E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Crigler-Najjar syndrome is associated with a complete or partial hepatic deficit of bilirubin glucuronosyltransferase activity and is apparent during the neonatal period by intense jaundice. The urea cycle disorders are inborn errors of metabolism that affect the transfer of nitrogen into urea. There are six disorders: N-Acetylglutamate synthase deficiency, Carbamoyl phosphate synthetase I deficiency, Ornithine transcarbamylase deficiency, citrullinemia, argininosuccinic aciduria and argininemia |
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E.1.1.1 | Medical condition in easily understood language |
Liver metabolic diseases: Crigler-Najjar disease and Urea Cycle disorders |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021601 |
E.1.2 | Term | Inborn error of metabolism NOS |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety of one cycle of HHALPC infusions up to six months in paediatric patients suffering from CN or UCD in terms of clinical status, portal-vein hemodynamics, morphology of the liver, de novo detection of circulating anti-HLA antibodies, and/or other immune related markers as well as Serious Adverse Events (SAEs) and clinically significant Adverse Events (AEs) related to infusion. |
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E.2.2 | Secondary objectives of the trial |
1.To assess the long term safety (up to 12 months) of one cycle of
HHALPC infusions in paediatric patients suffering from CN or UCD in
terms of clinical status, portal-vein hemodynamics, morphology of the
liver, de novo detection of circulating anti-HLA antibodies, and/or other
immune related markers as well as SAE's and clinically significant AEs
related to infusion.
2.To appraise the efficacy post-infusion of one cycle of HHALPC for each
individual patient and for all patients for a minimum of six and up to
twelve months as compared to his/her prior medical condition.
3.To investigate the engraftment of HHLAPC in the liver of all patients
(at 6 month, and optional at 12 month) by quantitative measurement of
enzymatic activity on the biopsies and/or establishing donor sequences
by real time PCR or in situ hybridisation (FISH) or
immunohistochemistry. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Peripheral Blood Mononuclear Cells (PBMC) sub-study, version 2.0, August 01 2012.
The purpose of the study is to learn more about the kinetics of an immune response following infusion of undifferentiated progenitor cells in patients suffering from urea cycle disorder and Crigler Najjar syndrome.
Patients of cohort I and II are eligible for the study. A written informed consent for this PBMC substudy must be provided prior to the start of the study (at the screening visit). |
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E.3 | Principal inclusion criteria |
General:
1. Subject shows patency of the portal vein and branches, with normal flow velocity in the main portal vein as confirmed by Doppler ultrasound and accessibility of the portal vein, or respectively, accessibility of the umbilical vein.
2. Subject (if capable of signing) and parents or legal representative have provided a written informed assent/consent.
3. Female subjects of childbearing potential need to have a negative pregnancy test and must agree to use an acceptable method of contraception throughout the study.
Crigler-Najjar Syndrome specific:
Patient presents with Crigler-Najjar syndrome type 1 and diagnosis must be confirmed by genetic mutation analysis if not available.
4. Patient presents with Crigler-Najjar syndrome type 2
- poorly controlled under phenobarbital treatment, or
- experiencing serious impairment in quality of life.
Diagnosis must be confirmed by genetic mutation analysis if not available.
Urea Cycle Disorders specific
5. Diagnosis of one of the urea cycle disorders (CPS I D, OCTD, ASSD, ASLD, Arginase deficiency, and NAGSD)
- of which the disease is of such severity to warrant liver transplantation or alternatives despite full conservative therapy, or
- subject experiencing serious impairment in quality of life despite full conservative therapy.
Diagnosis must be confirmed by genetic mutation analysis if not available. |
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E.4 | Principal exclusion criteria |
1. The subject is 18 years or older at time of screening.
2. The subject presents acute liver failure.
3. The subject presents clinical or radiological evidence of liver fibrosis or cirrhosis
4. The subject presents or has a history of hepatic or extrahepatic malignancy
5. The patient has a non-corrected cardiac malformation.
6. The subject has a known medical or family history of coagulopathy.
7. The subject participates currently in another clinical trial – except disease registry and observational HepaStem study.
8. The subject underwent previous mature liver cell or stem cell transplantation or received an organ liver transplant.
9. The subject has a contraindication to immunosuppressive therapy.
10. The subject has a known hypersensitivity or allergy to the recommended antibiotics to prevent post-operative infections according to institutional guidelines, and basiliximab, solumedrol or tacrolimus unless alternative drugs can be used without risk for the patient.
11. The subject has a known hypersensitivity or allergy to bivalirudin.
12. The subject had or has a renal insufficiency treated by dialysis.
13. The subject requires valproate therapy.
14. The subject has a known hypersensitivity or allergy to contrast agents that cannot be treated adequately.
15. The subject has a thrombosis of the portal vein or persisting impairment of anterograde portal blood flow.
16. The subject has a porto systemic shunt or fistula assessed by Doppler US.
17. For umbilical vein access: The subject has any contraindication for umbilical vein catheterization (eg omphalitis, peritonitis, necrotizing enterocolitis, etc)
18. Any significant condition which in the Investigator’s opinion may interfere with the subject’s optimal participation in the study.
19. Patients with disease of such severity that liver transplantation is an absolute indication.
20. Patients with mild disease severity, easily controlled under standard of care therapy with no recurrent metabolic crises. |
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E.5 End points |
E.5.1 | Primary end point(s) |
-Safety of the technical intervention (infusion of HepaStem in portal vein) common to both indications and to different weight cohorts (short-and mid-term safety):
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Four time windows will be assessed:
1. Inpatient period : Vo-Vdischarge: reactogenicity of infusion
2. Outpatient period: Vdischarge-V1month: short-term safety of infusion
3. Outpatient period: V1m-V6m: mid-term safety of infusion
4. Overall period: Vo-V6m
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E.5.2 | Secondary end point(s) |
-To characterize the safety profile of HepaStem for both indications and for different weight cohorts (long-term safety).
-To characterize the preliminary efficacy of HepaStem for both indications and for different weight cohorts (0 -6 months ; 6 -12 months).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessment of reactogenicity and safety of the treatment during 6 to12 months post infusion (long-term safety) will be evaluated
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last patient, last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 32 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 32 |
E.8.9.2 | In all countries concerned by the trial days | 0 |