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A Randomized, Double‑Blind Study of ORX750 versus Placebo for Excessive Daytime Sleepiness in Adults with Narcolepsy (Type 1 and Type 2)

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What is this trial about?

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

The study focuses on people who have Central Disorders of Hypersomnolence, which are conditions that cause extreme daytime sleepiness. Specifically, it includes individuals with Narcolepsy with Cataplexy (also called Narcolepsy Type 1) and those with Narcolepsy without Cataplexy (Narcolepsy Type 2). The medication being tested is an oral capsule called cleminorexton, which will be compared with a dummy pill known as placebo.

The main goal of the trial is to see whether cleminorexton can reduce the excessive sleepiness that participants experience during the day. Volunteers will be randomly assigned to receive either the active drug or the dummy pill, and neither the participants nor the researchers will know which one is given. The study will last about three months, during which participants will take the assigned capsule each day and attend regular clinic visits for safety checks and questionnaires.

To measure how well the treatment works, participants will undergo simple tests that check how quickly they fall asleep in a quiet setting, known as the MWT, and will complete a questionnaire called the ESS that asks about everyday sleepiness. These assessments, along with routine health checks, help determine any changes in sleepiness and ensure the medication is safe to use.

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 (Day 0)

    You arrive at the clinic after joining the study and complete a medical history questionnaire.

    A physical examination, vital‑sign measurements, weight check, and 12‑lead electrocardiogram (ECG) are performed.

    Blood samples are taken for routine laboratory tests and for baseline measurement of cleminorexton levels.

    You complete the Epworth Sleepiness Scale (ESS) and other sleep‑related questionnaires.

    A daytime sleep latency test (MWT) is conducted to measure how quickly you fall asleep.

  2. Step 2

    Randomization and First Dose

    Based on a computer‑generated list, you are assigned to receive either a 1 mg, 2 mg, or 3 mg oral capsule of cleminorexton, or a matching placebo capsule.

    You are given a supply of capsules sufficient for the first two weeks and written instructions to take one capsule each morning with water.

    The study is double‑blind, so you will not know which treatment you have received.

  3. Step 3

    Daily Medication (Weeks 1–12)

    You take one capsule every morning at the same time, without food restrictions.

    You record each dose and any symptoms or side effects in a study diary.

    No dose adjustments are made unless instructed by the study team.

  4. Step 4

    Weekly Safety Checks

    Each week you attend a brief clinic visit or telephone call to report any adverse events.

    Vital signs, weight, and a brief symptom review are performed.

    Additional blood tests may be ordered at the investigator’s discretion.

  5. Step 5

    Midpoint Assessment (Week 6)

    You return to the clinic for a second set of evaluations.

    The daytime sleep latency test (MWT) is repeated.

    You complete the ESS and other questionnaires again.

    Blood is drawn to measure cleminorexton concentration and to repeat laboratory safety tests.

  6. Step 6

    Final Assessment (Week 12)

    A comprehensive visit is scheduled at the end of the 12‑week treatment period.

    The MWT, ESS, and all other questionnaires are administered a third time.

    Vital signs, weight, ECG, and laboratory safety tests are repeated.

    Blood samples are taken for final pharmacokinetic analysis of cleminorexton.

    You receive the last dose of study medication and are instructed to stop taking it after this visit.

  7. Step 7

    Post‑Treatment Follow‑up (Week 14)

    A safety follow‑up call is made two weeks after the final visit to check for any lingering side effects.

    No additional study medication is taken after Week 12.

Who can join the trial?

7 criteria

  • Have a doctor’s written diagnosis of Narcolepsy Type 1 (the form with sudden loss of muscle tone) made using the official sleep disorder criteria (International Classification of Sleep Disorders, 3rd edition, Text Revision (ICSD‑3‑TR)) within the last 10 years.
  • Have a positive result for the human leukocyte antigen (HLA) DQB1*06:02 genetic marker (a specific immune‑system gene test), either from a recent test or a documented past test.
  • Show, on a Multiple Sleep Latency Test (MWT) (a test that measures how quickly you fall asleep), an average time to fall asleep of less than 21 minutes during the first four trials at the start of the study.
  • After stopping any medicines used for cataplexy (sudden loss of muscle strength), be able to fill out a daily diary about cataplexy for at least 11 of the 14 days before the first study visit, and have had at least four episodes of cataplexy per week on average during those 14 days.
  • Have a doctor’s written diagnosis of Narcolepsy Type 2 (the form without sudden loss of muscle tone) made using the official sleep disorder criteria (ICSD‑3‑TR) within the last 10 years.
  • Show, on the same Multiple Sleep Latency Test, an average time to fall asleep of less than 21 minutes during the first four trials at baseline.
  • Be either male or female, as the study accepts participants of both genders.

