis 
from simple steatosis or just fatty liver. Chen et al (45) showed that MRE had excellent accuracy 
(AUROC 0.93, sensitivity 94%) for differentiating simple fatty liver from steatohepatitis. Two studies 
have shown that MRE has excellent accuracy (92-94%) for distinguishing advanced fibrosis and 
cirrhosis in NASH patients from those with lesser degree of fibrosis in patients with NASH study (48; 
49).  Preliminary clinical experience has shown that MRE is useful in assessing treatment response in 
cases that included patients with fibrosis (50). MRE is therefore a useful noninvasive technique for 
detection, staging and assessment of treatment response. Since moving to UVA we are now using a 
Siemens scanner instead of GE so data are slightly different. The Liver fat % is comparable but the 
fibrosis scores are not the same from each scanner. Hence, we are opting to study some people with 
liver fibrosis stage 0 up at UVA. 
 
Glucose tolerance: 
The most frequently described conditions associated with NAFLD are obesity and T2DM, with insulin 
resistance (IR) as the underlying key factor for development of nonalcoholic fatty livers. Cusi et al 
have conducted elegant studies in patients with NAFLD and have shown reduced insulin sensitivity 
(Si) (eg, in liver and muscle), regardless of glucose tolerance status (51). People with impaired fasting 
glucose (IFG; fasting glucose concentration, 100-125 mg/dL) or impaired glucose tolerance (IGT; 2-
hour glucose, 140-199 mg/dL after the standard 75-g oral glucose tolerance test [OGTT]) have a 25% 
to 30% chance of T2DM development within the next 5 to 10 years (52-55). Numerous studies (56-
58) have shown that IGT, either alone or in combination with IFG (IFG/IGT), is associated with 
defects in insulin secretion and action. We will phenotype the subjects to gain better understanding of 
their metabolic status. 
 
 
Approach: 
We propose to combine the triple tracer cortisol technique with voxel matched MRS and MRE liver 
(pre vs. post) to evaluate hepatic cortisol production and hepatic fat and hepatic fibrosis.  We will 
conduct baseline testing in subjects to estimate baseline hepatic cortisone to cortisol conversion. We 
will also establish glucose tolerance status by our established labeled OGTT (6,6 2H2 glucose). 
Following baseline evaluation subjects with NASH, NAFLD, will be randomized to one of two groups 
and treated either with active drug (liver specific 11-HSD type 1 inhibitor) or placebo for 12 weeks +/- 
1 week. OGTT, liver MRS, MRE and triple tracer cortisol study will be repeated. Liver enzymes (AST, 
ALT, ALP) as well as other safety tests (CPK,TSH,INR,T bilirubin) will be measured before, monthly 
during therapy and at one month following therapy. Details in the DSMP. 
 
Specific Aim: Determine if inhibition of hepatic 11-HSD type 1 activity lowers hepatic fat in 
subjects with NAFLD or NASH.  
 
I) Primary Hypotheses:  
 a)  AZD4017 decreases hepatic fat  as compared to placebo.  
 b)  AZD4017 decreases hepatic conversion of [13C] cortisone to [13C] cortisol as compared to 
placebo. 
 
II) Secondary Hypotheses: 
a) Liver enzymes (AST, ALT) will be reduced in subjects treated with AZD4017 as compared to 
placebo. 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
4 
 
b) Liver fibrosis measured with MRE will be reduced in subjects treated with AZD4017 as 
compared to placebo. 
c) Total insulin sensitivity (Si) and hepatic insulin sensitivity (Si liver) will be improved after 
treatment with AZD4017 than at baseline. 
d) Total insulin sensitivity (Si) and hepatic insulin sensitivity (Si liver) will be improved in subjects 
treated with AZD4017 as compared to placebo. 
 
Exploratory Aim (future plan): We wish to analyze biomarkers of fibrosis and 11 β HSD 
polymorphisms since polymorphisms in the 11β-HSD1 gene are also associated with components of 
the metabolic syndrome (59; 60). We wish to test if polymorphisms are likely associated with who 
may or may not respond to the 11 β HSD inhibitor.  
 
Biomarkers: NAFLD, NASH and Inflammation: NAFLD and NASH are increasing in incidence and 
prevalence in the United States and worldwide, in parallel with the increasing rates of obesity (61). 
Both disorders are characterized by the 
presence of hepatic steatosis. NASH is 
distinguished from NAFLD on the basis of 
liver injury and liver inflammation (62). One 
disease pathogenesis paradigm holds 
hepatocyte cell death via lipoapoptotic 
pathways as a central event in the onset of 
progressive forms of NASH; furthermore, 
hepatocyte apoptosis correlates with 
fibrosis stage in NASH patients (63; 64).  
There are many circulating surrogate 
markers for fibrosis in NASH. The enhanced liver fibrosis (ELF) score is a function of serum levels of 
hyaluronic acid (HA), tissue inhibitor of metalloproteinases-1 (TIMP-1), and procollagen III N-terminal 
peptide (PIIINP) is a validated tool for assessing serum fibrosis (65).  Other clinical surrogates include 
the AST/platelet ratio index (APRI) and age-spleen-platelet ratio index (ASPRI); however, the ELF 
test is unique in its incorporation of three molecules involved in the synthesis and breakdown of 
extracellular matrix. Newer serum based scores such as APRI ( AST to platelet ratio index), FIB-4 ( 
Age, ALT,AST, platelet count), NAFLD fibrosis score (age,ALT,AST,platelet count,BMI,albumin, 
impaired fasting glucose/diabetes) and BARD ( ALT/AST ratio,BMI,diabetes) score may be calculated 
using the data gathered. In this study we will be able to correlate MRE results with circulating levels of 
all proposed biomarkers.   
 
Subjects: Detailed information is provided in the DSMP. However, in brief, otherwise healthy (age 
21-75 years), subjects (BMI >19kg/m2) with NAFLD (MRS liver fat ≥ 5%, total bilirubin (TB) <1.5 
xULN, INR <1.3) will be enrolled following IRB approval. Subjects with previous biopsy proven and/or 
MRE proven NASH will be included. Subjects with history suggestive of NAFLD/NASH per recent 
guidelines published by Loomba et al (66) will be invited to participate. If they meet criteria following 
initial screening they will be included in the study if their MRE shows F0 or greater fibrosis. Glucose 
tolerance status will be determined by OGTT. We will include subjects with type 2 diabetes who are 
on stable doses of medications (except pioglitazone) to control hyperglycemia and have baseline 
HbA1c of 10% or lower. Subjects will be chosen from  UVa databases and will be contacted by phone 
or in writing and invited to participate in the study.. If subjects recently (within 3 months) had any of 
the exams, tests or procedures involved in this study conducted as part of their clinical care or as part 
Subjects 
with 
NAFLD 
and 
NASH
Lab tests, 
OGTT
MRS and 
MRE -Liver
Triple Tracer
Cortisol 
study
11 ß HSD-1 
Inhibitor
12 weeks
(n=40)
Placebo
12 weeks
(n=40)
Pre treatment
Post treatment
Randomization
Screening
Consent
Lab tests, 
OGTT
MRS and MRE-
Liver
Triple Tracer
Cortisol study
N=80
Schematic diagram of study outline 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
5 
 
