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Trial record 2 of 3 for:    mtDNA depletion

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 5, 2019
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

Tracking Information
First Submitted Date  ICMJE August 7, 2018
First Posted Date  ICMJE August 21, 2018
Last Update Posted Date August 5, 2019
Actual Study Start Date  ICMJE May 16, 2017
Estimated Primary Completion Date April 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 18, 2018)
  • 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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 1, 2019)
  • Event-free survival [ Time Frame: Up to 60 months ]
    Time to mechanical ventilation, death, or both will be assessed.
  • 6-minute walk test [ Time Frame: Up to 60 months ]
    Distance walked in meters over 6 minutes will be measured in ambulatory patient.
  • 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.
  • 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.
  • Vital Capacity [ Time Frame: Up to 60 months ]
    Vital capacity (percent of predicted normal based on age and height) will be measure by spirometry
  • Time on Mechanical Ventilation [ Time Frame: Up to 60 months ]
    Number of hours per day that subjects use mechanical ventilation will be recorded.
  • euro 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).
  • 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).
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 18, 2018)
  • Event-free survival [ Time Frame: Up to 60 months ]
    Time to mechanical ventilation, death, or both will be assessed.
  • 6-minute walk test [ Time Frame: Up to 60 months ]
    Distance walked in meters over 6 minutes will be measured in ambulatory patient.
  • 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.
  • 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.
  • Vital Capacity [ Time Frame: Up to 60 months ]
    Vital capacity (percent of predicted normal based on age and height) will be measure by spirometry
  • Time on Mechanical Ventilation [ Time Frame: Up to 60 months ]
    Number of hours per day that subjects use mechanical ventilation will be recorded.
  • 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).
  • 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).
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of TK2 Deficiency With Thymidine and Deoxycytidine
Official Title  ICMJE Deoxythymidine and Deoxycytidine Treatment for Thymidine Kinase 2 (TK2) Deficiency
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Open label treatment with thymidine and deoxycytidine
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Mitochondrial DNA Depletion Syndrome 2 Myopathic Type
  • Thymidine Kinase 2 Deficiency
Intervention  ICMJE 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
Study Arms  ICMJE Experimental: Open label thymidine and deoxycytidine
All patients will receive open label thymidine and deoxycytidine
Intervention: Drug: Thymidine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: August 18, 2018)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 1, 2024
Estimated Primary Completion Date April 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03639701
Other Study ID Numbers  ICMJE AAAQ7552
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Responsible Party Michio Hirano, MD, Columbia University
Study Sponsor  ICMJE Columbia University
Collaborators  ICMJE
  • 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  ICMJE
Principal Investigator: Michio Hirano, MD Columbia University
PRS Account Columbia University
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP