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Efficacy of 2-Isopropyl-3H-Naphtho(1,2-d)Imidazole-4,5-Dione in Adult Primary Mitochondrial Disease: A Randomized, Double-Blind, Placebo-Controlled Study

Verified siteFast replyInvestigationalNo placebo
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What is this trial about?

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

This clinical trial is focused on studying primary mitochondrial disease, a condition that affects the energy production in cells, leading to symptoms like fatigue and muscle weakness. The study will test a new treatment called KL1333, which is taken as a tablet, and compare its effects to a placebo. The main goal is to see if KL1333 can help reduce fatigue and improve muscle strength and endurance in adults with this disease.

Participants in the study will receive either KL1333 or a placebo for a period of 48 weeks. During this time, the effects of the treatment on symptoms such as fatigue and muscle function will be closely monitored. The study is designed to be flexible, allowing adjustments to the dosage as needed to best assess the treatment's effectiveness.

The trial will use various methods to evaluate the impact of KL1333 on daily living and physical abilities. This includes patient-reported outcomes and tests like the 30 Second Sit-to-Stand Test, which measures lower body strength. The study aims to provide valuable insights into how KL1333 might improve the quality of life for those living with primary mitochondrial disease.

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

    Baseline Assessment and Randomization

    Baseline assessments are performed to record your current fatigue level, lower‑extremity strength, and overall health. You will complete questionnaires such as the PROMIS Fatigue short form and the 30‑Second Sit‑to‑Stand Test. After these evaluations, you are randomly assigned to receive either the study drug KL1333 or a matching placebo. The assignment is double‑blind, meaning neither you nor the study staff will know which treatment you receive.

  2. Step 2

    Start of Study Medication

    You begin taking the oral medication once daily. The active tablet contains napazimone 100 mg, while the placebo tablets contain no active substance. The tablets are taken with water and may be taken with or without food. This daily dosing continues for a total of 48 weeks.

  3. Step 3

    Regular Follow‑Up Visits

    Throughout the 48‑week treatment period you attend scheduled study visits. At each visit you will:

    - Report any side effects or health changes.

    - Complete the PROMIS Fatigue questionnaire again to track changes in fatigue.

    - Perform the 30‑Second Sit‑to‑Stand Test to evaluate lower‑extremity strength and endurance.

    - Answer additional questionnaires, such as the Neuro‑QOL Lower Extremity Function short form, Individual Activity Assessments, and Patient Global Impression of PMD severity and change.

    - Allow the study team to record clinical assessments, including the Newcastle Mitochondrial Disease Adult Scale and, if you have diabetes, a measurement of glycated haemoglobin (HbA1c).

  4. Step 4

    Mid‑Study Safety Check

    Around the middle of the treatment period (approximately week 24) a comprehensive safety review is performed. Blood samples may be taken to check organ function and, for participants with diabetes, to measure HbA1c. The study team evaluates whether any adjustments to the medication dose are needed, following the flexible‑dose design of the trial.

  5. Step 5

    Final Assessment at Week 48

    At the end of the 48‑week treatment period you complete the final set of assessments:

    - The PROMIS Fatigue short form and the 30‑Second Sit‑to‑Stand Test to determine the overall effect of the study drug on fatigue and strength.

    - All secondary questionnaires, including the Neuro‑QOL Lower Extremity Function short form, Individual Activity Assessments, and Patient Global Impression of PMD severity and change.

    - Clinical evaluations such as the Newcastle Mitochondrial Disease Adult Scale and, if applicable, a final HbA1c measurement.

    These results are compared with the baseline data to evaluate the efficacy of KL1333 versus placebo.

  6. Step 6

    Study Completion

    After the final visit, the study medication is discontinued. You receive a summary of the study procedures you completed, and any further medical care is arranged with your regular healthcare provider.

Who can join the trial?

16 criteria

  • Be at least 18 years old.
  • Take mitochondrial‑disease vitamins or supplements such as coenzyme Q10 (CoQ10), niacin/vitamin B3, or L‑arginine at the same dose for at least three months before joining the study and stay on the same dose while in the study.
  • Agree to stop taking the medication idebenone for the whole study period.
  • If you are a female, you must not be pregnant and you must follow one of these rules: either you are not able to become pregnant, or you must use a highly effective form of birth control and not try to become pregnant from the time you sign the consent until about five half‑lives of the study drug plus 30 days after the last dose.
  • If you are a male with a partner who could become pregnant, you must use a male condom together with a highly effective form of birth control during treatment and for about 96 days after the last dose. This also applies if your partner is pregnant or breastfeeding.
  • Female participants must agree not to breast‑feed from the screening visit through the study and for about 36 days after the last dose.
  • Female participants must not donate eggs (ova) during the study and for about 36 days after the last dose; male participants must not donate sperm during the study and for about 96 days after the last dose.
  • Have a confirmed diagnosis of primary mitochondrial disease (PMD) caused by a known harmful gene change or a deletion in the mitochondrial DNA, meeting recognized genetic criteria (ACMG/AMP) and showing disease affecting several body systems (examples include MELAS‑MIDD, KSS‑CPEO, or MERRF).
  • Experience chronic mitochondrial fatigue for at least three months before the screening visit and have at least a moderate level of fatigue, measured by a score of 27 or higher on the PROMIS® Fatigue PMD Short Form questionnaire at screening and baseline.
  • Show signs of mitochondrial muscle weakness (myopathy), defined as either:
    • Weakness in hip‑flexing muscles (minimal reduction, described as MRC 4+/5) as recorded on the NMDAS (Newcastle Mitochondrial Disease Adult Scale) assessment, or
    • Reduced ability to tolerate exercise, meaning you can walk on flat ground without trouble but become symptomatic on inclines or stairs, also recorded on the NMDAS.
    • Be able to do at least 2 repetitions but no more than 17 repetitions (if male) or 16 repetitions (if female) in a 30‑second sit‑to‑stand (STS) test during screening.
    • Be clinically stable (no new health problems other than those related to mitochondrial disease) at the screening and baseline visits, as judged by medical history, physical exam, 12‑lead ECG, vital signs, and lab tests.
    • Be willing and able to attend study appointments within the required time windows.
    • Be willing and able to complete electronic patient‑reported outcome questionnaires (ePROs).
    • Agree to keep a stable diet during the screening period and throughout the study.

