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

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ClinicalTrials.gov Identifier: NCT03845712
Recruitment Status : Enrolling by invitation
First Posted : February 19, 2019
Last Update Posted : July 24, 2019
Sponsor:
Information provided by (Responsible Party):
Modis Therapeutics, Inc.

Brief Summary:
This is a Phase 2 prospective, open-label treatment study of the safety and efficacy of MT1621 in TK2 deficient patients who participated in the retrospective Study MT-1621-101. Patients who are being treated with dC/dT and did not participate in MT-1621-101 may also be allowed to enroll with Sponsor approval. For all patients, it is important to ensure that collection of clinical and functional measurements prior to treatment with dC/dT are sufficient to serve as baseline assessments for purposes of evaluating safety and efficacy.

Condition or disease Intervention/treatment Phase
Thymidine Kinase 2 (TK2) Drug: MT1621 Phase 2

Detailed Description:

This is a Phase 2 prospective, open-label treatment study of the safety and efficacy of MT1621 in TK2 deficient patients who participated in the retrospective Study MT-1621-101. Patients who are being treated with dC/dT and did not participate in MT-1621-101 may also be allowed to enroll with Sponsor approval. For all patients, it is important to ensure that collection of clinical and functional measurements prior to treatment with dC/dT are sufficient to serve as baseline assessments for purposes of evaluating safety and efficacy.

After enrollment into this study, patients will transition from their current chemical-grade dC/dT or dCMP/dTMP to the same dose of MT1621, or continue use of MT1621 at their current dose (by weight), up to a maximum of 400 mg/kg/day. Patients who are on a dose <400 mg/kg/day dC/dT or dCMP/dTMP will initiate treatment with MT1621 at the same dose (by weight), and the Investigator will have the options of continuing at this dose or escalating to a higher dose, with the highest dose being 400 mg/kg/day MT1621. The dose may be reduced for tolerability reasons.

Safety and efficacy will be assessed upon enrollment, at 1 month, every 3 months through 18 months, every 6 months through 36 months, then annually thereafter, and at end of study participation. For patients who did not participate in Study MT-1621-101, specific assessments for each patient will be determined by the Sponsor in discussion with the Investigator based on data collected as baseline assessments for purposes of evaluating safety and efficacy.

The study will include sparse PK sampling.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is a Phase 2 prospective, open-label treatment study of the safety and efficacy of MT1621 in TK2 deficient patients.
Masking: None (Open Label)
Masking Description: Not applicable - this is an open label study.
Primary Purpose: Treatment
Official Title: A Phase 2 Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With Thymidine Kinase 2 Deficiency (TK2)
Actual Study Start Date : July 5, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Arm Intervention/treatment
Experimental: MT1621, dC/dT
This is an open label study with all participants in a single arm. Patients will take MT1621 up to a maximum of 400 mg/kg/day. MT1621 is deoxycytidine (dC) and deoxythymidine (dT) powders for solution for reconstitution in water. Study drug will be supplied as powder in packets containing 0.5 or 2.0 g of dC or dT, and is typically dosed three times/day.
Drug: MT1621
deoxythymidine/deoxythymidine substrate enhancement therapy
Other Name: dC/dT (deoxythymidine/deoxythymidine)




Primary Outcome Measures :
  1. Safety as adverse events (AEs): number of participants who experience adverse events [ Time Frame: Approximately 3 years ]
    Safety as determined by the number of participants who experience adverse events (AE), type of AE, severity of AE

  2. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from hematology (WBC in X10(3)/UL)

  3. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from hematology (hemoglobin in G/DL, hematocrit in %, platelets in X10(3)/UL)

  4. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from hematology (hematocrit in %, platelets in X10(3)/UL)

  5. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (sodium in MMOL/L)

  6. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (potassium in MMOL/L)

  7. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (chloride in MMOL/L)

  8. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (BUN in mg/dl)

  9. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (creatinine mg/dl)

  10. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (glucose in mg/dl)

  11. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (ALT/AST/GGT in u/l)

  12. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (bilirubin in mg/dl)

  13. Safety as determined by laboratory measurements [ Time Frame: Approximately 3 years ]
    Safety as determined by laboratory measurements from blood chemistry (albumin in g/dl)