of another study that are accessible they may not need to be repeated. It will be up to the study 
doctor to review and consider if previous findings are appropriate to use. Healthy will indicate that 
they generally are in good health and have no chronic medical condition including hepatic disease, 
stroke, Alzheimer’s disease, alcoholism or  increased alcohol consumption over the ADA guidelines 
or any disorder that may potentially impact the outcome measures. Thyroid medications, statins and 
antihypertensive medications that are metabolically neutral (e.g. low dose thiazides) will be permitted. 
At this time based on a prior human study done using a similar 11-βHSD1 inhibitor (Ref: Stefan et al, 
lancet, May 2014) suggests that usage of drugs potentially associated with non-alcoholic fatty liver 
disease (NAFLD) such as amiodarone, methotrexate, perhexiline, estrogens, tamoxifen, nifedipine, 
diltiazem, choloroquine and other hepatotoxic agents will need to be reviewed if used for more than 2 
consecutive weeks in the 2 years preceding the screen visit. Subjects taking TZD’s, Atazanavir, 
Indinavir, Ketoconazole, Valproic acid, Silybum marianum and Valeriana officinalis will be excluded. 
Additionally if subjects are taking drugs such Vit E, Ursodeoxycholic acid, Gemfibrozil, anti TNF 
therapies and probiotics will be allowed if on stable doses in the preceding 2 weeks and continued 
throughout the study. However as with all concomitant medication usage the study doctors will review 
on case by case basis prior to inclusion in trial. The final decision for enrollment will be based on the 
clinical judgement, discretion of the study doctors. 
Subjects that engage in vigorous physical exercise programs may be included. The level of exercise 
will be assessed by PI to determine if eligible to participate in study. Those actively losing weight will 
be excluded. Dietary advice will be provided by the research dietician to ensure that subjects maintain 
a constant body weight within 2% of their baseline during the trial period. Body composition may be 
measured during the screen visit in the body composition core using Lunar iDXA or similar machine 
at UVa to measure body composition. Mayo uses software version 6.10 (GE Healthcare 
Technologies, Madison, WI) to measure total body fat, and waist–hip measurements will be done to 
look at abdominal adiposity. Screen visit will also include blood and urine tests, height, weight, vital 
signs, ECG, a physical exam and review of their medical history. Hemoglobin must be greater than or 
equal to 12.0 in males and 11.0 in females. Subjects will report to UVa campus for screen visit and 
monthly outpatient visits. 
 
Study testing: Includes out-patient visits for iDXA (screen and 3 month), blood (screen/monthly) and 
urine tests (screen and 3 month), monthly prescription pick up visits, labeled OGTT (screen and 3 
month), MRS, MRE (screen and 3 month) and in-patient visits (see experimental design) to measure 
hepatic cortisone to cortisol conversion using our established triple tracer cortisol technique in 
subjects with NAFLD or NASH.  
 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
6 
 
Treatment: Subjects will be randomized to receive either AZD4017 800 mg/day for three months in 
two divided doses morning (400 mg) and evening (400 mg); matched placebo for three months. Pill 
counting will be done at monthly visits to monitor compliance and adherence to therapy. Unused pills 
will be returned and discarded by the research pharmacy. Both subjects and investigators will be 
masked to the type of treatment. We 
anticipate that 50 subjects in each of the 
two groups (with ~5 anticipated drop 
outs per group) will be sufficient to 
answer our primary hypotheses. 
Once enrolled in the study, subjects will 
be asked not to donate blood 12 weeks 
before and 12 weeks after the study. Per 
Institutional Review Board guidelines 
and blood bank the total amount of blood 
withdrawn in any 12 week period will not 
exceed 1 unit of blood (~550 ml) and this 
includes all screening bloods (~24 ml ), 
monthly safety bloods ( ~8 ml) , OGTT ( ~60 ml), Triple tracer cortisol study (~150 ml). 
 
Experimental design: 
MRS and MRE for liver fat and fibrosis will be done if not done previously following enrollment into 
study. For flexibility of scanning we will allow subjects to undergo MR scans at any time prior to the 
screening visit. A standard 75 gm labeled (6,6-2H2 glucose) OGTT will be performed over 240 mins to 
determine glucose tolerance status. OGTT: The labeled OGTT will enable us to concurrently measure 
various indices of insulin action, insulin secretion, and DI (composite measure of insulin secretion 
accounting for the prevailing level of IR). Furthermore, this protocol also allows measurement of EGP; 
this method was validated (41; 67-73) in various population cohorts in the US and Europe. OGTT will 
not be performed on subjects taking insulin for management of hyperglycemia. Subjects will be 
required to fast overnight and report to the CRTU at Mayo Clinic or  UVa campus on the morning of 
testing. Only sips of water will be allowed until testing is complete. An 18-gauge cannula will be 
inserted in a forearm for blood withdrawal. After baseline sampling (–15 and 0 minutes), a dextrose 
solution (Limeondex [Fisher]) will be consumed within a few minutes; this solution will contain 3 g of 
6,6- 2H2] glucose (~4% enrichment) in 72 g of dextrose. Blood samples will be withdrawn at 10, 20, 
30, 60, 90, 120, 150, 180, 210, and 240 minutes for measurement of glucose, insulin, C-peptide, 
glucagon, and [6,6- 2H2] glucose enrichment. At the end of the study, subjects will be provided a 
snack and dismissed.  
 
Cortisol study: 
Subjects will return on a different day for the in-patient visit.  Subjects will be admitted to the CRTU 
between 4 pm and 6 pm on the evening before the study and will be provided a standard supper 
(carbohydrate: protein: fat in the ratio of 50:20:30). consisting of ~33% of the subject’s total estimated 
calorie intake based on Harris Benedict + 20% calorie requirements. Urine pregnancy test will be 
done in women of child bearing potential. Subjects will be awakened the following morning and a 
catheter will be placed in a forearm vein for tracer infusion and in the dorsum of the opposite hand 
which will be placed in a heated box (~550C) to permit sampling of arterialized venous blood. A 
bladder catheter will be offered on the morning of study if subjects are unable to use a bedpan, urinal 
or bedside commode. A primed (24µCi) continuous (0.24 µCi/min) infusion of [1,2,6,7–3H] cortisol will 
 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
7 
 
be started at minus 120 minutes and blood will be collected for measurement of [3H] cortisol 
concentration at timed intervals in each subject to calculate basal production rate of cortisol. At time 
0, subjects will ingest 1.0 mg of [4-13C] cortisone and 1.0 mg of [9,12,12-2H3] cortisol. At time 0, the 
[3H] cortisol infusion rate will be increased in order to mimic the temporal pattern of change as 
previously published (23). Arterialized venous blood then will be sampled at periodic intervals 
(suggested timelines are -30,  0, 20, 40, 60, 75, 90, 120, 150, 180, 210, 240 minutes) for 
measurement of [2H] cortisol, [2H] cortisone, [13C] cortisone and [13C] cortisol enrichment, and [3H] 
cortisol [3H] cortisone specific activity (23). At UVa subjects will come in to CRU morning of study and 
all other interventions will be similar as outlined above. 
 
Analytical methods 
All blood samples will be immediately placed on ice, centrifuged at 40C, separated and stored at -
800C until analyses. Plasma glucose will be analyzed using YSI (yellow springs Ohio), plasma insulin 
will be measured using a chemiluminescence method with the Access Ultrasensitive 
Immunoenzymatic assay system (Beckman, Chaska, MN) and C-peptide and glucagon measured 
using a radioimmunoassay; Linco Research. Plasma [6,6-2H2] glucose enrichment will be measured 
using gas chromatographic mass spectrometry (74). Plasma cortisol, cortisone, D3 cortisol, D3 
cortisone, 13C cortisone and C13 cortisol enrichments will be measured using liquid chromatography 
tandem mass spectrometry as previously described (23; 75; 76). [3H] cortisol radioactivity will be 
measured using high performance liquid chromatography followed by liquid scintillation counting (23; 
77). Body composition will be measured using Lunar dual energy X-ray absorptiometry software (GE 
Healthcare Technologies). 
 
 
Calculations:  
[3H] cortisol will be used to trace the systemic rate of appearance of both [13C] cortisol and [2H] 
cortisol. Thus, the systemic rate of appearance (ug/min) of [13C] cortisol derived from the ingested 
[13C] cortisone will be calculated by using Steele’s steady state equation. Hepatic [13C] cortisol 
production will be calculated as the area under the curve for the rate of appearance of [13C] cortisol 
divided by one minus the hepatic extraction of [2H] cortisol (23; 78). Insulin sensitivity and secretion 
indices will be calculated using unlabeled and labeled models established by us previously (41; 61-
67) 
 
Statistical Analysis  
Demographics and baseline characteristics will be described by treatment group and the groups 
compared using two-sample t-tests.    
 
Primary analysis 
We will first compare the change in LFF from baseline (time 0) to post treatment (12 week) between 
the two treatment groups, one with patients treated with active drug and the other with patients 
treated with placebo, using analysis of covariance (ANCOVA) including baseline LFF as a covariate.  
This primary analysis will be based upon the intention to treat principle, including all patients 
randomized who have both baseline and post treatment measures of LFF.  
 
Next we will compare rates of hepatic conversion of [13C] cortisone to [13C] cortisol between the 
groups, again using ANCOVA, analogous to the analysis of LFF. 
 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
8 
 
Power for Primary Analysis 
A sample size of 45 in each group will have 80% power to detect a difference in means of 3.1 
assuming a mean square error (MSE) of 4.6 using an ANCOVA and a two-sided test with alpha 0.05.  
The MSE of 4.6 is estimated based upon the study of Stefan et al. (28) where an MSE of 4.6 and a 
difference in group means of 2.6 were observed.  We anticipate that as many as 5 patients could drop 
out of each treatment group and so will recruit additional patients to each treatment group for a total 
of 100 patients.  Based upon this our study is adequately sized to achieve our aims. We will now also 
include subjects with fibrosis score 0 up but with liver fat % >5 % as we believe data from these 
subjects will also be valuable and of interest in the final analyses. Since fibrosis scores are unlikely to 
change in the short duration of this trial and change in fibrosis is a secondary endpoint we believe this 
approach does not distract from our primary endpoint related to lowering of liver fat %.    
 
Secondary Analysis 
The data for the primary outcomes will be explored estimating treatment effects by sex.  These too 
will be tested in the ANCOVA, including interaction terms between treatment and sex.    
Outcomes related to secondary hypotheses will be analyzed analogously to the primary outcomes, 
using ANCOVA.      
 
 
 
Detailed human subjects protection plan/DSMP prepared as a separate document 
 
 
 
 
 
 
 
 
 
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with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids. Annals of the rheumatic 
diseases 2011;70:1887-1894 
12. Petersons CJ, Mangelsdorf BL, Jenkins AB, Poljak A, Smith MD, Greenfield JR, Thompson CH, Burt MG: 
Effects of low-dose prednisolone on hepatic and peripheral insulin sensitivity, insulin secretion, and abdominal 
adiposity in patients with inflammatory rheumatologic disease. Diabetes Care 2013;36:2822-2829 
13. Rizza R, Mandarino L, Gerich J: Cortisol-induced insulin resistance in man:  impaired suppression of 
glucose production and stimulation of glucose utilization due to a post-receptor defect of insulin action. 
J.Clin.Endocrinol.Metab. 1982;54:131-138 
14. van Raalte DH, Brands M, van der Zijl NJ, Muskiet MH, Pouwels PJ, Ackermans MT, Sauerwein HP, 
Serlie MJ, Diamant M: Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism 
in healthy humans: a randomised controlled trial. Diabetologia 2011;54:2103-2112 
15. Dirlewanger M, Schneiter PH, Paquot N, Jequier E, Rey V, Tappy L: Effects of glucocorticoids on hepatic 
sensitivity to insulin and glucagon in man. Clinical Nutrition 2000;19:29-34 
16. Nicod N, Giusti V, Besse C, Tappy L: Metabolic adaptations to dexamethasone-induced insulin resistance 
in healthy volunteers. Obesity Research 2003;11:625-631 
17. Larsson H, Ahren B: Short-term dexamethasone treatment increases plasma leptin independently of changes 
in insulin sensitivity in healthy women. Journal of Clinical Endocrinology and Metabolism 1996;81:4428-4432 
18. Hazlehurst JM, Gathercole LL, Nasiri M, Armstrong MJ, Borrows S, Yu J, Wagenmakers AJ, Stewart PM, 
Tomlinson JW: Glucocorticoids fail to cause insulin resistance in human subcutaneous adipose tissue in vivo. 
Journal of Clinical Endocrinology and Metabolism 2013;98:1631-1640 
19. Geer EB, Islam J, Buettner C: Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose 
tissue function and lipid metabolism. Endocrinology and Metabolism Clinics of North America 2014;43:75-102 
20. Zarkovic M, Beleslin B, Ciric J, Penezic Z, Stojkovic M, Trbojevic B, Drezgic M, Savic S: Glucocorticoid 
effect on insulin sensitivity: a time frame. Journal of Endocrinological Investigation 2008;31:238-242 
21. van Raalte DH, Diamant M: Steroid diabetes: from mechanism to treatment? Netherlands Journal of 
Medicine 2014;72:62-72 
22. Voice MW, Seckl JR, Edwards CRW, Chapman KE: 11β-hydroxysteroid dehydrogenase type 1 expression 
in 2S FAZA hepatoma cells is hormonally regulated:  a model system for the study of hepatic glucocorticoid 
metabolism. Biochem J 1996;317:621-625 
23. Dube S, Norby B, Pattan V, Lingineni RK, Singh RJ, Carter RE, Basu A, Basu R: Hepatic 11beta-
hydroxysteroid dehydrogenase type 1 activity in obesity and type 2 diabetes using a novel triple tracer cortisol 
technique. Diabetologia 2014 57:1446-1455 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
10 
 
24. Basu R, Singh RJ, Basu A, Chittilapilly EG, Johnson CM, Toffolo G, Cobelli C, Rizza RA: Obesity and 
type 2 diabetes do not alter splanchnic cortisol production in humans. J Clin Endocrinol Metab 2005;90:3919-
3926 
25. Dube S, Norby B, Basu A, Basu R: Differential regulation of 11B-Hydroxysteroid dehydronegase Type 1 
and 2 Enzyme Activities in Subcutaneous Adipose Tissue of Humans (abstract). Diabetes 2013;62 (Suppl 
1):A513 
26. Dube S, S. M, Basu A, Rizza R, Basu R: Glucocorticoid excess increases Hepatic 11 eta hydroxysteroid 
dehydrogenase-1 activity in Humans. (submitted); 
27. Zinker B, Mika A, Nguyen P, Wilcox D, Ohman L, von Geldern TW, Opgenorth T, Jacobson P: Liver-
selective glucocorticoid receptor antagonism decreases glucose production and increases glucose disposal, 
ameliorating insulin resistance. Metabolism: Clinical and Experimental 2007;56:380-387 
28. Stefan N, Ramsauer M, Jordan P, Nowotny B, Kantartzis K, Machann J, Hwang JH, Nowotny P, Kahl S, 
Harreiter J, Hornemann S, Sanyal AJ, Stewart PM, Pfeiffer AF, Kautzky-Willer A, Roden M, Haring HU, 
Furst-Recktenwald S: Inhibition of 11beta-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a 
multicentre, randomised, double-blind, placebo-controlled trial. The lancet. Diabetes & endocrinology 
2014;2:406-416 
29. Jou J, Choi SS, Diehl AM: Mechanisms of disease progression in nonalcoholic fatty liver disease. Seminars 
in liver disease 2008;28:370-379 
30. Torres DM, Williams CD, Harrison SA: Features, diagnosis, and treatment of nonalcoholic fatty liver 
disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American 
Gastroenterological Association 2012;10:837-858 
31. McCullough AJ: The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. 
Clinics in liver disease 2004;8:521-533, viii 
32. Reeder SB, Cruite I, Hamilton G, Sirlin CB: Quantitative assessment of liver fat with magnetic resonance 
imaging and spectroscopy. Journal of Magnetic Resonance Imaging 2011;34:729-749 
33. Cobbold JF, Patel JH, Goldin RD, North BV, Crossey MM, Fitzpatrick J, Wylezinska M, Thomas HC, Cox 
IJ, Taylor-Robinson SD: Hepatic lipid profiling in chronic hepatitis C: an in vitro and in vivo proton magnetic 
resonance spectroscopy study. Journal of hepatology 2010;52:16-24 
34. Johnson NA, Walton DW, Sachinwalla T, Thompson CH, Smith K, Ruell PA, Stannard SR, George J: 
Noninvasive assessment of hepatic lipid composition: Advancing understanding and management of fatty liver 
disorders. Hepatology 2008;47:1513-1523 
35. van Werven JR, Schreuder TC, Nederveen AJ, Lavini C, Jansen PL, Stoker J: Hepatic unsaturated fatty 
acids in patients with non-alcoholic fatty liver disease assessed by 3.0T MR spectroscopy. European journal of 
radiology 2010;75:e102-107 
36. Cowin GJ, Jonsson JR, Bauer JD, Ash S, Ali A, Osland EJ, Purdie DM, Clouston AD, Powell EE, Galloway 
GJ: Magnetic resonance imaging and spectroscopy for monitoring liver steatosis. Journal of magnetic resonance 
imaging : JMRI 2008;28:937-945 
37. Hamilton G, Yokoo T, Bydder M, Cruite I, Schroeder ME, Sirlin CB, Middleton MS: In vivo 
characterization of the liver fat (1)H MR spectrum. NMR in biomedicine 2011;24:784-790 
38. Provencher SW: Estimation of metabolite concentrations from localized in vivo proton NMR spectra. 
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society 
of Magnetic Resonance in Medicine 1993;30:672-679 
39. Port J, Errazuriz Cruzat I, Veettil S, Dube S, Carter RE, Basu A, Basu R: A Reliable and Reproducible MR 
Spectroscopic Method to Estimate Both Liver Fat Quantity and Composition Using LC Model (In submission).  
40. Errazuriz Cruzat I, Dalla Man C, Dube S, Cobelli C, Basu A, Port J, Basu R: Hepatic Fat is a Determinant 
of Hepatic Insulin Sensitivity in Prediabetes (abstract). Diabetes 2013;62 (Suppl 1):LB40 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
11 
 
41. Veettil S, Errazuriz Cruzat I, Visentin R, Dube S, Shonkwiler C, Norby B, Nayar S, Dalla Man C, Basu A, 
Cobelli C, Port J, Basu R: Effects of Nutritional Intervention on Hepatic Fat and Hepatic Insulin Sensitivity in 
Prediabetes (abstract). Diabetes 2014;63 (Suppl 1):A190 
42. Venkatesh SK, Yin M, Ehman RL: Magnetic resonance elastography of liver: technique, analysis, and 
clinical applications. Journal of magnetic resonance imaging : JMRI 2013;37:544-555 
43. Yin M, Woollard J, Wang X, Torres VE, Harris PC, Ward CJ, Glaser KJ, Manduca A, Ehman RL: 
Quantitative assessment of hepatic fibrosis in an animal model with magnetic resonance elastography. Magnetic 
resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of 
Magnetic Resonance in Medicine 2007;58:346-353 
44. Venkatesh SK, Wang G, Lim SG, Wee A: Magnetic resonance elastography for the detection and staging of 
liver fibrosis in chronic hepatitis B. European radiology 2014;24:70-78 
45. Chen J, Talwalkar JA, Yin M, Glaser KJ, Sanderson SO, Ehman RL: Early detection of nonalcoholic 
steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography. Radiology 
2011;259:749-756 
46. Ichikawa S, Motosugi U, Ichikawa T, Sano K, Morisaka H, Enomoto N, Matsuda M, Fujii H, Araki T: 
Magnetic resonance elastography for staging liver fibrosis in chronic hepatitis C. Magnetic resonance in 
medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine 
2012;11:291-297 
47. Huwart L, Sempoux C, Vicaut E, Salameh N, Annet L, Danse E, Peeters F, ter Beek LC, Rahier J, Sinkus R, 
Horsmans Y, Van Beers BE: Magnetic resonance elastography for the noninvasive staging of liver fibrosis. 
Gastroenterology 2008;135:32-40 
48. Kim D, Kim WR, Talwalkar JA, Kim HJ, Ehman RL: Advanced fibrosis in nonalcoholic fatty liver disease: 
noninvasive assessment with MR elastography. Radiology 2013;268:411-419 
49. Loomba R, Wolfson T, Ang B, Booker J, Behling C, Peterson M, Valasek M, Lin G, Brenner D, Gamst A, 
Ehman R, Sirlin C: Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic 
fatty liver disease: A prospective study. Hepatology 2014; 
50. Venkatesh SK, Yin M, Ehman RL: Magnetic resonance elastography of liver: clinical applications. Journal 
of computer assisted tomography 2013;37:887-896 
51. Ortiz-Lopez C, Lomonaco R, Orsak B, Finch J, Chang Z, Kochunov VG, Hardies J, Cusi K: Prevalence of 
prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). 
Diabetes care 2012;35:873-878 
52. Dinneen SF, Maldonado D, III, Leibson CL, Klee GG, Li H, Melton LJ, III, Rizza RA: Effects of changing 
diagnostic criteria on the risk of developing diabetes. Diabetes Care 1998;21:1408-1413 
53. Meigs JB, Muller DC, Nathan DM, Blake DR, Andres R: The natural history of progression from normal 
glucose tolerance to type 2 diabetes in the Baltimore longitudinal study of aging. Diabetes 2003;52:1475-1484 
54. Saad MF, Knowler WC, Pettitt DJ, Nelson FG, Mott DM, Bennett PH: The natural history of impaired 
glucose tolerance in the Pima Indians. N Engl J Med 1988;319:1500-1506 
55. de Vegt F, Dekker JM, Jager A, Hienkens E, Kostense PJ, Stehouwer CDA, Nijpels G, Bouter LM, Heine 
RJ: Relation of impaired fasting and postload glucose with incident type 2 diabetes in a Dutch population: the 
Hoorn Study. JAMA 2001;285:2109-2113 
56. Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA: Insulin secretion and action in 
subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration 
Genetic Epidemiology Study. Diabetes 2006;55:1430-1435 
57. Festa A, D'Agostino R, Jr., Hanley AJG, Karter AJ, Saad MF, Haffner SM: Differences in insulin resistance 
in nondiabetic subjects with isolated impaired glucose tolerance or isolated impaired fasting glucose. Diabetes 
2004;53:1549-1555 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
12 
 
