Clinical trial NCT03776656: Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency
Official title: Evaluation of a Treatment With Allopurinol on Autistic Disorders and Epilepsy in Adenylosuccinate Lyase Deficiency (ADSL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adenylosuccinate Lyase Deficiency
Keywords: Adenylosuccinate lyase
Deficit
Allopurinol
Autism
Epilepsy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: URC-CIC Paris Descartes Necker Cochin
First posted: 2018-12-17
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Measurement of adaptive functional improvement : composite total score for Vineland II adaptive behaviour Scale
timeFrame: 12 months
Secondary outcomes:
measure: Evolution of the Scores of different subdomains Vineland II scale from baseline
timeFrame: at 0, 6 months and 12 months
measure: Evolution of the Psycho-Educative Profile (PEP III/R) from baseline
timeFrame: at 0, 12 months
measure: Evolution of the Score ADI-R (Autism Diagnostic Interview-Revised) from baseline
timeFrame: at 0, 12 months
measure: Evolution of the Score ADOS-2 (Autism Diagnostic Observation Schedule 2) from baseline
timeFrame: at 0, 12 months
measure: Evolution of the Score on Conners hyperactivity Scale
timeFrame: at 0, 6 months and 12 months
measure: Evolution of the Score on ABC scale (Aberrant Behaviour Checklist)
timeFrame: at 0, 6 months and 12 months
measure: Evolution of SAICAr levels in the urine
timeFrame: at 0, 6 months and 12 months
measure: Evolution of S-Ado levels in the urine
timeFrame: at 0, 6 months and 12 months
measure: Evolution of SAICAr levels in the blood
timeFrame: at 0, 6 months and 12 months
measure: Evolution of S-Ado levels in the blood
timeFrame: at 0, 6 months and 12 months
measure: Evolution of the number of seizures from Baseline for epileptic patients
timeFrame: at 0 and 12 months
measure: Evolution of antiepileptic treatments from Baseline for epileptic patients
timeFrame: at 0 and 12 months
measure: Evolution of electroencephalogram tracing from Baseline for epileptic patients
timeFrame: at 0 and 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: LA PITIE-SALPETRIERE Hospital, AP-HP
city: Paris
country: France
facility: Department of Pediatry. Reference centre of Hereditary diseases of the metabolism of child and adult. Necker - Enfants malades Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Pascale De LONLAY, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Irène CEBALLOS-PICOT, MD, PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Laurence ROBEL-GALLI, MD
role: STUDY_DIRECTOR
References: