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A study testing sonlicromanol in adults with genetically confirmed mitochondrial DNA 3243A>G variant causing mitochondrial disease

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What is this trial about?

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

This study involves people with Primary Mitochondrial Disease caused by a specific genetic change called the mitochondrial DNA 3243A>G variant. This genetic variant can lead to different forms of the disease, including MIDD (a form that can affect diabetes and hearing), MELAS (a condition that can cause stroke-like episodes and other symptoms), and conditions affecting multiple body systems. People with this genetic change often experience ongoing tiredness and muscle weakness that affects their daily activities. The study will test a medication called sonlicromanol, which is also known by its code name KH176, and compare it to a placebo to see if it helps improve symptoms.

The purpose of this study is to find out if sonlicromanol can help reduce physical tiredness and improve muscle strength and balance in adults with this genetic form of mitochondrial disease. The study will also look at whether the medication affects quality of life and overall well-being. Participants will take either sonlicromanol tablets or placebo tablets by mouth for 52 weeks. The maximum daily dose of the study medication is 180 milligrams.

During the study, participants will complete questionnaires on electronic devices to report how they are feeling, including questions about tiredness, daily activities, mood, and overall health. They will also perform a physical test called the 5 Times Sit-to-Stand Test, which measures how long it takes to stand up and sit down five times in a row. This test helps assess leg muscle strength and balance. Additional assessments will include heart examinations using standard echocardiography or cardiac MRI to check heart wall thickness. Participants will need to maintain their usual exercise routine throughout the study and attend regular appointments for safety checks and to monitor how well the treatment is working.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Treatment period begins

    After joining the trial, treatment will begin. The treatment period will last for 52 weeks.

    During this period, medication will be taken orally (by mouth) in the form of a tablet.

    The medication used in this trial is called sonlicromanol, or a matching placebo tablet (an inactive substance that looks identical to the actual medication). The assignment to either the actual medication or placebo will be random, and neither the treating physician nor the patient will know which one is being received during the trial.

  2. Step 2

    Daily medication intake

    Throughout the 52-week treatment period, the assigned medication (either sonlicromanol or placebo) must be taken as instructed.

    The medication is administered as a tablet for oral use.

    The exact dosage, frequency, and specific timing of medication intake will be provided by the trial physician according to the study protocol.

  3. Step 3

    Maintaining stable exercise routine

    The current exercise routine must remain unchanged throughout the entire treatment period.

    Any exercise regimen that was established at least 4 weeks before joining the trial should be continued without modification for the duration of the study.

  4. Step 4

    Regular assessments during treatment

    During the 52-week treatment period, various assessments will be conducted to measure changes in health status.

    These assessments will measure physical fatigue symptoms and their impact on daily living and quality of life.

    Physical function will be evaluated, including lower limb muscle strength (strength in the legs) and dynamic balance control (ability to maintain balance while moving).

    A specific test called the 5 Times Sit-to-Stand Test will be performed. This test measures how long it takes to stand up and sit down five times from a chair.

    Several questionnaires will be completed to assess fatigue levels, physical functioning, mood, and overall severity of symptoms.

    These questionnaires include the NeuroQoL Fatigue questionnaire, the 36-Item Short Form Survey (which assesses physical functioning), the Fatigue Severity Scale, the Beck Depression Inventory (which assesses mood), and severity rating scales.

  5. Step 5

    Electronic patient-reported outcomes

    Throughout the trial, digital applications will be used to complete electronic patient-reported outcomes.

    These are questionnaires or assessments that are completed electronically to report symptoms, functioning, and quality of life.

    Responses should be provided within the specified time windows as instructed.

  6. Step 6

    Final assessment at week 52

    At the end of the 52-week treatment period, final assessments will be conducted.

    Changes from the beginning of the trial to week 52 will be measured in fatigue levels, physical function tests, questionnaire scores, and overall symptom severity.

    These measurements will help determine the effectiveness of the treatment received during the trial.

Who can join the trial?