58. Meyer C, Pimenta W, Woerle HJ, Van Haeften T, Szoke E, Mitrakou A, Gerich J: Different mechanisms for 
impaired fasting glucose and impaired postprandial glucose tolerance in humans. Diabetes Care 2006;29:1909-
1914 
59. Gelernter-Yaniv L, Feng N, Sebring NG, Hochberg Z, Yanovski JA: Associations between a polymorphism 
in the 11 beta hydroxysteroid dehydrogenase type I gene and body composition. International journal of obesity 
and related metabolic disorders : journal of the International Association for the Study of Obesity 2003;27:983-
986 
60. Nair S, Lee YH, Lindsay RS, Walker BR, Tataranni PA, Bogardus C, Baier LJ, Permana PA: 11beta-
Hydroxysteroid dehydrogenase Type 1: genetic polymorphisms are associated with Type 2 diabetes in Pima 
Indians independently of obesity and expression in adipocyte and muscle. Diabetologia 2004;47:1088-1095 
61. de Alwis NMW, Day CP: Non-alcoholic fatty liver disease: The mist gradually clears. Journal of 
Hepatology 2008;48, Supplement 1:S104-S112 
62. Argo CK, Northup PG, Al-Osaimi AMS, Caldwell SH: Systematic review of risk factors for fibrosis 
progression in non-alcoholic steatohepatitis. Journal of Hepatology 2009;51:371-379 
63. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ: Hepatocyte apoptosis and 
fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003;125:437-
443 
64. Feldstein AE, Alkhouri N, De Vito R, Alisi A, Lopez R, Nobili V: Serum cytokeratin-18 fragment levels are 
useful biomarkers for nonalcoholic steatohepatitis in children. The American journal of gastroenterology 
2013;108:1526-1531 
65. Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, Hubscher S, Roskams T, Pinzani M, 
Arthur MJ: Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 
2004;127:1704-1713 
66. Bazick J, Donithan M, Neuschwander-Tetri BA, Kleiner D, Brunt EM, Wilson L, Doo E, Lavine J, Tonascia 
J, Loomba R: Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: 
Guidelines for Referral in NAFLD. Diabetes Care 2015;38:1347-1355 
67. Dalla Man C, Campioni M, Polonsky KS, Basu R, Rizza RA, Toffolo G, Cobelli C: Two-hour seven-sample 
oral glucose tolerance test and meal protocol: minimal model assessment of -cell responsivity and insulin 
sensitivity in nondiabetic individuals. Diabetes 2005;54:3265-3273 
68. Dalla Man C, Caumo A, Basu R, Rizza RA, Toffolo G, Cobelli C: Minimal model estimation of glucose 
absorption and insulin sensitivity from oral test: validation with a tracer method. Am J Physiol Endocrinol 
Metab 2004;287:E637-E643 
69. Dalla Man C, Caumo A, Basu R, Rizza RA, Toffolo G, Cobelli C: Measurement of selective effect of 
insulin on glucose disposal from labeled glucose oral test minimal model. Am J Physiol Endocrinol Metab 
2005;289:E909-E914 
70. Dalla Man C, Yarasheski KE, Caumo A, Robertson H, Toffolo G, Polonsky KS, Cobelli C: Insulin 
sensitivity by oral glucose minimal models: validation against clamp. Am J Physiol Endocrinol Metab 
2005;289:E954-E959 
71. Cobelli C, Toffolo GM, Dalla Man C, Campioni M, Denti P, Caumo A, Butler P, Rizza R: Assessment of -
cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and 
oral glucose test. Am J Physiol Endocrinol Metab 2007;293:E1-E15 
72. Bock G, Dalla Man C, Campioni M, Chittilapilly E, Basu R, Toffolo G, Cobelli C, Rizza R: Effects of non-
glucose nutrients on insulin secretion and action in people with prediabetes. Diabetes 2007;56:1113-1119 
73. Cobelli C, Dalla Man C, Toffolo G, Basu R, Vella A, Rizza R: The oral minimal model method. Diabetes 
2014;63:1203-1213 
74. Basu R, Barosa C, Basu A, Pattan V, Saad A, Jones J, Rizza R: Transaldolase exchange and its effects on 
measurements of gluconeogenesis in humans. Am J Physiol Endocrinol Metab 2011;300:E296-303 


PI: R.Basu, 11 Beta HSD inhibitor in NAFLD or NASH 
 
13 
 
75. Taylor RL, Machacek D, Singh RJ: Validation of a high-throughput liquid chromatography-tandem mass 
spectrometry method for urinary cortisol and cortisone. Clin Chem 2003;48:1511 
76. Basu R, Singh RJ, Basu A, Chittilapilly EG, Johnson CM, Toffolo G, Cobelli C, Rizza RA: Splanchnic 
cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11- 
hydroxysteroid dehydrogenase (11- HSD) type 1 pathway. Diabetes 2004;53:2051-2059 
77. Basu A, Basu R, Shah P, Vella A, Johnson CM, Nair KS, Jensen MD, Schwenk WF, Rizza RA: Effects of 
type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism:  
evidence for a defect in hepatic glucokinase activity. Diabetes 2000;49:272-283 
78. Dube S, Errazuriz Cruzat I, Norby B, Shonkwiler C, Basu A, Basu R: Differential Regulation of 
Glucocorticoids and Insulin on Hepatic 11 beta-Hydroxysteroid Dehydrogenase Type 1 Enzyme Activity. 
Diabetes 2014;63 (Suppl 1):A483 
 
 

ICF_001.pdf: 
  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 0 of 17  
  
  
 
Study Title: Does inhibition of liver specific 
11β-hydroxysteroid dehydrogenase type 1 
enzyme lower liver fat in NAFLD or NASH? 
IRB Approval Date: 05-09-2019 
  
 
NCT Number: NCT02605616 
 
 
 


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 1 of 17  
  
  
  
  
RESEARCH PARTICIPANT CONSENT AND PRIVACY  
AUTHORIZATION FORM  
  
Participant’s Name: _________________Medical Record #: ___________________  
  
  
  
Study Title: Does inhibition of liver specific 11β-hydroxysteroid dehydrogenase type 1 enzyme 
lower liver fat in NAFLD or NASH?  
  
Mayo IRB#:   
     15-000013  
UVA IRB Tracking#:    20155  
  
Principal Investigator: Dr. Rita Basu and Colleagues  
  
Please read this information carefully. It tells you important things about this research study. A 
member of our research team will talk to you about taking part in this research study.  If you 
have questions at any time, please ask us.  
  
Take your time to decide.  Feel free to discuss the study with your family, friends, and healthcare 
provider before you make your decision.    
  
To help you decide if you want to take part in this study, you should know:  
• 
Taking part in this study is completely voluntary.   
• 
You can choose not to participate.   
• 
You are free to change your mind at any time if you choose to participate.    
• 
Your decision won’t cause any penalties or loss of benefits to which you’re otherwise 
entitled.  
• 
Your decision won’t change the access to medical care you get at the University of 
Virginia now or in the future if you choose not to participate or discontinue your 
participation.    
  
  


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 2 of 17  
  
  
If you decide to take part in this research study, you will sign this consent form to show that you 
want to take part. We will give you a copy of this form to keep. A copy of this form will be put 
in your medical record.  
  
  
  
  
  
You can contact:  
At:  
If you have questions about:  
Principal Investigator:  
Dr. Rita Basu  
  
Study Team Contact:  
Safia Sawleh  
  
Phone:  
(434) 924-5183  
  
Phone:  
(434) 243-2855  
(434) 924-3512  
  
Address:  
Department of Medicine-Division 
of Endocrinology  
University of Virginia Health  
System  
P.O. Box 801406  
Charlottesville, VA 22908  
  
  
 Study tests and procedures  
 Research-related injuries or 
emergencies  
 Any research-related concerns or 
complaints  
 Withdrawing from the research study  
 Materials you receive  
 Research-related appointments  
Mayo Clinic  
Institutional Review  
Board (IRB)  
Phone:  
(507) 266-4000  
  
Toll-Free:  
(866) 273-4681  
  
 Rights of a research participant  
  
UVA Research 
Compliance Manager  
Phone:   
(434) 924-8660  
  
Address:  
P.O. Box 801011   
Charlottesville, VA 22908  
 Rights of a research participant  
  


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 3 of 17  
  
  
  
  
Other Information:   
  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Website will not include information that can identify you. At most, the 
Website will include a summary of the results. You can search this Website at any time.  
  
 
  
1. 
Why are you being asked to take part in this research study?  
  
 
  
You are being asked to take part in this research study because you have biopsy/MRE proven 
nonalcoholic steatohepatitis (NASH) or you have been diagnosed with nonalcoholic fatty liver 
disease (NAFLD). The plan is to have up to 100 people age 21 to 75 participate in this study.  
  
 
  
2. 
Why is this research study being done?  
  
 
  
The purpose of this study is to determine if the drug AZD4017 reduces liver fat and liver fibrosis 
in people with NASH as compared to placebo. AZD4017 is still experimental and isn’t approved 
by the U.S. Food and Drug Administration (FDA). However, the FDA has allowed the use of this 
drug in this research study. In this study, we want to compare the effects, good and/or bad, of 
AZD4017 for your condition. In this study, you will get either the AZD4017 or the placebo. You 
won’t get both.   
  
 


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 4 of 17  
  
  
  
3. 
Information you should know  
  
 
  
Who is Funding the Study?  
  
Astra-Zeneca is funding the study.  Astra-Zeneca will pay the Principal Investigator or the 
institution to cover costs related to running the study.  
  
 
  
4. 
How long will you be in this research study?  
  
 
  
It will take you about 5 months to complete this research study.  During this time, we will ask 
you to make up to 10 study visits to UVA. These visits include up to 8 outpatient visits at  
Fontaine Research Park and 2 all day visits beginning at 5 am in the Clinical Research Unit 
(CRU) at the University of Virginia Health System. You will be in the study until the study visits 
are completed. If due to unforeseen issues (e.g. staffing or weather) it is difficult to arrive early 
for the long days, then you would stay in a hotel we provide for early arrival for the study visit.    
  
 
  
5. 
What will happen to you while you are in this research study?  
  
 
  
If you agree to be in this study, you will be asked to participate in the following:  
  
The Screening Visit will take about 3 to 6 hours. During this visit, we will do some tests and 
procedures to see if you are eligible to take part in this research study. If you recently had any of 
the exams, tests or procedures involved in this study conducted as part of your clinical care or as 
part of another study that are accessible, they may not need to be repeated. It will be up to your 
study doctor to review and consider if previous findings are appropriate to use. If you aren’t 
eligible, the Principal Investigator will tell you why. At this visit we will:   
  


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 5 of 17  
  
  
• 
Ask you about your medical history.   
• 
Give you a physical exam, including height, weight, and “vital signs” (blood pressure, 
temperature, heart, and breathing rates)   
• 
Electrocardiogram.  
• 
Draw blood samples.   
• 
Ask you for urine sample.   
• 
Measure your waist to hip ratio.  
• 
Measure your body fat with a machine called a DEXA scanner. This machine uses a 
small amount of radiation to determine the amount of fat and muscle in the body. During 
this test you will be asked to lie flat on a special table and the scanner will pass over your 
body. This will take about 15 minutes.   This study will take place in Memorial Gym and 
you will need to go to a different building for this study. This test may be omitted if you 
are unable to travel to the memorial gym area.   
• 
If you are a woman who can become pregnant, a urine pregnancy test will be done. You 
will not be able to participate in the in-patient study if you are pregnant. Magnetic 
Resonance Spectroscopy (MRS), Magnetic Resonance Elastography (MRE) 
questionnaire- a screening procedure for any contraindications. Contraindications are the 
usual for Magnetic Resonance Imaging (MRI): no pacemaker or automated internal 
coronary defibrillator (AICD), cochlear implants, cerebral aneurysm clips, any metallic 
pumps or indwelling catheters need to be checked, any history of metallic foreign bodies 
also needs to be checked.    MRE/MRS are non-invasive MRI scan techniques. This scan 
will take about 30-45 minutes to complete. MRE scan measures liver tissue stiffness; 
MRS measures the amount and type of fatty acids present in the liver.  
• 
Oral Glucose Tolerance Test (OGTT). This test may be done as an outpatient visit on a 
separate day if you have time constraints. This test will not be done if you have diabetes 
and are taking insulin. You will be asked to fast overnight prior to the test.  You will have 
a plastic needle placed in a vein in one of your hands or forearm to draw blood. A saline  
(salt water) solution will be running to keep the vein from clotting. You will have a small 
amount of blood drawn over ~ 4 hour period after drinking Trutol 75 (a sugar solution) 
containing small amount of stable glucose tracer.   
  
At the end of the study, you will be provided a snack and then may go home.    
  
Participants that engage in active sports or those actively losing weight will be excluded from 
this study. Dietary advice will be provided by the research dietician so you will maintain your 
body weight (within ~2 % of your weight at the start of the study) during this study. They will 
also question you about your dietary preferences for the evening meal and the study meal that 
you will eat during your study visit.  


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 6 of 17  
  
  
  
Study Visit 1:  
The evening prior to the study day, you will eat a weighed-controlled evening meal and then will 
not eat again, except for water, until the end of the study the next day. The study team will 
contact you with instructions to follow.    
  
The following morning, you will be asked to arrive at the CRU at the University of Virginia, at 
about 5 a.m.  If you are a female of childbearing potential, you will have a pregnancy test on 
arrival and if the pregnancy test is negative, you will be able to proceed with the study.   
  
A plastic needle (intravenous line) will be placed in a vein in one of your hands. This line will be 
used to draw blood, and your hand will then be kept in a “hot box”. The “hot box” is a large 
plastic box that blows warm air over your hand. The temperature will not be greater than 131 
degree F or 55 degree C. This may cause some mild discomfort and is intended to make blood 
flow through the skin and make drawing of blood easier. It will cause some reddening of your 
skin. This will go away when your hand is taken out of the “hot box”. Your hand will remain in 
this “hot box” throughout the duration of the study. Another plastic needle will be placed in a 
vein in your other arm for infusions.  
  
If you are unable to use a bedpan, urinal, or bedside commode, we will offer a urinary catheter as 
an alternative (this will be removed at the end of the study).   
  
You may then receive a small amount of radioactive trace substance of cortisol through your 
veins that will continue until the end of the study visit.   
  
Later in the morning, you will be given a small amount of stable tracer of cortisone and a stable 
tracer of cortisol by mouth.  
  
Blood samples will be drawn at various times throughout the study. The total amount of blood 
withdrawn in any 12 week period will not exceed one pint (~550 ml).  
  
In the afternoon, at the end of the study, both intravenous lines and the urinary catheter (if 
placed) will be removed.   
  
We will assign you by chance (like a coin toss) to either the AZD4017 drug group or the Placebo 
group.  You and the Principal Investigator can’t choose your study group.  You will have a 1 in 2 
chance of being assigned to the AZD4017 group. You will take either AZD4017 or placebo 400 
mg tablets twice a day for 12 weeks. You will be given a one month supply of either AZD4017 
or placebo.   


  
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Neither you nor the Principal Investigator will know which study treatment group you are in. In 
case of an emergency, this information will be available.  
  
This study uses a placebo. A placebo looks exactly like the study drug, but it contains no active 
ingredient. We use placebos in research studies to learn if the effects seen in research participants 
are truly from the study drug.  
  
You will be given a meal and dismissed from the CRU.   
  
Month 1: One month after inpatient study visit 1, you will report to the CRU for a study blood 
test and to pick up your next month supply of study medication. You will bring your pill bottle 
provided for the study medication with you. We will count the number of pills in the bottle and 
any pills left in the bottle will be returned to the research pharmacy and destroyed.   
  
Month 2: You will report to the CRU for a study blood test and to pick up your next month 
supply of study medication. You will bring your pill bottle provided for the study medication 
with you. We will count the number of pills in the bottle and any pills left in the bottle will be 
returned to the research pharmacy and destroyed.  
  
Month 3: Study Visit 2 will be 2 days: This visit will be exactly the same as visit 1.  The next 
day, you will repeat the screening blood tests, the OGTT, DEXA scan and the MRE/MRS. You 
will bring your pill bottle provided for the study medication with you. We will count the number 
of pills in the bottle and any pills left in the bottle will be returned to the research pharmacy and 
destroyed. The OGTT and the MRE/MRS will be scheduled as outpatient visits.  
  
Month 4: You will report to the CRU, or for your final study blood test.  
  
Once enrolled in the study, please do not donate blood during the study and for 12 weeks after 
the study.  
  
  
6.  
What are the possible risks or discomforts from being in this  research 
study?  
  
 
  


  
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May 9, 2019  
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The total amount of blood withdrawn during the entire study will be about one pint (~550 ml).  
Hemoglobin must be greater than or equal to 12.0 g in males and greater than or equal to 11.0 g 
in females to ensure that drawing this amount of blood will be safe.  
  
You will be exposed to radiation from one of the infusions and the DEXA scan in this research 
study. The amount of radiation you will receive has a low risk of harmful effects.   
  
Catheter insertion, intravenous infusion, and blood withdrawal are associated with a small risk of 
pain, bruising, and infection. This will be minimized by careful attention to sterile technique. If 
infection occurs, it will be treated conservatively with heat and when appropriate with 
antibiotics.  
  
During the electrocardiogram, we will need to attach sticky patches to your chest; chest hair may 
need to be shaved prior to the placement of the sticky pads. These tests could uncover a 
condition you did not know you had.  This can be stressful.  We will fully explain any results that 
are not normal.  
  
A urinary catheter may be placed in your bladder. This could cause irritation, bleeding, and/or 
painful spasm of the bladder and rarely infection. You will be observed and treated appropriately 
if any of this occurs.  
  
There is no radiation associated with MRE/MRS, but people who have metal devices like 
pacemakers cannot have a MRE/MRS and will not be able to participate in the study. Some 
people with claustrophobia may feel too closed in and may not tolerate MRE/MRS scanning. If 
you feel too confined in the scanner, you can inform the technologist and the scan will be 
stopped.  The MRE/MRS machine makes loud knocking sounds when it is scanning.  Because of 
this you will be asked to wear earplugs while getting your scan. The earplugs minimize 
discomfort from noise and keep the MRE/MRS noise within the safety range.  
  
Birth Control Requirements for Female Participants:  
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below in addition to using a condom (except in case of abstinence) for the 
duration of the study and for 3 weeks after the final dose of the study drug:  
• 
Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or 
implants  
• 
Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, 
cream, or gel that kills sperm)  
• 
Intrauterine device (IUD)  


  
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May 9, 2019  
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• 
Abstinence (no sex)  
• 
Bilateral tubal occlusion  
• 
Vasectomized partner  
  
You must use birth control for the entire study.   
  
If pregnancy occurs: If you miss a period, or think you might be pregnant during the study, you 
must tell the Principal Investigator immediately.    
  
Women cannot take part in this study if they are pregnant or breastfeeding.  
  
If you are a female, you must have a negative pregnancy test in order to participate in this study 
unless you cannot become pregnant.  
  
Birth Control Requirements for Male Participants:  
  
If you are sexually active with a female partner of child bearing potential,   
You must agree with the following for the duration of study and 3weeks after the final dose of 
study drug   
You must not  
• 
Donate sperms  
• 
Rely on barrier methods (condoms) and spermicide alone.  
You must either   
• 
Be surgically sterilized  
• 
Practice abstinence (no sex)  
• 
Agree with their partner to use one of the birth control methods listed below:  
1. Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or 
implants   
2. Intrauterine device (IUD)   
3. Abstinence (no sex)   
The temperature inside the “hot box” where your hand will be placed is maintained at 
approximately 55°C (or 131° F). With prolonged exposure to continuous heat, there is a potential 
risk of local skin irritation or a minor burn. If this occurs, it will be treated appropriately. 
However we have used this technique for the past 25 years and have had no instances of hot box 
related burns or injuries.  
  
Trutol 75 is a sugar solution. There are no known risks from drinking this solution.   


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
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Cortisol and cortisone are naturally occurring hormones in the body so trace substances of these 
hormones do not cause any side effects.  
  
The most common known side effects of the drug AZD4017 are mild/moderate headache, 
abdominal pain or diarrhea. You may have a slight increase in your liver and thyroid lab values. 
Many side effects go away shortly after AZD4017 is stopped, but in some cases side effects can 
be serious, long lasting, or may never go away.  Some side effects may not be known.  Side 
effects may range from mild to life-threatening. Other drugs may be given to make side effects 
less serious and less uncomfortable.  Talk to the researcher and/or your healthcare provider about 
side effects and ask any other questions. There may be other risks of AZD4017 that are currently 
unknown.  
  
As with any medication, allergic reactions are possible.  
  
For your safety during this study, please discuss all medications and supplements you are 
currently taking with the study doctor and call the Principal Investigator BEFORE you begin 
taking any:  
• 
New medications prescribed by your doctor  
• 
Other medications sold over-the-counter without a prescription  
• 
Dietary or herbal supplements  
  
As with all research, there is a chance that confidentiality could be compromised; however, we 
take precautions to minimize this risk.   
  
 
  
7. 
Are there reasons you might leave this research study early?  
  
 
  
You may decide to stop at any time.  You should tell the Principal Investigator if you decide to 
stop and you will be advised whether any additional tests may need to be done for your safety.   
  
In addition, the Principal Investigator, Astra-Zeneca or UVA may stop you from taking part in 
this study at any time:  
• 
If it is in your best interest,   


  
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May 9, 2019  
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• 
If you don’t follow the study procedures,  • If you don’t tolerate the study medication,  
• 
If the study is stopped.   
  
If you leave this research study early, or are withdrawn from the study, no more information 
about you will be collected; however, information already collected about you in the study may 
continue to be used.  
  
We will tell you about any new information that may affect your willingness to stay in the 
research study.  
  
 
  
8. 
What if you are injured from your participation in this research study?  
  
 
  
Where to get help:  
  
If you think you have suffered a research-related injury, you should promptly notify the Principal  
Investigator listed in the Contact Information at the beginning of this form. Staff at the  
University of Virginia will offer care for research-related injuries, including first aid, emergency 
treatment and follow-up care as needed.  
  
Who will pay for the treatment of research related injuries:  
  
You do not give up any legal rights, such as seeking compensation for injury, by signing this 
form.  If you feel you have been injured as a result of this study you may contact the Principal 
Investigator or the IRB (phone numbers are located near the end of this form).  If you are hurt as 
a result of being in this study, there are no plans to pay you for lost wages, disability, or 
discomfort.  The sponsor will reimburse the reasonable cost of necessary and appropriate 
emergency and/or acute medical care for injury or illness that is determined by the principal 
investigator and sponsor to be directly related to the study.  Injury related to the study does not 
include the normal progression of any disease or any underlying pre-existing medical conditions.  
  
  
9. 
What are the possible benefits from being in this research study?  
  
 


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
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You won’t benefit from taking part in this research study. It is for the benefit of research.  
  
 
  
10. 
What alternative do you have if you choose not to participate in this 
research study?  
  
 
  
This study is only being done to gather information.  You may choose not to take part in this 
study.  
  
 
  
11. 
What tests or procedures will you need to pay for if you take part  in this 
research study?   
  
 
  
Astra-Zeneca is providing AZD4017 at no cost and will also pay for:  
• 
Screening and monthly blood tests   
• 
Routine urine tests  
• 
Urine pregnancy test for females  
• 
All study specific tests during the study visits.  
• 
DEXA scans  
• 
MRS/MRE scans  
• 
CRU visits  
• 
Oral glucose tolerance tests  
• 
All medications, isotopes, and study related meals given for the study.  
  
  
However, you and/or your insurance will need to pay for all other tests and procedures that you 
would have as part of your clinical care, including co-payments and deductibles.  
  
  
12. 
Will you be paid for taking part in this research study?  


  
Approval Date:   
May 9, 2019  
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We will pay you $1200 if you complete the study.  If you don’t complete the study, we will pay 
you a prorated amount for each visit you complete. We will provide parking vouchers for this 
study. You will be reimbursed for mileage over a 40 mile radius at the current IRS mileage rate 
up to $100.  
  
 
  
13. 
What will happen to your samples?  
  
 
  
We would like to keep your sample for future research. You can still take part in this current 
study even if you don’t want your sample used for future research. If you agree to give your 
sample, it will be the property of UVA.  
  
Other researchers at UVA who aren’t involved with this study may ask to use your sample for 
future research. Researchers at other institutions may also ask for a part of your sample for future 
studies. Your sample will be sent to researchers in a coded format, which protects your identity.  
  
Some future studies may examine your DNA, which is the genetic information you inherited 
from your parents (genetic testing).  The Principal Investigator may contact you if there are 
findings which may be useful for your health care. You would be given general information on 
the potential risks, benefits, and costs of choosing to learn about the findings.    
  
Please read the following statements and mark your choices:  
  
1. I permit my sample to be stored and used in future research of NASH and NAFLD at 
UVA:  
  
 
  Yes  
  No   
Please initial here: ________Date: ________  
  
2. I permit my sample to be stored and used in future research at UVA to learn about, 
prevent, or treat any other health problems:  
  
 
  Yes  
  No   
Please initial here: ________Date: ________  


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 14 of 17  
  
  
  
3. I permit UVA to give my sample to researchers at other institutions:  
  
 
  Yes  
  No   
Please initial here: ________Date: ________  
  
There is a very small chance that some commercial value may result from the use of your 
donated sample.  If that happens, you won’t be offered a share in any profits.  
  
You may request to have your sample destroyed by writing to the Principal Investigator. 
The address is found in the “Contact Information" section of this consent form.  
  
Because we cannot predict how your sample will be used in the future, we cannot promise that 
samples can be retrieved and destroyed.  
  
 
  
14.  
How will your privacy and the confidentiality of your records be protected?  
  
 
  
UVA is committed to protecting the confidentiality of information obtained about you in 
connection with this research study.   
  
Your data will be stored in a database. The database is secured with password protection behind 
the UVA firewall and is accessible only to study staff. Electronic communication with outside 
collaborators involves only coded, unidentifiable information and is encrypted prior to 
transmission. If the results of the research are made public, information that identifies you will 
not be used.  
  
During this research, information about your health will be collected.  Under Federal law called 
the Privacy Rule, health information is private.  However, there are exceptions to this rule, and 
you should know who may be able to see, use and share your health information for research and 
why they may need to do so.  Information about you and your health cannot be used in this 
research study without your written permission.  If you sign this form, it will provide that 
permission.    
  
Health information may be collected about you from:  
• 
Past, present, and future medical records.  


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
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08 April 2019  
Page 15 of 17  
  
  
• 
Research procedures, including research office visits, tests, interviews, and 
questionnaires.  
  
Why will this information be used and/or given to others?  
• 
To do the research.  
• 
To report the results.  
• 
To see if the research was done correctly.  
  
If the results of this study are made public, information that identifies you will not be used.  
Who may use or share your health information?  
• 
UVA research staff involved in this study.   
• 
Astra-Zeneca  
  
With whom may your health information be shared?   
• 
The UVA Institutional Review Board that oversees the research.   
• 
Other UVA physicians involved in your clinical care.   
• 
Researchers involved in this study at other institutions.  
• 
Federal and State agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health and other United States 
agencies) or government agencies in other countries that oversee or review research.  
• 
The sponsor(s) of this study and the people or groups it hires to help perform this 
research.  
• 
A group that oversees the data (study information) and safety of this research.  
  
Is your health information protected after it has been shared with others?  
UVA asks anyone who receives your health information from us to protect your privacy; 
however, once your information is shared outside UVA, we cannot promise that it will remain 
private and it may no longer be protected by the Privacy Rule.  
  
Your Privacy Rights  
  
If you tell us that someone is hurting you, or that you might hurt yourself or someone else, the 
law may require us to let people in authority know so they can protect you and others.    
  
You do not have to sign this form, but if you do not, you cannot take part in this research study.  
  


  
Approval Date:   
May 9, 2019  
Not to be used after:  August 7, 2019  
  
IRB#: 17-000013 01  
UVA Tracking # 20155  
08 April 2019  
Page 16 of 17  
  
  
If you cancel your permission to use or share your health information, your participation in this 
study will end and no more information about you will be collected; however, information 
already collected about you in the study may continue to be used.  
  
If you choose not to take part or if you withdraw from this study, it will not harm your 
relationship with your own doctors or with UVA.  
  
You can cancel your permission to use or share your health information at any time by sending a 
letter to the address below:  
Mayo Clinic  
Office for Human Research Protection  
ATTN:  Notice of Revocation of Authorization  
200 1st Street SW  
Rochester, MN  55905  
Please be sure to include in your letter or email:  
• 
The name of the Principal Investigator, • The study IRB number and 
/or study name, and  
• 
Your contact information.  
  
Your permission lasts forever, unless you cancel it.   
  
  
 
  
ENROLLMENT AND PERMISSION SIGNATURES  
  
  
Your signature documents your permission
  
  
  
   
  
  
  
/        /   
  
  
h.   
  :  
       AM/PM    
Printed Name   
  
  
  
  
Date    
  
  
Time    
  


  
Approval Date:   
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Not to be used after:  August 7, 2019  
  
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Page 17 of 17  
  
  
  
_______________________________  
Signature  
  
  
  
Person Obtaining Consent   
• 
I have explained the research study to
• 
I have answered all questions about th
the best  
  
  
  
   
  
  
  
/        /   
  
  
of my ability.  
  :  
       AM/PM    
Printed Name   
  
  
  
Date    
  
  
Time            
  
  
_______________________________  
Signature