  14. Safety as determined by electrocardiograms (ECGs) [ Time Frame: Approximately 3 years ]
    Safety as determined by evaluation, review of electrocardiogram (ECGs) parameters, including P Wave (mV)

  15. Safety as determined by electrocardiograms (ECGs) [ Time Frame: Approximately 3 years ]
    Safety as determined by evaluation, review of electrocardiogram (ECGs) parameters, including QRS Complex (seconds)

  16. Safety as determined by electrocardiograms (ECGs) [ Time Frame: Approximately 3 years ]
    Safety as determined by evaluation, review of electrocardiogram (ECGs) parameters, including QT Interval (seconds)


Secondary Outcome Measures :
  1. Efficacy - Motor Function Assessments [ Time Frame: Approximately 3 years ]
    Patient or physician reported achievement (capable) or loss (not capable) of gross motor milestones, such as ability to sit upright, walk, climb stairs during routine motor milestone examination

  2. Efficacy - Motor Function Assessments: 6-minute walk test [ Time Frame: Approximately 3 years ]
    6-minute walk test (6MWT)

  3. Efficacy - Motor Function Assessments: CHOP INTEND [ Time Frame: Approximately 3 years ]
    CHOP INTEND

  4. Efficacy - Motor Function Assessments: Egen Klassifikation (EK) [ Time Frame: Approximately 3 years ]
    Egen Klassifikation (EK)

  5. Efficacy - Motor Function Assessments: North Star Ambulatory Assessment (NSAA) [ Time Frame: Approximately 3 years ]
    North Star Ambulatory Assessment (NSAA)

  6. Efficacy - Motor Function Assessments: Hammersmith Functional Motor Scale-Expanded (HFMSE) [ Time Frame: Approximately 3 years ]
    Hammersmith Functional Motor Scale-Expanded (HFMSE), which includes 28 physical assessments on a 0-2 point scale (with 0 = unable, 1 = partially able, and 2 able, and total score possible 56) of head control, sitting, grasping, kicking, rolling, crawling, climbing, standing, walking, jumping, hopping from various positions, including lying, sitting, standing

  7. Efficacy - Motor Function Assessments: Patient-Reported Outcomes Measurement Information System (PROMIS) [ Time Frame: Approximately 3 years ]
    Patient-Reported Outcomes Measurement Information System (PROMIS), for participants 12 years and older, on physical function in upper limb on a scale of 1-5, where 1 is unable to perform and 5 is ability to perform without difficult

  8. Efficacy - Motor Function Assessments: Patient-Reported Outcomes Measurement Information System (PROMIS) [ Time Frame: Approximately 3 years ]
    Patient-Reported Outcomes Measurement Information System (PROMIS), for participants 12 years and older, on mobility on a scale of 1-5, where 1 is unable to perform and 5 is ability to perform without difficult

  9. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
    Pulmonary Function Tests (PFTs), including Forced Expiratory Volume (FEV) measured at 1 second and expressed as a percentage

  10. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
    Pulmonary Function Tests (PFTs), including Forced Vital Capacity (FVC) which is a measurement of lung size or volume (in liters) and represents the volume of air in the lungs that can be exhaled following a deep inhalation

  11. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
    Pulmonary Function Tests (PFTs), including Maximum Expiratory and Inspiratory Pressure (MEP/MIP) which are non-invasive methods to measure respiratory muscle strength and are expressed as cmH2O

  12. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
    Pulmonary Function Tests (PFTs), including Sniff Nasal Inspiratory Pressure (SNIP) which is a non-invasive measure of inspiratory muscle strength through one nostril and is measured in cm H2O

  13. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
    Pulmonary Function Tests (PFTs), including Peak Expiratory Flow (PEF), which is the maximum speed of expiration as measured with a peak flow meter in units of liters/minute

  14. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
    Pulmonary Function Tests (PFTs), including Peak Cough Flow (PCF), which is a measurement of a patient's ability to cough and is measured with a hand held meter that reports units in liters/minute

  15. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
    Use of ventilatory support, including status (use vs non-use) and amount of time (all devices listed will be listed by use for hours/day) used by ventilator, BiPAP, CPAP, and/or supplemental oxygen

  16. Efficacy - Respiratory Status [ Time Frame: Approximately 3 years ]
    Occurrence of respiratory infection, including the number of times respiratory infection occurs during course of study

