Safety, Tolerability, and Efficacy of Monotherapy and Com... | NCT03987074

Status Module

Name	Class
Novo Nordisk A/S	INDUSTRY

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Semaglutide	Experimental	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) for 24 weeks	Drug: Semaglutide
Semaglutide + Firsocostat 20 mg	Experimental	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg for 24 weeks	Drug: Semaglutide Drug: Firsocostat
Semaglutide + Cilofexor 30 mg	Experimental	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 30 mg for 24 weeks	Drug: Semaglutide Drug: Cilofexor
Semaglutide + Cilofexor 100 mg	Experimental	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 100 mg for 24 weeks	Drug: Semaglutide Drug: Cilofexor
Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg	Experimental	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks	Drug: Semaglutide Drug: Firsocostat Drug: Cilofexor

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Semaglutide	Drug	Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly	Semaglutide Semaglutide + Cilofexor 100 mg Semaglutide + Cilofexor 30 mg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)	Treatment-emergent adverse events (TEAEs) were defined as, any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. Participants were assessed for AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	First dose date up to Week 24 plus 30 days
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities	Treatment-emergent laboratory abnormalities, defined as values that increase at least one toxicity grade from baseline at any time post-baseline up to and including the date of last dose of study drug plus 30 days, were summarized by treatment group. Graded laboratory abnormalities were defined using the grading scheme in the CTCAE 5.0.	First dose date up to 24 weeks plus 30 days

Eligibility Module

Eligibility Criteria

Key Inclusion Criteria:

Historical liver biopsy consistent with NASH with stage 2-3 fibrosis according to NASH Clinical Research Network (CRN) classification OR clinical diagnosis of nonalcoholic fatty liver disease and screening FibroTest, magnetic resonance imaging - proton density fat fraction (MRI-PDFF), and FibroScan
Screening laboratory parameters, as determined by central laboratory:
- Alanine aminotransferase (ALT) ≤ 5 x upper limit of the normal range (ULN)
- Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Modification of Diet in Renal Disease (MDRD) study equation
- HbA1c ≤ 9.5%
- International normalized ratio (INR) ≤ 1.2, unless due to therapeutic anti-coagulation therapy
- Platelet count ≥ 100,000/μL
- Total bilirubin < 1.3 x ULN unless alternate etiology such as Gilbert's syndrome present
- Calcitonin ≤ 100 ng/L
Body Mass Index (BMI) > 23 kg/m^2 and body weight of > 60 kg

Key Exclusion Criteria:

Any historical liver biopsy consistent with cirrhosis
Any history of decompensated liver disease, including ascites, hepatic encephalopathy, or variceal bleeding
Other causes of liver disease, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (eg, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment
History of liver transplantation
History of hepatocellular carcinoma
History of pancreatitis (acute or chronic)
Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the period from 90 days prior to the date of the Screening Visit
Individuals on antidiabetic medications must be on a stable dose for at least 90 days prior to the date of the Screening Visit and in the period between the date of the Screening Visit and Enrollment (Day -14)

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Name	Affiliation	Role
Gilead Study Director	Gilead Sciences	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Institute for Liver Health - Arizona Liver Health		Chandler	Arizona	85224	United States
Southern California Research Centers

PubMed Identifier	Type	Citation	Retractions
	Result	Alkhouri N et al. Safety and Efficacy of Combination Therapies Including Semaglutide, Cilofexor, and Firsocostat in Patients with NASH [accepted for oral presentation]. American Association for the Study of Liver Diseases (AASLD); 2020; Virtual.
35439567	Derived	Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A, Huss RS, Zhu Y, Billin AN, Damgaard LH, Buchholtz K, Kjaer MS, Balendran C, Myers RP, Loomba R, Noureddin M. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J Hepatol. 2022 Sep;77(3):607-618. doi: 10.1016/j.jhep.2022.04.003. Epub 2022 Apr 16.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Semaglutide	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks.
FG001	Semaglutide + Firsocostat 20 mg

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 22, 2019	May 24, 2021

Arm/Group Information

ID	Title	Description
BG000	Semaglutide	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks.
BG001	Semaglutide + Firsocostat 20 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily with or without food for 24 weeks.
BG002	Semaglutide + Cilofexor 30 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks.
BG003	Semaglutide + Cilofexor 100 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 100 mg tablet orally once daily with or without food for 24 weeks.
BG004	Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks.
BG005	Total	Total of all reporting groups

Units	Counts
Participants	BG00021 BG00122 BG00222 BG00322 BG00421 BG005108

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)

Treatment-emergent adverse events (TEAEs) were defined as, any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. Participants were assessed for AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

The Safety Analysis Set included participants who received at least 1 dose of study drug.

