Mitochondrial DNA Depletion Syndrome 2 Myopathic TypePhase 1/2NCT03639701
Treatment of TK2 Deficiency With Thymidine and Deoxycytidine
A Phase 1/2 study testing Thymidine in people with Mitochondrial DNA Depletion Syndrome 2 Myopathic Type and Thymidine Kinase 2 Deficiency, run by Columbia University at 1 site in United States.
Trial summary
Patients with confirmed mitochondrial DNA depletion syndrome 2 (thymidine kinase 2 [TK2] deficiency) have reduced levels of nucleotides (deoxythymidine monophosphate and deoxycytidine monophosphate) for mitochondrial DNA synthesis. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Mitochondrial DNA Depletion Syndrome 2 Myopathic Type, Thymidine Kinase 2 Deficiency
- What is being tested?
- Thymidine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 1 siteUnited States
- Study dates
- 16 May 2017to 31 Dec 2026
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Genetically confirmed diagnosis of TK2 deficiency
- Deemed by principle investigator to be symptomatic with TK2 deficiency
- Single gene disease; absence of polygenic disease
- Hematocrit within normal range for age group
- Patient or patient's guardian able to consent and comply with protocol requirements
- Presence of caregiver to ensure study compliance (if needed)
- Abstention from use of all pill-form dietary supplements and non-prescribed medications (except as allowed by the investigator)
- Abstention from use of other investigational medications or other medications according to the study investigator
Who cannot join
- Clinical history of bleeding or abnormal prothrombin time (PT)/partial thromboplastin time (PTT)
- Hepatic insufficiency with liver function tests (LFTs) greater than two times normal
- Renal insufficiency requiring dialysis
- Any other concurrent inborn errors of metabolism
- Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis
Trial locations and contacts
1 site in 1 country.
United States1 site
Columbia University Irving Medical Center
New York, New York, 10032
About this study
Official title: Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency
Patients with confirmed mitochondrial DNA depletion syndrome 2 (thymidine kinase 2 [TK2] deficiency) have reduced levels of nucleotides (deoxythymidine monophosphate and deoxycytidine monophosphate) for mitochondrial DNA synthesis. This results in mitochondrial DNA depletion syndrome (i.e less number of functional mitochondrial DNA). Patients with confirmed TK2 deficiency will be treated with open label deoxythymidine (dThd) and deoxycytidine (dCyt), which are nucleotide precursors, with the expectation that the cells could make additional mitochondrial DNA. This in turn may help reduce the clinical symptoms.
Read the detailed description
Mitochondrial are responsible for the production of cellular energy. Mitochondria contain DNA which is the encoding system ( "recipe") for making the proteins that allow the mitochondria to function. Reduced amount of mitochondrial DNA, caused by genetic mutations in certain genes, Mitochondrial DNA Depletion Syndrome. This can result in symptoms; such as fatigue, weakness, and deficiencies in various body systems. TK2 deficiency is considered a mitochondrial depletion syndrome. Patients with TK2 deficiency have weakness and walking difficulty. They also have depleted levels of chemicals (phosphorylated deoxythymidine and deoxycytidine) used to make mitochondrial DNA. Based on previous studies with a similar compound, patients reported more energy and better motor skills.
Eligible patients include those with genetic mutations in the TK2 gene who are willing to attend several outpatient visits, and have motor skills testing, neurological exam by doctor, and blood samples.
- Being tested
- Thymidine
- Keywords
- Thymidine, Deoxycytidine
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ThymidineDrug
Also called Deoxycytidine
Mitochondrial DNA nucleotide precursors. Dose escalation: 130mg/kg/day x 14 days, 260 mg/kg/day x 14 days, and 400mg/kg/day as tolerated. Compounds are taken orally and divided into 3 doses daily.
| Study group | Role | What they receive |
|---|---|---|
| Open label thymidine and deoxycytidine | Experimental | All patients will receive open label thymidine and deoxycytidine Receives: Drug: Thymidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Alanine aminotransferase
Number of participants with treatment-related elevated alanine aminotransferase (ALT) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Measured: Up to 60 months
Aspartate aminotransferase
Number of participants with treatment-related elevated aspartate aminotransferase (AST) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Measured: Up to 60 months
Gamma-glutamyltransferase
Number of participants with treatment-related elevated gamma-glutamyltransferase (GGT) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Measured: Up to 60 months
Blood lymphocyte count
Blood lymphocyte count increased relative to upper limit or normal or decreased relative to lower limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Measured: Up to 60 months
Creatinine
Serum creatinine level increased relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Measured: Up to 60 months
Electrocardiogram
Number of patients with treatment related electrocardiogram (ECG) QT corrected interval (QTc) grade 3 or higher as defined by CTCAE version 4.03.
Measured: Up to 60 months
Diarrhea
Patient-Reported Outcome Measurement Information System (PROMIS) Scale v1.0 - Gastrointestinal Diarrhea 6a score (score range 0-30 with higher scores indicating more severe diarrhea)
Measured: Up to 60 months
Secondary outcomes (9)
Event-free survival
Time to mechanical ventilation, death, or both will be assessed.
Measured: Up to 60 months
6-minute walk test
Distance walked in meters over 6 minutes will be measured in ambulatory patient.
Measured: Up to 60 months
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score (0-64 point range with higher scores indicating better function) will be assessed in infants to assess motor function.
Measured: Up to 60 months
Hammersmith Functional Motor Scale Expanded (HFMSE)
Hammersmith Functional Motor Scale Expanded (HFMSE) score (0-66 point range with higher scores indicating better function) will be measured in subjects >1 year-old.
Measured: Up to 60 months
Vital Capacity
Vital capacity (percent of predicted normal based on age and height) will be measure by spirometry
Measured: Up to 60 months
Time on Mechanical Ventilation
Number of hours per day that subjects use mechanical ventilation will be recorded.
Measured: Up to 60 months
euro Quality of Life (Neuro-QoL) in adults
Neuro Quality of Life (Neuro-QoL) short forms will be used to assess effects of muscle weakness on motor function and activities of daily living. In adults, Lower and Upper Extremity scales will be assessed (0-80 points with higher scores indicating better function).
Measured: Up to 60 months
Neuro Quality of Life (Neuro-QoL) in pediatric subjects
Neuro Quality of Life (Neuro-QoL) forms will be used to assess effects of muscle weakness on motor function and activities of daily living. In pediatric subjects (<18 years-old), Lower and Upper Extremity scales will be assessed (0-160 points with higher scores indicating better function).
Measured: Up to 60 months
Suicidal Ideation
Suicidal ideation will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), which contains 6 "yes" or "no" questions. Answer of "yes" to any question indicates possible suicide risk and answer of "yes: to questions 4, 5, or 6 indicates high-risk.
Measured: Up to 60 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Aug 2018
- Study start16 May 2017
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Mitochondrial DNA Depletion Syndrome 2 Myopathic TypeStudies of the same condition, open and under way.
- More trials run by Columbia UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Open label treatment with thymidine and deoxycytidine
- Masking
- None (open label)
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Columbia University
- Sponsor type
- University, hospital or other
- Collaborators
- Muscular Dystrophy Association, Hospital Universitario 12 de Octubre, Instituto de Salud Carlos III, University of Seville, Medical Research Council Mitochondrial Biology Unit, Consorcio Centro de Investigación Biomédica en Red (CIBER), Hospitales Universitarios Virgen del Rocío, Universitat Autonoma de Barcelona
- Responsible party
- Principal investigator, Michio Hirano, MD, Columbia University
- Investigators
- Michio Hirano, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03639701
- Sponsor's protocol ID
- AAAQ7552
- Status last verified
- Jan 2026
- First submitted
- 7 Aug 2018
- Last updated
- 28 Jan 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Since there are very few patients in the world with TK2 Deficiency, we may share de-identified data with other researchers who are treating patients with TK2 Deficiency
Publications
Garone C, Taylor RW, Nascimento A, Poulton J, Fratter C, Dominguez-Gonzalez C, Evans JC, Loos M, Isohanni P, Suomalainen A, Ram D, Hughes MI, McFarland R, Barca E, Lopez Gomez C, Jayawant S, Thomas ND, Manzur AY, Kleinsteuber K, Martin MA, Kerr T, Gorman GS, Sommerville EW, Chinnery PF, Hofer M, Karch C, Ralph J, Camara Y, Madruga-Garrido M, Dominguez-Carral J, Ortez C, Emperador S, Montoya J, Chakrapani A, Kriger JF, Schoenaker R, Levin B, Thompson JLP, Long Y, Rahman S, Donati MA, DiMauro S, Hirano M. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018 Aug;55(8):515-521. doi: 10.1136/jmedgenet-2017-105012. Epub 2018 Mar 30.
PubMed 29602790Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, Tadesse S, Garone C, Hirano M. Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017 May;81(5):641-652. doi: 10.1002/ana.24922. Epub 2017 May 4.
PubMed 28318037Garone C, Garcia-Diaz B, Emmanuele V, Lopez LC, Tadesse S, Akman HO, Tanji K, Quinzii CM, Hirano M. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med. 2014 Aug;6(8):1016-27. doi: 10.15252/emmm.201404092.
PubMed 24968719Chanprasert S, Wang J, Weng SW, Enns GM, Boue DR, Wong BL, Mendell JR, Perry DA, Sahenk Z, Craigen WJ, Alcala FJ, Pascual JM, Melancon S, Zhang VW, Scaglia F, Wong LJ. Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. Mol Genet Metab. 2013 Sep-Oct;110(1-2):153-61. doi: 10.1016/j.ymgme.2013.07.009. Epub 2013 Jul 17.
PubMed 23932787
Study at a glance
From the registry record, last updated by the sponsor on 28 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency
- ClinicalTrials.gov ID
- NCT03639701
- Acronym / sponsor ID
- AAAQ7552
- Keywords
- Thymidine, Deoxycytidine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Columbia UniversityUniversity, hospital or other
- Collaborators
- Muscular Dystrophy Association, Hospital Universitario 12 de Octubre, Instituto de Salud Carlos III, University of Seville, Medical Research Council Mitochondrial Biology Unit, Consorcio Centro de Investigación Biomédica en Red (CIBER), Hospitales Universitarios Virgen del Rocío, Universitat Autonoma de Barcelona
- Study start
- 16 May 2017 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 21 Aug 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Patients with confirmed mitochondrial DNA depletion syndrome 2 (thymidine kinase 2 [TK2] deficiency) have reduced levels of nucleotides (deoxythymidine monophosphate and deoxycytidine monophosphate) for mitochondrial DNA synthesis. This results in mitochondrial DNA depletion syndrome (i.e less number of functional mitochondrial DNA). Patients with confirmed TK2 deficiency will be treated with open label deoxythymidine (dThd) and deoxycytidine (dCyt), which are nucleotide precursors, with the expectation that the cells could make additional mitochondrial DNA. This in turn may help reduce the clinical symptoms.
Detailed description
Mitochondrial are responsible for the production of cellular energy. Mitochondria contain DNA which is the encoding system ( "recipe") for making the proteins that allow the mitochondria to function. Reduced amount of mitochondrial DNA, caused by genetic mutations in certain genes, Mitochondrial DNA Depletion Syndrome. This can result in symptoms; such as fatigue, weakness, and deficiencies in various body systems. TK2 deficiency is considered a mitochondrial depletion syndrome. Patients with TK2 deficiency have weakness and walking difficulty. They also have depleted levels of chemicals (phosphorylated deoxythymidine and deoxycytidine) used to make mitochondrial DNA. Based on previous studies with a similar compound, patients reported more energy and better motor skills.
Eligible patients include those with genetic mutations in the TK2 gene who are willing to attend several outpatient visits, and have motor skills testing, neurological exam by doctor, and blood samples.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Open label treatment with thymidine and deoxycytidine
| Arm | Type | Receives |
|---|---|---|
| Open label thymidine and deoxycytidine | Experimental | Drug: ThymidineAll patients will receive open label thymidine and deoxycytidine |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- Genetically confirmed diagnosis of TK2 deficiency
- Deemed by principle investigator to be symptomatic with TK2 deficiency
- Single gene disease; absence of polygenic disease
- Hematocrit within normal range for age group
- Patient or patient's guardian able to consent and comply with protocol requirements
Key exclusion criteria (5 listed)
- Clinical history of bleeding or abnormal prothrombin time (PT)/partial thromboplastin time (PTT)
- Hepatic insufficiency with liver function tests (LFTs) greater than two times normal
- Renal insufficiency requiring dialysis
- Any other concurrent inborn errors of metabolism
- Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ThymidineAlso: DeoxycytidineMitochondrial DNA nucleotide precursors. Dose escalation: 130mg/kg/day x 14 days, 260 mg/kg/day x 14 days, and 400mg/kg/day as tolerated. Compounds are taken orally and divided into 3 doses daily. | Drug | Open label thymidine and deoxycytidine |
Primary outcome
Alanine aminotransferase
Time frame: Up to 60 months
Number of participants with treatment-related elevated alanine aminotransferase (ALT) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Aspartate aminotransferase
Time frame: Up to 60 months
Number of participants with treatment-related elevated aspartate aminotransferase (AST) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Gamma-glutamyltransferase
Time frame: Up to 60 months
Number of participants with treatment-related elevated gamma-glutamyltransferase (GGT) serum level relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Blood lymphocyte count
Time frame: Up to 60 months
Blood lymphocyte count increased relative to upper limit or normal or decreased relative to lower limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Creatinine
Time frame: Up to 60 months
Serum creatinine level increased relative to upper limit of normal (expressed as ratios) grade 3 or higher as defined by CTCAE 4.03.
