Nonalcoholic Fatty Liver Disease (NAFLD)
Conditions
Keywords
Nonalcoholic Fatty Liver Disease (NAFLD), Cysteamine bitartrate delayed release, Children
Brief summary
CyNCh is a multi-center, placebo-controlled clinical trial of children ages 8 to 17 years with biopsy-confirmed moderate to severe nonalcoholic fatty liver disease (NAFLD). The primary objective is to evaluate whether 52 weeks of treatment with cysteamine bitartrate delayed-release capsules will result in improvement in liver disease severity.
Interventions
DRUGDR cysteamine bitartrate capsule
* 600 mg/day (four 75 mg capsules twice daily) for patients ≤ 65 kg at baseline * 750 mg/day (five 75 mg capsules twice daily) for patients \>65 - 80 kg at baseline * 900 mg/day (six 75 mg capsules twice daily) for patients \>80 kg at baseline
OTHERDR cysteamine bitartrate placebo
* 600 mg/day (four 75 mg capsules twice daily) for patients ≤ 65 kg at baseline * 750 mg/day (five 75 mg capsules twice daily) for patients \>65 - 80 kg at baseline * 900 mg/day (six 75 mg capsules twice daily) for patients \>80 kg at baseline
Sponsors
National Center for Advancing Translational Sciences (NCATS)
National Cancer Institute (NCI)
Raptor Pharmaceuticals
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Children age 8-17 years * Liver biopsy obtained within 90 days of screening visit and not more than 120 days before randomization * Clinical history consistent with nonalcoholic fatty liver disease (NAFLD) * Definite NAFLD based upon liver histology * No evidence of any other liver disease by clinical history or histological evaluation * A histological severity of: NAFLD Activity Score (NAS) ≥ 4. * Sexually active female participants of childbearing potential (i.e., not surgically sterile \[defined as tubal ligation, hysterectomy, or bilateral oophorectomy\]) must agree to utilize the same two acceptable forms of contraception from screening through completion of the study and to complete a serum pregnancy test at each study visit. The acceptable forms of contraception for this study include hormonal contraceptives (oral, implant, transdermal patch, or injection) at a stable dose for at least 3 months prior to screening, and barrier (condom with spermicide, diaphragm with spermicide). Sexual activity will be ascertained at each study visit for post-menarchal females and if sexually active, subject must verify use of the same 2 acceptable forms of contraception. For pre-pubescent children, a documented attestation of abstinence from their parent or guardian will be acceptable. * Participants must be able to swallow DR Cysteamine tablets with the tablet intact * Written informed consent from parent or legal guardian * Written informed assent from the child
Exclusion criteria
* There will be no
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) | 52 weeks | Centrally scored and masked assessment of histologic improvement in Nonalcholic Fatty Liver Disease (NAFLD) between the baseline liver biopsy and follow-up biopsy after 52 weeks of treatment, where improvement is defined as: (1) decrease in the NAFLD Activity Score (NAS) of 2 or more and (2) no worsening of fibrosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) | 52 weeks | Change from baseline in the NAFLD Activity Score (NAS), which is a composite score equal to the sum of the steatosis grade (0-3), lobular inflammation grade (0-3), and hepatocellular ballooning grade (0-2), from centralized pathologist scoring of liver biopsies. The overall scale of the NAS is 0-8, with higher scores indicating more severe disease. The outcome measure, change from baseline in NAFLD Activity Score (NAS), has a possible range from -8 to +8, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome. Components of the NAS are scored as follows: Steatosis grade 0=\<5% steatosis, 1=5-33% steatosis, 2=34-66% steatosis, 3=\>66% steatosis. Lobular inflammation grade=amount of lobular inflammation (combines mononuclear, fat granulomas, and polymorphonuclear (pmn) foci): 0=0, 1=\<2 under 20x magnification, 2=2-4 under 20x magnification, 3=\>4 under 20x magnification. Hepatocellular ballooning 0=none, 1=mild, 2=more than mild. |
| Steatosis: Patients With Improvement | 52 weeks | Improvement in steatosis defined as any decrease in steatosis grade comparing 52-week biopsy to baseline. |
