Phase 3 of GS-9674 in Subjects with Primary Sclerosing Cholangitis
Research type
Research Study
Full title
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Non-Cirrhotic Subjects with Primary Sclerosing Cholangitis
IRAS ID
255747
Contact name
Deepak Joshi
Contact email
Sponsor organisation
Gilead Science, Inc.
Eudract number
2019-000204-14
Clinicaltrials.gov Identifier
IND Number, 131031
Duration of Study in the UK
2 years, 10 months, 29 days
Research summary
Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease of unknown cause in which the bile ducts inside and outside the liver become inflamed, scarred (cirrhosis) and narrowed or blocked (cholestasis). This results in liver damage. 1.6 in 10,000 people are affected by PSC in the EU.
The sponsor Gilead Sciences, Inc., is running a research study to evaluate whether the study medicine, GS-9674, will reduce the risk of liver damage progression in participants with PSC (non-cirrhotic participants) yet to experience scarring of the liver and assess the safety and tolerability.
GS-9674 is a potent FXR (hormone receptor that regulates bile acid activity) agonist that acts by inducing an endocrine peptide called fibroblast growth factor 19 (FGF19) production which drives results in the decrease of bile acid levels.
Approximately 400 male and female PSC participants will be enrolled at about 200 sites across the world. Participants will be randomised into 2 different treatment groups with 2 out of 3 chances (67%) to receive GS-9674 (100 mg) and 1 out of 3 chances (33%) to receive Placebo (100 mg).
The study will be double-blind so neither the participant nor the study team will know which medication the participant is taking. The active GS-9674 as well as the matching placebo will be supplied by Gilead Sciences, Inc.
Participation will last 108 weeks including Screening Period (up to 8 weeks), Treatment period (96 weeks) and a Safety Follow-up Period (up to 4 weeks) after the 96 week visit.
Eligible participants will visit their study site 14 times during the 96 week treatment period to undergo various study procedures to see if GS-9674 can be useful to slow the liver scaring process in participants with PSC.
Throughout the study, participants will have study visits for safety monitoring and additional examinations (including
blood sampling).Summary of Results
The purpose of the study was to learn if treatment with cilofexor can lower the risk of progression of liver damage in participants with primary sclerosing cholangitis (PSC) who were at risk of severe liver damage.
PSC is a long lasting disease that affects bile ducts. Bile ducts are tubes inside and outside of the liver that carry bile fluid. Bile fluid is made in the liver and aids digestion, absorption of nutrients from food, and the removal of toxins from the body. Bile ducts outside the liver carry bile fluid from the liver to the gall bladder and small intestine.
PSC is a condition in which the bile ducts get damaged. Over time, the ducts become narrow, scarred, and block the flow of bile, which causes it to build up in the liver. This causes damage to the liver. Common symptoms include itching, feeling tired, fever, diarrhea, and jaundice (yellowing of the eyes and skin).
Liver cells try to repair themselves but, in the process, form scar tissue. The scar tissue prevents the liver from working properly. The scarring of the liver is called liver fibrosis. As scarring gets worse, called progression of fibrosis, it leads to liver cirrhosis. Cirrhosis is a late stage of scarring of the liver, which leads to severe liver damage. People with PSC may develop complications of cirrhosis that can lead to liver failure or cancer of the bile ducts.Liver transplants have been effective in treating PSC where the damaged liver is removed and replaced by a healthy one from a donor. However, beyond that there are limited treatment options available for people with PSC.
In this study, researchers tested the study drug cilofexor in people with PSC, who did not have cirrhosis, but were at a high risk of developing cirrhosis. Cilofexor acts by reducing the amount of bile formed which could help reduce the damage to the liver in people with PSC.
This was a phase 3 clinical study, where researchers looked at how cilofexor worked in a large group of people with PSC.
The main questions the researchers wanted to answer in this study were:
• How many participants had progression in liver fibrosis at Week 96 of the study, if any?
• What side effects did participants have during the study, if any?
Who took part in the study?
• 419 participants with PSC in 16 countries around the world.
