Linerixibat for Itching in Cholangitis

No longer recruiting at 157 trial locations

Overseen By US GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: GlaxoSmithKline

Must not be taking: Obeticholic acid, SSRIs, Antihistamines, others

Disqualifiers: Hepatitis B, Hepatitis C, Hepatic decompensation, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called linerixibat to determine if it reduces itching in individuals with primary biliary cholangitis (PBC). The study compares linerixibat with a placebo to evaluate its effectiveness, safety, and impact on quality of life. Individuals diagnosed with PBC who experience moderate to severe itching may be suitable for this trial. Participants will receive either linerixibat or a placebo in different phases of the study to assess the treatment's effectiveness. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the chance to contribute to potentially bringing a new treatment to market.

Will I have to stop taking my current medications?

The trial requires that you do not start, stop, or change the dose of certain medications like ursodeoxycholic acid, bezafibrate, fenofibrate, obeticholic acid, bile acid binding resins, and some others in the 8 weeks before screening. If you are on these medications, you may need to maintain your current regimen.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that linerixibat has been tested in earlier studies to assess its safety and effectiveness. These studies found that linerixibat can significantly reduce itching in people with certain liver conditions, and most participants tolerated the treatment well.

In one study, patients taking linerixibat reported fewer side effects than those taking a placebo (a pill with no active medicine). The most common side effects were mild stomach issues, such as an upset stomach, while serious side effects were rare.

Since this trial is in a later phase, earlier research has already provided some confidence in the safety of linerixibat. This indicates that the treatment has undergone several rounds of testing to ensure its safety for use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cholangitis?

Linerixibat is unique because it targets the root cause of itching in cholangitis by blocking the ileal bile acid transporter (IBAT), which reduces bile acid levels in the body. Unlike current treatments that mainly focus on alleviating symptoms, Linerixibat directly addresses the underlying biochemical pathway responsible for the itch. Researchers are excited about Linerixibat because it offers a new mechanism of action and has the potential to significantly improve quality of life for patients with this condition.

What evidence suggests that linerixibat might be an effective treatment for itching in cholangitis?

Research has shown that linerixibat, which participants in this trial may receive, can significantly reduce itching in people with primary biliary cholangitis (PBC), a liver disease. One study found that patients taking linerixibat experienced a greater decrease in itching compared to those on a placebo. The reduction in itchiness was particularly noticeable over 24 weeks with linerixibat. This treatment works by blocking a specific transporter in the intestine, helping to control bile acids that cause itching. Overall, linerixibat has shown promising results in improving comfort for those with PBC-related itching. ^{1 3 5 6 7}

Who Is on the Research Team?

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with Primary Biliary Cholangitis (PBC) who suffer from moderate to severe itching. Candidates must have documented PBC and cannot have certain liver complications, changes in itch medication within the last 8 weeks, primary sleep disorders, or active viral infections among other exclusions.

Inclusion Criteria

I experience moderate to severe itching.

You have been diagnosed with primary biliary cholangitis (PBC).

I experience moderate to severe itching.

Exclusion Criteria

Your liver test results show very high levels of alanine aminotransferase, which could indicate liver problems.

I do not have ongoing severe diarrhea or active inflammatory bowel disease.

I have a diagnosed sleep disorder like sleep apnea or narcolepsy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive linerixibat or placebo for the treatment of cholestatic pruritus in PBC

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Linerixibat
• Placebo

Trial Overview The GLISTEN study is testing the effectiveness and safety of a drug called Linerixibat against a placebo in relieving itch caused by PBC. It also looks at how this treatment affects patients' quality of life.

How Is the Trial Designed?

Group I: Part B: Placebo in Part A and Linerixibat 40 mg in Part B Experimental Treatment 2 Interventions

Participants who were randomized to receive Placebo (up to Week 24) orally twice a day (BID) in Part A, switched to receive linerixibat 40 mg tablet orally twice a day (BID) (from Week 24 to Week 32) in Part B.

Group II: Part B: Linerixibat 40 mg in Part A and Placebo in Part B Experimental Treatment 2 Interventions

Participants who were randomized to receive linerixibat 40 mg tablet orally BID (up to Week 24) in Part A, switched to receive Placebo (from Week 24 to Week 32) orally twice a day (BID) in Part B.

Group III: Part B: Linerixibat 40 mg in Part A and Part B Experimental Treatment 1 Intervention

Participants who were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) (up to Week 24) in Part A, continued to receive linerixibat 40 mg twice a day (BID) (from Week 24 to Week 32) in Part B.

Group IV: Part A: Placebo Experimental Treatment 2 Interventions

Participants were randomized to receive Placebo orally twice a day (BID) in Part A (up to Week 24).

Group V: Part A: Linerixibat 40 milligrams (mg) Experimental Treatment 1 Intervention

Participants were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) in Part A (up to Week 24).

Group VI: Part B: Placebo in Part A and Part B Placebo Group 1 Intervention

Participants who were randomized to receive Placebo (up to Week 24) orally twice a day (BID) in Part A, continued to receive Placebo (from Week 24 to Week 32) orally twice a day (BID) in Part B.

Linerixibat is already approved in European Union, United States for the following indications:

Approved in European Union as Linerixibat for:

• None approved yet; orphan designation granted for primary biliary cholangitis (PBC) and associated cholestatic pruritus

Approved in United States as Linerixibat for:

• None approved yet; orphan drug designation granted for primary biliary cholangitis (PBC) and associated cholestatic pruritus

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Published Research Related to This Trial

In the Phase 2b GLIMMER study involving 147 adults with primary biliary cholangitis and moderate-to-severe itching, linerixibat showed a dose-dependent reduction in itch scores, particularly at higher doses, although the primary analysis did not show significant differences from placebo.

Diarrhea was the most common side effect associated with linerixibat, and its incidence increased with the dose, indicating a need for careful dose management in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Levy, C., Kendrick, S., Bowlus, CL., et al.[2023]

In a systematic review of 23 randomized controlled trials involving 2,194 patients, UDCA, methotrexate, and GSK2330672 were found to significantly relieve itching in patients with primary biliary cholangitis (PBC).

While these treatments showed promise for itching relief, the evidence for their effects on improving serum alkaline phosphatase (ALP) or γ-glutamyl transpeptidase (γ-GGT) levels was inconclusive due to high variability among studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pharmacological interventions for pruritus in primary biliary cholangitis: A systematic review and meta-analysis. Xu, C., Yue, R., Lv, X., et al.[2022]

In a study involving 44 patients with primary biliary cholangitis (PBC) suffering from moderate to severe pruritus, nalfurafine hydrochloride significantly reduced itch severity after 12 weeks of treatment, as shown by a decrease in both PBC-40 itch scores and visual analog scale (VAS) scores.

While nalfurafine effectively alleviated pruritus, it did not significantly improve overall health-related quality of life (HRQOL) measures, indicating that while it helps with itching, it may not address other quality of life issues in PBC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is patient-reported outcome improved by nalfurafine hydrochloride in patients with primary biliary cholangitis and refractory pruritus? A post-marketing, single-arm, prospective study. Yagi, M., Tanaka, A., Namisaki, T., et al.[2019]

Linerixibat, an oral medication for cholestatic pruritus, showed minimal absorption in humans, with an absolute oral bioavailability of only 0.05%, meaning most of the drug is not absorbed into the bloodstream.

The majority of linerixibat is excreted unchanged through feces (over 90%), indicating that it acts primarily in the intestine without significant systemic exposure, which may enhance its safety profile for treating conditions like primary biliary cholangitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers. Zamek-Gliszczynski, MJ., Kenworthy, D., Bershas, DA., et al.[2022]

Linerixibat, a selective inhibitor of the ileal bile acid transporter, effectively reduces cholestatic pruritus in patients with primary biliary cholangitis (PBC) by lowering serum bile acids, as demonstrated in the phase IIb GLIMMER trial.

The study found a dose-dependent relationship where higher doses of linerixibat increased the number of patients experiencing significant itch relief, but also raised the likelihood of diarrhea, leading to the selection of a 40 mg twice-daily dose for further testing in the phase III GLISTEN trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat. Carreño, F., Karatza, E., Mehta, R., et al.[2023]

In a phase 2a trial involving 22 patients with primary biliary cholangitis, the drug GSK2330672 was found to be safe and effective in significantly reducing pruritus (itch) severity over 14 days, with a 57% reduction in itch scores on a numerical rating scale.

While GSK2330672 showed promising results in alleviating itch and reducing serum bile acids, the most common side effect was diarrhea, which could limit its long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Hegade, VS., Kendrick, SF., Dobbins, RL., et al.[2022]

Citations

1. gsk.com gsk.com/en-gb/media/press-releases/glisten-phase-iii-trial-results-show-linerixibat-significantly-improves-cholestatic-pruritus/

GLISTEN phase III trial results show linerixibat significantly ... GLISTEN phase III trial results show linerixibat significantly improves cholestatic pruritus (relentless itch) in primary biliary cholangitis ( ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04950127

NCT04950127 | Global Linerixibat Itch Study of Efficacy ... This is a 2-part study in PBC participants with cholestatic pruritus and will evaluate the efficacy, safety and impact on health-related quality of life of ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36343847/

A Randomized Phase 2b Dose-Ranging Trial of Linerixibat ... GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus.

4. gut.bmj.com gut.bmj.com/content/74/Suppl_4/A6.abstract

O8 Linerixibat significantly improves cholestatic pruritus in ... Pruritus improvement over 24 weeks was significantly greater with linerixibat than placebo: least-squares (LS) mean change -2.86 versus -2.15, adjusted mean ...

5. gsk.com gsk.com/en-gb/media/press-releases/linerixibat-shows-positive-phase-iii-results-in-cholestatic-pruritus/

Linerixibat shows positive Phase III results in cholestatic ... Primary endpoint met with a statistically significant improvement in itch over 24 weeks compared with placebo.

6. gsk.com gsk.com/en-gb/media/press-releases/linerixibat-accepted-for-review-by-the-european-medicines-agency/

Linerixibat accepted for review by the European Medicines ... The primary analysis evaluated the efficacy and safety of linerixibat compared with placebo. The primary and key secondary endpoints of the ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S246812532500192X

Linerixibat in patients with primary biliary cholangitis and ... Patients receiving linerixibat experienced significant improvement in pruritus over 24 weeks compared with placebo (least-squares mean change ...