The Safety, Tolerability, Pharmacodynamics, and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP) in Patients With MNGIE
Trial Snapshot
- Phase
- Phase 2
- Status
- Withdrawn
- Primary Endpoint
- The safety of EE-TP as measured by the vital sign measurement respiratory rate
Study Overview
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.
Detailed Description
This is a multi centre, multiple dose, open label study to investigate the safety, tolerability, pharmacodynamics 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 Independent Data Monitoring Committee (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.
Screening failures and patients withdrawing from the study may be substituted with IDMC approval. Patients who have previously received EE-TP on a 'compassionate use' basis may be included in the study, if they meet eligibility criteria; these patients will be additional and will not be included in the sample size of 12.
The total sample size of 12 adult treatment naïve patients is not based on a formal statistical assessment, but is dictated by practical considerations mainly due to the rarity of the condition.
All patients will be administered EE-TP by intravenous (IV) infusion. There are 3 planned dose levels:
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 12 Years to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
Exclusion Criteria
- •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.
- •Patients with any current malignancy, or a history of malignancy within 5 years prior to Screening, with the exception of adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
- •Patients who are currently enrolled in, or are planning to participate in, or discontinued within the last 30 days from a clinical study involving an investigational medicinal product or concurrently enrolled in medical research judged not to be scientifically or medically compatible with EE-TP.
- •Patients with any medical condition, which in the opinion of the Investigator, would make the patient unsuitable for enrolment or could interfere with the patient's participation in, or completion of, the study.
Outcomes
Primary Outcomes
The safety of EE-TP as measured by the vital sign measurement respiratory rate
Time Frame: Day -120 to Follow-up visit (90 days post-final dose) at 31 months
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.
The safety of EE-TP as measured by the incidence, frequency, and severity of treatment emergent adverse events
Time Frame: Day -120 to Follow-up visit (90 days post-final dose) at 31 months
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).
The safety of EE-TP as measured by the vital sign measurement heart rate
Time Frame: Day -120 to Follow-up visit (90 days post-final dose) at 31 months
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.
The safety of EE-TP as measured by the vital sign measurement body temperature
Time Frame: Day -120 to Follow-up visit (90 days post-final dose) at 31 months
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.
The safety of EE-TP as measured by 12 lead ECG parameters
Time Frame: Day -120 to Follow-up visit (90 days post-final dose) at 31 months
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.
The safety of EE-TP as measured by the incidence of laboratory abnormalities, based on haematology, serum biochemistry, and urinalysis test
Time Frame: Day -120 to Follow-up visit (90 days post-final dose) at 31 months
Incidence of laboratory abnormalities outside the clinical reference ranges based on haematology, serum biochemistry, and urinalysis test
The safety of EE-TP as measured by the vital sign measurements systolic and diastolic blood pressure
Time Frame: Day -120 to Follow-up visit (90 days post-final dose) at 31 months
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.
The safety of EE-TP as measured by the use of concomitant medication(s)
Time Frame: Day -120 to Follow-up visit (90 days post-final dose) at 31 months
The use of concomitant medication(s) will be listed
The assessment of pharmacodynamic effects of EE-TP by the measurement of urine thymidine and deoxyuridine concentrations
Time Frame: Plasma and urine metabolites: Day -120 to Follow-up visit at 31 months; antibodies Day -1 to follow-up visit at 31 months
Changes from baseline in urine concentrations of thymidine and deoxyuridine will be calculated using Day 0 or Day 1 as the baseline.
The efficacy of EE-TP as measured by change in body mass index (BMI) by recording weight and height
Time Frame: Study day -120 to end of study treatment at 24 months
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.
The assessment of pharmacodynamic effects of EE-TP by the measurement of plasma thymidine and deoxyuridine concentrations
Time Frame: Plasma and urine metabolites: Day -120 to Follow-up visit at 31 months
Changes from baseline in plasma concentrations of thymidine and deoxyuridine will be calculated using Day 0 or Day 1 as the baseline.
Secondary Outcomes
- 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 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 Patient Global Impression of Change (PGIC).(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 muscle strength using the MRC scale(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 sensory impairment scoring(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 improvement of the most disabling symptom for each patient using the visual analogue scale (VAS)(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 gastrointestinal Symptoms symptoms using the Patient Reported Outcomes Measurement Information System (PROMIS) short form scales(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 reflex responses using neurological examination tests(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 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 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)
- To assess changes in clinical assessments as measured by Clinical Global Impression - Improvement Scale (CGI I)(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 Quality of life measured using EuroQol 5-dimensions(Change from baseline (Day -91 to Day 0) to end of study treatment at 24 months)