KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases

NCT06451757 | Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: Khondrion B.V.
• Study Type: interventional
• Target: 220
• Locations: 7 countries
• Sites: 10

Brief Summary

The KHENERFIN study aims to determine whether the study medicine, sonlicromanol, is able to reduce symptoms of fatigue and the impact of fatigue on daily life, and whether sonlicromanol is able to improve physical abilities of people like balance control and lower limb skeletal muscle strength in people with mitochondrial disease. In this study, the effects of sonlicromanol are compared against a placebo, a tablet identical in appearance and taste but without the active drug. Participants take either sonlicromanol or placebo twice daily for a treatment duration of 52 weeks. In addition to these primary objectives, the study evaluates the efficacy of sonlicromanol on secondary and exploratory outcomes, as well as its safety and tolerability after one year of treatment.

Conditions

Mitochondrial Diseases; Maternally Inherited Diabetes and Deafness (MIDD); Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS); Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation

Keywords

Mitochondrial Diseases; Oxidative Phosphorylation (OXPHOS); Maternally Inherited Diabetes and Deafness (MIDD); Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation; Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS); Sonlicromanol

Outcome Measures

Primary Outcomes (2)

• Neuro-QoL Fatigue Short Form v1

  Change from baseline compared to placebo at week 52 and at other relevant study visits of the Quality of Life in Neurological Disorders Fatigue Short Form version 1 (Neuro-QoL Fatigue - SF v1): The Neuro-QoL Fatigue SF v1 is an 8-item self-assessment questionnaire evaluating the perception of fatigue and its impact in daily life activities. Each question is scored as following: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Always. Total raw scores range from 8-40. T-scores are calculated from the short form scoring table provided in the instruments´ manual. T-score distributions rescale raw scores into standardized scores with a mean of 50 and a standard deviation (SD) of 10. Change from baseline: Negative numbers mean less fatigue, better outcome, positive score means more fatigue, worse outcome.

  Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

• Five Times Sit-To-Stand Test (5XSST)

  Change from Baseline compared to placebo at week 52 and at other relevant study visits of the 5xSST in total time (in seconds) to complete the 5xSTS. The 5xSST scoring is based on the amount of time (to the nearest decimal in seconds a subject is able to transfer from a seated to a standing position and back to sitting five times. Inability to complete five repetitions without assistance or use of upper extremity support indicates 'failure to perform of test, any modifications should be documented. Participant is directed to stand up straight as quickly as possible 5 times, without stopping in between, keeping arms folded across the chest. When 5xSST is not reached within 30.0 seconds the test is stopped and the actual number of sit to stands reached within those 30 seconds is recorded. Faster times (in sec) denotes better performance.

  Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

Secondary Outcomes (5)

• 36-Item Short Form Survey (SF-36)

  Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

• The PROMIS Fatigue Primary Mitochondrial Disease Short Form (PROMIS) Fatigue PMD SF)

  Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

• Beck Depression Inventory-2 (BDI-2)

  Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

• Patient-scored Global Impression of Severity scale (PGI-S)

  Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

• Clinician-scored Global Impression of Severity (CGI-S)

  Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

Other Outcomes (22)

• Newcastle Mitochondrial Disease Adult Scale (NMDAS)

  Baseline (Day 1), Weeks 26, 52 (End of Trial Visit)

• Brief Pain Inventory Short Form (BPI-SF)

  Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit)

• Health Economics and Outcomes Research (HEOR) Assessments: EQ-5D-5L

  Screening, Baseline (Day 1), Weeks 13, 26, 39, 52 (End of Trial Visit) and at week 54 (Follow-up)

Study Arms (2)

Sonlicromanol (KH176)

EXPERIMENTAL

Administration of 90 mg sonlicromanol (equivalent to 100 mg sonlicromanol.HCl) twice daily

Drug: Sonlicromanol

Matching Placebo

PLACEBO COMPARATOR

Administration of 100 mg matching placebo twice daily

Drug: Placebo

Interventions

Sonlicromanol DRUG

Administration of 90 mg sonlicromanol (100 mg sonlicromanol.HCl) twice daily during 52 weeks

Sonlicromanol (KH176)

Placebo DRUG

Administration of 100 mg placebo twice daily during 52 weeks

Matching Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Informed Consent
• Males and females aged ≥18 years with a multi-system primary mitochondrial disease.
• A confirmed mitochondrial DNA tRNALeu(UUR) m.3243A\>G mutation (m.3243A\>G PMD) plus an age adjusted heteroplasmy percentage ≥ 20% in white blood cells \[=blood heteroplasmy/0.977(age+12)\]. Or in urine (urinary epithelial cells), or buccal smear or skeletal muscle (results (obtained per local guidance) ≥ 20% must be available prior to the subject being randomized).
• Presence of chronic fatigue (not attributable to other etiologies than PMD):
• Patient self-reported chronic fatigue for at least 3 months prior to the Screening Visit and recorded in the clinical patient files; AND
• Presence of fatigue (raw total score \>22), assessed by Neuro-QoL SFv1-F at Screening.
• Presence of mitochondrial myopathy defined as:
• xSST at Screening and Baseline should be ≥ 11 seconds and participant must demonstrate the ability to complete the test at baseline (i.e., complete the test within 30 seconds).

