Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy

NCT03866954 | Withdrawn Phase 2 DMC

• 2 other identifiers: 2018.01582018-003000-39
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to determine the safety, tolerability, action and effectiveness of repeated doses of Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP) for the treatment of patients with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE). MNGIE is a rare inherited disease that mainly affects the digestive and nervous system and is caused by a defect in the function of an enzyme called thymidine phosphorylase. This loss of function causes certain molecules (thymidine and deoxyuridine) to accumulate in cells which leads to toxic damage to these cells. The disease can be confirmed by detecting variations (mutations) in the thymidine phosphorylase gene (TYMP). Currently there are no specific treatments for patients with MNGIE, whose effectiveness has been shown through clinical trials. The potential treatment for MNGIE offered in this trial is an enzyme replacement therapy, i.e. replacing functional thymidine phosphorylase. This treatment uses the patients own red blood cells in which thymidine phosphorylase is encapsulated to produce EE-TP (the study drug). EE-TP is created using a machine named a Red Cell Loader (RCL) and is then administered back to the patient.

Conditions

Mitochondrial Diseases; Metabolic Disease; Inborn Errors of Metabolism

Keywords

neuropathy; gastrointestinal disease; thymidine phosphorylase; enyme replacement

Outcome Measures

Primary Outcomes (11)

• The safety of EE-TP as measured by the incidence, frequency, and severity of treatment emergent adverse events

  Incidence, frequency, and severity of adverse events will be summarised by dose level, maximum severity, and , Medical Dictionary for Regulatory Activities system organ class, and preferred term. The intensity/severity will be graded by Common terminology criteria for adverse events (CTCAE) criteria, including relation to treatment (IMP and/or infusion).

  Day -120 to Follow-up visit (90 days post-final dose) at 31 months

• The safety of EE-TP as measured by the incidence of laboratory abnormalities, based on haematology, serum biochemistry, and urinalysis test

  Incidence of laboratory abnormalities outside the clinical reference ranges based on haematology, serum biochemistry, and urinalysis test

  Day -120 to Follow-up visit (90 days post-final dose) at 31 months

• The safety of EE-TP as measured by the vital sign measurements systolic and diastolic blood pressure

  Systolic and diastolic blood pressure measured in units of millimeters of mercury (mmHg) will be recorded. Measurements outside the clinical reference ranges will be summarised by dose level, together with changes from baseline.

  Day -120 to Follow-up visit (90 days post-final dose) at 31 months

• The safety of EE-TP as measured by the vital sign measurement heart rate

  Heart rate measured as beats per minute (BPM) will be recorded. Measurements outside the clinical reference ranges will be summarised by dose level, together with changes from baseline.

  Day -120 to Follow-up visit (90 days post-final dose) at 31 months

• The safety of EE-TP as measured by the vital sign measurement respiratory rate

  Respiratory rate measured as number of breaths taken per minute will be recorded. Measurements outside the clinical reference ranges will be summarised by dose level, together with changes from baseline.

  Day -120 to Follow-up visit (90 days post-final dose) at 31 months

• The safety of EE-TP as measured by the vital sign measurement body temperature

  Body temperature measured in degrees Celsius will be recorded. Measurements outside the clinical reference ranges will be summarised by dose level, together with changes from baseline.

  Day -120 to Follow-up visit (90 days post-final dose) at 31 months

• The safety of EE-TP as measured by 12 lead ECG parameters

  12 lead ECG parameter data (QTc, QTcB, QTcF, the PR and QT intervals, QRS duration, and heart rate) outside the clinical reference ranges will be summarised by dose level.

  Day -120 to Follow-up visit (90 days post-final dose) at 31 months

• The safety of EE-TP as measured by the use of concomitant medication(s)

  The use of concomitant medication(s) will be listed

  Day -120 to Follow-up visit (90 days post-final dose) at 31 months

• The assessment of pharmacodynamic effects of EE-TP by the measurement of plasma thymidine and deoxyuridine concentrations

  Changes from baseline in plasma concentrations of thymidine and deoxyuridine will be calculated using Day 0 or Day 1 as the baseline.

  Plasma and urine metabolites: Day -120 to Follow-up visit at 31 months

• The assessment of pharmacodynamic effects of EE-TP by the measurement of urine thymidine and deoxyuridine concentrations

  Changes from baseline in urine concentrations of thymidine and deoxyuridine will be calculated using Day 0 or Day 1 as the baseline.

  Plasma and urine metabolites: Day -120 to Follow-up visit at 31 months; antibodies Day -1 to follow-up visit at 31 months

• The efficacy of EE-TP as measured by change in body mass index (BMI) by recording weight and height

  Body weight in Kilograms (Kg), in underclothes will be recorded at the same time of day using calibrated equipment. In patients aged 18 years or older, height in meters (m) will only be measured during Run-in and at Follow-up. In juvenile patients, height will be measured at all time-points with weight from Screening until Day 77, and every 3 months once metabolic correction has been achieved. BMI will be calculated by an individual's body mass divided by the square of his/her height \[kg/m2\]. Absolute and changes from baseline in BMI will be plotted against plasma and urine concentrations of thymidine and deoxyuridine.

  Study day -120 to end of study treatment at 24 months

Secondary Outcomes (13)

• To assess the immunogenicity of EE-TP by monitoring the development of anti-thymidine phosphorylase antibodies

  Baseline (Day -91 to Day 0) to end of study treatment at 24 months

• To assess changes in clinical assessments as measured by total parenteral nutrition use

  Change from baseline (Day -91 to Day 0) to end of study treatment at 24 months

• To assess changes in clinical assessments as measured by Handgrip strength using handgrip dynamometry

  Change from baseline (Day -91 to Day 0) to end of study treatment at 24 months

• To assess changes in clinical assessments as measured by Disability measured using the Rasch built Overall Disability Scale (RODS)

  Change from baseline (Day -91 to Day 0) to end of study treatment at 24 months

• To assess changes in clinical assessments as measured by ambulatory function measured using the timed 10 metre walk test

  Change from baseline (Day -91 to Day 0) to end of study treatment at 24 months

Other Outcomes (5)

• Exploratory Objective: to assess the effects of EE-TP on serum and plasma biomarkers of mitochondrial condition

  Days 0, 1, 7, 14, 21, 28, 35, 42, 43, 49, 56, 63, 64, 70, and 77, and at each clinic visit from Day 78 until the end of the study

• Exploratory Objective:to assess the effects of EE-TP on MRI brain

  Change from baseline (Day -91 to Day 0) to 12 and 24 months

• Exploratory Objective:to assess the effects of EE-TP on abdominal ultrasound

  Change from baseline (Day -91 to Day 0) to 12 and 24 months

Study Arms (1)

Intravenous administration of EE-TP

EXPERIMENTAL

Intravenous administration of EE-TP. The starting dose will be Dose Level 1, with potential subsequent dose levels of Dose Level 2 and Dose Level 3 dependent on whether metabolic correction is achieved or not.

Combination Product: EE-TP

Interventions

EE-TP COMBINATION_PRODUCT

Ecoli thymidine phoshorylase encapsulated within autologous erythrocytes

Intravenous administration of EE-TP

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be male or female, of any race, aged 18 years or older at Screening.
• Having IDMC reviewed the benefit risk profile and recommended progression to juvenile cohorts the age range will be extended to include patients:
• aged 16 years or older after at least 24 patient months of exposure in patients aged 18 years or over.
• aged 12 years or older after at least 24 patient months of exposure in patients aged \<18 years at the time of enrolment.
• Patients must be diagnosed with MNGIE by demonstrating all of the following:
• \<18% normal thymidine phosphorylase activity in the buffy coat;
• \>3 μmol/L plasma thymidine;
• \>5 μmol/L plasma deoxyuridine;
• Confirmation of the presence of a pathogenic mutation in TYMP by sequencing.
• Patients must be able to undergo study procedures.
• Patients must agree to either remain completely true abstinent or to use 2 effective contraceptive methods from Screening until completion of the Follow up Visit
• Patients must be willing to sign and date the written informed consent form after the benefits and risks of taking part in this study have been explained to them, and to comply with the study restrictions.

You may not qualify if:

• Patients who meet any of the following criteria will not be eligible to participate in the study:
• Patients who have received a successful liver or bone marrow transplant.
• Patients suitable for allogeneic haematopoietic stem cell transplantation (AHSCT).
• Patients with a matched AHSCT donor.
• Patients with a known history of human immunodeficiency virus, hepatitis B infection, or an active hepatitis C infection.
• Patients who are severely disabled (e.g., patient bed bound, incontinent, and unable to carry out any daily activities), or with a life expectancy of less than 12 months at Screening, based on the Investigator's judgment.
• Female patients who are:
• pregnant, planning a pregnancy, or are unwilling to use contraception
• breastfeeding or lactating.
• Patients who have donated blood in the 90 days prior to Screening.
• Patients with a confirmed red blood cell count of \<3.0 × 10\^9 per mL.
• Patients who have a significant history of alcoholism or drug/chemical abuse within 1 year prior to Screening, as determined by the Investigator.
• Patients who have an abnormality in heart rate, blood pressure, or body temperature at Screening that, in the opinion of the Investigator, increases the risk of participating in the study.
• Patients who have an abnormality in the 12 lead electrocardiogram (ECG) at Screening that, in the opinion of the Investigator, increases the risk of participating in the study.
• Patients who have, or have a history of, any clinically significant neurological, GI, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological, or other major disorder (except for MNGIE, or disorders associated with MNGIE that, in the Investigator's opinion, do not constitute a risk when taking study drug and would not interfere with the study objectives) as determined by the Investigator.

Sponsors & Collaborators

• St George's, University of London: lead
• Neovii Biotech: collaborator

Related Publications (4)

• Moran NF, Bain MD, Muqit MM, Bax BE. Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE. Neurology. 2008 Aug 26;71(9):686-8. doi: 10.1212/01.wnl.0000324602.97205.ab. No abstract available.

  PMID: 18725595 RESULT

• Bax BE, Bain MD, Scarpelli M, Filosto M, Tonin P, Moran N. Clinical and biochemical improvements in a patient with MNGIE following enzyme replacement. Neurology. 2013 Oct 1;81(14):1269-71. doi: 10.1212/WNL.0b013e3182a6cb4b. Epub 2013 Aug 21.

  PMID: 23966250 RESULT

• Bourgeaux V, Lanao JM, Bax BE, Godfrin Y. Drug-loaded erythrocytes: on the road toward marketing approval. Drug Des Devel Ther. 2016 Feb 11;10:665-76. doi: 10.2147/DDDT.S96470. eCollection 2016.

  PMID: 26929599 RESULT

• Pacitti D, Levene M, Garone C, Nirmalananthan N, Bax BE. Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far. Front Genet. 2018 Dec 21;9:669. doi: 10.3389/fgene.2018.00669. eCollection 2018.

  PMID: 30627136 RESULT

MeSH Terms

Conditions

Mitochondrial Diseases; Metabolic Diseases; Metabolism, Inborn Errors; Gastrointestinal Diseases

Condition Hierarchy (Ancestors)

Nutritional and Metabolic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Digestive System Diseases

Study Officials

• Niranjanan Nirmalananthan, MBBS

  St George's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This will be a multi-centre, multiple dose, open label study to investigate the safety, tolerability, PD, and efficacy of EE TP in patients with MNGIE. The study will be conducted in an open label manner with all patients receiving EE TP. The study will enrol 12 adult treatment naïve patients with MNGIE, aged 18 years or older at Screening. With IDMC approval, a further four juvenile patients (aged 16-17) will be recruited after at least 24 patient-months exposure to treatment. With IDMC approval, a further four juvenile patients (aged 12-15) will be recruited after at least 24 patient-months exposure to treatment in the 16-17 year old patient group.

Study Record Dates

• First Submitted: February 4, 2019
• First Posted: March 7, 2019
• Study Start: November 1, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: October 11, 2023

Record last verified: 2023-07