Study to test the safety and the initial efficacy of an investigational medicinal product, abbreviated as AAV9-hSGSH, in children with Sanfilippo A Syndrom.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Esteve Pharmaceuticals S.A.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

20 Mar 2018 → 2 Oct 2025

Decision date (initial)

2024-07-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-515835-31-00

EudraCT number

2015-000359-26

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Therapy, Dose response, Efficacy

The main objective of this study is to determine the safety and tolerability, including the immune response, after intracerebroventricular (ICV) administration of a single dose of Adenoassociated viral vector serotype 9 containing human sulfamidase gene (AAV9-CAG-coh-SGSH) in three dosage cohorts of patients with Mucopolysaccharidosis type IIIA (MPSIIIA) or Sanfilippo A syndrome.

Secondary objectives 4

1. To assess the pharmacodynamic profile and the initial efficacy after ICV administration of a single dose of AAV9-CAG-coh-SGSH in three dosage cohorts of patients with MPSIIIA to estimate the dose required to significantly ameliorate the phenotype.
2. To evaluate the correlation between the pharmacodynamic assessments and the clinical evolution in order to establish the optimal biomarker to assess the evolution / amelioration of the disease.
3. To collect data regarding potential tests that can be evaluation criteria for the subsequent pivotal study.
4. To assess viral shedding.

Conditions and MedDRA coding

Mucopolysaccharidosis type IIIA (Sanfilippo A syndrome)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Male and female children aged 2 years or older.
2. Patients with confirmed MPSIIIA (by genotype), with underlying missense mutation at least in one of the alleles for the disease and documented deficiency in sulfamidase enzyme activity in leukocytes of less than or equal to 10%.
3. Onset of clinical manifestations related to MPSIIIA during the first 6 years of life.
4. Patients with an adaptive behaviour score between 40 and 90 as evaluated by Vineland Adaptive Behaviour Scale (Vineland-III).
5. Patients not dependent on a wheelchair.
6. Patients without severe sensory deficit (blindness, deafness that requires headset).
7. Patients with stable symptomatic treatment (depending on weight) within the last 3 months, with no anticipated changes in medication regimen.
8. Patients with no contraindication for surgical procedure and/or anaesthesia. Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) should discontinue their use.
9. Patients medically stable to accommodate the protocol requirements, including travelling and assessments.
10. Family understanding the procedure and the informed consent.
11. Signed informed consent.

Exclusion criteria 9

1. Patient deterioration that may compromise the interpretation of the study results.
2. Patients with neutralising antibodies (NAb) against AAV9 in cerebrospinal fluid.
3. Epilepsy resistant to treatment.
4. Patients with significant co-morbid conditions.
5. Any other medical and/or complementary evaluations condition not related to MPSIIIA that could contraindicate the study participation.
6. Any contraindication for anaesthesia and product administration procedure, including major risk factors for haemorrhage.
7. Any condition that would contraindicate treatment with immunosuppressants.
8. Any vaccination 30 days before investigational product administration.
9. Patients who have received any medication with the objective of modifying the natural course of the disease, i.e. gene transfer agents or enzyme replacement therapy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Physical examination.
2. Adverse events.
3. Blood laboratory tests (haematology and chemistry) and Urinalysis.
4. Inflammatory response assessment in blood.
5. Immune response: interferon gamma ELISPOT, intracellular cytokine staining and lymphocyte proliferation in peripheral blood mononuclear cells, neutralizing antibodies (nAb) to the AAV9 vector in cerebrospinal fluid (CSF) and serum and total antibodies to the AAV9 vector and to the transgene quantified in CSF and serum.
6. ECG.
7. Vital signs.
8. Imaging Assessments: Magnetic Resonance Imaging (MRI) and brain volume, Hepatic Ultrasonography assessing volume and structure.

Secondary endpoints 10

1. Sulfamidase enzymatic activity quantified in CSF and blood (leukocytes). At very specific time points, an additional determination of Sulfamidase enzymatic activity in cultured skin fibroblasts will be done.
2. Heparan Sulfate (HS) levels quantified in CSF, plasma, and urine.
3. Neurological and physical examination.
4. Neurobehavioural skills assessed by Vineland Adaptive Behaviour Scale.
5. Cognitive, language, social-emotional, motor and adaptive development assessed by Bayley Scales of Infant Development or verbal, performance and full Intelligence Quotients (IQs) assessed by Wechsler Scale of Intelligence.
6. The specific recently developed Sanfilippo Behaviour Rating Scale.
7. Evaluation of quality of life by PedsQL scale.
8. Sleep assessment by Polysomnography and Sleep Disturbance Scale for Children.
9. Brain Auditory Evoked Potentials (BAEP).
10. Real-time ultrasound elastography of the Achilles tendon.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Esteve Pharmaceuticals S.A.

Sponsor organisation

Esteve Pharmaceuticals S.A.

Address

Passeig De La Zona Franca 109 Planta 4

City

Barcelona

Postcode

08038

Country

Spain

Scientific contact point

Organisation

Esteve Pharmaceuticals S.A.

Contact name

Adelaida Morte

Public contact point

Organisation

Esteve Pharmaceuticals S.A.

Contact name

Adelaida Morte

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications