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Evaluation of the Efficacy and Safety of Ponesimod in Patients with Moderate to Severe Ulcerative Colitis

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What is this trial about?

A plain-language summary of the goals, design and what participants do

People with ulcerative colitis have long‑lasting inflammation of the large intestine that can cause frequent diarrhea, abdominal pain, and bleeding from the rectum. In this study participants will take a daily oral tablet that contains the investigational medicine ponesimod, or a look‑alike tablet that contains no active drug, called a placebo. The medicine is intended to reduce the inflammation that drives the disease.

The purpose of the study is to find out whether ponesimod can safely bring about clinical remission in individuals with moderate to severe ulcerative colitis. Researchers will use a tool called the Mayo score, which adds together numbers for stool frequency, rectal bleeding, and a view of the colon taken with a camera (endoscopy) to measure how active the disease is. Clinical remission means the score becomes very low, indicating little or no symptoms and no bleeding.

Participants will be randomly assigned to receive either the active medicine or the placebo, and neither the participants nor the doctors will know which is being taken. The tablets will be taken every day for about 16 weeks, with regular clinic visits for symptom checks, blood tests, and a brief endoscopic examination to look at the colon lining. Throughout the study, safety and how well the medicine is tolerated will be closely monitored.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization and Receipt of Study Medication

    After agreeing to join the study, you will be randomly assigned to receive either ponesimod tablets or matching placebo tablets that look the same.

    The study medication will be provided in film‑coated tablets that you will take by mouth.

  2. Step 2

    Baseline Assessments

    Before starting the medication, a series of assessments will be performed to document the current status of your ulcerative colitis. These may include a physical exam, blood tests, stool sample analysis, and a colonoscopy.

    The results will be used as a reference point for later comparisons.

  3. Step 3

    Start of Medication – Dose Escalation Phase

    You will begin taking a low dose of the study tablet, typically a 2 mg tablet, once each day.

    Each week the dose will be increased by 2 mg until you reach the target dose of 20 mg per day. The increase follows a fixed schedule that your study team will explain.

  4. Step 4

    Daily Medication Intake

    Once the target dose of 20 mg is reached, you will continue to take one 20 mg tablet every day for the remainder of the treatment period.

    If you are assigned to the placebo group, you will follow the same schedule using identical tablets that contain no active drug.

  5. Step 5

    Regular Clinic Visits for Safety Monitoring

    During the first 8 weeks, you will attend a clinic visit approximately every week to allow the study staff to check your health, review any side effects, and confirm that the dose escalation is proceeding safely.

    After week 8, visits will be scheduled roughly every 4 weeks until week 16.

  6. Step 6

    Week 16 Efficacy Assessment

    At the end of week 16, a comprehensive assessment will be performed, including another colonoscopy, blood tests, and symptom questionnaires.

    These evaluations will determine whether you have achieved clinical remission or improvement according to the study’s predefined criteria.

  7. Step 7

    End of Treatment and Follow‑Up

    After the week‑16 assessment, you will stop taking the study medication.

    A final follow‑up visit may be scheduled a few weeks later to review any lasting effects and to ensure your safety.

Who can join the trial?

12 criteria

  • Be between 18 and 75 years old at the start of the study.
  • If you are a woman who could become pregnant, you must have a negative pregnancy test in the blood at the screening visit and a negative urine pregnancy test at the baseline visit before receiving any study medication.
  • You must show proof that you are immune to chickenpox (varicella‑zoster) either by a blood test that detects IgG antibodies or by having completed the chickenpox vaccine at least 30 days before you are randomly assigned to a treatment group.
  • You must agree to use birth control: men who can father children must use an acceptable method of contraception from the day you are randomly assigned until one month after the last dose; women who could become pregnant must use an acceptable method of contraception from one month before randomization (or screening) until one month after the last dose. Acceptable methods include pills, patches, injections, intrauterine devices, or condoms.
  • You must be able to sign a written informed consent form agreeing to take part in the study.
  • You must be willing to attend all scheduled study visits and must not take part in any other interventional trial while you are in this study.
  • You must have been diagnosed with moderately to severely active ulcerative colitis for at least 90 days before the screening visit.
  • Your ulcerative colitis must be confirmed as active by an endoscopy (a camera placed in the colon) that shows at least 10 cm of the rectum involved and a three‑component Mayo score between 5 and 9, with an endoscopic subscore of 2 or higher and a rectal bleeding subscore of 1 or higher. The Mayo score is a number doctors use to measure how much inflammation is present.
  • If you have extensive disease (pancolitis for more than 8 years) or left‑sided disease for more than 12 years, you must have had a surveillance colonoscopy (a detailed exam of the colon) within the past 12 months; otherwise a colonoscopy will be done at screening.
  • You must have a documented history of not responding well, losing response, or being unable to tolerate at least one approved ulcerative colitis treatment. Approved treatments include conventional therapy (such as oral aminosalicylates, corticosteroids, or thiopurines), biologic therapy (such as anti‑TNFα, anti‑integrin, or anti‑IL‑12/23 drugs), and JAK inhibitor therapy (such as tofacitinib or upadacitinib).
  • You may continue certain medications if they have been at a stable dose for a set time before randomization: oral aminosalicylate (stable for at least 4 weeks), oral corticosteroids (prednisone ≤20 mg per day or budesonide ≤9 mg per day, stable for at least 4 weeks), and probiotics (stable for at least 2 weeks). Immunosuppressive drugs such as azathioprine or 6‑mercaptopurine must be stopped at least 2 weeks before randomization, and any recent stop of aminosalicylate or corticosteroid must be at least 2 weeks before the screening endoscopy.
  • You must be judged to be in generally good health based on your medical history, laboratory tests, physical exam, and a 12‑lead electrocardiogram (ECG) (a test that records the heart’s electrical activity) performed during screening.

Who cannot join the trial?

41 criteria

  • Having a very serious form of ulcerative colitis, such as a recent severe flare, a dangerous swelling of the colon called toxic megacolon, a hole in the intestine (bowel perforation), previous removal of part or all of the colon (colectomy), recent hospital stay, treatment with strong steroids given through a vein (intravenous corticosteroids), or meeting specific signs of acute severe disease (many bloody stools, fast heartbeat, fever, low blood‑cell level, or high inflammation marker).
  • Being infected with HIV (human immunodeficiency virus) or testing positive for HIV antibodies.
  • Having a current or past active tuberculosis (TB) infection, or an untreated hidden (latent) TB infection.
  • Having any active infection within the last 28 days, or having received medication through a vein within the last 14 days.
  • Having an active or chronic infection with hepatitis B virus (HBV).
  • Having a current infection with hepatitis C virus (HCV).
  • Having moderate or severe liver disease (classified as Child‑Pugh class B or C) or a condition called primary sclerosing cholangitis that affects the bile ducts.
  • Previously taking or possibly being exposed to drugs that affect the S1P receptor (examples: fingolimod, ozanimod, etrasimod, natalizumab).
  • Having received a biologic therapy (a special type of medication that targets the immune system) within the past 8 weeks, or a JAK inhibitor (another immune‑targeting drug) within the time it takes for the drug to leave the body five times.
  • Having taken four or more different biologic medicines, or three biologics plus a JAK inhibitor, for ulcerative colitis.
  • Having taken immunosuppressive medicines such as azathioprine (AZA), 6‑mercaptopurine (6‑MP), or methotrexate within the past 4 weeks.
  • Being diagnosed with other types of colitis, such as indeterminate, microscopic, ischemic, radiation‑related, or infectious colitis.
  • Using steroid ointments or suppositories placed in the rectum (topical rectal steroids) within the past 2 weeks.
  • Using methotrexate within the past 8 weeks or drugs like cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within the past 16 weeks.
  • Receiving intravenous immune globulin (IVIg) or a procedure called plasmapheresis within the past 3 months.
  • Having taken therapies that remove lymphocytes (a type of white blood cell).
  • Having undergone fecal microbial transplantation (a stool‑based therapy) within the past 30 days.
  • Using medicines such as D‑penicillamine, thalidomide, dimethyl fumarate, or drugs that block pyrimidine synthesis.
  • Taking non‑steroidal anti‑inflammatory drugs (NSAIDs) like ibuprofen within the past 7 days (except for topical NSAIDs or low‑dose aspirin used for heart protection).
  • Receiving a live vaccine (a vaccine that contains a weakened form of the germ) within the past 4 weeks.
  • Using medicines that strongly affect liver enzymes called cytochrome P450 3A4 or the enzyme UGT1A1 within the past 4 weeks.
  • Having a blood test showing a creatinine level higher than 1.4 mg/dL for women or 1.6 mg/dL for men (a sign of reduced kidney function).
  • Being diagnosed with Crohn’s disease or having a fistula (an abnormal tunnel) that is typical of Crohn’s disease.
  • Having liver enzymes (AST or ALT) more than 1.5 times the normal upper limit, or a direct bilirubin level more than 1.5 times normal.
  • Having a platelet count lower than 100,000 per microliter of blood.
  • Having a hemoglobin level lower than 8.5 g/dL (a measure of red blood cells).
  • Having a neutrophil count (a type of white blood cell) lower than 1,500 per microliter.
  • Having a total white‑blood‑cell count lower than 3,500 per microliter.
  • Having a lymphocyte count (another white‑blood‑cell type) lower than 800 per microliter.
  • Having an electrocardiogram (ECG) that shows a serious heart problem, such as a recent heart attack, stroke, severe heart failure, dangerous heart‑rhythm issues (e.g., certain types of AV block, sick‑sinus syndrome), a resting heart rate below 50 beats per minute, low blood pressure, a prolonged QT interval, or repeated episodes of very slow heart rate or fainting.
  • Having lung function tests (FEV1 or FVC) that are less than 70 % of the predicted normal values.
  • Being pregnant, breastfeeding, planning to become pregnant during the study, or having a positive pregnancy test at screening.
  • Having a known allergy or strong sensitivity to any ingredient of the study drug or its similar products.
  • Having other serious heart or medical conditions that could make the study unsafe or affect the results.
  • Having taken any other investigational medication (including placebos) within the past 60 days.
  • Being employed by, closely related to, or otherwise affiliated with the study site or sponsor, or feeling pressured to join the study, or any other reason the investigator believes participation would be unsafe or could interfere with the study.
  • Having uncontrolled diabetes, defined as a hemoglobin A1c (HbA1c) greater than 9 % or diabetes with serious complications such as eye disease.
  • Having a history of rare infections that occur when the immune system is weak (e.g., Pneumocystis jirovecii pneumonia, cryptococcal meningitis, progressive multifocal leukoencephalopathy), eye inflammation (uveitis), or unknown swelling of the macula (central part of the retina).
  • Having a history of cancer, except for certain skin cancers (basal cell carcinoma or in‑situ squamous cell carcinoma) that have been completely removed.
  • Having a history of alcohol or drug abuse within the past year.
  • Having a primary or secondary immune deficiency (a condition that weakens the body’s ability to fight infections).
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Investigated drugs

Ponvory is an oral tablet that contains the medicine ponesimod. In this study, participants took Ponvory to see if it could help reduce the signs and symptoms of moderately to severely active ulcerative colitis. The drug works by gently lowering the activity of certain immune cells that cause inflammation in the colon, which may lead to improvement in bowel function and a lower disease score. Researchers compared the effects of Ponvory with a placebo to determine how well it can bring patients into clinical remission by week 16.

What is already known about the treatment

Ponesimod - Ponesimod is taken by mouth as a film‑coated tablet, with doses ranging from 2 mg to 10 mg depending on the study schedule. It is an approved medicine (brand name Ponvory) for treating relapsing forms of multiple sclerosis and is currently being investigated for ulcerative colitis in clinical research. The drug works by selectively binding to the sphingosine‑1‑phosphate receptor 1 on immune cells, which keeps these cells from leaving lymph nodes and reduces inflammation in the gut. Pharmacologically, ponesimod is classified as an oral selective S1P‑1 receptor modulator (immunomodulator).

Investigated diseases

Ulcerative colitis - a long‑lasting inflammation that affects the lining of the large intestine, beginning in the rectum and often spreading upward. It causes the inner surface to become ulcerated, leading to frequent loose stools, blood in the stool, and a strong urge to go. The disease can start with mild irritation and gradually involve larger portions of the colon, increasing the amount of bleeding and urgency. Over time, the inflammation may become more extensive and persistent, resulting in continuous symptoms throughout the day. The condition follows a pattern of flare‑ups and periods of less activity, with each flare potentially worsening the extent of the affected colon.
Trial detailsLast updated 14 Nov 2026
Age18+ yearsPhasePhase IIITrial ID2025-524520-22-00Protocol codeVP-VSP-128-3201Estimated enrolment134 patientsSponsorVanda Pharmaceuticals Inc.

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