| Steatosis: Change in Score | 52 weeks | Change from baseline in steatosis score. Steatosis score is based on central pathologist grading of liver biopsies: 0=\<5% steatosis; 1=5-33% steatosis, 2=34-66% steatosis, 3=\>66% steatosis. Change in steatosis score has a possible range of -3 to +3, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement). |
| Lobular Inflammation: Patients With Improvement | 52 weeks | Improvement in lobular inflammation defined as any decrease in lobular inflammation grade comparing 52-week biopsy to baseline. |
| Lobular Inflammation: Change in Score | 52 weeks | Change from baseline in lobular inflammation score. The amount of lobular inflammation is based on central pathologist grading of liver biopsies, and combines mononuclear, fat granulomas, and polymorphonuclear (pmn) foci: 0=none; 1=\<2 under 20x magnification, 2=2-4 under 20x magnification, 3=\>4 under 20x magnification. Change in lobular inflammation score has a possible range of -3 to +3, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement). |
| Hepatocellular Ballooning: Patients With Improvement | 52 weeks | Improvement in hepatocellular ballooning defined as any decrease in hepatocellular ballooning score comparing 52-week biopsy to baseline. |
| Hepatocellular Ballooning: Change in Score | 52 weeks | Change from baseline in hepatocellular ballooning score. The amount of hepatocellular ballooning is based on central pathologist grading of liver biopsies: 0=none; 1=few ballooned hepatocytes, 2=many ballooned hepatocytes. Change in hepatocellular ballooning score has a possible range of -2 to +2, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement). |
| Portal Inflammation: Patients With Improvement | 52 weeks | Improvement in portal inflammation defined as any decrease in portal inflammation score comparing 52-week biopsy to baseline. |
| Portal Inflammation: Change in Score | 52 weeks | Change from baseline in portal inflammation score. The amount of portal inflammation is based on central pathologist grading of liver biopsies: 0=none; 1=mild, 2=more than mild. Change in portal inflammation score has a possible range of -2 to +2, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement). |
| Fibrosis: Patients With Improvement | 52 weeks | Improvement in fibrosis stage defined as any decrease in fibrosis stage comparing 52-week biopsy to baseline. |
| Fibrosis: Change in Stage | 52 weeks | Change from baseline in fibrosis stage. The amount of fibrosis is based on central pathologist grading of liver biopsies: 0=none; 1a=mild, zone 3 perisinusoidal, 1b=moderate, zone 3, perisinusoidal, 1c=portal/periportal only, 2=zone 3 and periportal, any combination, 3=bridging, 4=cirrhosis. Fibrosis stages 1a, 1b, 1c recoded as 1, so the possible range of values for fibrosis stage was 0-4. Change in fibrosis stage has a possible range of -4 to +4, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement). |
| Change in Pediatric Quality of Life Inventory (PedsQL) Score | 52 weeks | Pediatric Quality of Life Inventory (PedsQL) version 4.0 is completed by both the child and parent/caregiver, and is composed of 23 items comprising 4 dimensions: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Scores are transformed on a scale from 0 to 100, with higher scores indicating better health-related quality of life. Physical Health Summary Score =Physical Functioning Scale Score. Psychosocial Health Summary Score = Sum of items over the number of items answered in the Emotional, Social, and School Functioning Scales. |
| Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase | 52 weeks | — |
| Change in Weight (kg) | 52 weeks | — |
| Change in Body-mass Index | 52 weeks | — |
| Change in Body-mass Index Z-score | 52 weeks | — |
| Change in Waist Circumference | 52 weeks | — |
| Change in Fasting Serum Glucose | 52 weeks | — |
| Change in Fasting Insulin | 52 weeks | — |
| Change in HOMA-IR | 52 weeks | (Glucose (mmol/L) x insulin (pmol/L))/22.5 |
| Change in Systolic Blood Pressure | 52 weeks | — |
| Change in Diastolic Blood Pressure | 52 weeks | — |
| Reduction in MRI-determined Hepatic Fat Fraction | 52 weeks | Change from baseline in MRI Proton Density Fat Fraction (PDFF) (%). |
| Resolution of NASH | 52 weeks | Patients with a change from a histological diagnosis of definite NASH or indeterminate for NASH to not NASH at end of treatment |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled at 10 NASH CRN clinical centers from June 2012 to January 2014.
Participants by arm
| Arm | Count |
|---|---|
| DR Cysteamine Bitartrate Capsule Active DR cysteamine bitartrate capsule
DR cysteamine bitartrate capsule: ◦ 600 mg/day (four 75 mg capsules twice daily) for patients ≤ 65 kg at baseline
* 750 mg/day (five 75 mg capsules twice daily) for patients \>65 - 80 kg at baseline
* 900 mg/day (six 75 mg capsules twice daily) for patients \>80 kg at baseline | 88 |
| DR Cysteamine Bitartrate Placebo Placebo DR cysteamine bitartrate capsule
DR cysteamine bitartrate placebo: ◦ 600 mg/day (four 75 mg capsules twice daily) for patients ≤ 65 kg at baseline
* 750 mg/day (five 75 mg capsules twice daily) for patients \>65 - 80 kg at baseline
* 900 mg/day (six 75 mg capsules twice daily) for patients \>80 kg at baseline | 81 |
| Total | 169 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 9 | 3 |
| Overall Study | Moved | 3 | 0 |
Baseline characteristics
| Characteristic | DR Cysteamine Bitartrate Capsule | DR Cysteamine Bitartrate Placebo | Total |
|---|---|---|---|
| Age, Continuous | 13.8 years STANDARD_DEVIATION 2.9 | 13.6 years STANDARD_DEVIATION 2.5 | 13.7 years STANDARD_DEVIATION 2.7 |
| Alanine aminotransferase | 140 U/L STANDARD_DEVIATION 118 | 103 U/L STANDARD_DEVIATION 76 | 123 U/L STANDARD_DEVIATION 101 |
| Aspartate aminotransferase | 82 U/L STANDARD_DEVIATION 71 | 59 U/L STANDARD_DEVIATION 38 | 71 U/L STANDARD_DEVIATION 59 |
| Race/Ethnicity, Customized American Indian/Alaska Native | 5 participants | 6 participants | 11 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Black or African-American | 3 participants | 3 participants | 6 participants |
| Race/Ethnicity, Customized More than one race | 3 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Refusal/not stated | 21 participants | 23 participants | 44 participants |
| Race/Ethnicity, Customized White | 56 participants | 46 participants | 102 participants |
| Region of Enrollment United States | 88 participants | 81 participants | 169 participants |
| Sex: Female, Male Female | 25 Participants | 25 Participants | 50 Participants |
| Sex: Female, Male Male | 63 Participants | 56 Participants | 119 Participants |
| Weight group >65-80 kg | 14 participants | 10 participants | 24 participants |
| Weight group >80 kg | 50 participants | 48 participants | 98 participants |
| Weight group Less than or equal to 65 kg | 24 participants | 23 participants | 47 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 88 | 0 / 81 |
| other Total, other adverse events | 62 / 88 | 55 / 81 |
| serious Total, serious adverse events | 5 / 88 | 4 / 81 |
Outcome results
Primary
Improvement in Nonalcoholic Fatty Liver Disease (NAFLD)
Centrally scored and masked assessment of histologic improvement in Nonalcholic Fatty Liver Disease (NAFLD) between the baseline liver biopsy and follow-up biopsy after 52 weeks of treatment, where improvement is defined as: (1) decrease in the NAFLD Activity Score (NAS) of 2 or more and (2) no worsening of fibrosis.
Time frame: 52 weeks
Population: Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DR Cysteamine Bitartrate Capsule | Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) | 25 participants |
| DR Cysteamine Bitartrate Placebo | Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) | 18 participants |
p-value: 0.3495% CI: [0.8, 2.1]Cochran-Mantel-Haenszel
Secondary
Change in Body-mass Index
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Body-mass Index | 0.8 kg/m^2 | Standard Deviation 2.8 |
| DR Cysteamine Bitartrate Placebo | Change in Body-mass Index | 1.1 kg/m^2 | Standard Deviation 2.2 |
Comparison: Adjusted difference in mean changes in body mass index (BMI). The change in BMI is adjusted for the baseline BMI value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.4295% CI: [-1.1, 0.5]ANCOVA
Secondary
Change in Body-mass Index Z-score
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Body-mass Index Z-score | -0.1 SD | Standard Deviation 0.3 |
| DR Cysteamine Bitartrate Placebo | Change in Body-mass Index Z-score | 0 SD | Standard Deviation 0.2 |