Who cannot join the trial?

16 criteria

  • You cannot join if you have a type of primary mitochondrial disease that mainly causes neuro‑degenerative problems such as Leigh syndrome, Leber hereditary optic neuropathy (LHON) or Neuropathy‑ataxia‑retinitis pigmentosa syndrome (NARP).
  • You cannot join if you have taken the medication idebenone within the 14 days before the first study dose.
  • You cannot join if you have a history of unstable or severe lung (pulmonary), immune (immunological), cancer (oncological), liver (hepatic), or kidney (renal) disease, or any other serious illness that could affect safety or study results, or if you are taking medicines that might interfere with the study.
  • You cannot join if, in the doctor’s opinion, you are unlikely to follow the study plan because of problems such as memory or thinking difficulties (cognitive impairment) or any other reason.
  • You cannot join if an immediate family member who lives at the same address is also taking part in the study.
  • You cannot join if you are a female and are pregnant at the screening visit or at the start of the study.
  • You cannot join if you have received another experimental (investigational) drug within the past 30 days or five drug‑half‑lives (whichever is longer), or if you plan to use another experimental drug during the study.
  • You cannot join if you are allergic (hypersensitive) to the study drug, any of its inactive ingredients, or the placebo.
  • You cannot join if your mitochondrial disease is caused by certain nuclear DNA changes or by mitochondrial DNA changes that make the DNA unstable, or if the genetic changes are of uncertain significance or have low heteroplasmy (meaning only a small proportion of cells carry the mutation).
  • You cannot join if your fatigue or muscle weakness is caused by something other than mitochondrial disease, as judged by the investigator.
  • You cannot join if you have serious heart problems, such as ongoing abnormal heart rhythms (arrhythmia), an enlarged or weak heart, a type of heart block called Mobitz II or worse, or an abnormal heart test (ECG) that the doctor considers significant. A heart‑rate‑corrected QT interval (QTcF) longer than 450 ms for men or 470 ms for women also excludes you.
  • You cannot join if you have had recent unstable disease or uncontrolled neurological issues, including a stroke‑like episode in the past 6 months, more than one seizure per month in the past 6 months, hospitalization for prolonged seizures (status epilepticus) in the past 6 months, or migraines lasting more than 4 days per month in the past 6 months.
  • You cannot join if you have a history of inflammatory bowel disease, stomach lining damage (gastric erosions), peptic ulcer disease, any gastrointestinal bleeding, or gastro‑esophageal reflux disease (GERD) that was diagnosed by an endoscopy or imaging test and has been symptomatic in the last 6 months.
  • You cannot join if laboratory tests taken at screening show values that could be unsafe, such as an estimated kidney filtration rate (eGFR) below 30 mL/min/1.73 m², a total bilirubin level more than 1.5 times the normal upper limit (unless due to a harmless condition called Gilbert’s syndrome), or liver enzymes (ALT or AST) more than twice the normal upper limit (unless the doctor can rule out serious liver problems).
  • You cannot join if you have severe coordination problems (ataxia), nerve damage (neuropathy), balance issues, or any other condition that would make it difficult to perform the 30‑second sit‑to‑stand test used in the study.
  • You cannot join if you have sleep apnea that has not been treated or is not adequately treated, according to the investigator.
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Investigated drugs

NAPAZIMONE is an investigational oral tablet being studied as a possible treatment for adults with primary mitochondrial disease. In the trial, participants take the tablet by mouth. The medicine is being tested to see if it can reduce fatigue, help people perform daily activities more easily, and improve the strength and endurance of the lower legs. It is classified as an orphan drug, meaning it is intended for a rare condition.

What is already known about the treatment

NAPAZIMONE - NAPAZIMONE is taken as a 100 mg oral tablet taken by mouth. It is an investigational orphan drug that is currently being studied in clinical trials for adults with primary mitochondrial disease. The medicine works by helping the cell’s energy factories work better, which can lessen fatigue and improve muscle strength. It is classified as a mitochondrial‑function enhancer or metabolic modulator.

Investigated diseases

Primary mitochondrial disease - Primary mitochondrial disease is a genetic disorder that impairs the cell’s energy factories, the mitochondria. It reduces the ability of cells to produce energy, leading to muscle weakness, fatigue, and problems in organs that need a lot of energy. In adults, symptoms often appear gradually and may include difficulty walking, balance issues, and changes in thinking. The condition can worsen over time as more cells become unable to generate sufficient energy. It may also affect the heart, eyes, and hormone‑producing systems, adding extra symptoms. Progression varies between individuals, with some experiencing steady decline while others have periods of stability.
Trial detailsLast updated 7 Nov 2026
Age18+ yearsPhasePhase IIITrial ID2023-508624-35-00Protocol codeKL1333 2020-104AEstimated enrolment195 patientsSponsorPharming Technologies B.V.

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