Posted

Number

percentage of participants

First dose date up to Week 24 plus 30 days

ID	Title	Description
OG000	Semaglutide	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks.
OG001	Semaglutide + Firsocostat 20 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily with or without food for 24 weeks.
OG002	Semaglutide + Cilofexor 30 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks.
OG003	Semaglutide + Cilofexor 100 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 100 mg tablet orally once daily with or without food for 24 weeks.
OG004	Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks.

Units	Counts
Participants	OG00021 OG00122 OG00222 OG003

Title

Denominators

Categories

Title	Measurements
	OG00081.0 OG00186.4 OG00281.8 OG003

Primary

Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities

Treatment-emergent laboratory abnormalities, defined as values that increase at least one toxicity grade from baseline at any time post-baseline up to and including the date of last dose of study drug plus 30 days, were summarized by treatment group. Graded laboratory abnormalities were defined using the grading scheme in the CTCAE 5.0.

Participants in the Safety Analysis Set were analyzed.

Posted

Number

percentage of participants

First dose date up to 24 weeks plus 30 days

ID	Title	Description
OG000	Semaglutide	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks.
OG001	Semaglutide + Firsocostat 20 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily with or without food for 24 weeks.
OG002	Semaglutide + Cilofexor 30 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Semaglutide	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks.	21	1	21	16	21
EG001	Semaglutide + Firsocostat 20 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily with or without food for 24 weeks.	22	0	22	17	22
EG002	Semaglutide + Cilofexor 30 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks.	22	0	22	18	22
EG003	Semaglutide + Cilofexor 100 mg	Semaglutide + Cilofexor 100 mg Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + cilofexor 100 mg tablet orally once daily with or without food for 24 weeks.	22	1	22	13	22
EG004	Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg	Participants received semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) subcutaneously with prefilled PDS290 pen-injector once weekly for 24 weeks + firsocostat 20 mg tablet orally once daily + cilofexor 30 mg tablet orally once daily with or without food for 24 weeks.	21	0	21	17	21

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Vision blurred	Eye disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0010 affected22 at risk EG0022 affected22 at risk EG0030 affected22 at risk EG0040 affected21 at risk
Visual impairment	Eye disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0012 affected22 at risk EG0020 affected22 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0013 affected22 at risk EG0020 affected22 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected21 at risk EG0014 affected22 at risk EG0021 affected22 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0003 affected21 at risk EG0011 affected22 at risk EG0021 affected22 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected21 at risk EG0012 affected22 at risk EG0025 affected22 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0005 affected21 at risk EG0014 affected22 at risk EG0025 affected22 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0012 affected22 at risk EG0020 affected22 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected21 at risk EG0011 affected22 at risk EG0022 affected22 at risk EG003
Eructation	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected22 at risk EG0021 affected22 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0014 affected22 at risk EG0021 affected22 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0009 affected21 at risk EG0013 affected22 at risk EG0028 affected22 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected21 at risk EG0012 affected22 at risk EG0022 affected22 at risk EG003
Early satiety	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected21 at risk EG0013 affected22 at risk EG0020 affected22 at risk EG003
Fatigue	General disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected21 at risk EG0011 affected22 at risk EG0023 affected22 at risk EG003
Pyrexia	General disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0010 affected22 at risk EG0020 affected22 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0011 affected22 at risk EG0020 affected22 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected21 at risk EG0011 affected22 at risk EG0022 affected22 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected22 at risk EG0022 affected22 at risk EG003
Blood creatine phosphokinase increased	Investigations	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0010 affected22 at risk EG0020 affected22 at risk EG003
Weight decreased	Investigations	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0010 affected22 at risk EG0022 affected22 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0004 affected21 at risk EG0014 affected22 at risk EG0026 affected22 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0012 affected22 at risk EG0024 affected22 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG0005 affected21 at risk EG0010 affected22 at risk EG0020 affected22 at risk EG003
Dizziness	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected21 at risk EG0011 affected22 at risk EG0023 affected22 at risk EG003
Headache	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected21 at risk EG0013 affected22 at risk EG0021 affected22 at risk EG003
Dysuria	Renal and urinary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected22 at risk EG0020 affected22 at risk EG003
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0011 affected22 at risk EG0020 affected22 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected21 at risk EG0010 affected22 at risk EG0021 affected22 at risk EG003

ID	Term
D005234	Fatty Liver
D008107	Liver Diseases
D004066	Digestive System Diseases

ID	Term
C000591245	semaglutide
C000629250	firsocostat
C000717094	cilofexor