Dasatinib and quercetin, a combination of senolytics to treat fibrotic non-alcoholic fatty liver disease; The TRUTH study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amsterdam UMC Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18], Diseases [C] - Digestive System Diseases [C06]

Trial duration

14 Oct 2024 → 18 Feb 2026

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517593-21-00

EudraCT number

2021-005859-37

ClinicalTrials.gov

NCT05506488

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To examine the effect of oral dasatinib plus quercetin on liver fibrosis as assessed by histology in individuals with biopsy-proven NAFLD with fibrosis by performing a double‐blind randomized controlled proof‐of‐principle study. The primary endpoint is the binary outcome improvement of fibrosis with at least 1-point without worsening of fibrosis and NAFLD score based on histology after 21 weeks (yes/no).

Secondary objectives 6

1. To examine the effect of dasatinib plus quercetin on liver related histological parameters and high dimensional data
2. To examine the effect of dasatinib plus quercetin on biomarkers of NAFLD
3. To examine the effect of dasatinib plus quercetin on glucose metabolism-related parameters
4. To examine the effect of dasatinib plus quercetin on patient reported outcome
5. To examine the safety of dasatinib plus quercetin
6. To examine the effect of dasatinib plus quercetin on physical parameters and clinical lab values

Conditions and MedDRA coding

MASLD

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Adult individuals, age > 18 ≤70 years
2. NAFLD according to Non-invasive liver tests (FIB-4, APRI)
3. Individuals agree to have a liver biopsy performed after the treatment
4. Compensated liver disease with the following hematologic and biochemical criteria on entry into study: o ALAT <10x ULN o Hemoglobin > 11g/dL for females and 12 g/dL for males o White blood cell (WBC) > 2.5 K/ μL o Neutrophil count > 1.5 K μL o Platelets > 100 K/μL o Total bilirubin <35 μmol/L o Albumin >30 g/L o TP >80% or INR <1.4 o Serum creatinine <1.3 mg/dL (men) or <1.1 mg/dL (women) or estimated glomerular filtration rate (eGFR) > 60mL/min/1.73m
5. Have a stable weight defined by no more than a 5% loss of initial body weight
6. Negative pregnancy test or post-menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile) must be using a highly effective method of contraception (i.e. combined (estrogen and progestogen containing) hormonal/ progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormonereleasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence)
7. Subjects should be able to give informed consent

Exclusion criteria 16

1. Evidence of another form of liver disease
2. History of sustained excess alcohol ingestion: daily consumption >30g/day (3 drinks per day) for males and >20 g/day (2 drinks per day) for females
3. Unstable metabolic condition: weight change > 5 kg in the last three months, diabetes with unstable glycaemic control introduction of an antidiabetic or anti-obesity drug; malabsorptive or restrictive bariatric (weight loss) surgery in the past 6 months prior to screening
4. Bariatric surgery
5. ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose oestrogens, methotrexate, tetracycline or amiodarone in the previous 6 months
6. Significant systemic or major illnesses other than liver disease, including congestive heart failure (class C and D of the AHA), unstable coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, serious psychiatric disease, active malignancy, compromised immunity
7. Body mass index (BMI) >45 kg/m2
8. Type 1 diabetes
9. Haemostasis disorders or current treatment with anticoagulants
10. Contra-indication for liver biopsy
11. History of/or current cardiac dysrhythmias and/or a history of cardiovascular events including myocardial infarction, except patients with only well-controlled hypertension
12. QTc >450 msec on ECG
13. individuals who are lactose hypersensitive or have lactase deficiency
14. Pregnancy/lactation or inability to adhere to adequate contraception in women of child- bearing potentia
15. Use of prescribed drugs dependent on CYP3A4 with narrow therapeutic window and strong inducers or inhibitors of CYP3A4
16. Use of H2-antagonists and/or Proton Pump Inhibitors

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the binary outcome improvement of fibrosis with at least 1-point without worsening of fibrosis and NAFLD score based on histology after 21 weeks (yes/no). Individuals will be labeled as responder or non-responder.

Secondary endpoints 10

1. Mean change in number of senescent cells at baseline and end of treatment (week 21)
2. Percent of patients with reversal of NAFLD (Steatosis without ballooning and with or without mild inflammation) and no worsening of fibrosis) from baseline to end of treatment (week 21).
3. Global hepatic mRNA expression baseline to end of treatment (week 21)
4. Change from baseline to week 21 in NAFLD activity score (NAS)
5. Activity component of steatosis-activity-fibrosis (SAF) score: steatosis -1 point, lobular inflammation -1 point, ballooning -1 point EPOS score a 7 item scoring system (0-6) which represent the seven stages of fibrosis.
6. Change from baseline to week 21 in: Fibrosis-4 score (Fib-4 score) and NAFLD Fibrosis Score (NFS) Liver enzymes and synthesis function: ALT, AST and yGT, albumin, INR Liver stiffness and liver steatosis (with controlled attenuation parameter) measurement by Fibroscan
7. Change from baseline to 21 weeks in: Glycosylated haemoglobin type A1c (HbA1c), Fasting plasma glucose (FPG), Fasting insulin and glucagon , Homeostatic model assessment of insulin resistance (HOMA-IR) , Glucose day curve (Freestyle libre)
8. Change from baseline to 21 weeks in: RAND-36 and EQ-5D-5L: physical and mental component summary scores and scores on the individual sub-domains: Physical functioning, role functioning, bodily pain, general health, vitality, social functioning, role emotional and mental health.
9. Safety endpoints
10. Change from baseline to 21 weeks in: Pulse and ECG , Physical examination ,Haematology (haemoglobin, thrombocytes, erythrocytes, leucocytes, differential count) , Biochemistry (creatinine, creatinine phosphokinase, urea, bilirubin (total), alkaline phosphatase, ferritin, sodium, potassium, calcium. Fecal microbiota composition (morning stool and bile acids)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amsterdam UMC Stichting

Sponsor organisation

Amsterdam UMC Stichting

Address

De Boelelaan 1117

City

Amsterdam

Postcode

1081 HV

Country

Netherlands

Scientific contact point

Organisation

Amsterdam UMC Stichting

Contact name

Prof. Nieuwdorp

Public contact point

Organisation

Amsterdam UMC Stichting

Contact name

Prof. Nieuwdorp

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications