CyNCh: Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01529268
• Collaborator: National Center for Advancing Translational Science (NCATS) (NIH), National Cancer Institute (NCI) (NIH), Raptor Pharmaceuticals (Other)
• Enrollment: 169
• Locations: 10
• Arms: 2
• Duration (Months): 39
• Patients Per Site: 16.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Nonalcoholic Fatty Liver Disease (NAFLD)	Drug: DR cysteamine bitartrate capsule; Other: DR cysteamine bitartrate placebo	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 169 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Children (CyNCh)
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: DR cysteamine bitartrate capsule Active DR cysteamine bitartrate capsule	Drug: 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; Other Names: cysteamine bitartrate delayed-release
Placebo Comparator: DR cysteamine bitartrate placebo Placebo DR cysteamine bitartrate capsule	Other: 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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Steatosis: Patients With Improvement [52 weeks]

   Improvement in steatosis defined as any decrease in steatosis grade comparing 52-week biopsy to baseline.

3. 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).

4. 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.

5. 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).

6. 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.

7. 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).

8. 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.

9. 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).

10. Fibrosis: Patients With Improvement [52 weeks]

    Improvement in fibrosis stage defined as any decrease in fibrosis stage comparing 52-week biopsy to baseline.

11. 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).

12. 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

13. Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase [52 weeks]

14. Change in Weight (kg) [52 weeks]

15. Change in Body-mass Index [52 weeks]

16. Change in Body-mass Index Z-score [52 weeks]

17. Change in Waist Circumference [52 weeks]

18. Change in Fasting Serum Glucose [52 weeks]

19. Change in Fasting Insulin [52 weeks]

20. Change in HOMA-IR [52 weeks]

    (Glucose (mmol/L) x insulin (pmol/L))/22.5

21. Change in Systolic Blood Pressure [52 weeks]

22. Change in Diastolic Blood Pressure [52 weeks]

23. 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.

24. Reduction in MRI-determined Hepatic Fat Fraction [52 weeks]

    Change from baseline in MRI Proton Density Fat Fraction (PDFF) (%).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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 exclusion criteria based on race, ethnicity or gender.

• Participants with a current history of the following conditions or any other health issues that make it unsafe for them to participate in the opinion of the

Investigators:

• Inflammatory bowel disease (if currently active) or prior resection of small intestine

• Heart disease (e.g., myocardial infarction, heart failure, unstable arrhythmias)

• Seizure disorder

• Active coagulopathy

• Gastrointestinal ulcers/bleeding

• Renal dysfunction with a creatinine clearance < 90 mL/min/m2

• History of active malignant disease requiring chemotherapy within the past 12 months prior to randomization

• History of significant alcohol intake (AUDIT questionnaire) or inability to quantify alcohol consumption

• Chronic use (more than 2 consecutive weeks) of medications known to cause hepatic steatosis or steatohepatitis (systemic glucocorticoids, tetracycline, anabolic steroids, valproic acid, salicylates, tamoxifen) in the past year.

• The use of other known hepatotoxins within 90 days of liver biopsy or within 120 days of randomization

• Initiation of medications with the intent to treat NAFLD/NASH in the time period following liver biopsy and prior to randomization

• History of total parenteral nutrition (TPN) use in year prior to screening

• History of bariatric surgery or planning to undergo bariatric surgery during study duration

• Clinically significant depression (patients hospitalized for suicidal ideations or suicide attempts within the past 12 months)

• Any female nursing, planning a pregnancy, known or suspected to be pregnant, or who has a positive serum pregnancy screen.

• Non-compensated liver disease with any one of the following hematologic, biochemical, and serological criteria on entry into protocol:

• Hemoglobin < 10 g/dL;

• White blood cell (WBC) < 3,500 cells/mm3 of blood;

• Neutrophil count < 1,500 cells/mm3 of blood;

• Platelets < 130,000 cells/mm3 of blood;

• Direct bilirubin > 1.0 mg/dL

• Total bilirubin >3 mg/dL

• Albumin < 3.2 g/dL

• International normalized ratio (INR) > 1.4

• Poorly controlled diabetes mellitus (hemoglobin A1c (HbA1c) > 9%)

• Evidence of other chronic liver disease:

• Biopsy consistent with histological evidence of autoimmune hepatitis

• Serum hepatitis B surface antigen (HBsAg) positive.

