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Treatment of TK2 Deficiency With Thymidine and Deoxycytidine

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ClinicalTrials.gov Identifier: NCT03639701
Recruitment Status : Enrolling by invitation
First Posted : August 21, 2018
Last Update Posted : August 23, 2018
Sponsor:
Collaborators:
Muscular Dystrophy Association
Hospital Universitario 12 de Octubre
Instituto de Salud Carlos III
University of Seville
Medical Research Council Mitochondrial Biology Unit
Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Spain
Hospitales Universitarios Virgen del Rocío
Vall d'Hebron Research Institute
Information provided by (Responsible Party):
Michio Hirano, MD, Columbia University

Brief 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. 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.

Condition or disease Intervention/treatment Phase
Mitochondrial DNA Depletion Syndrome 2 Myopathic Type Thymidine Kinase 2 Deficiency Drug: Thymidine Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Open label treatment with thymidine and deoxycytidine
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency
Actual Study Start Date : May 16, 2017
Estimated Primary Completion Date : April 1, 2024
Estimated Study Completion Date : April 1, 2024


Arm Intervention/treatment
Experimental: Open label thymidine and deoxycytidine
All patients will receive open label thymidine and deoxycytidine
Drug: Thymidine
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.
Other Name: Deoxycytidine




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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)


Secondary Outcome Measures :
  1. Event-free survival [ Time Frame: Up to 60 months ]
    Time to mechanical ventilation, death, or both will be assessed.

  2. 6-minute walk test [ Time Frame: Up to 60 months ]
    Distance walked in meters over 6 minutes will be measured in ambulatory patient.

  3. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) [ Time Frame: Up to 60 months ]
    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.

  4. Hammersmith Functional Motor Scale Expanded (HFMSE) [ Time Frame: Up to 60 months ]
    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.

  5. Vital Capacity [ Time Frame: Up to 60 months ]
    Vital capacity (percent of predicted normal based on age and height) will be measure by spirometry

  6. Time on Mechanical Ventilation [ Time Frame: Up to 60 months ]
    Number of hours per day that subjects use mechanical ventilation will be recorded.

  7. Neuro Quality of Life (Neuro-QoL) in adults [ Time Frame: Up to 60 months ]
    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).

  8. Neuro Quality of Life (Neuro-QoL) in pediatric subjects [ Time Frame: Up to 60 months ]
    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).

  9. Suicidal Ideation [ Time Frame: Up to 60 months. ]
    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.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03639701


Locations
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United States, New York
Columbia University
New York, New York, United States, 10032
Sponsors and Collaborators
Columbia University
Muscular Dystrophy Association
Hospital Universitario 12 de Octubre
Instituto de Salud Carlos III
University of Seville
Medical Research Council Mitochondrial Biology Unit
Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Spain
Hospitales Universitarios Virgen del Rocío
Vall d'Hebron Research Institute
Investigators
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Principal Investigator: Michio Hirano, MD Columbia University

Publications of Results:

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Responsible Party: Michio Hirano, MD, Professor of Neurology, Columbia University
ClinicalTrials.gov Identifier: NCT03639701     History of Changes
Other Study ID Numbers: AAAQ7552
First Posted: August 21, 2018    Key Record Dates
Last Update Posted: August 23, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: 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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Michio Hirano, MD, Columbia University:
Thymidine
Deoxycytidine