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

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ClinicalTrials.gov Identifier: NCT03776656
Recruitment Status : Not yet recruiting
First Posted : December 17, 2018
Last Update Posted : February 20, 2019
Sponsor:
Collaborator:
URC-CIC Paris Descartes Necker Cochin
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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


Condition or disease Intervention/treatment Phase
Adenylosuccinate Lyase Deficiency Drug: Allopurinol Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 8 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of a Treatment With Allopurinol on Autistic Disorders and Epilepsy in Adenylosuccinate Lyase Deficiency (ADSL)
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : November 2021


Arm Intervention/treatment
Experimental: 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
Drug: Allopurinol
Daily oral administration
Other Name: Zyloric®




Primary Outcome Measures :
  1. Measurement of adaptive functional improvement : composite total score for Vineland II adaptive behaviour Scale [ Time Frame: 12 months ]

    to assess Efficacy of Allopurinol (Zyloric)® treatment from Baseline : For each scale : Mean : 100 SD : 15

    • Adaptive behaviour composite : Range 20 to 180 -Domains scores : Range 20 to 140 -Communication : Range 20 to 140 -Daily living skills : Range 20 to 140 -Socialization : 20 to 140 -Motor skills : 20 to 140 For each scale values are considered to be better or worse outcome :High 130 to 140 -Moderately High 115 to 129 -Adequate 86 to 114 -Moderately Low 71 to 85 -Low 20 to 70 Total score is obtained by summing the subdomains scores


Secondary Outcome Measures :
  1. Evolution of the Scores of different subdomains Vineland II scale from baseline [ Time Frame: at 0, 6 months and 12 months ]
    Clinical evolution for developmental and cognitive assessment

  2. Evolution of the Psycho-Educative Profile (PEP III/R) from baseline [ Time Frame: at 0, 12 months ]
    Clinical evolution for developmental and cognitive assessment

  3. Evolution of the Score ADI-R (Autism Diagnostic Interview-Revised) from baseline [ Time Frame: at 0, 12 months ]

    Clinical evaluation for autistic symptoms : scale ranges :

    • A : Social interactions: 0 to 30 (significative if >10)
    • B : Communication : 0 to 26 (significative if > 7 or 8)
    • C : Repetitive and restricted interests : 0 to 16 (significative if >3)
    • D : Developmental abnormality present before 36 months : 0 to 5 (significative if >1)

    better score : 0 (non autistic) - worse score : the higher score is the worst


  4. Evolution of the Score ADOS-2 (Autism Diagnostic Observation Schedule 2) from baseline [ Time Frame: at 0, 12 months ]

    Clinical evaluation for autistic symptoms. Scale ranges :

    • A : Socialization : social interactions and communication : 0 to 20 (social interactions : 0 to 6 -communication : 0 to 14)
    • B : Restricted and repetitive interests : 0 to 8
    • Total : A+B : 0 to 28

    Autism : total score>12 - Autism Spectrum Disorder : total score >8

    Better score : 0 - Worse score : the highest score is the worst


  5. Evolution of the Score on Conners hyperactivity Scale [ Time Frame: at 0, 6 months and 12 months ]

    Clinical evolution for behavioral disorders and adaptive functioning

    Conners Scale for Parents :

    - Subscales : Behavioural difficulties (items 2-8-14-19-20-27-35-39) : 0 to 24 Learning difficulties (items 10-25-31-37) : 0 to 12 Somatisation (items 32-41-43-44) : 0 to 12 Impulsivity, hyperactivity (items 4-5-11-13): 0 to 12 Anxiety (items 12-16-24-47): 0 to 12

    -Hyperactivity index : sum of the items (4-7-11-13-14-25-31-33-37-38) divided by 10 : 0 to 3

    Conners Scale for teachers :

    - Subscales : Behavioural difficulties (items 4-5-6-10-11-12-23-27) : 0 to 24 Impulsivity, hyperactivity (items 1-2-3-8-14-15-16) : 0 to 21 Inattention, passivity (items 7-9-18-20-21-22-26-28) : 0 to 24

    -Hyperactivity index (sum of the items 1-5-7-8-10-11-14-15-21-26 divided by 10) : 0 to 3

    Better score : 0 - Worse score : the highest score is the worst -Hyperactivity index : Significative if> 1,5


  6. Evolution of the Score on ABC scale (Aberrant Behaviour Checklist) [ Time Frame: at 0, 6 months and 12 months ]

    Clinical evolution for behavioral disorders and adaptive functioning scale ranges :

    • Irritability : 0 to 45
    • Lethargy : 0 to 48
    • Stereotypy : 0 to 21
    • Hyperactivity : 0 to 48
    • Inappropriate speech : 0 to 12

    Better score : 0 -Worse score : the highest score is the worst on each scale- there is no total score


  7. Evolution of SAICAr levels in the urine [ Time Frame: at 0, 6 months and 12 months ]
    Evolution of the quantity of urinary metabolites from Baseline

  8. Evolution of S-Ado levels in the urine [ Time Frame: at 0, 6 months and 12 months ]
    Evolution of the quantity of urinary metabolites from Baseline

  9. Evolution of SAICAr levels in the blood [ Time Frame: at 0, 6 months and 12 months ]
    Evolution of the quantity of plasma metabolites from Baseline

  10. Evolution of S-Ado levels in the blood [ Time Frame: at 0, 6 months and 12 months ]
    Evolution of the quantity of plasma metabolites from Baseline

  11. Evolution of the number of seizures from Baseline for epileptic patients [ Time Frame: at 0 and 12 months ]
    at baseline, performing neurological examinations and interrogation

  12. Evolution of antiepileptic treatments from Baseline for epileptic patients [ Time Frame: at 0 and 12 months ]
    at baseline, performing neurological examinations and interrogation

  13. Evolution of electroencephalogram tracing from Baseline for epileptic patients [ Time Frame: at 0 and 12 months ]
    normal/abnormal



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03776656


Contacts
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Contact: Pascale DE LONLAY, MD, PhD +33-1-44-49-48-52 pascale.delonlay@aphp.fr
Contact: Prissile BAKOUBOULA, PhD +33-1-71-19-64-94 prissile.bakouboula@aphp.fr

Locations
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France
LA PITIE-SALPETRIERE Hospital, AP-HP Not yet recruiting
Paris, France, 75013
Contact: Fanny MOCHEL, MD, PhD    01 42 16 00 00    fanny.mochel@aphp.fr   
Principal Investigator: Fanny MOCHEL, MD, PhD         
Sub-Investigator: Vincent KRIEGER, MD         
Department of Pediatry. Reference centre of Hereditary diseases of the metabolism of child and adult. Necker - Enfants malades Hospital Not yet recruiting
Paris, France, 75015
Contact: Pascale DE LONLAY, MD, PhD    +33-1-44-49-48-52    pascale.delonlay@aphp.fr   
Principal Investigator: Pascale DE LONLAY         
Sub-Investigator: Laurence ROBEL-GALLI         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Investigators
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Principal Investigator: Pascale De LONLAY, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Irène CEBALLOS-PICOT, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Laurence ROBEL-GALLI, MD Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03776656     History of Changes
Other Study ID Numbers: P160902J
2017-002155-28 ( EudraCT Number )
First Posted: December 17, 2018    Key Record Dates
Last Update Posted: February 20, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Adenylosuccinate lyase
Deficit
Allopurinol
Autism
Epilepsy
Additional relevant MeSH terms:
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Purine-Pyrimidine Metabolism, Inborn Errors
Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Allopurinol
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Physiological Effects of Drugs