• Serum hepatitis C antibody (anti-HCV) positive.

• Iron/total iron binding capacity (TIBC) ratio (transferrin saturation) > 45% with histological evidence of iron overload

• Alpha-1-antitrypsin (A1AT) phenotype ZZ or SZ

• Wilson's disease

• Children who are currently enrolled in a clinical trial or who received an investigational study drug within 180 days of screening or liver biopsy.

• Subjects who are not able or willing to comply with the protocol or have any other condition that would impede compliance or hinder completion of the study, in the opinion of the investigator.

• Failure to give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92103
2	University of California, San Francisco	San Francisco	California	United States	94143
3	Emory University	Atlanta	Georgia	United States	30322
4	Ann & Robert H. Lurie Children's Hospital of Chicago (NWU)	Chicago	Illinois	United States	60611-2605
5	Indiana University	Indianapolis	Indiana	United States	46202
6	St. Louis University	Saint Louis	Missouri	United States	63104
7	Columbia University	New York	New York	United States	10032
8	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
9	Texas Children's Hospital	Houston	Texas	United States	77030
10	University of Washington, Seattle Children's Hospital	Seattle	Washington	United States	98105

Sponsors and Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• National Center for Advancing Translational Science (NCATS)
• National Cancer Institute (NCI)
• Raptor Pharmaceuticals

Investigators

• Study Director: Edward Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Nonalcoholic Steatohepatitis Clinical Research Network Centers
• The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications

None provided.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT01529268
• Other Study ID Numbers: NASH-CyNCh; U01DK061718; U01DK061728; U01DK061731; U01DK061732; U01DK061734; U01DK061737; U01DK061738; U01DK061730; U01DK061713
• First Posted: Feb 8, 2012
• Last Update Posted: Jun 10, 2021
• Last Verified: Aug 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Nonalcoholic Fatty Liver Disease (NAFLD); Cysteamine bitartrate delayed release; Children
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Cysteamine

Study Results

Participant Flow

Recruitment Details	Patients were enrolled at 10 NASH CRN clinical centers from June 2012 to January 2014.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	88	81
Completed 52-week Biopsy	71	75
COMPLETED	76	78
NOT COMPLETED	12	3

Baseline Characteristics

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	88	81	169
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.8 (2.9)	13.6 (2.5)	13.7 (2.7)
Sex: Female, Male (Count of Participants)
Female	25 28.4%	25 30.9%	50 29.6%
Male	63 71.6%	56 69.1%	119 70.4%
Race/Ethnicity, Customized (participants) [Number]
American Indian/Alaska Native	5 5.7%	6 7.4%	11 6.5%
Asian	0 0%	2 2.5%	2 1.2%
Black or African-American	3 3.4%	3 3.7%	6 3.6%
White	56 63.6%	46 56.8%	102 60.4%
More than one race	3 3.4%	1 1.2%	4 2.4%
Refusal/not stated	21 23.9%	23 28.4%	44 26%
Region of Enrollment (participants) [Number]
United States	88 100%	81 100%	169 100%
Alanine aminotransferase (U/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/L]	140 (118)	103 (76)	123 (101)
Aspartate aminotransferase (U/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/L]	82 (71)	59 (38)	71 (59)
Weight group (participants) [Number]
Less than or equal to 65 kg	24 27.3%	23 28.4%	47 27.8%
>65-80 kg	14 15.9%	10 12.3%	24 14.2%
>80 kg	50 56.8%	48 59.3%	98 58%

Outcome Measures

1. Primary Outcome

Title	Improvement in Nonalcoholic Fatty Liver Disease (NAFLD)
Description	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

Outcome Measure Data

Analysis Population Description

Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	88	81
Number [participants]	25 28.4%	18 22.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Relative risks and p-values were calculated with the Cochran-Mantel-Haenszel chi-square tests, stratified by clinic and weight group, for binary outcomes.
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95%; 0.8 to 2.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)
Description	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

