Norursodeoxycholic acid vs. placebo in NASH
Research type
Research Study
Full title
Double-blind, randomised, placebo-controlled, phase IIb trial on the efficacy and safety of norursodeoxycholic acid tablets in patients with non-alcoholic steatohepatitis (NASH)
IRAS ID
262054
Contact name
Michael Stieß
Contact email
Sponsor organisation
Dr. Falk Pharma GmbH
Eudract number
2018-003443-31
Duration of Study in the UK
3 years, 2 months, 16 days
Research summary
Non-alcoholic fatty liver disease (NAFLD) is a very common cause of chronic liver disease in industrialised countries. NAFLD comprises a disease spectrum ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), liver cirrhosis and liver cancer.
So far, no drug has been approved for the treatment of NAFLD or NASH. Dietary changes and lifestyle modifications are the only available and recommended options for therapeutic management of this disease.The present trial is expected to provide efficacy and safety data for long-term treatment over 72 weeks with 1000 mg or 1500 mg of norursodeoxycholic acid (norUDCA) versus placebo in patients with NASH.
To confirm the diagnosis, a liver biopsy must be done at the start of the study if there is no historical biopsy of less than 3 months. Once the diagnosis is confirmed and the other eligibility criteria are met, participants will be assigned to one of 3 treatment groups (1000 mg norUDCA, 1500 mg norUDCA or placebo). The study drug is to be taken orally, once daily with fluid. The assignment to the treatment group is done independently and can’t be influenced by the people involved in the study. Neither the participant, nor the investigator will know which study drug a participant is taking.
The maximum duration of the study is 19 to 20 months for each participant, with 10 visits at the research site. Apart from liver biopsies at screening and end of study, diagnostic procedures and examinations exercised in this clinical trial are mostly routine or non-invasive procedures.
The study will be conducted in 13 European countries. 90 hepatologists/gastroenterologists will participate with the aim to enroll 360 participants.
Lay summary of study results: Summary Of Study Results Double-blind, randomised, placebo-controlled, phase IIb trial on the efficacy and safety of norursodeoxycholic acid tablets in patients with non-alcoholic steatohepatitis (NASH) NUT-3/NAS Thank you for participating in this study!
Dr. Falk Pharma GmbH, the sponsor of this clinical study, sincerely thanks you for taking part in this study. Your involvement has been important in helping researchers answer important health questions and advance knowledge on treating patients with Metabolic Dysfunction-associated Steatohepatitis (MASH) treated with norursodeoxycholic acid, now known as norucholic acid (NCA). Dr. Falk Pharma GmbH thinks it is important for every study participant to know the results and to share them with the general public.
This is the summary of study results. We hope this helps to understand the significance of this study and the key role of study participants in medical research.
1. What was this study about and what was the purpose of this study?
The full title of the study is “Double-blind, randomised, placebo-controlled, phase IIb trial on the efficacy and safety of norUDCA tablets in patients with non-alcoholic steatohepatitis (NASH)”. This study is also known as NUT-3/NAS (EudraCT No.: 2018-003443-31).
• Metabolic Dysfunction-associated Steatohepatitis (MASH)
MASH, formerly known as non-alcoholic steatohepatitis (NASH) is a liver disease caused by too much fat in the liver. This can lead to inflammation and scarring (fibrosis), and in severe cases, liver failure. MASH is not caused by alcohol but is often linked to being overweight, having diabetes, or high cholesterol. Most people with MASH do not notice symptoms at first. Some may feel tired, weak, or have mild pain or discomfort in the upper right side of the abdomen. Treating MASH is important because it can get worse over time. The disease is becoming more common worldwide, especially as being overweight and diabetes occur more frequently. When the study took place, there were no approved medicines available to treat MASH. Doctors usually recommend lifestyle changes such as losing weight, eating a balanced diet, and staying physically active to help reduce fat in the liver and slow down liver damage.
• Norucholic Acid (NCA)
Norucholic Acid (NCA), formerly known as norursodeoxycholic acid (norUDCA) is a medication that is being tested to treat MASH. NCA is a synthetic version of a natural substance called bile acid. NCA may help by: Reducing inflammation in the liver, Lowering the harmful effects of fat on liver cells (called lipotoxicity), Slowing down scarring (fibrosis) that can make the liver less able to work properly, Preventing uncontrolled cell growth within the liver.
• Study
In this study, 153 patients with MASH received NCA. The researchers wanted to find out if patients’ conditions can be improved by using NCA and to find the optimal dose of NCA for patients with MASH. To find this out, researchers gave different doses of NCA to patients with MASH and observed which dose was tolerated best and whether the patients’ condition improved. To measure whether the improvements are truly due to NCA-treatment, researchers also compared NCA to placebo. Placebos are identically looking tablets but with no medicine in them. In total, 63 patients received placebo tablets. This study is also known as NUT-3/NAS (EudraCT No.: 2018-003443-31). This summary only shows the results from this one study. Other studies may find different results.