Who cannot join the trial?

11 criteria

  • Having any other medical problem that can cause excessive daytime sleepiness, such as untreated moderate‑to‑severe sleep‑apnea (a type of sleep‑disordered breathing) or frequent leg movements during sleep (a periodic limb‑movement‑arousal index greater than 15).
  • Having a cerebrospinal fluid (CSF) level of orexin A higher than 110 pg/mL (if this test is done). CSF is the fluid surrounding the brain and spinal cord; orexin A is a chemical that helps keep you awake.
  • Taking any medicines that could change how cataplexy is measured (including antidepressants) within the 7 days before starting the sleep diary, and not having returned to your normal level of cataplexy by that time. Cataplexy is a sudden loss of muscle tone triggered by strong emotions.
  • Having significant cardiac (heart), malignancy (cancer), gastrointestinal (stomach/intestine), endocrine (hormone), neurologic (nervous‑system), psychiatric (mental‑health), immunologic (immune‑system) or other serious conditions that would make it unsafe or unreliable to join the study.
  • Using medicines that treat excessive daytime sleepiness, such as wake‑promoting agents, stimulants, sodium oxybate or mixed‑salt oxybate, unless a proper wash‑out period has been observed.
  • Using any drugs that could affect the measurement of excessive daytime sleepiness, for example medications that stimulate the central nervous system (CNS). The CNS includes the brain and spinal cord.
  • Taking sleep‑inducing drugs (hypnotics), including melatonin.
  • Having a positive pregnancy test, being currently pregnant, or lactating (breastfeeding).
  • Having a prolonged QT interval on an electrocardiogram (ECG) – more than 450 milliseconds for men or more than 470 milliseconds for women – or having other serious heart‑electrical problems such as second‑ or third‑degree atrioventricular block or left bundle branch block. The QT interval measures the time of electrical activity in the heart; an ECG records the heart’s electrical pattern.
  • Having abnormal blood pressure (systolic higher than 140 mm Hg or lower than 90 mm Hg; diastolic higher than 90 mm Hg or lower than 50 mm Hg) or an abnormal pulse rate (heart beating faster than 100 beats per minute or slower than 40 beats per minute) at screening.
  • Usually going to bed later than 1:00 AM.
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Investigated drugs

ORX750 is an experimental oral capsule being tested in this study. Participants take the capsule by mouth, and researchers are looking to see if it can help reduce excessive daytime sleepiness that occurs with certain sleep disorders. The trial will also check how safe the medication is, how well participants tolerate it, and how the drug moves through the body. This information will help determine whether ORX750 could become a useful treatment for people with central disorders of hypersomnolence.

What is already known about the treatment

ORX750 - ORX750 is taken as an oral capsule, with doses ranging from 1 mg to 4 mg taken by mouth. It is an investigational drug that is still being studied and has not yet received market approval. The medication is being evaluated for the treatment of narcolepsy, a disorder that causes excessive daytime sleepiness. It works by activating orexin receptors in the brain, helping to stabilize the sleep‑wake cycle, and it belongs to the class of orexin‑receptor agonists. Placebo - The placebo is an inactive oral capsule that looks identical to the active drug but contains no therapeutic ingredients. It is used in the trial as a control to compare the effects of the active medication. As it has no active substance, it has no therapeutic indication, mechanism of action, or pharmacological classification.

Investigated diseases

  • Narcolepsy type 1

    A chronic sleep disorder marked by excessive daytime sleepiness and sudden loss of muscle tone (cataplexy). It often begins in adolescence or early adulthood. Individuals may fall asleep abruptly during routine activities. Cataplexy episodes are usually triggered by strong emotions such as laughter or surprise. Over time, the frequency of sleep attacks and cataplexy can increase. Symptoms tend to persist and may vary day to day.

  • Narcolepsy type 2

    A chronic sleep disorder characterized by excessive daytime sleepiness without cataplexy. It typically starts in the same age range as type 1. People experience sudden urges to sleep during normal waking periods. Nighttime sleep may be fragmented, leading to further daytime fatigue. The intensity of sleepiness can grow gradually over the years. The condition remains throughout life, with symptoms that may fluctuate.

Trial detailsLast updated 11 Nov 2026
Age18+ yearsPhasePhase IVTrial ID2026-525961-37-00Protocol codeORX750-004Estimated enrolment97 patientsSponsorCentessa Pharmaceuticals UK Limited

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