Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency

NCT ID: NCT03776656

Last Updated: 2022-10-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-14
• Study Completion Date: 2022-06-17

Brief Summary

The aim of this study is to evaluate the effectiveness of allopurinol treatment at 12 months on the adaptive and cognitive functioning of patients with adenylosuccinate lyase deficiency (ADSL). The psychiatric evaluation will involve the use of standardized tools prior to initiation of treatment, and will be repeated 6 months and 12 months after the start of treatment.

The decrease in the concentration of SAICAR and S-Ado metabolites, which are markers of adenylosuccinate lyase (ADSL) deficiency, will also be quantified.

Similarly, the efficacy of allopurinol on epileptic seizures for epileptic patients and on electrocardiogram abnormalities will be evaluated secondarily

Detailed Description

Adenylosuccinate lyase deficiency (ADSL) is a rare disorder of purine metabolism whose symptoms are mental retardation, autistic disorders, epilepsy, related to the accumulation of succinylpurines: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S- Ado). The S-Ado / SAICAr ratio in the cerebrospinal fluid (CSF) is correlated with the clinical severity: the cerebral toxicity of SAICAr is incriminated. There is no specific treatment.

Based on the work of Gertrude B. Elion (1988 Nobel Prize in Medicine), who reports that allopurinol (a structural analogue of hypoxanthine) can be a substrate for hypoxanthine phosphoribosyltransferase (HPRT) and thus produce allopurinol ribonucleotides with as a first step in the de novo synthesis of purines, investigators tested the hypothesis that treatment with allopurinol in children with ADSL deficiency would reduce the production of the toxic metabolite SAICAr.

This hypothesis was validated in 3 minor patients with biological and clinical improvement.

So the investigators put the phase II, non-comparative study based on 4 visits to Necker-Enfants malades Hospital or La Pitié-Salpêtrière Hospital: Month 0 (before treatment), Month 3, Month 6 and Month 12 after the start of treatment.

After verification of the inclusion criteria and information of the parents or the patient or guardian, signature of the consent and inclusion of the patient:

• Clinical and neurological evaluation;
• Psychiatric assessment with standardized tests;
• Biological evaluation: determination of urinary and plasma metabolites (SAICAr, S-Ado, ...) Experimental treatment: Allopurinol (Zyloric®) will be administered orally for 12 months without exceeding 400 mg / day in children and 900 mg / day in adults, with dosage adjustment in case of renal failure.

Conditions

Adenylosuccinate Lyase Deficiency

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Allopurinol

Oral administration of Allopurinol (Zyloric®) for 12 months without exceeding 400 mg / day in children and 900 mg / day in adults, with dosage adjustment in case of renal failure

Group Type: EXPERIMENTAL

Allopurinol

Intervention Type: DRUG

Daily oral administration

Interventions

Allopurinol

Daily oral administration

Intervention Type: DRUG

Other Intervention Names

Zyloric®

Eligibility Criteria

Inclusion Criteria

• Child (minimum age 18 months) or adult with adenylosuccinate lyase; deficiency (ADSL) confirmed by quantification of SAICAr and S-Ado urinary;
• Girls / women of childbearing age must:

• have a negative pregnancy test;
• agree to use a reliable method of contraception from the baseline visit to the last dose of study treatment
• Consent of the patient, his parents or his legal representative;
• Beneficiary of social security (affiliated or entitled).

Exclusion Criteria

• Refusal of the child, his parents or the patient or his representative;
• Allergy known to allopurinol or to one of the constituents of the product (lactose in particular);
• Patients treated with Antipurines (azathioprine, mercaptopurine);
• Patients treated with vidarabine, cytotoxic drugs (eg cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halides), ciclosporin, or didanosine
• Renal failure characterized by creatinine clearance <80 ml/mn
• Hepatic insufficiency
• Medullary insufficiency but possibly serious
• Breastfeeding
• Pregnancy or wishing to conceive during the study period

• Minimum Eligible Age: 18 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

URC-CIC Paris Descartes Necker Cochin

OTHER

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pascale De LONLAY, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Irène CEBALLOS-PICOT, MD, PhD

Role: STUDY_DIRECTOR

Assistance Publique - Hôpitaux de Paris

Laurence ROBEL-GALLI, MD

Role: STUDY_DIRECTOR

Assistance Publique - Hôpitaux de Paris

Locations

LA PITIE-SALPETRIERE Hospital, AP-HP

Paris, , France

Department of Pediatry. Reference centre of Hereditary diseases of the metabolism of child and adult. Necker - Enfants malades Hospital

Paris, , France

Countries

France

Other Identifiers

2017-002155-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

P160902J

Identifier Type: -

Identifier Source: org_study_id