Clinical trial NCT04768166: Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
Official title: Phase 2 Pharmacological Trial to Evaluate the Safety of Miglustat Administration in Subjects With Spastic Paraplegia 11 (TreatSPG11)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hereditary Spastic Paraparesis
Keywords: Autophagic Lysosome Reformation
SPG11
Miglustat
Lisosomal Storage Disorders
Lead sponsor: IRCCS Fondazione Stella Maris
Sponsor class: OTHER
First posted: 2021-02-24
Enrollment: 10
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Hereditary spastic paraparesis type 11 (SPG11) is caused by mutations in the SPG11 gene that produces spatacsin, a protein involved in lysosomal function. Studies performed in skin cells (fibroblasts) from SPG11 patients, mice and zebrafish models of the disease showed that the material accumulated in the lysosomes is made of glycosphingolipids (GSL).

Miglustat is a drug that inhibits an enzyme called glucosylceramide synthetase (GCS) which is used for the production of GSL. Miglustat, therefore, helps to delay the production of GSL. This study aims to collect preliminary data on the safety of miglustat on the SPG11 disease and to assess biomarkers.

Detailed description: We will analyze the safety of Miglustat

Eligibility criteria: Inclusion Criteria:

* Written signed informed consent;
* Confirmed diagnosis of SPG11;
* Age \> 13 years;
* SPRS score ≥ 10 or ≤35;
* Use of effective contraceptive methods and the performance of pregnancy tests (only fertile subjects).

Exclusion Criteria:

* Diagnosis of other concomitant neurodegenerative diseases;
* Outcomes of severe pre- or peri-natal suffering;
* Age ≤ 13 years;
* SPRS score ≥ 35 or ≤10;
* Hypersensitivity or intolerance to miglustat;
* Participation in other pharmacological studies within 30 days of the first Study visit (T0);
* The inability to take the drug;
* Any additional medical conditions;
* Subjects with severe renal impairment;
* Refusal to use effective contraceptive methods and the performance of pregnancy tests (only fertile subjects).

Primary outcomes:
measure: 1-Changes from baseline blood tests at 24 weeks 2-Changes from baseline neurophysiological tests at 24 weeks 3-Report of severe adverse events
timeFrame: At baseline, 24 weeks
Secondary outcomes:
measure: Changes from baseline GM2/GM3 levels at 24 weeks
timeFrame: At baseline, 24 weeks
measure: Assess changes in the scores of the Spastic Paraplegia Rating Scale (SPRS) at 24 weeks
timeFrame: At baseline, 24 weeks
Other outcomes:
Locations:
city: Pisa
country: Italy
facility: IRCCS Fondazione Stella Maris
state: PI
Study officials:
affiliation: IRCCS Stella Maris
name: Filippo M Santorelli, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bellofatto M, De Michele G, Iovino A, Filla A, Santorelli FM. Management of Hereditary Spastic Paraplegia: A Systematic Review of the Literature. Front Neurol. 2019 Jan 22;10:3. doi: 10.3389/fneur.2019.00003. eCollection 2019.
citation: Boutry M, Branchu J, Lustremant C, Pujol C, Pernelle J, Matusiak R, Seyer A, Poirel M, Chu-Van E, Pierga A, Dobrenis K, Puech JP, Caillaud C, Durr A, Brice A, Colsch B, Mochel F, El Hachimi KH, Stevanin G, Darios F. Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration. Cell Rep. 2018 Jun 26;23(13):3813-3826. doi: 10.1016/j.celrep.2018.05.098.
citation: Branchu J, Boutry M, Sourd L, Depp M, Leone C, Corriger A, Vallucci M, Esteves T, Matusiak R, Dumont M, Muriel MP, Santorelli FM, Brice A, El Hachimi KH, Stevanin G, Darios F. Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration. Neurobiol Dis. 2017 Jun;102:21-37. doi: 10.1016/j.nbd.2017.02.007. Epub 2017 Feb 22.
citation: Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A. Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol. 2014 Nov;261:518-39. doi: 10.1016/j.expneurol.2014.06.011. Epub 2014 Jun 20.
citation: Platt FM, Jeyakumar M, Andersson U, Heare T, Dwek RA, Butters TD. Substrate reduction therapy in mouse models of the glycosphingolipidoses. Philos Trans R Soc Lond B Biol Sci. 2003 May 29;358(1433):947-54. doi: 10.1098/rstb.2003.1279.