p-value: 0.1195% CI: [-0.1, 0]ANCOVA
Secondary
Change in Diastolic Blood Pressure
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Diastolic Blood Pressure | -1 mmHg | Standard Deviation 9 |
| DR Cysteamine Bitartrate Placebo | Change in Diastolic Blood Pressure | 1 mmHg | Standard Deviation 9 |
Comparison: Adjusted difference in mean changes in diastolic blood pressure. The change in diastolic blood pressure is adjusted for the baseline diastolic blood pressure value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.3195% CI: [-4, 1]ANCOVA
Secondary
Change in Fasting Insulin
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Fasting Insulin | 6 μU/mL | Standard Deviation 36 |
| DR Cysteamine Bitartrate Placebo | Change in Fasting Insulin | 10 μU/mL | Standard Deviation 40 |
Comparison: Adjusted difference in mean changes in fasting insulin. The change in fasting insulin is adjusted for the baseline fasting insulin value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.3495% CI: [-18, 6]ANCOVA
Secondary
Change in Fasting Serum Glucose
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Fasting Serum Glucose | 1 mg/dL | Standard Deviation 12 |
| DR Cysteamine Bitartrate Placebo | Change in Fasting Serum Glucose | 5 mg/dL | Standard Deviation 27 |
Comparison: Adjusted difference in mean changes in fasting serum glucose. The change in fasting serum glucose is adjusted for the baseline fasting serum glucose value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.2495% CI: [-11, 3]ANCOVA
Secondary
Change in HOMA-IR
(Glucose (mmol/L) x insulin (pmol/L))/22.5
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in HOMA-IR | 1.4 (10E-15 mol^2)/L^2 | Standard Deviation 9.2 |
| DR Cysteamine Bitartrate Placebo | Change in HOMA-IR | 3.6 (10E-15 mol^2)/L^2 | Standard Deviation 12.5 |
Comparison: Adjusted difference in mean changes in HOMA-IR. The change in HOMA-IR is adjusted for the baseline HOMA-IR value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.1595% CI: [-6.2, 1]ANCOVA
Secondary
Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)
Change from baseline in the NAFLD Activity Score (NAS), which is a composite score equal to the sum of the steatosis grade (0-3), lobular inflammation grade (0-3), and hepatocellular ballooning grade (0-2), from centralized pathologist scoring of liver biopsies. The overall scale of the NAS is 0-8, with higher scores indicating more severe disease. The outcome measure, change from baseline in NAFLD Activity Score (NAS), has a possible range from -8 to +8, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome. Components of the NAS are scored as follows: Steatosis grade 0=\<5% steatosis, 1=5-33% steatosis, 2=34-66% steatosis, 3=\>66% steatosis. Lobular inflammation grade=amount of lobular inflammation (combines mononuclear, fat granulomas, and polymorphonuclear (pmn) foci): 0=0, 1=\<2 under 20x magnification, 2=2-4 under 20x magnification, 3=\>4 under 20x magnification. Hepatocellular ballooning 0=none, 1=mild, 2=more than mild.
Time frame: 52 weeks
Population: The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) | -0.8 units on a scale | Standard Deviation 1.8 |
| DR Cysteamine Bitartrate Placebo | Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) | -0.8 units on a scale | Standard Deviation 1.8 |
p-value: 0.995% CI: [-0.6, 0.5]ANCOVA
Secondary
Change in Pediatric Quality of Life Inventory (PedsQL) Score
Pediatric Quality of Life Inventory (PedsQL) version 4.0 is completed by both the child and parent/caregiver, and is composed of 23 items comprising 4 dimensions: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Scores are transformed on a scale from 0 to 100, with higher scores indicating better health-related quality of life. Physical Health Summary Score =Physical Functioning Scale Score. Psychosocial Health Summary Score = Sum of items over the number of items answered in the Emotional, Social, and School Functioning Scales.
Time frame: 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Pediatric Quality of Life Inventory (PedsQL) Score | Self-reported physical health | 4 units on a scale | Standard Deviation 17 |
| DR Cysteamine Bitartrate Capsule | Change in Pediatric Quality of Life Inventory (PedsQL) Score | Parent/guardian-reported physical health | 4 units on a scale | Standard Deviation 27 |
| DR Cysteamine Bitartrate Capsule | Change in Pediatric Quality of Life Inventory (PedsQL) Score | Self-reported psychosocial health | 4 units on a scale | Standard Deviation 15 |
| DR Cysteamine Bitartrate Capsule | Change in Pediatric Quality of Life Inventory (PedsQL) Score | Parent/guardian-reported psychosocial health | 5 units on a scale | Standard Deviation 18 |
| DR Cysteamine Bitartrate Placebo | Change in Pediatric Quality of Life Inventory (PedsQL) Score | Parent/guardian-reported psychosocial health | 6 units on a scale | Standard Deviation 24 |
| DR Cysteamine Bitartrate Placebo | Change in Pediatric Quality of Life Inventory (PedsQL) Score | Self-reported physical health | 5 units on a scale | Standard Deviation 16 |
| DR Cysteamine Bitartrate Placebo | Change in Pediatric Quality of Life Inventory (PedsQL) Score | Self-reported psychosocial health | 5 units on a scale | Standard Deviation 14 |
| DR Cysteamine Bitartrate Placebo | Change in Pediatric Quality of Life Inventory (PedsQL) Score | Parent/guardian-reported physical health | 5 units on a scale | Standard Deviation 24 |
Comparison: Adjusted difference in mean changes from baseline in self-reported Physical Health summary score from the Pediatric Quality of Life Inventory (PedsQL). The difference in mean changes in Physical Health summary score is adjusted for the baseline Physical Health summary score; therefore, the adjusted difference in mean changes is not equal to the net change. Higher scores indicate better health-related quality of life.p-value: 0.7795% CI: [-5, 3]ANCOVA
Comparison: Adjusted difference in mean changes from baseline in self-reported Psychosocial Health summary score from the Pediatric Quality of Life Inventory (PedsQL). The difference in mean changes in Psychosocial Health summary score is adjusted for the baseline Psychosocial Health summary score; therefore, the adjusted difference in mean changes is not equal to the net change. Higher scores indicate better health-related quality of life.p-value: 0.6495% CI: [-5, 3]ANCOVA
Comparison: Adjusted difference in mean changes from baseline in parent/guardian-reported Physical Health summary score from the Pediatric Quality of Life Inventory (PedsQL). The difference in mean changes in parent/guardian-reported Physical Health summary score is adjusted for the baseline parent/guardian-reported Physical Health summary score; therefore, the adjusted difference in mean changes is not equal to the net change. Higher scores indicate better health-related quality of life.p-value: 0.5895% CI: [-9, 5]ANCOVA
Comparison: Adjusted difference in mean changes from baseline in parent/guardian-reported Psychosocial Health summary score from the Pediatric Quality of Life Inventory (PedsQL). The difference in mean changes in parent/guardian-reported Psychosocial Health summary score is adjusted for the baseline parent/guardian-reported Psychosocial Health summary score; therefore, the adjusted difference in mean changes is not equal to the net change. Higher scores indicate better health-related quality of life.p-value: 0.8595% CI: [-6, 5]ANCOVA
Secondary
Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase
Time frame: 52 weeks
Population: The smaller number of participants analyzed is due to missing 52-week laboratory data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase | Alanine aminotransferase | -53 U/L | Standard Deviation 88 |
| DR Cysteamine Bitartrate Capsule | Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase | Aspartate aminotransferase | -31 U/L | Standard Deviation 52 |
| DR Cysteamine Bitartrate Capsule | Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase | Gamma-glutamyl transpeptidase | -10 U/L | Standard Deviation 23 |
| DR Cysteamine Bitartrate Placebo | Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase | Alanine aminotransferase | -8 U/L | Standard Deviation 77 |
| DR Cysteamine Bitartrate Placebo | Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase | Aspartate aminotransferase | -4 U/L | Standard Deviation 36 |
| DR Cysteamine Bitartrate Placebo | Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase | Gamma-glutamyl transpeptidase | -1 U/L | Standard Deviation 16 |
Comparison: Adjusted difference in mean changes in serum alanine aminotransferase (ALT). The change in ALT is adjusted for the baseline ALT value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.0295% CI: [-44, -4]ANCOVA
Comparison: Adjusted difference in mean changes in serum aspartate aminotransferase (AST). The change in AST is adjusted for the baseline AST value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.00895% CI: [-26, -4]ANCOVA
Comparison: Adjusted difference in mean changes in serum gamma-glutamyl transpeptidase (GGT). The change in GGT is adjusted for the baseline GGTvalue; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.0295% CI: [-13, -1]ANCOVA
Secondary
Change in Systolic Blood Pressure
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Systolic Blood Pressure | 3 mmHg | Standard Deviation 12 |
| DR Cysteamine Bitartrate Placebo | Change in Systolic Blood Pressure | 2 mmHg | Standard Deviation 12 |
Comparison: Adjusted difference in mean changes in systolic blood pressure. The change in systolic blood pressure is adjusted for the baseline systolic blood pressure value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.7195% CI: [-3, 4]ANCOVA
Secondary
Change in Waist Circumference
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Waist Circumference | 2.5 cm | Standard Deviation 7.7 |
| DR Cysteamine Bitartrate Placebo | Change in Waist Circumference | 2.3 cm | Standard Deviation 7.5 |
Comparison: Adjusted difference in mean changes in waist circumference (cm). The change in waist circumference is adjusted for the baseline waist circumference value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.8995% CI: [-2.3, 2.6]ANCOVA
Secondary
Change in Weight (kg)
Time frame: 52 weeks
Population: Smaller number of patients analyzed due to missing 52-week weight measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Change in Weight (kg) | 6.3 kg | Standard Deviation 9.3 |
| DR Cysteamine Bitartrate Placebo | Change in Weight (kg) | 7.8 kg | Standard Deviation 6.6 |
Comparison: Adjusted difference in mean changes in weight (kg). The change in weight is adjusted for the baseline weight value; therefore, the adjusted difference in mean changes is not equal to the net change.p-value: 0.2595% CI: [-4.1, 1.1]ANCOVA
Secondary
Fibrosis: Change in Stage
Change from baseline in fibrosis stage. The amount of fibrosis is based on central pathologist grading of liver biopsies: 0=none; 1a=mild, zone 3 perisinusoidal, 1b=moderate, zone 3, perisinusoidal, 1c=portal/periportal only, 2=zone 3 and periportal, any combination, 3=bridging, 4=cirrhosis. Fibrosis stages 1a, 1b, 1c recoded as 1, so the possible range of values for fibrosis stage was 0-4. Change in fibrosis stage has a possible range of -4 to +4, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).
Time frame: 52 weeks
Population: The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Fibrosis: Change in Stage | -0.3 units on a scale | Standard Deviation 0.9 |
| DR Cysteamine Bitartrate Placebo | Fibrosis: Change in Stage | -0.1 units on a scale | Standard Deviation 1 |
p-value: 0.2495% CI: [-0.4, 0.1]ANCOVA
Secondary
Fibrosis: Patients With Improvement
Improvement in fibrosis stage defined as any decrease in fibrosis stage comparing 52-week biopsy to baseline.
Time frame: 52 weeks
Population: Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DR Cysteamine Bitartrate Capsule | Fibrosis: Patients With Improvement | 25 participants |
| DR Cysteamine Bitartrate Placebo | Fibrosis: Patients With Improvement | 23 participants |
p-value: 0.9895% CI: [0.6, 1.6]Cochran-Mantel-Haenszel
Secondary
Hepatocellular Ballooning: Change in Score
Change from baseline in hepatocellular ballooning score. The amount of hepatocellular ballooning is based on central pathologist grading of liver biopsies: 0=none; 1=few ballooned hepatocytes, 2=many ballooned hepatocytes. Change in hepatocellular ballooning score has a possible range of -2 to +2, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).
Time frame: 52 weeks
Population: The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Hepatocellular Ballooning: Change in Score | -0.1 units on a scale | Standard Deviation 0.7 |
| DR Cysteamine Bitartrate Placebo | Hepatocellular Ballooning: Change in Score | -0.3 units on a scale | Standard Deviation 0.8 |
p-value: 0.1595% CI: [-0.1, 0.3]ANCOVA
Secondary
Hepatocellular Ballooning: Patients With Improvement
Improvement in hepatocellular ballooning defined as any decrease in hepatocellular ballooning score comparing 52-week biopsy to baseline.
Time frame: 52 weeks
Population: Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DR Cysteamine Bitartrate Capsule | Hepatocellular Ballooning: Patients With Improvement | 17 participants |
| DR Cysteamine Bitartrate Placebo | Hepatocellular Ballooning: Patients With Improvement | 21 participants |
p-value: 0.2995% CI: [0.4, 1.3]Cochran-Mantel-Haenszel
Secondary
Lobular Inflammation: Change in Score
Change from baseline in lobular inflammation score. The amount of lobular inflammation is based on central pathologist grading of liver biopsies, and combines mononuclear, fat granulomas, and polymorphonuclear (pmn) foci: 0=none; 1=\<2 under 20x magnification, 2=2-4 under 20x magnification, 3=\>4 under 20x magnification. Change in lobular inflammation score has a possible range of -3 to +3, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).