  17. Efficacy - Growth/Nutrition [ Time Frame: Approximately 3 years ]
    Growth in patients over time compared to normals using the WHO reference standards and expressed as Z scores

  18. Efficacy - Growth/Nutrition [ Time Frame: Approximately 3 years ]
    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)

  19. Pharmacokinetics (PK) [ Time Frame: Approximately 3 years ]
    PK of dC/dT (Cmax - peak plasma concentration)

  20. Pharmacokinetics (PK) [ Time Frame: Approximately 3 years ]
    PK of dC/dT (Tmax - time to maximum plasma concentration)

  21. Pharmacokinetics (PK) [ Time Frame: Approximately 3 years ]
    PK of dC/dT (AUC - area under the plasma concentration time curve)

  22. Pharmacokinetics (PK) [ Time Frame: Approximately 3 years ]
    PK of dC/dT (t 1/2 - time to half life of drug or period of time required for plasma concentration or amount in the body to be reduced by exactly one-half)

  23. Biomarkers (plasma from blood) [ Time Frame: Approximately 3 years ]
    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)

  24. Biomarkers (plasma from blood) [ Time Frame: Approximately 3 years ]
    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)

  25. Quality of life through patient questionnaire - Individualized Neuromuscular Quality of Life (INQoL) [ Time Frame: Approximately 3 years ]
    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

  26. Characterization of health care utilization [ Time Frame: Approximately 3 years ]
    Hospitalizations - number of hospitalizations that occur during course of the study to determine if yearly number of hospitalizations (and type of hospitalizations) change over the course of time

  27. Characterization of health care utilization [ Time Frame: Approximately 3 years ]
    Surgeries - number of surgeries that occur during the course of the study to determine if yearly number of surgeries (and type of surgeries) change over the course of time and if patients have similar surgerical needs

  28. Characterization of health care utilization [ Time Frame: Approximately 3 years ]
    Use of health care resources (recording of respiratory care required during course of the study to determine if yearly health care needs and burden of illness change)

  29. Characterization of health care utilization [ Time Frame: Approximately 3 years ]
    Use of health care resources (recording of nursing care (full-time, part-time, or on occasion) that are used during course of the study to determine if yearly health care needs and burden of illness change)

  30. Characterization of health care utilization [ Time Frame: Approximately 3 years ]
    Use of health care resources (recording of physical therapy (number of PT sessions/week and type of sessions: land vs water) that are used during course of the study to determine if yearly health care needs and burden of illness change)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  1. Signed informed consent by the parent(s) or legally authorized representative (LAR) and/or assent by the patient (when applicable).
  2. Confirmed genetic mutation in the TK2 gene.
  3. Absence of other genetic disease or polygenic disease.
  4. Current treatment with nucleos(t)ides for TK2 deficiency. Patients who were not previously enrolled in MT 1621 101 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.
  5. Female patients 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 patients 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.
  6. Willingness to maintain current treatment regimen and current exercise regimen for the duration of the clinical study.
  7. Willingness to comply with the study protocol, including but not limited to, all study procedures, study visits, and study drug compliance.

Exclusion Criteria:

  1. History of liver disease, or liver function test results (ALT, AST, or total bilirubin) ≥2× upper limit of normal without prior Sponsor approval.
  2. Other significant medical condition that, in the opinion of the Investigator or Study Sponsor, may confound interpretation of the clinical course of TK2 deficiency.

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): NCT03845712


Locations
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United States, New York
New York Presbyterian Hospital-Columbia University Medical Center
New York, New York, United States, 10032
Israel
Rambam Hospital
Haifa, Israel, 3109601
Wolfson Medical Center
H̱olon, Israel, 5822012
Western Galilee Hospital
Nahariya, Israel, 89 כביש
Spain
Hospital Vall d'Hebron
Barcelona, Spain, 08035
Sant Joan de Deu Hospital
Barcelona, Spain, 08950
Hospital 12 de Octubre
Madrid, Spain, 28041
Hospital Universitario Virgen del Rocio
Seville, Spain, 41013
Sponsors and Collaborators
Modis Therapeutics, Inc.
Investigators
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Study Director: Joanne Quan, MD Modis Therapeutics

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Responsible Party: Modis Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03845712     History of Changes
Other Study ID Numbers: MT-1621-102
First Posted: February 19, 2019    Key Record Dates
Last Update Posted: July 24, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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