• 3 participants left the study before taking cilofexor or placebo and were not included in the study results.
The participants enrolled in the study were between the ages of 18 to 74 years from around the world.
What happened during the study?
At the start of the study, the study doctor checked participants to see if they could take part in the study. Each participant had suitable tests to check for PSC and the level of liver fibrosis before they received the study treatment There were 2 parts to this study:
Part 1 of the study was randomized and double blinded.
Randomized: This means the researchers used a computer program to randomly choose the treatment each participant took. This helped make sure the treatments were chosen fairly.
Participants were randomized in 2:1 ratio, which means that there were twice as many participants receiving cilofexor treatment as those receiving the placebo.
Double blinded: This means that the participants, doctors, or other study staff, and the sponsor, i.e. Gilead personnel, did not know what study treatment each participant took. This was done to make sure that the study results were not influenced in any way.
During this part of the study, participants were randomized into 1 of the 2 treatment groups. Participants took the following treatments for up to 96 weeks:
• Cilofexor 100 milligram (mg) tablet, 1 time every day or A placebo looks like a • Placebo tablet, 1 time every day A placebo looks like a treatment but does not have any active ingredient (drug) in it. Researchers use a placebo as a point of comparison to identify whether a new treatment is effective and safe. Placebo was chosen to compare with cilofexor because there is no standard treatment available for people with PSC.
Participants visited the clinic multiple times during Part 1. Participants had tests to see if there were any changes in the severity of their PSC from the start of the study to the end of Week 96 of the study. Participants were also checked for any medical events they had during the study. About 30 days after the participants stopped taking the study treatments, they visited the study site to complete a follow-up visit.
Part 2 of the study was open label.
Open label: This means the participants, doctors, and study staff knew what treatment each participant took.
Participants who completed Part 1 and did not have cirrhosis could receive cilofexor during Part 2. Participants who received placebo during Part 1 could also receive cilofexor during this part of the study.
In Part 2, all the participants received:
• Cilofexor 100 mg tablet, 1 time every day, for up to 96 weeks Participants visited the clinic multiple times during Part 2. During the visits, study doctors checked participants for any medical events and other health problems. About 30 days after the participants stopped taking the study treatments, they visited the study site to complete a follow-up visit.
After 160 participants were treated and evaluated at Week 96 during Part 1, the results obtained from these participants were assessed. Gilead Sciences decided to stop the study because the study treatment did not work as expected.
What were the results of the study?
This is a summary of the main results from this study. The individual results of each participant might be different and are not presented in this summary. A detailed presentation of the results can be found on the websites listed at the end of this summary.
How many participants had progression in liver fibrosis at Week 96 of the study, if any?
Researchers wanted to know the number of participants whose liver fibrosis had got worse. Worsening liver fibrosis meant there was an increase in the scarring of the liver. Researchers performed liver biopsies to check participants for progression in liver fibrosis from the start of the study to the end of Week 96 of the study.
A liver biopsy involves taking a sample of liver tissue and examining it under a microscope to determine the presence and stage of liver fibrosis.
Researchers evaluated the liver tissue samples using a system called the Ludwig classification. It rates the stage of liver fibrosis based on how much scarring has taken place overtime. Fibrosis is described in 5 stages: F0 - lack of scarring, F1 - Mild scarring, F2 – Moderate scarring, F3 – Severe scarring, F4 Cirrhosis (late-stage scarring of the liver).
Participants were said to have progression of liver fibrosis if they had an increase in the scarring of the liver by one or more stages. The results included 197 participants who were evaluated at the start of the study and at Week 96.
The number of participants who had a progression of liver fibrosis at Week 96 during Part 1 of the study are as follows:
• 41 (31%) of participants on Cilofexor 100 mg (out of 133 participants)
• 21 (33%) of participants on Placebo (out of 64 participants)
The difference between the cilofexor and placebo treatment groups was small. A similar percentage of participants had a progression of liver fibrosis in the cilofexor and placebo groups.
What side effects did participants have during the study?