12 criteria

  • You must be 18 years of age or older, male or female
  • You must have a multi-system primary mitochondrial disease, which is a condition that affects the energy-producing parts of your cells and can impact multiple organs in your body
  • You must have a confirmed mitochondrial DNA mutation called m.3243A>G with at least 20% heteroplasmy. Heteroplasmy means the percentage of cells that carry this specific genetic change. This must be measured in your blood, urine, cells from inside your cheek, or muscle tissue. The test results must be available before you can join the study
  • You must have experienced chronic fatigue (long-lasting tiredness) for at least 3 months before joining the study. This fatigue should not be caused by other health conditions. Your doctor must have noted this in your medical records, and you must score above 22 on a specific fatigue questionnaire
  • You must have mitochondrial myopathy, which is muscle weakness caused by mitochondrial disease. This will be tested using a five times sit-to-stand test, where you stand up and sit down five times. You must take at least 11 seconds or more to complete this test, and you must be able to perform it
  • You must be willing and able to provide written informed consent, which means signing a document showing you understand and agree to participate in the study before any screening tests begin
  • You must be able to attend all study appointments within the scheduled time periods
  • You must be able to follow the study instructions, take the study medication by mouth, and use digital devices to complete questionnaires on electronic devices
  • You must be clinically stable, meaning your overall health condition (apart from your mitochondrial disease symptoms) is steady and not changing rapidly. This will be checked through medical history, physical examination, vital signs (like blood pressure and heart rate), heart tracing, and blood tests
  • You must have maintained the same exercise routine for at least 4 weeks before joining the study, and you must be willing to keep this routine unchanged throughout the study period
  • Your heart muscle wall thickness must be 15 millimeters or less, as measured by echocardiography (an ultrasound of the heart) or cardiac MRI (a special scan of the heart)
  • If you are a woman who is able to become pregnant, you must use highly effective birth control methods during the study. Acceptable methods include: complete avoidance of sexual intercourse with men; hormonal birth control pills, patches, injections, or implants that prevent ovulation (release of eggs); an intrauterine device or intrauterine system (devices placed in the uterus to prevent pregnancy); surgical sterilization (having your ovaries removed, with or without removal of the uterus, at least six weeks before starting the study); or having a male partner who has had a vasectomy (surgical procedure to prevent pregnancy) that has been confirmed successful by a doctor, provided he is your only sexual partner

Who cannot join the trial?

3 criteria

  • The study does not list specific reasons why patients cannot participate
  • Patients should discuss with their doctor whether this study is appropriate for them based on their individual health situation
  • General medical safety requirements will be reviewed by the study team during the screening process
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Investigated drugs

  • Sonlicromanol

    is an investigational medication being studied in this trial. It is being tested to see if it can help reduce physical fatigue and improve muscle strength and balance in adults with a specific genetic condition affecting their mitochondria (the parts of cells that produce energy). This medication is being compared to a placebo to determine if it is effective and safe for treating symptoms related to this genetic variant.

  • Placebo

    is an inactive substance that looks like the real medication but contains no active treatment. It is used in this study to compare against sonlicromanol to help researchers understand whether any improvements seen are due to the actual medication or other factors.

What is already known about the treatment

Sonlicromanol – Sonlicromanol is an investigational medication currently being studied in Phase III clinical trials for the treatment of primary mitochondrial disease caused by a specific genetic mutation in mitochondrial DNA (the 3243A>G variant). This medication is being tested as an oral treatment to help improve physical fatigue, muscle strength in the legs, and balance control in adults with this genetic condition. Sonlicromanol works at the cellular level by supporting the function of mitochondria, which are the energy-producing structures inside cells, and it belongs to a class of drugs designed to protect cells from damage and improve energy production. The medication aims to reduce the impact of debilitating symptoms on patients' daily activities and overall quality of life.

Investigated diseases

  • Primary Mitochondrial Disease with Mitochondrial DNA 3243A>G variant

    This is a genetic disorder caused by a specific mutation in the mitochondrial DNA at position 3243, where adenine is replaced by guanine. Mitochondria are the energy-producing structures within cells, and when they do not function properly due to this genetic change, various body systems can be affected. The disease can appear in different forms depending on which organs are most impacted by the faulty mitochondria. Symptoms may develop at any age and can vary widely between individuals, even within the same family. The condition is inherited through the mother, as mitochondrial DNA is passed down only from the maternal line. Over time, the disease may progress as more cells are affected by the malfunctioning mitochondria.

  • Maternally Inherited Diabetes and Deafness

    This condition is one of the forms associated with the mitochondrial DNA 3243A>G mutation, characterized primarily by diabetes and hearing loss. The diabetes typically develops in adulthood and occurs because the insulin-producing cells in the pancreas require large amounts of energy and are particularly vulnerable to mitochondrial dysfunction. Hearing loss usually affects both ears and tends to worsen gradually over time. The condition may also affect other body systems to varying degrees, though diabetes and deafness are the main features. Symptoms usually appear between the ages of 20 and 40 years.

  • Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes

    This is a severe form of mitochondrial disease that affects multiple body systems, particularly the brain and muscles. Individuals experience episodes that resemble strokes, causing sudden weakness, vision problems, or seizures, though these are not caused by blocked blood vessels like typical strokes. The brain and muscles accumulate lactic acid due to impaired energy production, leading to fatigue, muscle weakness, and exercise intolerance. Additional symptoms may include headaches, vomiting, and difficulty with coordination and movement. These stroke-like episodes can occur repeatedly and may lead to progressive neurological decline over time.

Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2025-522361-30-00Protocol codeKH176-301Estimated enrolment220 patientsSponsorKhondrion B.V.

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