You may not qualify if:

• Treatment with any IMP within 3 months (or 5 times the half-life of the IMP, whichever is longer) prior to screening or plans to use an IMP (other than the study intervention) during the study.
• Bone deformities, motor abnormalities or chronic ulcers that in the opinion of the PI may interfere with and/or confound the interpretation of the subject's performance during the 5 times sit to stand test (5XSST).
• Surgery of gastrointestinal tract that might interfere with drug absorption. Or severe GI dysmotility, chronic vomiting, diarrhea, bouts of pseudo-obstruction which will impair appropriate IMP absorption in the opinion of the investigator.
• Clinically significant respiratory disease and/or cardiac disease (medical history or current clinical findings) in the opinion of the investigator.
• Prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening.
• QTcF \> 450 msec (men) or QTcF \> 470 msec (women).
• Structural heart disease based on cardiac MRI or Echocardiography (e.g., clinically significant valve disease; i.e., aortic or mitral valve stenosis or regurgitation) and/or abnormal conduction (QRS \>120 msec, PR \> 120 msec), and/or repolarization (QTcF \> 450 msec (men) or QTcF \> 470 msec (women)). Myocardial function (LVEF \<52% in men and \< 54% in women), symptomatic ischemic heart disease (inducible ischemia or coronary obstruction), and/or pathologic hypertrophy (e.g. \> 15mm septal or posterior wall thickness), that is not well controlled under current specialized care. Subjects with congestive heart failure class II and above should also be excluded.
• Family history of unexplained/uninvestigated syncope or congenital long and short QT syndrome or sudden death (under the age of 60). ECG evidence of acute or recent ischemia, acute or Recent Myocardial Infraction, atrial fibrillation, high grade AV Blocks (Second Degree AV Block Type II or Third-degree AV Block), complete Heart Block or active conduction system abnormalities with the exception of any of the following:
• First degree atrioventricular (AV)-block
• Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
• Right bundle branch block.
• History of acute heart failure (within the last 3 months).
• Higher degree of AV-blocks (AVB II° or III°).

Sponsors & Collaborators

• Khondrion BV: lead

Study Sites (10)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

NOT YET RECRUITING

Cleveland Clinic Neurological Institute Mellen Center

Cleveland, Ohio, 44195, United States

NOT YET RECRUITING

The University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

NOT YET RECRUITING

Rigshospitalet, University of Copenhagen

Kopenhagen, Region Sjælland, DK2100, Denmark

NOT YET RECRUITING

CHU de Bordeaux - Hôpital Pellegrin Service Gynecologie Obstetrique

Bordeaux, Gironde, 33000, France

NOT YET RECRUITING

Groupe Hospitalier Pitie-Salpetriere - Charles-Foix Clinical Investigation Center Paris-Est

Paris, Paris, 75013, France

NOT YET RECRUITING

Klinikum der Universität München Friedrich-Baur-Institut

München, 80336, Germany

NOT YET RECRUITING

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, Milano, 20133, Italy

NOT YET RECRUITING

Radboud University Medical Center

Nijmegen, Gelderland, 6525, Netherlands

RECRUITING

University College London Hospitals NHS Foundation Trust National Hospital for Neurology and Neurosurgery

London, Greater London, WC1N 3BG, United Kingdom

RECRUITING

MeSH Terms

Conditions

Mitochondrial Diseases; Noninsulin-dependent diabetes mellitus with deafness; MELAS Syndrome

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Muscular Diseases; Musculoskeletal Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Neuromuscular Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Central Study Contacts

Jasper Levink, MSc.

CONTACT

+31 24 7635000; Khenerfin@khondrion.com

G. Ruiterkamp, MSc.

CONTACT

+31 24 7635000; Khenerfin@khondrion.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Trial personnel and subjects will be blinded to treatment until the database is locked. Investigators will contact the Sponsor prior to unblinding any subject's treatment unless in the instance of a medical emergency.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Model Details: The study will be a double-blind, randomised, placebo-controlled, multi-centre, parallel-group study. 220 subjects, with a confirmed mitochondrial DNA tRNALeu(UUR) 3243A\>G mutation will be randomised in a 1:1 ratio to receive oral administration of 90 mg sonlicromanol (100 mg sonlicromanol.HCl) or placebo twice daily.

Study Record Dates

• First Submitted: May 29, 2024
• First Posted: June 11, 2024
• Study Start: February 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: January 29, 2026

Record last verified: 2026-01

Locations

US (3); FR (2); DE (1); IT (1); GB (1); DK (1); NL (1)