Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency (ADSL)

Assistance Publique - Hôpitaux de Paris

Status and phase: Completed; Phase 2

Conditions: Adenylosuccinate Lyase Deficiency

Treatments: Drug: Allopurinol

Study type: Interventional

Funder types: Other

Identifiers

NCT03776656

2017-002155-28 (EudraCT Number)

P160902J

Details and patient eligibility

About

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

Full 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.

Enrollment: 8 patients

Sex: All

Ages: 18+ months old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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8 participants in 1 patient group

Allopurinol

Experimental group

Description:

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

Treatment:

Drug: Allopurinol