A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, Dose-Ranging Study Evaluating the Efficacy and Safety of GS-5290 in Participants With Moderately to Severely Active Ulcerative Colitis
- Trial ID
- 2022-501119-14-01
- Protocol
- GS-US-457-6411
- Sponsor
- Gilead Sciences Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2, double-blinded, randomized, placebo-controlled, dose-ranging study is to evaluate the **efficacy** of GS-5290 in achieving Clinical Response at Week 12 in participants with moderately to severely active **Ulcerative Colitis**. This is clinically relevant as achieving a clinical response can significantly improve patient outcomes and quality of life by reducing symptoms and inflammation associated with the disease.
Secondary objectives include:
- Demonstrating the efficacy of GS-5290, compared to placebo, in achieving Clinical Remission at Week 12.
- Assessing the efficacy of GS-5290 in achieving an endoscopic response at Week 12 compared to placebo.
- Evaluating the efficacy of GS-5290 in achieving Histologic Endoscopic Mucosal Improvement at Week 12 compared to placebo.
Participants
The clinical trial investigating the efficacy of GS-5290 in achieving clinical response in **ulcerative colitis** involves a total of 98 participants. The study population includes individuals assigned male at birth and nonpregnant, nonlactating individuals assigned female at birth, aged between 18 to 75 years. Participants were selected based on a confirmed diagnosis of ulcerative colitis of at least 90 days' duration, with a minimum disease extent of 15 cm from the anal verge, and a history of moderately to severely active disease as determined by a modified Mayo Clinic Score. The trial includes both male and female subjects, and the population is considered vulnerable. Participants have a documented history of previous treatment with approved ulcerative colitis therapies, with a failure of no more than three different advanced therapy mechanisms. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection criteria ensure that participants have undergone a surveillance colonoscopy within the 24 months prior to screening if they have a history of ulcerative colitis for eight or more years.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of GS-5290 in participants with moderately to severely active **ulcerative colitis**. The trial aims to demonstrate the efficacy of GS-5290 compared to placebo in achieving a clinical response at Week 12. The study will involve participants aged 18 to 75 years, with a confirmed diagnosis of ulcerative colitis of at least 90 days duration prior to randomization. The trial is expected to run from October 2023 to December 2025, with a maximum treatment period of 64 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including a modified Mayo Clinic Score and previous treatment history. Following randomization, participants will receive either GS-5290 or a placebo, administered orally in the form of film-coated tablets. The primary endpoint is a clinical response, defined as a significant decrease in the modified Mayo Clinic Score components at Week 12. Secondary endpoints include clinical remission, endoscopic response, and histologic endoscopic mucosal improvement.
Study visits will be scheduled at regular intervals to monitor the participants' health and response to the treatment. These visits will include assessments of stool frequency, rectal bleeding, and endoscopic findings. The end-of-study visit will occur at the conclusion of the treatment period, where final evaluations will be conducted to assess the overall efficacy and safety of the treatment. Participants may be withdrawn from the study early if they experience adverse effects or if they do not adhere to the study protocol. The trial is structured to ensure rigorous data collection and analysis, maintaining the integrity and reliability of the results.
Treatment
The clinical trial involves the evaluation of **GS-5290**, a small molecule serine/threonine kinase inhibitor, in participants with moderately to severely active **ulcerative colitis**. The experimental medication, GS-5290, is administered in the form of film-coated tablets available in two dosages: 150 mg and 300 mg. The active substance in GS-5290 is chemically identified as (phosphonooxy)methyln-[(s)-[1-(bicyclo[1.1.1]pentan1-yl)-1h-1,2,3-triazol-4-yl](2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl]-n-{8-chloro-3-cyano-4-[(2,2-dimethylpropyl)amino]quinolin-6-yl]carbamate. The medication is administered orally, with a maximum daily dose of 600 mg and a maximum total dose of 184,800 mg over a treatment period of up to 64 days. Participant compliance with the dosing schedule is monitored throughout the study.
In addition to the experimental treatment, a placebo control is utilized in this double-blinded, randomized, placebo-controlled study. The placebo is designed to match the GS-5290 tablets in appearance and is administered in the same manner, ensuring blinding is maintained. The primary objective of the trial is to assess the efficacy of GS-5290 in achieving clinical response at Week 12 compared to the placebo. The study is conducted under the sponsorship of Gilead Sciences Inc., and the trial design ensures rigorous monitoring of participant adherence to the treatment regimen.
Efficacy
The efficacy of GS-5290 in participants with moderately to severely active **Ulcerative Colitis** will be assessed through a series of predefined endpoints. The primary endpoint is the achievement of Clinical Response at Week 12, defined as a decrease from baseline of ≥ 2 points and at least 30% in three components of the modified Mayo Clinic Score (MCS): Stool Frequency, Rectal Bleeding, and Endoscopic Findings. Additionally, there must be a ≥ 1 point decrease from baseline in the Rectal Bleeding subscore or a Rectal Bleeding subscore of ≤ 1 at Week 12.
Secondary endpoints include Clinical Remission, Endoscopic Response, and Histologic Endoscopic Mucosal Improvement, all evaluated at Week 12. Clinical Remission is defined as a Stool Frequency subscore ≤ 1 and not greater than baseline, a Rectal Bleeding subscore of 0, and an Endoscopic Findings subscore ≤ 1. Endoscopic Response is characterized by an Endoscopic Findings subscore ≤ 1. Histologic Endoscopic Mucosal Improvement is defined by an Endoscopic Findings subscore ≤ 1 and a Geboes score < 3.1, indicating neutrophil infiltration in < 5% of crypts, with no crypt destruction, erosions, ulcerations, or granulation tissue.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants assigned male at birth, or nonpregnant, nonlactating participants assigned female at birth, 18 to 75 years of age based on the date of the screening visit.
- UC of at least 90-day duration before randomization confirmed by endoscopy and histology at any time in the past AND a minimum disease extent of 15 cm from the anal verge. Documentation of endoscopy and histology consistent with the diagnosis of UC must be available in the source documents prior to the initiation of screening.
- Moderately to severely active UC as determined during screening with a modified Mayo Clinic Score based on the sum of Stool Frequency, Rectal Bleeding, and Endoscopic Finding of 5 to 9 points and an endoscopic subscore of 2 to 3 (determined by central reader).
- Previous treatment history of approved UC therapy with at least one of the following advanced therapy mechanisms of action but failure (ie, loss of response or lack of response) of no more than 3 different advanced therapy mechanisms of action. a. TNFα inhibitor (eg, infliximab, adalimumab, golimumab, or approved biosimilars) b. IL-12/23 inhibitor (eg, ustekinumab or approved biosimilar) c. Leukocyte trafficking modulator (eg, vedolizumab, ozanimod, or approved biosimilar/generic) d. Janus kinase inhibitor (eg, tofacitinib, filgotinib, upadacitinib, or approved generic) e. IL-23 inhibitor (eg, risankizumab or approved biosimilar)
- Must have the ability to understand and sign a written informed consent form.
- May be receiving concomitant therapy for UC at the time of enrollment as specified in Section 5.6, provided the dose prescribed has been stable as indicated prior to randomization.
- A surveillance colonoscopy for dysplasia is required prior to randomization if indicated by regional guidelines for patients with UC.
- Meet the following tuberculosis (TB) screening criteria: a. No evidence of active TB, latent TB, or inadequately treated TB as evidenced by 1 of the following: i. A negative QuantiFERON test or equivalent assay reported by the central laboratory at screening or within 90 days prior to randomization for participants re-screening. OR ii. A history of fully treated active or latent TB according to local standard of care. Investigator must verify adequate previous anti-TB treatment and provide documentation; these participants do not require QuantiFERON testing and eligibility must be approved by the sponsor prior to enrollment in the study. AND b. A chest radiograph (views as per local guidelines with the report or films available for investigator review) taken at screening or within the 4 months prior to randomization without evidence of active or latent TB infection.
- Laboratory assessments at screening, including baseline hematology and chemistry at Day −5 to Day −3), within the following parameters: a. Aspartate aminotransferase (AST) and, alanine aminotransferase (ALT), and total bilirubin ≤ 2 ×× upper limit of normal (ULN) b. Estimated glomerular filtration rate ≥ 60 mL/min (1.0 mL/sec) as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) {Inker 2012} cystatin C formula as described in Section 6.3.9.2. c. Hemoglobin ≥ 8 g/dL (≥ 80 g/L) d. Absolute neutrophil count ≥ 1.5 × 103/μL (≥ 1.5 GI/L) e. Platelets ≥ 100 × 103/μL (≥ 100 GI/L) f. White blood cells ≥ 3 × 103/μL (≥ 3 GI/L) g. Absolute lymphocyte count ≥ 0.75 × 103/μL (≥ 0.75 GI/L)
- Stool sample test result negative for enteric pathogens.
- Stool sample test result negative for ova and parasites unless approved by the medical monitor.
- Negative human immunodeficiency virus (HIV) antibody test.
- Negative hepatitis B virus (HBV) surface antigen test. Participants with negative hepatitis B virus surface antigen (HBsAg) test and positive hepatitis B virus core antibody (HBcAb) test must have an HBV DNA less than the lower limit of quantification (LLOQ).
- Negative hepatitis C virus (HCV) antibody test or HCV RNA less than the LLOQ as described in Section 6.3.9.6.
- Negative urine drug screen result. A positive drug screen will exclude participants unless it can be explained by the use of a medication (prescription or nonprescription) that is being used under the direction of a physician. Cocaine use is exclusionary.
- Participants assigned female at birth of childbearing potential (as defined in Appendix 11.3) must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result on Day 1 prior to randomization.
- Participants assigned male at birth and participants assigned female at birth and of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 11.3. Note: other protocol-defined inclusion criteria may apply.
Exclusion Criteria
- Current diagnosis of CD or diagnosis of indeterminate colitis due to an enteric pathogen, lymphocytic or collagenous colitis.
- Participants with disease limited to the rectum (ulcerative proctitis) during screening endoscopy.
- Participants assigned female at birth who are pregnant, breastfeeding, intend to become pregnant, or are of childbearing potential and not using an adequate contraceptive method as described in Appendix 11.3.
- Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
- Participants susceptible to hyperbilirubinemia as determined by UGT1A1 genotyping.
- Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.6.2.
- Prior surgery for UC.
- Participants who are likely to require any type of major surgery during the study. Cataract surgery, breast surgery without reconstruction, laparoscopic cholecystectomy, laparoscopic tubal ligation and most cutaneous, superficial, dermatologic, gastrointestinal endoscopic and arthroscopic procedures can be considered minor surgeries.
- Have had any major surgery or trauma within 8 weeks prior to randomization.
- History or evidence of incompletely resected colonic mucosal dysplasia.
- History of malignancy in the last 5 years except for participants who have been treated or resected for either nonmelanoma skin cancer or cervical carcinoma in situ.
- History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma.
- Any chronic medical condition (including, but not limited to, cardiac or pulmonary disease) or psychiatric problem (including, but not limited to alcohol or drug abuse) that, in the opinion of the investigator or sponsor, would make the participant unsuitable for the study or would prevent compliance with the study protocol.
- History of immunodeficiency syndrome.
- Have a stoma or ileoanal pouch.
- Dependence on total parenteral nutrition.
- Have a transplanted organ with exception of a corneal transplant.
- Active clinically significant infection, or any infection requiring hospitalization or treatment with intravenous anti-infectives within 8 weeks of randomization; or any infection requiring oral anti-infective therapy within 6 weeks of randomization.
- History of opportunistic infection.
- History of symptomatic herpes zoster within 16 weeks of randomization, or any history of disseminated herpes simplex, disseminated herpes zoster, ophthalmic zoster, or Varicella Zoster virus central nervous system infections.
- Currently on any chronic systemic (oral or intravenous) anti-infective therapy for chronic infection (such as pneumocystis, cytomegalovirus, herpes zoster, or atypical mycobacteria).
- Current diagnosis of acute severe colitis, fulminant colitis, or toxic megacolon.
- Administration of a live or attenuated vaccine within 4 weeks of randomization (Section 5.7).
- Participants assigned female at birth who may wish to become pregnant and/or plan to undergo egg donation or egg harvesting for the purpose of current or future fertilization during the course of the study and up to 7 days after last dose of the study drug.
- Participants assigned male at birth unwilling to refrain from sperm donation for at least 7 days after last dose of the study drug.
- Established or suspected diagnosis of primary sclerosing cholangitis. Note: other protocol-defined exclusion criteria may apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 02 Oct 2023 | 5 |
 Belgium | Recruiting | 02 Oct 2023 | 10 |
 France | Recruiting | 02 Oct 2023 | 13 |
 Germany | Recruiting | 02 Oct 2023 | 14 |
 Hungary | Recruiting | 02 Oct 2023 | 9 |
 Italy | Recruiting | 02 Oct 2023 | 8 |
 Poland | Recruiting | 02 Oct 2023 | 19 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PTM GS‑5290 tablets 300 mg | Placebo | N/A | — | — | — | N/A |
GS-5290 tablets 300 mg | Test | FILM-COATED TABLET | ORAL | 600 | 64 | PRD10022462 |
GS-5290 tablets 150 mg | Test | FILM-COATED TABLET | ORAL | 600 | 64 | PRD10022461 |
PTM GS‑5290 tablets 150 mg | Placebo | N/A | — | — | — | N/A |