A phase I/II trial for evaluating both safety and preliminary efficacy of one cycle of Promethera HepaStem® in Urea Cycle Disorders and Crigler-Najjar Syndrome patients

• Register: EUCTR
• Last refreshed on: 4 August 2015
• Main ID: EUCTR2011-004074-28-GB
• Date of registration: 28/09/2011
• Prospective Registration: Yes
• Primary sponsor: Promethera Biosciences
• Public title: A phase I/II trial for evaluating both safety and preliminary efficacy of one cycle of Promethera HepaStem® in Urea Cycle Disorders and Crigler-Najjar Syndrome patients
• Scientific title: A prospective, open label, multicenter, randomized, safety and preliminary efficacy study of one cycle of Promethera HepaStem® in Urea Cycle Disorders and Crigler-Najjar Syndrome patients - UKHEP001
• Date of first enrolment: 20/07/2012
• Target sample size: 21
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-004074-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no

Countries of recruitment

Belgium, Italy, United Kingdom

Contacts

• Name: Vinciane Wouters
• Affiliation: Promethera Biosciences

• Name: Vinciane Wouters
• Affiliation: Promethera Biosciences

Key inclusion & exclusion criteria

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:
4.Patient presents with Crigler-Najjar syndrome type 1 and diagnosis must be confirmed by genetic mutation analysis if not available.
5.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
6.Diagnosis of one of the urea cycle disorders (CPSID, 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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 20
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1.The subject is 16 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

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
MedDRA version: 17.0 Level: LLT Classification code 10021601 Term: Inborn error of metabolism NOS System Organ Class: 100000004850

Intervention(s)

Product Name: HepaStem
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: Heterologous Human Adult Liver-derived Progenitor Cells
CAS Number: NA
Current Sponsor code: HHALPC
Other descriptive name: NA
Concentration unit: million organisms/ml million organisms/millilitre
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Secondary Objective: 1. To assess the long term safety (up to 12 months) of one cycle of HHALPC infusions in paediatric patients (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 min of 6 and up to 12 months by as compared to his/her prior medical condition.
3. To investigate the engraftment of HHALPC in the liver (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 FISH or immunohistochemistry

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

Main Objective: 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.

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)

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Assessment of reactogenicity and safety of the treatment during 6 to 12 months post infusion (long-term safety) will be evaluated

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).

Secondary ID(s)

UKHEP001

Source(s) of Monetary Support

Promethera Biosciences