Electrocardiogram
Time frame: Up to 60 months
Number of patients with treatment related electrocardiogram (ECG) QT corrected interval (QTc) grade 3 or higher as defined by CTCAE version 4.03.
Diarrhea
Time frame: Up to 60 months
Patient-Reported Outcome Measurement Information System (PROMIS) Scale v1.0 - Gastrointestinal Diarrhea 6a score (score range 0-30 with higher scores indicating more severe diarrhea)
9 secondary outcomes
Event-free survival
Time frame: Up to 60 months
6-minute walk test
Time frame: Up to 60 months
Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)
Time frame: Up to 60 months
Hammersmith Functional Motor Scale Expanded (HFMSE)
Time frame: Up to 60 months
Vital Capacity
Time frame: Up to 60 months
Time on Mechanical Ventilation
Time frame: Up to 60 months
euro Quality of Life (Neuro-QoL) in adults
Time frame: Up to 60 months
Neuro Quality of Life (Neuro-QoL) in pediatric subjects
Time frame: Up to 60 months
Suicidal Ideation
Time frame: Up to 60 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jan 2026.
- Results publication: PubMed 29602790Garone C, Taylor RW, Nascimento A, Poulton J, Fratter C, Dominguez-Gonzalez C, Evans JC, Loos M, Isohanni P, Suomalainen A, Ram D, Hughes MI, McFarland R, Barca E, Lopez Gomez C, Jayawant S, Thomas ND, Manzur AY, Kleinsteuber K, Martin MA, Kerr T, Gorman GS, Sommerville EW, Chinnery PF, Hofer M, Karch C, Ralph J, Camara Y, Madruga-Garrido M, Dominguez-Carral J, Ortez C, Emperador S, Montoya J, Chakrapani A, Kriger JF, Schoenaker R, Levin B, Thompson JLP, Long Y, Rahman S, Donati MA, DiMauro S, Hirano M. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018 Aug;55(8):515-521. doi: 10.1136/jmedgenet-2017-105012. Epub 2018 Mar 30.
- Results publication: PubMed 28318037Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, Tadesse S, Garone C, Hirano M. Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017 May;81(5):641-652. doi: 10.1002/ana.24922. Epub 2017 May 4.
- Results publication: PubMed 24968719Garone C, Garcia-Diaz B, Emmanuele V, Lopez LC, Tadesse S, Akman HO, Tanji K, Quinzii CM, Hirano M. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med. 2014 Aug;6(8):1016-27. doi: 10.15252/emmm.201404092.
- Results publication: PubMed 23932787Chanprasert S, Wang J, Weng SW, Enns GM, Boue DR, Wong BL, Mendell JR, Perry DA, Sahenk Z, Craigen WJ, Alcala FJ, Pascual JM, Melancon S, Zhang VW, Scaglia F, Wong LJ. Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. Mol Genet Metab. 2013 Sep-Oct;110(1-2):153-61. doi: 10.1016/j.ymgme.2013.07.009. Epub 2013 Jul 17.
- Individual participant dataSharing planned: Undecided. Since there are very few patients in the world with TK2 Deficiency, we may share de-identified data with other researchers who are treating patients with TK2 Deficiency
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michio Hirano, MD principal investigator
Columbia University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Thymidine in people with Mitochondrial DNA Depletion Syndrome 2 Myopathic Type and Thymidine Kinase 2 Deficiency, run by Columbia University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 28 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Alanine aminotransferase (time frame: Up to 60 months). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03639701, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jan 2026; AzTrials last refreshed its copy on 7 Nov 2026.