Outcome Measure Data

Analysis Population Description

The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	71	75
Mean (Standard Deviation) [units on a scale]	-0.8 (1.8)	-0.8 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	P-values and mean changes from baseline were calculated using ANCOVA, regressing change from baseline to 52 weeks on treatment group and baseline value of the outcome, for outcome scores.
Statistical Test of Hypothesis	p-Value	0.90
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Steatosis: Patients With Improvement
Description	Improvement in steatosis defined as any decrease in steatosis grade comparing 52-week biopsy to baseline.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	88	81
Number [participants]	26 29.5%	33 40.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	Steatosis: patients with improvement
	Type of Statistical Test	Superiority
	Comments	Relative risks and p-values were calculated with the Cochran-Mantel-Haenszel chi-square tests, stratified by clinic and weight group, for binary outcomes.
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Steatosis: Change in Score
Description	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

Outcome Measure Data

Analysis Population Description

The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	71	75
Mean (Standard Deviation) [units on a scale]	-0.3 (0.9)	-0.4 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	Steatosis: change in score
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	P-values and mean changes from baseline were calculated using ANCOVA, regressing change from baseline to 52 weeks on treatment group and baseline value of the outcome, for outcome scores.
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Lobular Inflammation: Patients With Improvement
Description	Improvement in lobular inflammation defined as any decrease in lobular inflammation grade comparing 52-week biopsy to baseline.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	88	81
Number [participants]	32 36.4%	17 21%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Relative risks and p-values were calculated with the Cochran-Mantel-Haenszel chi-square tests, stratified by clinic and weight group, for binary outcomes.
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; 1.1 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Lobular Inflammation: Change in Score
Description	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

Outcome Measure Data

Analysis Population Description

The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	71	75
Mean (Standard Deviation) [units on a scale]	-0.4 (0.8)	-0.1 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	P-values and mean changes from baseline were calculated using ANCOVA, regressing change from baseline to 52 weeks on treatment group and baseline value of the outcome, for outcome scores.
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Hepatocellular Ballooning: Patients With Improvement
Description	Improvement in hepatocellular ballooning defined as any decrease in hepatocellular ballooning score comparing 52-week biopsy to baseline.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	88	81
Number [participants]	17 19.3%	21 25.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Relative risks and p-values were calculated with the Cochran-Mantel-Haenszel chi-square tests, stratified by clinic and weight group, for binary outcomes.
Statistical Test of Hypothesis	p-Value	0.29
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.4 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Hepatocellular Ballooning: Change in Score
Description	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

Outcome Measure Data

Analysis Population Description

The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	71	75
Mean (Standard Deviation) [units on a scale]	-0.1 (0.7)	-0.3 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	P-values and mean changes from baseline were calculated using ANCOVA, regressing change from baseline to 52 weeks on treatment group and baseline value of the outcome, for outcome scores.
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Portal Inflammation: Patients With Improvement
Description	Improvement in portal inflammation defined as any decrease in portal inflammation score comparing 52-week biopsy to baseline.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	88	81
Number [participants]	18 20.5%	14 17.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Relative risks and p-values were calculated with the Cochran-Mantel-Haenszel chi-square tests, stratified by clinic and weight group, for binary outcomes.
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; 0.6 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Portal Inflammation: Change in Score
Description	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

Outcome Measure Data

Analysis Population Description

The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	71	75
Mean (Standard Deviation) [units on a scale]	-0.1 (0.6)	-0.1 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	P-values and mean changes from baseline were calculated using ANCOVA, regressing change from baseline to 52 weeks on treatment group and baseline value of the outcome, for outcome scores.
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Fibrosis: Patients With Improvement
Description	Improvement in fibrosis stage defined as any decrease in fibrosis stage comparing 52-week biopsy to baseline.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Analysis based on intention to treat; patients with missing 52-week biopsy were imputed as lack of improvement.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	88	81
Number [participants]	25 28.4%	23 28.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Relative risks and p-values were calculated with the Cochran-Mantel-Haenszel chi-square tests, stratified by clinic and weight group, for binary outcomes.
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.6 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Fibrosis: Change in Stage
Description	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

Outcome Measure Data

Analysis Population Description

The smaller number of participants analyzed is due to missing 52-week biopsies (complete case analysis).

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	71	75
Mean (Standard Deviation) [units on a scale]	-0.3 (0.9)	-0.1 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	P-values and mean changes from baseline were calculated using ANCOVA, regressing change from baseline to 52 weeks on treatment group and baseline value of the outcome, for outcome scores.
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Resolution of NASH
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was limited to patients with a diagnosis of definite NASH at baseline.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	24	23
Number [participants]	4 4.5%	2 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Relative risks and p-values were calculated with the Cochran-Mantel-Haenszel chi-square tests, stratified by clinic and weight group, for binary outcomes.
Statistical Test of Hypothesis	p-Value	0.29
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by clinic and weight group
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	2.7
	Confidence Interval	(2-Sided) 95%; 0.4 to 18.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

The smaller number of participants analyzed is due to missing 52-week laboratory data.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Alanine aminotransferase	-53 (88)	-8 (77)
Aspartate aminotransferase	-31 (52)	-4 (36)
Gamma-glutamyl transpeptidase	-10 (23)	-1 (16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-value and difference in mean changes from baseline were calculated using ANCOVA models, regressing change from baseline to 52 weeks in serum alanine aminotransferase on treatment group and baseline value of serum alanine aminotransferase.
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline serum alanine aminotransferase
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-24
	Confidence Interval	(2-Sided) 95%; -44 to -4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-value and difference in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in serum aspartate aminotransferase on treatment group and baseline value of serum aspartate aminotransferase.
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline serum aspartate aminotransferase.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-15
	Confidence Interval	(2-Sided) 95%; -26 to -4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-value and difference in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in gamma-glutamyl transpeptidase on treatment group and baseline value of gamma-glutamyl transpeptidase.
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline gamma-glutamyl transpeptidase
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7
	Confidence Interval	(2-Sided) 95%; -13 to -1
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change in Weight (kg)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Smaller number of patients analyzed due to missing 52-week weight measurement.

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [kg]	6.3 (9.3)	7.8 (6.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	P-value and adjusted difference in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in weight (kg) on treatment group and baseline weight (kg).
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline weight (kg).
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -4.1 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change in Body-mass Index
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [kg/m^2]	0.8 (2.8)	1.1 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-values and differences in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks on treatment group and baseline value of the outcome.
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline BMI (kg/m2)
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -1.1 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change in Body-mass Index Z-score
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [SD]	-0.1 (0.3)	0 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	P-values and differences in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks on treatment group and baseline value of the outcome.
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change in Waist Circumference
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [cm]	2.5 (7.7)	2.3 (7.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-values and differences in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in waist circumference on treatment group and baseline value of waist circumference.
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline waist circumference (cm)
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -2.3 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Change in Fasting Serum Glucose
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [mg/dL]	1 (12)	5 (27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	P-values and differences in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in fasting serum glucose on treatment group and baseline fasting serum glucose value.
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline serum glucose value.
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-4
	Confidence Interval	(2-Sided) 95%; -11 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Change in Fasting Insulin
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [μU/mL]	6 (36)	10 (40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-value and difference in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in fasting insulin on treatment group and baseline fasting insulin.
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline fasting insulin.
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-6
	Confidence Interval	(2-Sided) 95%; -18 to 6
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Change in HOMA-IR
Description	(Glucose (mmol/L) x insulin (pmol/L))/22.5
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [(10E-15 mol^2)/L^2]	1.4 (9.2)	3.6 (12.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-values and differences in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in HOMA-IR on treatment group and baseline HOMA-IR value.
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline HOMA-IR.
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -6.2 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Change in Systolic Blood Pressure
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [mmHg]	3 (12)	2 (12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-values and differences in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in systolic blood pressure on treatment group and baseline systolic blood pressure value.
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline systolic blood pressure.
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	1
	Confidence Interval	(2-Sided) 95%; -3 to 4
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change in Diastolic Blood Pressure
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Mean (Standard Deviation) [mmHg]	-1 (9)	1 (9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-values and differences in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in diastolic blood pressure on treatment group and baseline diastolic blood pressure value.
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline diastolic blood pressure.
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -4 to 1
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Change in Pediatric Quality of Life Inventory (PedsQL) Score
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	75	77
Self-reported physical health	4 (17)	5 (16)
Self-reported psychosocial health	4 (15)	5 (14)
Parent/guardian-reported physical health	4 (27)	5 (24)
Parent/guardian-reported psychosocial health	5 (18)	6 (24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-value and difference in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in self-reported Physical Health summary score on treatment group and baseline value of the Physical Health summary score.
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline self-reported Physical Health summary score.
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -5 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-value and difference in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in Pyschosocial Health summary score on treatment group and baseline Psychosocial Health summary score.
Statistical Test of Hypothesis	p-Value	0.64
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline Psychosocial Health summary score.
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -5 to 3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-value and difference in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in parent/guardian-reported Physical Health summary score on treatment group and baseline value of the parent/guardian-reported Physical Health summary score.
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	ANCOVA
	Comments	Adjusted for baseline parent/guardian-reported Physical Health summary score.
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-2
	Confidence Interval	(2-Sided) 95%; -9 to 5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	P-value and difference in mean changes from baseline were calculated using ANCOVA models, regressing changes from baseline to 52 weeks in parent/guardian-reported Psychosocial Health summary score on treatment group and baseline value of the parent/guardian-reported Psychosocial Health summary score.
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted difference in mean changes
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -6 to 5
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Reduction in MRI-determined Hepatic Fat Fraction
Description	Change from baseline in MRI Proton Density Fat Fraction (PDFF) (%).
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	DR Cysteamine Bitartrate Capsule	DR Cysteamine Bitartrate Placebo
Arm/Group Description	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	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
Measure Participants	38	46
Mean (Standard Deviation) [percentage of PDFF]	-5.3 (7.1)	-2.6 (7.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DR Cysteamine Bitartrate Capsule, DR Cysteamine Bitartrate Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	52 weeks
Arm/Group Title	DR Cysteamine Bitartrate Capsule		DR Cysteamine Bitartrate Placebo
Arm/Group Description	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		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
All Cause Mortality
	DR Cysteamine Bitartrate Capsule		DR Cysteamine Bitartrate Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/88 (0%)		0/81 (0%)
Serious Adverse Events
	DR Cysteamine Bitartrate Capsule		DR Cysteamine Bitartrate Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/88 (5.7%)		4/81 (4.9%)
Endocrine disorders
Diabetes	1/88 (1.1%)	1	1/81 (1.2%)	1
Gastrointestinal disorders
Pain - Abdomen NOS	1/88 (1.1%)	1	0/81 (0%)	0
Hepatobiliary disorders
Pain - Gallbladder	1/88 (1.1%)	1	0/81 (0%)	0
Cholecystitis	1/88 (1.1%)	1	0/81 (0%)	0
Infections and infestations
Infection - Appendix	0/88 (0%)	0	1/81 (1.2%)	1
Musculoskeletal and connective tissue disorders
Soft tissue necrosis	0/88 (0%)	0	1/81 (1.2%)	1
Psychiatric disorders
Mood alteration - depression	1/88 (1.1%)	2	1/81 (1.2%)	1
Personality/behavioral	1/88 (1.1%)	1	0/81 (0%)	0
Other (Not Including Serious) Adverse Events
	DR Cysteamine Bitartrate Capsule		DR Cysteamine Bitartrate Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/88 (70.5%)		55/81 (67.9%)
Cardiac disorders
Hypertension	1/88 (1.1%)	1	3/81 (3.7%)	3
Palpitations	1/88 (1.1%)	1	1/81 (1.2%)	1
Ear and labyrinth disorders
Pain - middle ear	2/88 (2.3%)	2	2/81 (2.5%)	2
Endocrine disorders
Diabetes	1/88 (1.1%)	1	1/81 (1.2%)	1
Metabolic/lab - other	1/88 (1.1%)	1	0/81 (0%)	0
Metabolic/lab - other	1/88 (1.1%)	1	0/81 (0%)	0
Eye disorders
Ocular - other	1/88 (1.1%)	1	0/81 (0%)	0
Ocular surface disease	0/88 (0%)	0	1/81 (1.2%)	1
Ocular - other	0/88 (0%)	0	1/81 (1.2%)	1
Ocular - other (eye redness, allergies)	0/88 (0%)	0	1/81 (1.2%)	1
Gastrointestinal disorders
Pain - abdomen NOS	11/88 (12.5%)	11	8/81 (9.9%)	9