2 Who sponsored this study?
This study was sponsored by Dr. Falk Pharma GmbH. If you have questions about the study, please contact Dr. Falk Pharma GmbH, Leinenweberstr. 5, 79108 Freiburg, Germany, email: zentrale@drfalkpharma.de.
3 Who participated in this study?
216 patients participated in 18 countries all over Europe and Asia in this study. The study started in August 2019 and ended in March 2025. The study took place in the following countries:
Belgium, Denmark, France, Ireland, Netherlands, United Kingdom, Austria, Czech Republic, Germany , Hungary, Poland, Switzerland, Italy Portugal, Spain, Georgia, Israel, Turkey For participating in this study, participants had to meet following key criteria:
• Having been diagnosed with MASH
• Aged 18 years or older and under 75 years • Having liver fibrosis, determined by liver biopsy. A liver biopsy is a medical test in which a small sample of liver tissue is taken with a needle and examined to diagnose or assess liver disease.
Patients could not join if they had a history of (among others):
• Significant alcohol consumption,
• Other liver diseases (e.g. hepatitis B or C, primary biliary cholangitis or primary sclerosing cholangitis), • Liver transplantation, • Type 1 diabetes mellitus or • Uncontrolled type 2 diabetes mellitus.
4 How was the study conducted?
The study was conducted in two stages: a pre-treatment phase and a treatment phase.
Pre-treatment phase:
In the pre-treatment phase, patients were informed about the study and gave their consent to take part. Researchers assessed general health status of the patients before these received NCA. They also performed further tests, as required by the study instructions. The tests included:
• A general physical check-up
• Blood and urine tests
• Ultrasound, Fibroscan (a quick, painless ultrasound test that measures liver scarring and fat without needles), and biopsy of the liver (these are different ways to look at liver health and its structure) • A 12-lead electrocardiogram, which records how the heart is working If researchers found that the patients met all criteria, most of which were listed above, they were able to be included in the study.
Treatment phase:
Before the actual treatment started, patients were divided into three different treatment groups by chance. Each group received different treatments or dosing. This random grouping, which is called randomisation, is important to reduce differences between the groups and to make the comparison between the groups fairer. This study was also “double blinded”, which means that neither patients nor researchers knew who received what kind of treatment. The purpose of this so-called “blinding” is to ensure that the study results were not influenced in any way.
All patients in group A took 1500 mg of NCA once a day over a period of 72 weeks. Patients in group B took 1000 mg of NCA once a day over a period of 72 weeks. Patients of group C took placebo once a day over a period of 72 weeks. Placebo tablets look identical to the NCA tablets but do not contain the actual medicine.
During the treatment period, all patients visited the study centre nine times. At these visits, the researchers checked the patients’ health and carried out again several tests, which included the following:
• A general physical check-up
• Blood and urine tests
• Ultrasound, Fibroscan (a quick, painless ultrasound test that measures liver scarring and fat without needles), MRI and, at the last visit, another biopsy of the liver • A 12-lead electrocardiogram, which records how the heart is working Patients also completed questionnaires about their quality of life, diet, and alcohol consumption.
Not every test was performed at each centre visit.
In total, 113 (52 %) women and 103 (48 %) men took part in the study. The average age of the participants was 56 years.
5 What were the main outcomes of this study? What were the overall results of the study?
This is a summary of what researchers learnt after study completion. In the following, we discuss the overall results of all study participants and not of individuals.
The main goal was to see if NCA could heal MASH or reduce liver scarring.
Result: NCA was not better than placebo for the main goal.
Specifically, this study found that NCA did not work better than placebo in MASH resolution (healing) and in improving liver fibrosis in patients with MASH, regardless of the dose tested. 28 of 83 patients (33.7%) in group A (NCA 1500 mg) and 14 of 70 patients (20%) in group B (NCA 1000 mg) reached resolution (healing) of MASH and/or improvement of fibrosis. In group C (Placebo) 19 of 63 patients (30.2%) reached resolution of MASH and/or improvement of fibrosis. However, the higher dose (1500 mg) showed improvements in other areas:
• It reduced inflammation in the liver
• It also improved the microscopic appearance of the liver.
• Liver enzyme levels were lower.
Study challenges: The study took place during the COVID-19 pandemic and the Russia-Ukraine conflict, and more patients than previously thought did not fulfil the criteria to participate. Therefore, it was difficult to find suitable patients for this study. Eventually, the study included fewer patients. These challenges did not change the results of the study.
6 Did the study participants have any unwanted effects or complications?
During the study, participants reported all medical problems or complications they had to the investigators. Additionally, investigators documented any significant or relevant changes observed during medical assessments. All unwanted medical problems or complications which happened during the study were reported, no matter if the study treatment caused them or not. In case the researchers thought that the study treatment caused the medical problem, they considered the problem as potential side effect. Not all participants in this study experienced side effects. This section informs on common and serious side effects, which have been experienced by the study participants. In total, in 63 out of 216 participants (29%) side effects occurred. In participants who received placebo, side effects were generally less frequent. The most common side effect was “diarrhoea”.