Time frame: 52 weeks
Population: The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Lobular Inflammation: Change in Score | -0.4 units on a scale | Standard Deviation 0.8 |
| DR Cysteamine Bitartrate Placebo | Lobular Inflammation: Change in Score | -0.1 units on a scale | Standard Deviation 0.8 |
p-value: 0.0695% CI: [-0.4, 0]ANCOVA
Secondary
Lobular Inflammation: Patients With Improvement
Improvement in lobular inflammation defined as any decrease in lobular inflammation grade comparing 52-week biopsy to baseline.
Time frame: 52 weeks
Population: Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DR Cysteamine Bitartrate Capsule | Lobular Inflammation: Patients With Improvement | 32 participants |
| DR Cysteamine Bitartrate Placebo | Lobular Inflammation: Patients With Improvement | 17 participants |
p-value: 0.0395% CI: [1.1, 2.9]Cochran-Mantel-Haenszel
Secondary
Portal Inflammation: Change in Score
Change from baseline in portal inflammation score. The amount of portal inflammation is based on central pathologist grading of liver biopsies: 0=none; 1=mild, 2=more than mild. Change in portal inflammation score has a possible range of -2 to +2, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).
Time frame: 52 weeks
Population: The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Portal Inflammation: Change in Score | -0.1 units on a scale | Standard Deviation 0.6 |
| DR Cysteamine Bitartrate Placebo | Portal Inflammation: Change in Score | -0.1 units on a scale | Standard Deviation 0.6 |
p-value: 0.7695% CI: [-0.2, 0.2]ANCOVA
Secondary
Portal Inflammation: Patients With Improvement
Improvement in portal inflammation defined as any decrease in portal inflammation score comparing 52-week biopsy to baseline.
Time frame: 52 weeks
Population: Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DR Cysteamine Bitartrate Capsule | Portal Inflammation: Patients With Improvement | 18 participants |
| DR Cysteamine Bitartrate Placebo | Portal Inflammation: Patients With Improvement | 14 participants |
p-value: 0.5795% CI: [0.6, 2.3]Cochran-Mantel-Haenszel
Secondary
Reduction in MRI-determined Hepatic Fat Fraction
Change from baseline in MRI Proton Density Fat Fraction (PDFF) (%).
Time frame: 52 weeks
Population: The smaller number of observations is because MRI was an optional procedure. This is the number with MRI exams at both baseline and 52 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Reduction in MRI-determined Hepatic Fat Fraction | -5.3 percentage of PDFF | Standard Deviation 7.1 |
| DR Cysteamine Bitartrate Placebo | Reduction in MRI-determined Hepatic Fat Fraction | -2.6 percentage of PDFF | Standard Deviation 7.6 |
p-value: 0.11ANCOVA
Secondary
Resolution of NASH
Patients with a change from a histological diagnosis of definite NASH or indeterminate for NASH to not NASH at end of treatment
Time frame: 52 weeks
Population: Analysis was limited to patients with a diagnosis of definite NASH at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DR Cysteamine Bitartrate Capsule | Resolution of NASH | 4 participants |
| DR Cysteamine Bitartrate Placebo | Resolution of NASH | 2 participants |
p-value: 0.2995% CI: [0.4, 18.3]Cochran-Mantel-Haenszel
Secondary
Steatosis: Change in Score
Change from baseline in steatosis score. Steatosis score is based on central pathologist grading of liver biopsies: 0=\<5% steatosis; 1=5-33% steatosis, 2=34-66% steatosis, 3=\>66% steatosis. Change in steatosis score has a possible range of -3 to +3, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).
Time frame: 52 weeks
Population: The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DR Cysteamine Bitartrate Capsule | Steatosis: Change in Score | -0.3 units on a scale | Standard Deviation 0.9 |
| DR Cysteamine Bitartrate Placebo | Steatosis: Change in Score | -0.4 units on a scale | Standard Deviation 0.9 |
Comparison: Steatosis: change in scorep-value: 0.5995% CI: [-0.2, 0.4]ANCOVA
Secondary
Steatosis: Patients With Improvement
Improvement in steatosis defined as any decrease in steatosis grade comparing 52-week biopsy to baseline.
Time frame: 52 weeks
Population: Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DR Cysteamine Bitartrate Capsule | Steatosis: Patients With Improvement | 26 participants |
| DR Cysteamine Bitartrate Placebo | Steatosis: Patients With Improvement | 33 participants |
Comparison: Steatosis: patients with improvementp-value: 0.1595% CI: [0.5, 1.1]Cochran-Mantel-Haenszel