Constipation	4/88 (4.5%)	4	4/81 (4.9%)	5
Teeth	2/88 (2.3%)	2	0/81 (0%)	0
Diarrhea	12/88 (13.6%)	12	11/81 (13.6%)	13
Vomiting	6/88 (6.8%)	7	9/81 (11.1%)	10
Pain - stomach	4/88 (4.5%)	4	4/81 (4.9%)	4
Nausea	5/88 (5.7%)	5	5/81 (6.2%)	6
Hemorrhage, GI - rectum	0/88 (0%)	0	2/81 (2.5%)	2
Heartburn	2/88 (2.3%)	2	3/81 (3.7%)	5
Flatulence	0/88 (0%)	0	1/81 (1.2%)	1
Enteritis	0/88 (0%)	0	2/81 (2.5%)	2
General disorders
Hemorrhage - pulmonary - nose	3/88 (3.4%)	5	4/81 (4.9%)	8
Fatigue	1/88 (1.1%)	1	1/81 (1.2%)	1
Insomnia	0/88 (0%)	0	1/81 (1.2%)	1
Flu-like syndrome	3/88 (3.4%)	3	0/81 (0%)	0
Hepatobiliary disorders
Metabolic/lab - other	0/88 (0%)	0	1/81 (1.2%)	1
Immune system disorders
Allergic reaction	1/88 (1.1%)	1	1/81 (1.2%)	1
Rhinitis	3/88 (3.4%)	3	5/81 (6.2%)	5
Allergy - other	0/88 (0%)	0	1/81 (1.2%)	1
Infections and infestations
Infection - skin	1/88 (1.1%)	1	2/81 (2.5%)	2
Infection - urinary tract NOS	1/88 (1.1%)	1	1/81 (1.2%)	1
Infection - ungual	2/88 (2.3%)	2	0/81 (0%)	0
Fever	3/88 (3.4%)	3	0/81 (0%)	0
Infection - pharynx	1/88 (1.1%)	1	1/81 (1.2%)	1
Infection - larynx	0/88 (0%)	0	1/81 (1.2%)	1
Infection - stomach	1/88 (1.1%)	1	1/81 (1.2%)	1
Infection - middle ear (otitis media)	4/88 (4.5%)	5	3/81 (3.7%)	3
Infection (middle ear) with unknown ANC	1/88 (1.1%)	1	0/81 (0%)	0
Infection (ungual) with unknown ANC	0/88 (0%)	0	1/81 (1.2%)	1
Infection (sinus) with unknown ANC	0/88 (0%)	0	1/81 (1.2%)	1
Infection - upper airway NOS	3/88 (3.4%)	4	3/81 (3.7%)	3
Infection - bronchus	0/88 (0%)	0	1/81 (1.2%)	1
Infection - sinus	0/88 (0%)	0	1/81 (1.2%)	1
Infection (documented clinically) - pharynx	1/88 (1.1%)	1	0/81 (0%)	0
Infection - lung (pneumonia)	1/88 (1.1%)	1	0/81 (0%)	0
Injury, poisoning and procedural complications
Pain - bone	1/88 (1.1%)	1	1/81 (1.2%)	1
Neurology - other (concussion)	1/88 (1.1%)	1	0/81 (0%)	0
Intraop injury - liver	1/88 (1.1%)	1	1/81 (1.2%)	1
Dermatology - other	0/88 (0%)	0	1/81 (1.2%)	1
Musculoskeletal - other (ankle sprain)	1/88 (1.1%)	1	0/81 (0%)	0
Musculoskeletal - other (wrist sprain)	1/88 (1.1%)	1	1/81 (1.2%)	1
Musculoskeletal - other (finger sprain)	0/88 (0%)	0	1/81 (1.2%)	1
Cervical spine ROM	0/88 (0%)	0	1/81 (1.2%)	1
Metabolism and nutrition disorders
Hypertriglyceridemia	0/88 (0%)	0	1/81 (1.2%)	1
Musculoskeletal and connective tissue disorders
Arthritis	0/88 (0%)	0	1/81 (1.2%)	1
Fracture	4/88 (4.5%)	4	1/81 (1.2%)	1
Pain - joint	1/88 (1.1%)	1	0/81 (0%)	0
Bone growth - spine	0/88 (0%)	0	1/81 (1.2%)	1
Extremity - upper	1/88 (1.1%)	1	0/81 (0%)	0
Joint - function	1/88 (1.1%)	1	3/81 (3.7%)	3
Lumbar spine ROM	1/88 (1.1%)	1	0/81 (0%)	0
Pain (extremity - limb)	3/88 (3.4%)	3	3/81 (3.7%)	4
Joint - function	0/88 (0%)	0	2/81 (2.5%)	2
Musculoskletal - other (spondylosis)	1/88 (1.1%)	1	0/81 (0%)	0
Nervous system disorders
Dizziness	2/88 (2.3%)	2	1/81 (1.2%)	1
Pain - head/headache	9/88 (10.2%)	9	6/81 (7.4%)	6
Neuropathy - sensory	2/88 (2.3%)	2	0/81 (0%)	0
Psychiatric disorders
Mood alteration - anxiety	2/88 (2.3%)	2	0/81 (0%)	0
Mood alteration - not specified	0/88 (0%)	0	2/81 (2.5%)	2
Mood alteration - depression	2/88 (2.3%)	2	1/81 (1.2%)	1
Mood alteration - irritability	1/88 (1.1%)	1	0/81 (0%)	0
Renal and urinary disorders
Cystitis	1/88 (1.1%)	1	0/81 (0%)	0
Reproductive system and breast disorders
Pain - testicle	0/88 (0%)	0	1/81 (1.2%)	1
Pain - breast	0/88 (0%)	0	1/81 (1.2%)	1
Hemorrhage, GU - vaginal	1/88 (1.1%)	1	0/81 (0%)	0
Gynecomastia	1/88 (1.1%)	1	0/81 (0%)	0
Irregular menses	2/88 (2.3%)	2	0/81 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchospasm	2/88 (2.3%)	2	1/81 (1.2%)	1
Cough	6/88 (6.8%)	7	8/81 (9.9%)	10
Dyspnea	0/88 (0%)	0	2/81 (2.5%)	2
Pain - chest/thorax NOS	4/88 (4.5%)	4	1/81 (1.2%)	2
Nasal/paranasal reactions	1/88 (1.1%)	1	0/81 (0%)	0
Pain - chest wall	0/88 (0%)	0	1/81 (1.2%)	1
Pneumonitis	0/88 (0%)	0	1/81 (1.2%)	1
Pulmonary - other (cold)	3/88 (3.4%)	3	3/81 (3.7%)	3
Pulmonary - other	0/88 (0%)	0	1/81 (1.2%)	1
Pain - throat/pharynx/larynx	0/88 (0%)	0	2/81 (2.5%)	2
Skin and subcutaneous tissue disorders
Alopecia	0/88 (0%)	0	1/81 (1.2%)	1
Pruritis	3/88 (3.4%)	3	0/81 (0%)	0
Rash	4/88 (4.5%)	5	1/81 (1.2%)	2
Striae	1/88 (1.1%)	1	1/81 (1.2%)	2
Hyperpigmentation	0/88 (0%)	0	1/81 (1.2%)	1
Hypopigmentation	0/88 (0%)	0	2/81 (2.5%)	3
Pain - skin	1/88 (1.1%)	1	0/81 (0%)	0
Ulceration	0/88 (0%)	0	1/81 (1.2%)	1
Urticaria	1/88 (1.1%)	1	0/81 (0%)	0
Dermatology - other	1/88 (1.1%)	1	0/81 (0%)	0
Dermatology - other (warts, HPV)	1/88 (1.1%)	1	0/81 (0%)	0
Surgical and medical procedures
Sexual - other (orchiopexy)	0/88 (0%)	0	1/81 (1.2%)	1
Tonsillectomy	0/88 (0%)	0	2/81 (2.5%)	2
Vascular disorders
Vasculitis	1/88 (1.1%)	1	0/81 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.