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Efficacy and safety of remibrutinib, tacrolimus and pimecrolimus in adults with severe chronic pruritus of unknown origin: a randomized, placebo‑controlled trial

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What is this trial about?

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

Chronic Pruritus of Unknown Origin is a condition in which adults experience severe, long‑lasting itching without an identifiable cause, often leading to disturbed sleep and reduced quality of life. The trial compares an oral medication called remibrutinib with a placebo tablet, both taken once daily.

The purpose of the study is to determine whether remibrutinib reduces itch severity more than placebo. Participants will receive the assigned tablet for about 12 weeks and will be asked to rate their worst itch each day on a scale from 0 to 10; the weekly average of these scores is called the WI‑NRS. Additional questionnaires include the PGIS, a simple rating of overall itch severity, and the SD‑NRS, which measures how much itching interferes with sleep. Safety monitoring involves routine lab tests and vital‑sign checks, and participants continue to be followed for up to 52 weeks.

The study is randomized and double‑blind, meaning that neither the participants nor the study staff know which tablet is being taken, and the comparison focuses on the change in itch scores and any side effects observed during the trial period.

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

    Baseline Visit and Randomization

    During the first visit after joining the study, you will undergo medical examinations, answer questionnaires about your itch, and provide blood samples. The study staff will assign you randomly to receive either the active drug remibrutinib or a matching placebo. The assignment is double‑blind, meaning neither you nor the study staff will know which one you receive.

    You may continue using any prescribed topical treatments such as tacrolimus, pimecrolimus, or corticosteroid creams, and oral antihistamines, as these are considered background therapy.

  2. Step 2

    Start of Study Medication

    You will begin taking one film‑coated tablet by mouth each day. The tablet contains either remibrutinib (the active drug) or a placebo that looks identical. The exact dose is defined by the study protocol and is taken once daily for the duration of the trial, up to 52 weeks.

  3. Step 3

    Daily Itch and Sleep Rating

    Each day you will record your worst itch intensity on a scale from 0 (no itch) to 10 (worst imaginable itch). This is called the Worst‑Itch Numerical Rating Scale (WI‑NRS). You will also rate how much itch disrupts your sleep on a similar 0‑10 scale, known as the Sleep Disturbance Numerical Rating Scale (SD‑NRS). These ratings are entered into an electronic diary or paper log as instructed.

  4. Step 4

    Week 4 Assessment

    Four weeks after starting the medication, you will return to the clinic for a brief visit. The staff will review your daily itch scores, check for any side effects, and may perform a physical examination and laboratory tests.

  5. Step 5

    Week 12 Primary Evaluation

    At the end of the 12‑week period, you will attend a study visit where the average weekly WI‑NRS score will be calculated. The primary goal of the trial is to determine whether your WI‑NRS has improved by at least four points compared with the baseline value. You will also complete the Patient Global Impression of Severity (PGIS) questionnaire, which asks you to rate the overall severity of your itch as none, mild, moderate, severe, or very severe.

    Laboratory tests and vital‑sign measurements will be taken to monitor safety.

  6. Step 6

    Week 24 Follow‑up

    At 24 weeks you will have another clinic visit. The PGIS questionnaire will be completed again to assess whether your itch is rated as none or mild. Ongoing safety checks, including blood tests and vital signs, will be performed.

  7. Step 7

    Continued Treatment to Week 52

    You will continue taking the study tablet daily for the remaining weeks, up to a total of 52 weeks. Throughout this period, you will keep recording daily WI‑NRS and SD‑NRS scores, and you will report any new symptoms or side effects to the study team.

    At the final 52‑week visit, comprehensive safety assessments will be performed, including laboratory evaluations, vital‑sign checks, and a review of any adverse events that occurred during the study.

Who can join the trial?

8 criteria

  • Be at least 18 years old when you sign the consent form.
  • Have had chronic itching (pruritus) for four months or more before the screening visit.
  • Your itching must be judged by the doctor to be of unknown origin, meaning it is not caused by a known skin disease, internal medical condition, nerve problem, psychological issue, medication, or allergy. Having mild‑to‑moderate dry skin (xerosis) is allowed only if the doctor decides it is not the main reason for the itch; if dry skin is the main cause, you cannot join.
  • The itch must involve at least two of these areas: the trunk (body), the arms, or the legs. It cannot be limited to just one side of the body or follow a nerve pattern.
  • You must still have severe, ongoing itching even though you are using moisturizers (emollients) and you must be a candidate for a medication taken by mouth or injection (systemic therapy).
  • Your itch severity must be scored at 7 or higher on the WI‑NRS (a 0‑10 rating where 0 = no itch and 10 = worst possible itch) during the screening visit.
  • During the 7 days before the randomization visit, your average WI‑NRS score must also be 7 or higher, and you need to have recorded at least four daily scores in your diary.
  • At both the screening and baseline visits, you must rate your overall itch as a 3 (“severe”) on the PGIS (Patient Global Impression of Severity) scale.

Who cannot join the trial?

8 criteria

  • Active skin conditions such as eczema (atopic dermatitis) or psoriasis that could interfere with measuring itch severity.
  • Systemic conditions or medicines that can cause chronic itching, including hives, swelling (angioedema), rare disorders like systemic mastocytosis or mast cell activation syndromes, and drugs such as opioids, immunotherapy, cytokines, growth factors, or any medication that can activate mast cells, if the doctor believes they are the main cause of the itch.
  • Use of other investigational drugs within a washout period: any study drug taken within 5 half‑lives (the time for half the drug to leave the body) or within 30 days for small pills, or until the effect of biologic medicines (large protein drugs) returns to normal. Also, you must not have taken biologic treatments for CPUO such as dupilumab or nemolizumab in the 3 months before joining the study.
  • Active or recurring infectious disease that could make participation unsafe, such as tuberculosis, atypical mycobacterial infections, listeriosis, aspergillosis, or known or suspected HIV infection.
  • History of malignancy (cancer) in any organ, except for localized basal cell carcinoma of the skin or early‑stage (in situ) cervical cancer, treated or untreated, within the past 5 years.
  • Significant health problems in major organ systems—heart, brain, mental health, lungs, kidneys, liver, hormones, blood, digestive system, or immune system—that the investigator feels could compromise safety, affect study results, or prevent you from following the study plan. Examples include recent heart attack, unstable heart disease, severe heart failure (NYHA Class III/IV), irregular heartbeat, or uncontrolled high blood pressure.
  • Significant bleeding risk or coagulation disorders, including a history of serious gastrointestinal bleeding that required medical treatment or blood transfusion. You may not be on strong blood‑thinners except low‑dose aspirin (up to 100 mg/day) or clopidogrel (up to 75 mg/day). Using both aspirin and clopidogrel together (dual anti‑platelet therapy) is not allowed.
  • Current liver disease or abnormal liver tests, such as acute or chronic hepatitis, cirrhosis, liver failure, or liver enzyme levels (AST/ALT) more than 1.5 times the normal upper limit, or an International Normalized Ratio (INR) greater than 1.5 at screening.
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Investigated drugs

  • Tacrolimus

    is a cream applied to the skin that calms the immune system. It helps reduce skin inflammation and itching, and is used as a background treatment in the study.

  • Pimecrolimus

    is also a skin‑applied cream that works by soothing the immune response in the skin. It lessens inflammation and itching, and participants may be using it alongside the study medication.

  • Remibrutinib

    (code name LOU064) is an oral tablet that blocks a specific enzyme involved in the itch pathway. It is the experimental drug being tested to see if it can lower severe chronic itching.

  • Systemic antihistamine

    refers to a pill taken by mouth that blocks histamine, a substance that can cause itching and allergic reactions. It is allowed as a background therapy for participants.

  • Topical corticosteroid

    is a cream or ointment applied to the skin that reduces inflammation and itching. It is also permitted as a background treatment during the trial.

What is already known about the treatment

  • Tacrolimus

    This medication is applied to the skin as a cream or ointment and works locally on the affected area. It is an approved immunosuppressant that is widely used to treat eczema and other inflammatory skin conditions. Tacrolimus binds to a protein called FKBP‑12 and blocks an enzyme named calcineurin, which stops T‑cells from releasing chemicals that cause itching and inflammation. It belongs to the class of topical calcineurin inhibitors.

  • Pimecrolimus

    Pimecrolimus is also a skin‑applied cream that is used to calm inflammation in conditions such as atopic dermatitis. It is an approved drug that has been on the market for many years and is considered safe for short‑term use. The drug works by attaching to FKBP‑12 and inhibiting calcineurin, thereby reducing the activity of T‑cells and the release of itch‑triggering substances. It is classified as a topical calcineurin inhibitor.

  • Remibrutinib

    Remibrutinib is taken by mouth as a film‑coated tablet and is being studied as a new treatment for severe chronic itching of unknown cause. It is currently in clinical trials and not yet approved for general medical use. The drug blocks an enzyme called Bruton’s tyrosine kinase (BTK), which interferes with signals that activate immune cells and lead to itch sensations. It is classified as an oral BTK inhibitor and an immunomodulatory agent.

Investigated diseases

Chronic Pruritus of Unknown Origin (CPUO) - A persistent, intense itching that lasts for weeks or months without an identifiable skin disease or systemic cause. The sensation can be constant or come and go, affecting any part of the body. Over time the itch often becomes more bothersome and may lead to repeated scratching. Repeated scratching can cause skin changes such as thickening, redness, or small sores. The severity of the itch may vary day to day and can be worsened by factors like heat, stress, or dry skin.
Trial detailsLast updated 25 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2025-524497-41-00Protocol codeCLOU064R12301Estimated enrolment130 patientsSponsorNovartis Pharma AG

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