Study of Safety, Tolerability, and Efficacy of a Combination Treatment of LJN452 and CVC in Adult Patients With NASH and Liver Fibrosis (TANDEM)

• ClinicalTrials.gov Identifier: NCT03517540
• Recruitment Status: Completed
• First Posted: May 7, 2018
• Results First Posted: November 12, 2021
• Last Update Posted: April 29, 2022
• Sponsor: Novartis Pharmaceuticals
• Collaborator: Allergan
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 9, 2018
• First Posted Date: May 7, 2018
• Results First Submitted Date: October 14, 2021
• Results First Posted Date: November 12, 2021
• Last Update Posted Date: April 29, 2022
• Actual Study Start Date: September 11, 2018
• Actual Primary Completion Date: September 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 14, 2021)

Number of Participants With Adverse Events [ Time Frame: AEs were collected from first dose of study treatment until end of study treatment at week 48 and then up to maximum duration of 66 weeks ]

Occurrence of adverse events and serious adverse events Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment and then up to 66 weeks

Original Primary Outcome Measures (submitted: April 24, 2018)

Number of participants with Adverse Events [ Time Frame: 48 Weeks ]

Occurrence of adverse events and serious adverse events

Current Secondary Outcome Measures (submitted: October 14, 2021)

• Proportion of Participants Who Have at Least a One Point Improvement in Fibrosis [ Time Frame: baseline to 48 Weeks ]
  Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy
• Proportion of Participants With Resolution of Steatohepatitis [ Time Frame: baseline to 48 weeks ]
  Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy

Original Secondary Outcome Measures (submitted: April 24, 2018)

• Proportion of participants who have at least a one point improvement in fibrosis [ Time Frame: baseline to 48 Weeks ]
  Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy
• Proportion of participants with resolution of steatohepatitis [ Time Frame: baseline to 48 weeks ]
  Efficacy of tropifexor + CVC in patients with Nonalcoholic steatohepatitis (NASH) with fibrosis stage F2/F3 as assessed by histological improvement after 48 weeks of treatment compared to monotherapies (tropifexor and CVC) compared to baseline biopsy

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Safety, Tolerability, and Efficacy of a Combination Treatment of LJN452 and CVC in Adult Patients With NASH and Liver Fibrosis
• Official Title: A Randomized, Double-blind, Multicenter Study to Assess the Safety, Tolerability, and Efficacy of a Combination Treatment of Tropifexor (LJN452) and Cenicriviroc (CVC) in Adult Patients With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis
• Brief Summary: The purpose of this study was to assess the safety, tolerability, and efficacy of a combination treatment of tropifexor (LJN452) and cenicriviroc (CVC) in adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Non-alcoholic Steatohepatitis (NASH)

Intervention

• Drug: Tropifexor (LJN452)
  Comparison with monotherapy and different combination doses
  Other Name: LJN452
• Drug: Cenicriviroc (CVC)
  Comparison with monotherapy and different combination doses
  Other Name: CVC

Study Arms

• Experimental: Arm A: Tropifexor (LJN452) - Dose 1
  tropifexor 140 mcg, once daily; given orally
  Intervention: Drug: Tropifexor (LJN452)
• Experimental: Arm B: Cenicriviroc (CVC)
  CVC 150 mg, once daily; given orally
  Intervention: Drug: Cenicriviroc (CVC)
• Experimental: Arm C: Tropifexor (LJN452) Dose 1 + CVC
  tropifexor 140 mcg + CVC 150 mg, once daily; given orally
  Interventions:

  • Drug: Tropifexor (LJN452)
  • Drug: Cenicriviroc (CVC)
• Experimental: Arm D: Tropifexor Dose 2 + CVC
  tropifexor 90 mcg + CVC 150 mg, once daily; given orally
  Interventions:

  • Drug: Tropifexor (LJN452)
  • Drug: Cenicriviroc (CVC)

Publications *

• Pedrosa M, Seyedkazemi S, Francque S, Sanyal A, Rinella M, Charlton M, Loomba R, Ratziu V, Kochuparampil J, Fischer L, Vaidyanathan S, Anstee QM. A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial. Contemp Clin Trials. 2020 Jan;88:105889. doi: 10.1016/j.cct.2019.105889. Epub 2019 Nov 13.
• Parthasarathy G, Malhi H. Macrophage Heterogeneity in NASH: More Than Just Nomenclature. Hepatology. 2021 Jul;74(1):515-518. doi: 10.1002/hep.31790. Epub 2021 May 22. No abstract available.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 31, 2020): 193
• Original Estimated Enrollment (submitted: April 24, 2018): 200
• Actual Study Completion Date: October 15, 2020
• Actual Primary Completion Date: September 15, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Written informed consent Male and female patients 18 years or older (at the time of the screening visit). Patients must weigh at least 50 kg (110 lb) and no more than 200 kg (440 lb) to participate in the study.

Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Adequate liver biopsy sample for evaluation by Central Reader. Presence of NASH as demonstrated by histologic evidence based on liver biopsy - NASH with fibrosis stage F2/F3, demonstrated on liver biopsy during the screening period. Alternatively, a historical biopsy can be used if performed within 6 months prior to screening.

Exclusion Criteria:

Use of other investigational drugs within 5 half-lives of enrollment or within 30 days whichever is longer.

History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes.

Previous exposure to elafibranor, CVC, tropifexor, obeticholic acid (OCA), LMB763 or other FXR agonist.

Participated in a clinical trial and treated with any investigational product being evaluated for the treatment of liver fibrosis or NASH in the 6 months before screening.

Patients taking medications prohibited by the protocol. History of treated or untreated malignancy of any organ system, other than localized basal cell carcinoma of the skin or treated cervical intraepithelial neoplasia, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases .

Pregnant or nursing (lactating) women. Women of child-bearing potential. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 g/day in females and more than 30 g/day in males, on average) and/or a score on the modified AUDIT questionnaire ≥ 8.

Inability to reliably quantify alcohol consumption. History or evidence of ongoing drug abuse, within the last 6 months prior to randomization.

Prior or planned (during the study) bariatric surgery. Uncontrolled diabetes defined as HbA1c ≥ 9% at screening Clinical evidence of hepatic decompensation or severe liver impairment. Previous diagnosis of other forms of chronic liver disease. Calculated eGFR less than 60 mL/min (using the MDRD formula). History of biliary diversion History of liver transplantation or planned liver transplant. Known positivity for HIV. History or current diagnosis of ECG abnormalities indicating significant risk of safety for the patient to participate.

History of inflammatory bowel disease. Patients who are not candidates for liver biopsy. Presence of cirrhosis on liver biopsy (F4 by NASH CRN System) or medical history Patients with an abnormal platelet count (referring to reference ranges from the central lab).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Belgium, Canada, Czechia, Egypt, France, Germany, India, Israel, Italy, Latvia, Russian Federation, Singapore, Spain, Turkey, United Kingdom, United States
• Removed Location Countries: Estonia, Hong Kong, Portugal, Switzerland

Administrative Information

• NCT Number: NCT03517540
• Other Study ID Numbers: CLJC242A2201J; 2017-004208-24 ( EudraCT Number ); LJC242A2201J ( Other Identifier: Novartis )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Allergan

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: April 2022