Doxecitin and Doxribthymine in Adult Subjects With Thymidine Kinase 2 (TK2) Deficiency

NCT06754098 | Recruiting Phase 2

• 2 other identifiers: LOTK2D2024-510763-35-00
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this clinical trial is to evaluate the efficacy and safety of Doxecitin and Doxribtimine (dC+dT) in adult participants with thymidine kinase 2 (TK2) deficiency attended in the Neuromuscular Unit of '12 de Octubre' Hospital. The main questions it aims to answer are:

• Is dT+dC effective in the treatment of the adult participants with TK2 deficiency?
• Is dT+dC safe in the treatment of adult participants with TK2 deficiency? Researchers will evaluate the effectiveness of the treatment doxecitin and doxribthymine in adult participants with TK2 deficiency. In addition, the mitochondrial DNA levels before and after treatment (extracted from the muscle and from uroepithelial cells) of these participants will be also studied.

Conditions

Thymidine Kinase 2 (TK2 ) Deficiency; Mitochondrial Myopathies

Keywords

TK2 deficiency; Primary Mitochondrial Myopathy; Deoxycytidine (dC); Deoxythymidine (dT); Mitochondrial DNA depletion and multiple deletions syndromes (MDDS)

Outcome Measures

Primary Outcomes (10)

• Efficacy - Motor Function Assessments: Neurological Exam using Medical Research Council (MRC Scale) Scale for Muscle Strength

  Motor Function will be measured using the MRC scale. The scale provides a measure of Muscle Strength across a range from 0 (No visible muscle contraction) to 5 (Full strength)

  Day 1, Months 1, 2, 3, 12, 15, 18, 21 and 24

• Efficacy - Motor Function Assessments: 6-minute walk test

  Motor Function will be measured using the 6-minute walk test (6MWT). Distance walked in meters over 6 minutes will be measured

  Day 1, Months 1, 2, 3, 12, 15, 18, 21 and 24

• Efficacy - Motor Function Assessments: North Star Ambulatory Assessment (NSAA)

  Motor function will be assessed using the NSAA scale. The NSAA is a 17-item scale that grades performance of various functional activities on a scale graded 0 (unable to complete the activity), 1 (completes the activity independently but with modifications), and 2 (completes the activity without modifications)

  Day 1, Months 1, 2, 3, 12, 15, 18, 21 and 24

• Efficacy - Motor Function Assessments: 100 meter-time velocity test

  Time to run 100 meters measured in seconds (sec)

  Day 1, Months 1, 2, 3, 12, 15, 18, 21 and 24

• Efficacy - Motor Function Assessments: Fatigue Scale test

  Motor function will be assessed Fatigue Scale test. The FACIT-Fatigue is a 13-item patient-reported outcome measure (range from 0 to 52: 0 = very much fatigued, 52 = not at all fatigued) assessing fatigue over the previous week

  Day 1, Months 1, 2, 3, 12, 15, 18, 21 and 24

• Efficacy - Respiratory Assessments measured by spirometry

  * Sitting Forced Vital Capacity (Sitting FVC) measure in percentage (%) * Drop in FVC lying down measured in percentage (%) * Maximal Inspiratory Pressure (MIP) measure in percentage: Evaluation of the strength of respiratory muscles is performed with measurements of MIP expressed in percentage (%) * Maximal Inspiratory Pressure (MEP) measure in percentage: Evaluation of the strength of respiratory muscles is performed with measurements of MEP expressed in percentage (%)

  Day 1, Months 1, 2, 3, 12, 15, 18, 21 and 24

• Efficacy - Respiratory Assessments: Use of ventilatory support (Use and Type )

  Use and Type of mechanical ventilation (MV) \[bilevel positive airway pressure (BiPAP) and/or continuous positive airway pressure (CPAP)\] per subject will be assessed

  Day 1, Months 1, 2, 3, 12, 15, 18, 21 and 24

• Efficacy - Respiratory Assessments: Time of use of ventilatory support

  Total of hours of use of mechanical ventilation (MV) per subject will be assessed

  Day 1, Months 1, 2, 3, 12, 15, 18, 21 and 24

• Serum Biomarkers: lactate levels

  Number of participants with normal vs abnormal lactate levels measured in mmol/l

  Up to 24 months

• Serum Biomarkers: Growth/differentiation factor-15 (GDF15 )

  Number of participants with normal vs abnormal Growth/differentiation factor-15 (GDF15) levels measured in mmol/l compared to normal ranges

  Up to 24 months

Secondary Outcomes (2)

• Safety as adverse events (AEs)

  Up to 24 months

• Safety as serious adverse events (SAEs)adverse events

  Up to 24 months

Other Outcomes (2)

• Changes in the mtDNA levels before and after treatment

  6 month

• Changes in the peak oxygen consumption (VO2 max) test

  6 month

Study Arms (1)

doxecitin and doxribthymine (dT+dC)

EXPERIMENTAL

This is an open label study with all participants in a single arm. Study participants will take doxecitine and doxribtimine up to a maximum of 800 mg/kg/day (400 mg/kg/day doxecitine and 400 mg/kg/day doxiribtimine).

Drug: Doxecitine and Doxribtimine

Interventions

Doxecitine and Doxribtimine DRUG

A combination of doxecitine and doxribtimine is administered orally in 3 equal doses given approximately 6 to 8 hours apart .Dose will be increased if the tolerability profile is good.

doxecitin and doxribthymine (dT+dC)

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 by the subject.
• Subject must be greater than 18 years of age at time of consent.
• Genetic diagnosis of TK2 deficiency
• Subject should have evidence of a moderate to severe disease, with motor and or respiratory involvement, shown by one of the following:
• North Star Ambulatory Assessment Scale (NSAA) less than 30
• minute walking test less than 450 meters
• Force Vital Capacity in the sitting position less than 70 percent or a drop in the decubitus position greater than 10 percent or need for mechanical ventilation.
• Disabling symptoms and evidence of motor and/or respiratory function progressive decline.
• Female subjects must have no intention to become pregnant during the study. Female subjects who are of childbearing potential (that is, following menarche until at least 1 year post-menopausal if not anatomically and physiologically incapable of becoming pregnant) must agree and commit to the use of highly effective methods of birth control for the duration of the study and for 30 days after the end of the study, and be willing to have additional pregnancy tests conducted during the study. Acceptable methods are defined as those that result, alone or in combination, in a low failure rate (that is, less than 1 percent per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method.
• Male subjects with partners of childbearing potential must agree to use effective contraception methods during the study and for at least 90 days after the last dose of the study medication. Acceptable methods include the use of condoms combined with spermicidal foam/gel/film/cream/suppository.
• Willingness to comply with the study protocol, including but not limited to, all study procedures, study visits, and study drug compliance.

You may not qualify if:

• History of liver disease, or liver function test results (alanine aminotransferase \[ALT\], aspartate transaminase \[AST\], or total bilirubin) greater than or equal2 times (2X) the upper limit of normal. Patients with transaminases greater than 2 times (2X) can participate with the approval and monitoring of a doctor specializing in liver toxicity.
• Participation in a previous trial of any investigational agent for primary mitochondrial disease within 1 year prior to informed consent, or use of any other investigational therapy within 30 days (or 3 half-lives, whichever is longer) prior to informed consent, or participation in other clinical studies, within 30 days prior to informed consent, which in the opinion of the study Sponsor, may potentially confound results from this study.
• Pregnant (females 10.0 years old or older will have a pregnancy test at screening), or breastfeeding

Sponsors & Collaborators

• Cristina Domínguez González: lead
• UCB Pharma: collaborator

Study Sites (1)

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

RECRUITING

Related Publications (4)

• Dominguez-Gonzalez C, Badosa C, Madruga-Garrido M, Marti I, Paradas C, Ortez C, Diaz-Manera J, Berardo A, Alonso-Perez J, Trifunov S, Cuadras D, Kalko SG, Blazquez-Bermejo C, Camara Y, Marti R, Mavillard F, Martin MA, Montoya J, Ruiz-Pesini E, Villarroya J, Montero R, Villarroya F, Artuch R, Hirano M, Nascimento A, Jimenez-Mallebrera C. Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy. Sci Rep. 2020 Jun 22;10(1):10111. doi: 10.1038/s41598-020-66940-8.

  PMID: 32572108 BACKGROUND

• Berardo A, Dominguez-Gonzalez C, Engelstad K, Hirano M. Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies. J Neuromuscul Dis. 2022;9(2):225-235. doi: 10.3233/JND-210786.

  PMID: 35094997 BACKGROUND

• Bermejo-Guerrero L, Hernandez-Voth A, Serrano-Lorenzo P, Blazquez A, Martin-Jimenez P, Martin MA, Dominguez-Gonzalez C. Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report. Mitochondrion. 2024 May;76:101879. doi: 10.1016/j.mito.2024.101879. Epub 2024 Apr 9.

  PMID: 38599303 BACKGROUND

• Dominguez-Gonzalez C, Madruga-Garrido M, Mavillard F, Garone C, Aguirre-Rodriguez FJ, Donati MA, Kleinsteuber K, Marti I, Martin-Hernandez E, Morealejo-Aycinena JP, Munell F, Nascimento A, Kalko SG, Sardina MD, Alvarez Del Vayo C, Serrano O, Long Y, Tu Y, Levin B, Thompson JLP, Engelstad K, Uddin J, Torres-Torronteras J, Jimenez-Mallebrera C, Marti R, Paradas C, Hirano M. Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy. Ann Neurol. 2019 Aug;86(2):293-303. doi: 10.1002/ana.25506. Epub 2019 Jun 17.

  PMID: 31125140 BACKGROUND

MeSH Terms

Conditions

Mitochondrial Myopathies

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Mitochondrial Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Cristina D Domínguez González, Dra.

  Hospital 12 de Octubre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cristina Domínguez González, Dra.

CONTACT

+34 917792582; cdgonzalez@salud.madrid.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Doctor

Model Details: The study seeks to enroll 10 to 15 patients under follow-up in the Neuromuscular Unit of '12 de Octubre' Hospital. All subjects will be required to attend a screening visit at which their eligibility for the study will be determined.

Study Record Dates

• First Submitted: December 23, 2024
• First Posted: December 31, 2024
• Study Start: January 1, 2025
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: July 28, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)