In the following there is a list of observed side effects. These are displayed by organ system (bold font), e.g. „Gastrointestinal disorders“. In addition, numbers for any individual side effects, e.g. „diarrhoea“, are shown if occurred in more than 2 participants.Gastrointestinal disorders were the most frequently reported adverse events across all study groups, occurring in 20.5% of participants receiving NCA 1500 mg (Group A), 11.4% in the NCA 1000 mg group (Group B), and 6.3% in the placebo group (Group C). Diarrhoea was reported at relatively similar frequencies across groups, while dry mouth and dyspepsia were observed only among participants receiving NCA. Abdominal distension was reported only in the 1000 mg group (4.3%), whereas abdominal pain and lip swelling occurred only in the 1500 mg group (2.4% each). Nausea was slightly more common in the placebo group (3.2%) compared to the treatment groups. In terms of laboratory investigations, elevated liver enzymes were reported in the NCA groups but not in the placebo group, with alanine aminotransferase and aspartate aminotransferase increases occurring in 2.4% of participants in the 1500 mg group and 1.4% in the 1000 mg group. Overall, adverse events were more frequently reported among participants receiving the higher dose of NCA compared with the lower dose and placebo.
Serious” side effects are side effects that are life-threatening, or require the participant to go to hospital, or cause permanent damage or death. In this study, 1 out of 216 participants (0.005%) had a serious side effect, which was reported as dyspnoea. “Serious” adverse events are any medical problems that occur around the time of treatment and are lifethreatening, or require the participant to go to hospital, or cause permanent damage or death, but are not necessarily caused by the drug. Serious adverse events occurred in 30 out of 216 participants (13.89%). No participant died during this study.
7 How has this study helped patients and researchers?
This study contributed to research of NCA treatment in patients with MASH. NCA 1500 mg improved some of the additional health measures which were assessed. However, it did not work better than placebo for the main outcome the study focused on, especially for measures of liver scarring (fibrosis). Further studies are needed before NCA can be prescribed for the treatment of MASH. It is not yet clear whether the effects seen on liver inflammation are meaningful in improving the overall disease. Please note that this summary reflects the outcome of one single study. Other clinical studies that are ongoing or might follow in the future may show something different. The results of many clinical studies are necessary to understand whether a treatment is efficient and safe.
8 Are there plans for further studies?
Further clinical studies with NCA for the treatment of MASH are under discussion. NCA is also tested for several other liver diseases.
9 Where can I find more information about this study?
To learn more about this study, visit https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.clinicaltrialsregister.eu%252Fctr-search%252Fsearch%253Fquery%253D2018-003443-31%2FNBTI%2FcPPDAQ%2FAQ%2F333a3ddc-d6e6-4a1d-819c-5506e0cac356%2F1%2F3xxJugYKUb&data=05%7C02%7Cleicestercentral.rec%40hra.nhs.uk%7Cf2ddfc82bbf146f7e22708de7f9fd783%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C639088521659814690%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=pf4SQx5sE3Po%2BqBp56DGq427waz5BxawPk%2F7euyIsaI%3D&reserved=0
For more information about the disease/condition: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fmy.clevelandclinic.org%252Fhealth%252Fdiseases%252F22988-nonalcoholic-steatohepatitis%2FNBTI%2FcPPDAQ%2FAQ%2F333a3ddc-d6e6-4a1d-819c-5506e0cac356%2F2%2FdCNIL3YpoB&data=05%7C02%7Cleicestercentral.rec%40hra.nhs.uk%7Cf2ddfc82bbf146f7e22708de7f9fd783%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C639088521659826643%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=IU65nsbcZ8k8L2hLaFUg00gMRAbXZ2ORUyPqOrxxky0%3D&reserved=0 https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fstanfordhealthcare.org%252Fmedical-conditions%252Fliver-kidneys-and-urinary-system%252Fmeta%2FNBTI%2FcPPDAQ%2FAQ%2F333a3ddc-d6e6-4a1d-819c-5506e0cac356%2F3%2FaAk6knyHz9&data=05%7C02%7Cleicestercentral.rec%40hra.nhs.uk%7Cf2ddfc82bbf146f7e22708de7f9fd783%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C639088521659841735%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=e6%2FueIoRtMyZJNaYhSXEAkMLlsGYH7aDgd757UGB3p8%3D&reserved=0 bolic-dysfunction-associated-steatohepatitis.html https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fliverfoundation.org%252Fliver-diseases%252Ffatty-liver-disease%252Fnonalcoholic-steatohepatitis%2FNBTI%2FcPPDAQ%2FAQ%2F333a3ddc-d6e6-4a1d-819c-5506e0cac356%2F4%2F0UPwTZfACf&data=05%7C02%7Cleicestercentral.rec%40hra.nhs.uk%7Cf2ddfc82bbf146f7e22708de7f9fd783%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C639088521659854361%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=bJtViGjoTvyBQPK4m5HSEdsjkvUwhcRKyWkCHblpVSo%3D&reserved=0 nash/mash-definition-prevalence/REC name
East Midlands - Leicester Central Research Ethics Committee
REC reference
19/EM/0105
Date of REC Opinion
20 May 2019
REC opinion
Further Information Favourable Opinion