For the purpose of this summary, side effects are defined as unwanted medical events that the study doctors thought might be related to the study treatment.
A side effect is considered serious if it:
• results in death
• is life-threatening
• considered by the study doctor to be medically important • causes lasting problems • requires hospital care The results from several studies are usually needed to help decide if a treatment actually causes a side effect.
No participants died from any side effects.
At the following URL you can find tables describing overall side effects, serious side effects, and most common non-serious side effects for participants in this study: https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.gileadclinicaltrials.com%2F&data=05%7C02%7Champshirea.rec%40hra.nhs.uk%7C178fe31c348b4c65ce5d08dc01714324%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638386833166019658%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=1KGqXdMYdjj2PdhGETA3ISVnGElApwzI3Gnf6xKRRjk%3D&reserved=0.
The top 6 most common non-serious side effects that occurred during the study were itching, feeling tired, belly above the belly button, feeling sick to the stomach, belly pain, and headache.
There were other side effects, but those occurred in fewer participants. Some participants may have had more than one side effect.
How has this study helped researchers?
Even though the study did not continue as planned, it helped the researchers to learn how well and safe cilofexor was in people living with PSC.
The results from several studies are needed to help decide which treatments work and are safe. This summary shows only the main results from this one study. Other studies may provide new information or different results. Always talk to a doctor before making any treatment changes.
The results of this study will be used in other studies to learn if cilofexor could help people with PSC.
Gilead Sciences does not plan to have further studies with cilofexor in PSC.
Where can I learn more about this study?
You can find more information about this study on the websites listed below:
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C02%7Champshirea.rec%40hra.nhs.uk%7C178fe31c348b4c65ce5d08dc01714324%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638386833166019658%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=C4qjS0tr7f5i9QBcwZ8%2F0n4oMEXSqxtWO4hnIqqCPO4%3D&reserved=0: type NCT03890120 into the search box and click Search
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C02%7Champshirea.rec%40hra.nhs.uk%7C178fe31c348b4c65ce5d08dc01714324%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638386833166019658%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=BiLkwLSVdz4DPvE4%2B%2F7Ea9VpC%2BZUIG9coVeqm2cgtfM%3D&reserved=0: Once you are on the website, click Home and Search, then type 2019-000204-14 into the search box and click Search
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.gileadclinicaltrials.com%2F&data=05%7C02%7Champshirea.rec%40hra.nhs.uk%7C178fe31c348b4c65ce5d08dc01714324%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638386833166019658%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=1KGqXdMYdjj2PdhGETA3ISVnGElApwzI3Gnf6xKRRjk%3D&reserved=0: Once you are on the website, type GS-US-428-4194 into the search box and click Search Now National Clinical Trials Number: NCT03890120 EU Clinical Trials Number: 2019-000204-14 Please note that information on these websites may be presented in a different way from this summary.
Full Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Subjects With Primary Sclerosing Cholangitis For more information about clinical trials: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbUglsYQ93JiRYt-2BaxLKZu7WWjo-2FHyMJgnwFl5mHWnxWi1KujAz-2FjoPfTEO-2FvIYY7Ggd7NaIWiTrP3WL3r1PVDZk-3DmBWV_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJUDBfo2GSNi1DzDYbYBpOEa73Ne0I60Am-2BPyCwsSEudhuYGawjKj03mC7V0EV1HHW9hGreub-2Bee0n-2FD5KThG2k1-2FAPPJAfQE4ZzmVVvsc9wwG2EtmPPjGx1OwOC6edk4iVA82koH-2BdLCnY3MQb0qBitZH2zmhXUFfw9dyAiClM2A-3D-3D&data=05%7C02%7Champshirea.rec%40hra.nhs.uk%7C178fe31c348b4c65ce5d08dc01714324%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638386833166019658%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=Fx8m%2FJe28V6V9hHkKpIpO5OU9p6OQqb7hCgJLTHtkKA%3D&reserved=0REC name
South Central - Hampshire A Research Ethics Committee
REC reference
19/SC/0352
Date of REC Opinion
15 Jul 2019
REC opinion
Favourable Opinion