An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency

Study Overview
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Brief Summary
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This is a Phase 2 prospective open-label treatment study of the safety and efficacy of doxecitine and doxribtimine in study participants with thymidine kinase 2 (TK2) deficiency who participated in the retrospective study MT-1621-101 [NCT03701568] or who were receiving nucleos(t)ide treatment and were approved by the Sponsor.

Official Title
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A Phase 2 Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With Thymidine Kinase 2 Deficiency (TK2)

Conditions
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Thymidine Kinase 2 Deficiency

Intervention / Treatment
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* Drug: doxecitine and doxribtimine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent by the parent(s) or legally authorized representative (LAR) and/or assent by the study participant (when applicable). Confirmed genetic mutation in the TK2 gene. Absence of other genetic disease or polygenic disease. Current treatment with nucleos(t)ides for TK2 deficiency. Study participants who were not previously enrolled in MT-1621-101 [NCT03701568] will require Sponsor approval to ensure that collection of clinical and functional measurements prior to treatment are sufficient to serve as baseline assessments for purposes of evaluating safety and efficacy. Female study participants must not be breastfeeding, have a negative pregnancy test at screening (females ≥10 years old), and have no intention to become pregnant during the course of the study. Female study participants who are of childbearing potential (ie, following menarche until ≥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. Acceptable methods are defined as those that result, alone or in combination, in a low failure rate (ie, <1% per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method. In certain countries (if permitted by law), women of childbearing potential may instead agree to abide by heterosexual sexual abstinence during the study and for 30 days after the end of the study. Male study participants with sexual partners should use condoms for the duration of the study and for 30 days after the last dose of study drug to prevent passing study drug to the partner in the ejaculate. Male participants should be advised not to donate sperm for 30 days after the last dose of study drug. Willingness to maintain current treatment regimen and current exercise regimen for the duration of the clinical study. Willingness to comply with the study protocol, including but not limited to, all study procedures, study visits, and study drug compliance. Exclusion Criteria: History of liver disease, or liver function test results (ALT, AST, or total bilirubin) ≥2× upper limit of normal without prior Sponsor approval. Other significant medical condition that, in the opinion of the Investigator or Study Sponsor, may confound interpretation of the clinical course of TK2 deficiency.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: doxecitine and doxribtimine<br>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<br>* Doxecitine and doxribtimine is administered orally in 3 equal doses given approximately 6 to 8 hours apart. Doxecitine and doxribtimine is administered with food.<br>* Other names: GMP grade dC/dT (deoxycytidine and deoxythymidine);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as adverse events (AEs): number of participants who experience adverse events | Safety as determined by the number of participants who experience adverse events (AE), type of AE, severity of AE. | Approximately 3 years | 
| Safety as determined by laboratory measurements | Number of Participants Who Experience a Clinically Significant Change from Baseline in Clinical Laboratory Tests. | Approximately 3 years | 
| Safety as determined by electrocardiograms (ECGs) | Number of Participants Who Experience a Clinically Significant Change from Baseline ECG. | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Motor Function Assessments | Patient or physician reported achievement (capable) or loss (not capable) of gross motor milestones. | Approximately 3 years | 
| Efficacy - Respiratory Status | Pulmonary Function Tests (PFTs). | Approximately 3 years | 
| Efficacy - Growth/Nutrition | Growth in patients over time compared to normals using the WHO reference standards and expressed as Z scores. | Approximately 3 years | 
| Efficacy - Growth/Nutrition | Requirement for supplemental feeding/feeding tube within 1 patient over time and time to change of status of use of supplemental feeding/feeding tube (tube inserted for feeding use vs tube removed). | Approximately 3 years | 
| Maximum plasma concentration (Cmax) of deoxycytidine and deoxythymidine | PK of dC and dT (Cmax - peak plasma concentration) | Approximately 3 years | 
| Time to maximum plasma concentration (Tmax) of deoxycytidine and deoxythymidine | PK of dC and dT (Tmax - time to maximum plasma concentration) | Approximately 3 years | 
| AUC - area under the plasma concentration time curve of deoxycytidine and deoxythymidine | PK of dC and dT (AUC - area under the plasma concentration time curve) | Approximately 3 years | 
| Apparent elimination half-life (t1/2) of deoxycytidine and deoxythymidine | PK of dC and dT (t1/2 - apparent elimination half-life) | Approximately 3 years | 
| Biomarkers (plasma from blood) | Biomarkers which may be related to TK2 disease and/or drug treatment (eg, number of participants with normal vs abnormal creatine kinase measured in u/l compared to normal ranges). | Approximately 3 years | 
| Biomarkers (plasma from blood) | Biomarkers which may be related to TK2 disease and/or drug treatment (eg, number of participants with normal vs abnormal lactate levels measured in mmol/l compared to normal ranges). | Approximately 3 years | 
| Quality of life through patient questionnaire - Individualized Neuromuscular Quality of Life (INQoL) | INQOL Questionnaire with 15 questions in 3 sections about muscle weakness, pain, fatigue, locking of muscles, droopy eyelids, vision, swallowing, daily activity, independence, relationships, feelings, appearance, and treatment where patients aged 12 years and older rate how they feel and their muscles function to accomplish daily activities on a scale of 0 to 7, where lower values are generally associated with a better outcome. | Approximately 3 years | 
| Characterization of health care utilization |  | Approximately 3 years | 
| Efficacy Assessment: Clinical Global Impression of Improvement (CGI-I) and Patient Global Impression of Improvement (PGI-I) | Clinical Global Impression of Improvement (CGI-I) completed by Investigator and Patient Global Impression of Improvement (PGI-I) completed by the patient/caregiver. | Approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thymidine Kinase 2 Deficiency, TK2d, mitochondrial disorder, mitochondrial disease, Mitochondria, deoxycytidine and deoxythymidine, doxecitine and doxribtimine, MT1621, primary mitochondrial myopathy, mitochondrial depletion syndrome, Muscle weakness, Muscle atrophy, Loss of mobility