HEP002 is a clinical study designed for paediatric patients with urea cycle disorders (UCD). UCD patients will receive several infusions of HepaStem. The efficacy as well as the safety of the medicinal product will be assessed during the year following infusions.

• Register: EUCTR
• Last refreshed on: 5 April 2021
• Main ID: EUCTR2014-000650-11-BE
• Date of registration: 01/07/2014
• Prospective Registration: Yes
• Primary sponsor: Promethera Biosciences
• Public title: HEP002 is a clinical study designed for paediatric patients with urea cycle disorders (UCD). UCD patients will receive several infusions of HepaStem. The efficacy as well as the safety of the medicinal product will be assessed during the year following infusions.
• Scientific title: A prospective, open label, multicountry, efficacy and safety study of several infusions of HepaStem in Urea Cycle Disorders pediatric patients. - HEP002
• Date of first enrolment: 15/09/2014
• Target sample size: 20
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000650-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; 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
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, France, Poland, Spain

Contacts

• Name: Vinciane Wouters
• Affiliation: Promethera Biosciences

• Name: Vinciane Wouters
• Affiliation: Promethera Biosciences

Key inclusion & exclusion criteria

Inclusion criteria:
A patient who meets all of the following inclusion criteria will be eligible for participation in the study:
1. The patient is a pediatric patient <12 years prior to infusion.
2. The patient presents with one of the following UCDs (carbamoylphosphate synthetase 1 deficiency [CPS1 D], ornithine transcarbamylase deficiency [OTCD], argininosuccinic acid synthetase deficiency [ASSD], argininosuccinic acid lyase deficiency [ASLD], arginase deficiency [ARGD].
3. The patient has severe disease with impaired protein tolerance defined as: chronic protein restricted diet AND chronic treatment with at least one nitrogen scavenger.
4. The following retrospective data are available:
- at least 1 metabolic evaluation and 1 global energy balance evaluation (diet evaluation) have been performed within 3 months before study inclusion
- at least 2 height measurements have been performed at least 3 months apart within 1 year before inclusion
- 1 neurocognitive evaluation (such as Wechsler test) has been performed 6 to 18 months before study inclusion.
5. The patient shows patency of the portal vein and its branches including mesenteric veins, with normal flow velocity as confirmed by Doppler US and accessibility of the portal vein and /or affluants.
6. The patient (if capable of signing) and parents or legal representative have signed a written informed assent/consent form.

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:
A patient who meets any of the following exclusion criteria will not be enrolled in the study:
1. The patient presents acute liver failure.
2. The patient presents clinical or radiological evidence of liver cirrhosis.
3. The patient presents or has a history of hepatic or extrahepatic malignancy.
4. The patient has a known clinically significant cardiac malformation.
5. The patient has a personal history of venous thrombosis, or has a clinically significant abnormal value for protein S, protein C, anti-thrombin III, and /or activated Protein C Resistance (aPCR) at screening. In case of known family history, a complete coagulation work-up should be performed. In all above described cases, results need to be discussed with PB before enrolling the patient in the study.
6. The patient participates currently in another clinical trial – except disease registry and observational HepaStem study.
7. The patient underwent previous mature liver cell or stem cell transplantation or received an organ liver transplant or received HepaStem infusion.
8. The patient has a contraindication to methylprednisolone, tacrolimus.
9. The patient has a known hypersensitivity or allergy to bivalirudin.
10. The patient has a known hypersensitivity or allergy to the antibiotics preventing post-operative infections that are prescribed according to institutional guidelines, and no alternative prophylaxis can be found.
11. The patient had or has a renal insufficiency treated by dialysis.
12. The patient requires valproate therapy.
13. The patient has a known hypersensitivity or allergy to contrast agents (if applicable) that cannot be treated adequately.
14. The patient has a thrombosis of the portal vein or persisting impairment of anterograde portal blood flow.
15. The patient has a porto systemic shunt or fistula assessed by Doppler US or an Arantius channel or portal hypertension.
16. The site where the catheter is intended to be placed has previously suffered from venous thrombosis or vascular surgical procedures.
17. The patient has an ongoing infection or suffered from an infection in the last 2 weeks (including active EBV infection at screening). The patient may be enrolled after resolution of the infection.
18. There is any significant condition or disability that, in the Investigator’s opinion, may interfere with the patient’s optimal participation in the study.



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

Health Condition(s) or Problem(s) studied

The urea cycle disorders are inborn errors of metabolism that affect the transfer of nitrogen into urea. There are seven disorders to be investigated: carbamoylphosphate synthetase I deficiency [CPS ID], ornithine transcarbamylase deficiency [OTCD], argininosuccinic acid synthetase deficiency [ASSD], argininosuccinic acid lyase deficiency [ASLD], arginase deficiency [ARGD], N-acetylglutamate synthase deficiency [NAGSD], and citrine deficiency.
MedDRA version: 18.0 Level: LLT Classification code 10013373 Term: Disorders of urea cycle metabolism System Organ Class: 100000004861

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

Intervention(s)

Product Name: HepaStem
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: Heterologous Human Adult Liver-derived Progenitor Cells
Current Sponsor code: HHALPC
Concentration unit: million organisms/ml million organisms/millilitre
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Primary end point(s): Ureagenesis improvement at 6 month post first infusion day (FU visit 3): absolute 13C blood urea AUC-120 min quantified with the 13C Tracer method at FU visits 3 compared with baseline evaluations (measurements at BL visit 1, BL visit 2 and BL visit 3).

