Testing Miglustat Administration in Subjects With Spastic Paraplegia 11 (TreatSPG11)

Phase 2 Pharmacological Trial to Evaluate the Safety of Miglustat Administration in Subjects With Spastic Paraplegia 11 (TreatSPG11)

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.

Study Overview

• Status: Completed
• Conditions: Hereditary Spastic Paraparesis
• Intervention / Treatment: Drug: Miglustat 100 MG

Detailed Description

We will analyze the safety of Miglustat

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • PI
    • Pisa, PI, Italy, 56128
      • IRCCS Fondazione Stella Maris

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evaluate the safety of Miglustat administration in subjects with Spastic Paraplegia 11; 100 mg of Miglustat, 3 caps per day for first 4 weeks; 100 mg of Miglustat, 6 caps per day for 8 weeks	Drug: Miglustat 100 MG; 100mg/TID in 4w then 200mg/TID in 8 w; Other Names: Genorph

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-Changes from baseline blood tests at 24 weeks 2-Changes from baseline neurophysiological tests at 24 weeks 3-Report of severe adverse events	routine blood test	At baseline, 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from baseline GM2/GM3 levels at 24 weeks	lipid assessments	At baseline, 24 weeks
Assess changes in the scores of the Spastic Paraplegia Rating Scale (SPRS) at 24 weeks	SPRS rates disease severity (0-52) with lower numbers indicating less impairement	At baseline, 24 weeks

Collaborators and Investigators

• Sponsor: IRCCS Fondazione Stella Maris
• Investigators: Principal Investigator: Filippo M Santorelli, MD PhD, IRCCS Stella Maris

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2021
• Primary Completion (Actual): August 30, 2021
• Study Completion (Actual): September 15, 2021

Study Registration Dates

• First Submitted: February 12, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 24, 2021

Study Record Updates

• Last Update Posted (Actual): April 11, 2022
• Last Update Submitted That Met QC Criteria: April 1, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Miglustat; Autophagic Lysosome Reformation; SPG11; Lisosomal Storage Disorders
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Paralysis; Muscle Hypertonia; Paresis; Muscle Spasticity; Paraparesis; Paraparesis, Spastic; Paraplegia; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Glycoside Hydrolase Inhibitors; Miglustat
• Other Study ID Numbers: TreatSPG11; 2019-002827-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No