Cardiac allograft vasculopathy (CAV) Circulatory System
Conditions
Interventions
Autologous thymus-derived Tregs (TR006) infused at one of two doses (in a 3+3 design):
1. Low dose: 1 - 3 x 106 Tregs/Kg
or
2. High (and highest) dose: 5 - 10 x 106 Tregs/Kg
Sponsors
Great Ormond Street Hospital
Eligibility
Sex/Gender
All
Age
6 Months to 16 Years
Inclusion criteria
Inclusion criteria: 1. Male or female children aged between 0.5 and 16 (inclusive) years of age at the date of consent/assent and date of transplant 2. Written informed consent obtained from a parent/legal guardian 3. Registered on the heart transplant list at the date of consent and received a heart transplant on enrolment 4. Receiving a single transplanted organ 5. Willing and able to comply with the study visit schedule
Exclusion criteria
Exclusion criteria: 1. Active viral infection (with HIV, hepatitis B, hepatitis C and syphilis) at date of admission for transplant 2. Age under 0.5 year or over 16 years at date of consent and at date of transplant 3. Multi-organ transplant 4. Highly sensitive patients at high risk of rejection assessed by HLA antibody measurement 5. Allergy to any component / excipients used for the manufacture of TR006 6. Previous recipient of any organ transplant 7. History of previous sternotomy surgical procedure for congenital heart defect during which has had previous partial or full thymectomy 8. Confirmed diagnosis of DiGeorge Syndrome with absent thymus 9. Participation in another interventional Clinical Trial of Investigational Medicinal Product during the study or within 28 days prior to date of transplant (at the Chief Investigator’s discretion) 10. Pregnant and lactating patients (females of childbearing potential* with a positive urine pregnancy test at date of transplant) 11. Female patients of childbearing potential* who are not willing to use a highly effective method of contraception** for the duration of the trial (defined as from date of transplant to 12 months post Treg infusion) to prevent pregnancy, or abstain from heterosexual activity *Females of child-bearing potential are females who have experienced menarche and are not surgically sterilised (e.g., hysterectomy, bilateral salpingectomy or bilateral oophorectomy) or post-menopausal. Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with more than one FSH measurement is required. ** Highly effective methods of contraception are those with a failure rate of < 1% per year when employed consistently and correctly. For example: • Combined (oestrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation – oral, intravaginal, transdermal. • Transdermal progestogen-only hormonal contraception associated with inhibition of ovulation – oral, injectable, implantable. • Intrauterine device (IUD). • Intrauterine hormone-releasing system (IUS) • Bilateral tubal occlusion • Vasectomised partner, provided that partner is the sole sexual partner of the FOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success. Sexual abstinence is considered to be a highly effective method only if defined as refraining from heterosexual activity from the date of transplant until 12 months post Treg infusion. The reliability of this method should be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. 12. Male patients who are not willing to use an effective method of contraception (condoms), for the duration of the study (date of transplant to 12 months post-Treg infusion), when engaging in sexual activity with a female of childbearing potential 13. The patient is considered by the Chief Investigator, for any reason, to be an unsuitable candidate for the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The safety and optimal tolerated dose of TR006 to prevent CAV in paediatric heart transplant patients measured using the occurrence and nature of Dose-Limiting Toxicities (DLTs) occurring within 4 weeks post-infusion of the expanded autologous thymus-derived Treg product (ATIMP) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary outcome measures: 1. To assess the feasibility of generating TR006 in the Good Manufacturing Practice facility is measured using the amount of TR006 manufactured per patient 2. To investigate the clinical and immunological responses to TR006 in paediatric heart transplant patients is measured using the amount of TR006 manufactured per patient Assessment of Immunological Response: 1. Frequency of circulating leukocyte subsets 2. Quantity of alloantigen-specific conventional T cells, Tregs and CD8+ 3. The presence of anti-HLA is used to evaluate tissue infiltrating cells Assessment of clinical response: 1. Diagnosis of CAV as measured by coronary angiography within 24 months post-infusion of TR006 2. Graft loss as measured by inclusion of patient on the re-transplant waiting list through rejection (acute or chronic) within 24 months post-infusion of TR006 3. Recipient mortality within 24 months post-infusion of TR006 4. Acute graft rejection as measured by endomyocardial biopsy (EMB) within 24 months post-infusion of TR006 5. Antibody-mediated rejection as measured by the development of donor-specific antibodies within 24 months post-infusion of TR006 6. Infection-related rehospitalisation events within 24 months post-infusion of TR006 7. (Cardiac function) Left ventricular ejection fraction measured by echocardiography monthly for 12 months and 24 months post-infusion of TR006 8. (Renal function) Mean calculated GFR at 24 months post-infusion of TR006 9. Description of non-DLT adverse events and those occurring beyond week 4 and up to 24 months post-infusion of TR006 10. Immunosuppressive doses at 12 and 24 months post-infusion of TR006 Additional measures: The feasibility of retaining participants for the duration of the study and completion of study visits and assessments was measured using the number of study visits completed per participant and responses to items in questionnaires or surveys exploring the study and treatment experience of the partici | — |
Countries
England, United Kingdom
Contacts
Public ContactMichael Burch
Outcome results
None listed