The results of the first 5 patients will first be assessed. If the positive benefit risk ratio for the study is confirmed after the first five patients having completed FU visit 3 (6 m post first infusion), the study will be continued.

Timepoint(s) of evaluation of this end point: Ureagenesis improvement at 6 month post first infusion day (FU visit 3): absolute 13C blood urea AUC-120 min quantified with the 13C Tracer method at FU visits 3 compared with baseline evaluations (measurements at BL visit 1, BL visit 2 and BL visit 3).

Secondary Objective: 1. To evaluate the efficacy of HepaStem in terms of functional, clinical, and biochemical parameters up to one year after initiation of HepaStem infusion.
2. To evaluate the safety of HepaStem up to one year after initiation of HepaStem infusion.

Main Objective: To demonstrate the functional efficacy of HepaStem at 6 months after initiation of infusion in terms of ureagenesis improvement based on a functional test (13C tracer method).
A stopping rule is introduced as a particular measure to protect pediatric patients: If the positive benefit risk ratio for the study is confirmed after the first five patients having completed FU visit 3 (6 m post first infusion), the study will be continued.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. Functional parameters: at month 3, month 9 and month 12 post first infusion day (FU visits 1, 5, 7)
2. Clinical and biochemical parameters: Efficacy up to 12 months post-first infusion day
3. Individual medical assessment: clinical improvement will be evaluated on a complete file of each patient after 6 months and after 12 months of initiation of HepaStem administration.
4. The safety parameters will be assessed for 4 periods
- Screening Period
- Baseline period
- Active Treatment Period
Events will be evaluated according to time from catheter placement, time from the first infusion and time from the last infusion received.
- Follow-up Period
Events will be evaluated according to time from the first infusion and time from the last infusion received.

Secondary end point(s): 1. Functional parameter
Ureagenesis improvement at month 3, month 9 and month 12 post first infusion day (FU visits 1, 5, 7): absolute 13C blood urea AUC-120 min quantified with the 13C Tracer method at these visits compared with baseline evaluations (measurements at BL visit 1, BL visit 2 and BL visit).
2. Clinical and biochemical parameters:
Efficacy up to 12 months post-first infusion day as compared to prior medical condition based on:
- Chronic protein intake (total and natural protein, reported in mg/kg/day and reported as compared to WHO safe level for age) considering diet evaluations at study visits during baseline period and at scheduled study visits during the follow-up period.
- Chronic nitrogen scavenger dose (mg/kg/day) considering reported doses at scheduled study visits during baseline period and at scheduled study visits during the follow-up period.
- Blood ammonia considering values measured at scheduled study visits during screening and baseline periods and at scheduled study visits during the follow-up period.
- Relevant blood amino acids considering values measured at scheduled study visits during the screening and baseline periods and at scheduled study visits during the follow-up period.
- Metabolic decompensations (hyperammonemia episodes with evocative symptomatology such as drowsiness, gastrointestinal symptoms and treated at hospital), considering all collected events during screening and baseline periods, during active treatment period, during follow-up period.
- Chronic single amino acid intake considering reported doses at study visits during baseline period and at study visits during the follow-up period.
- Growth parameters collected during retrospective period (for a max of 3 years prior to study inclusion) and measured at scheduled study visits.
- Cognitive skills considering evaluation during the baseline period at baseline visit 1 (BL visit 1) and during follow-up period at 12 month post first infusion (FU visit 7).
- Behavior and health-related QoL indicators considering evaluations during BL visit 1, during follow-up period at 4.5 m, 7.5 m and 12 m post first fusion (FU visits 2, 4, 7).
3. Individual medical assessment
The clinical and biological parameters evaluated as secondary endpoints will be reviewed by a Data Review Committee (DRC) composed of external experts in metabolic diseases. DRC members will evaluate whether there is a clinical improvement or not based on a complete file of each patient after 6 months and after 12 months of initiation of HepaStem administration.

4. Safety during the study
Safety evaluation in terms of:
- Clinical status (physical examination and vital signs)
- Portal-vein hemodynamics
- Morphology of the liver, bile ducts, and portal system
- Laboratory tests
- De novo detection of donor-specific circulating anti-human leukocyte antigen (HLA) antibodies at mean fluorescence intensity (MFI) >1500, and/or other immune-related markers
- Serious Adverse Events (SAEs) and clinically significant Adverse Events (AEs) related to HepaStem (infusion and follow-up), technical intervention, and concomitant treatments.

Secondary ID(s)

HEP002

Source(s) of Monetary Support

Promethera Biosciences

Ethics review

Status: Approved
Approval date: 28/07/2014
Contact: