Clinical trial NCT03822013: Effects of Miglustat Therapy on Infantile Type of Sandhoff and Taysachs Diseases (EMTISTD)
Official title: Survey of Miglustat Therapeutic Effects on Neurological and Systemic Symptoms of Infantile Type of Sandhoff and Taysachs Diseases
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: GM2 Gangliosidosis
Supportive Care
Keywords: Sandhoff Disease
Tay-Sachs Disease
Miglustat
Lead sponsor: Tehran University of Medical Sciences
Sponsor class: OTHER
Collaborators: name: Mashhad University of Medical Sciences
name: Kashan University of Medical Sciences
First posted: 2019-01-30
Enrollment: 30
Sex: ALL
Minimum age (years): 6
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Although randomized control trial is the gold standard for clinical trial studies; there are ethical concerns about placebo control group in rare diseases such as Sandhoff and Tay sachs diseases.
Primary purpose: SUPPORTIVE_CARE

Brief summary: GM2 gangliosidosis is an autosomal recessive subtype of Lysosomal Storage Diseases in which, Hexosaminidase A-B deficiency is caused by HEXA-B gene. HEXA deficiency is seen in Tay sachs and HEXB deficiency causes Sandhoff disease.

Infantile forms of Sandhoff and Tay sachs are often lethal and management of the patients is supportive including nutrition, hydration, seizure control and management of respiratory problems. Recent studies have suggested new methods of treatment, such as enzyme replacement therapy, bone marrow transplantation and substrate reduction therapy.

The first drug used in SRT was Miglustat. It was introduced in 1980 as an anti HIV agent and later, it was registered under the trademark of Zavesca in 2009 and was used in treatment of Gaucher and Niemann-Pick disease. Zavesca passes blood brain barrier, so causes reduction of cholesterol and glycosphingolipids CNS neurons and relief of neurologic manifestations. Improvements were seen in oculomotor function, cognition, swallowing, motor disturbances and psychological problems after treatment with Zavesca. No effect has been proved on visceral involvement. Weight loss during first year of treatment, diarrhea and dyspepsia are seen as side effects.

Studies on SRT in lysosomal storage disease have different results. Some show improvements in manifestations of Gausche, Sandhoff \& Tay sachs disease, while others show no valuable benefit for this method of treatment.

Finding an effective treatment for these chronic diseases can improve quality of life for the patients and their families, and also reduce costs for healthcare services. The controversy persists and more studies are needed for judgment. So this study is done to evaluate the effect of Miglustat therapy in Sandhoff and Tay sachs disease, and is believed to help for further studies in this field.

Detailed description: This study is a case- control, open label clinical trial. Patients are all registered with diagnosis of Sandhoff and Tay sachs, and recruited at children's medical center Tehran-IRAN. Diagnosis is confirmed by enzyme level and genetic tests. Case group receive Miglustat therapy for 1 year and frequently assessed. Patients in control group are also assessed for 1 year without receiving Miglustat.

Patients are evaluated for neurologic examination, seizure, nasogastric tube insertion, aspiration pneumonia and quality of life at the beginning of study and every 3 months. Miglustat is considered as an Orphan drug so clinical trials about this drug are designed small and adjusted to limited population.

Variables in neurologic examination are Muscle tone, Muscular atrophy and contracture. motor function is scored according to "Gross Motor Function Classification System" (GMFCS) and quality of life is assessed by Infant Toddle Quality Of Life (ITQOL) questionnaire, with confirmed validity and stability.

Data gathered during frequent visits is registered in check lists and analyzed with SPSS version 18. Quantitative variables express with mean and standard deviation and qualitative variables with frequency and percentile. Analysis of variance for repeated measurements (ANOVA) and nonparametric freedman are tests using for comparisons of Outcomes. Sample size is calculated by formula for clinical trials with repeated measures.

Miglustat is FDA approved for Gaucher and Niemann pick diseases. All patients fill the informed consent and the nature of the study is explained to them. The information of participants is kept confidential. They are informed about side effects of the drug. If any cases at any time decides to exclude themselves from the study they are free to do so.

Eligibility criteria: Inclusion Criteria:

* Clinically and enzymatically suspected infants of Sandhoff (SD)/Tay-Sachs (TSD) diseases followed confirmation by molecular study.

Exclusion Criteria:

* Renal impairment
* Loss of follow up
* Other systemic diseases
* Concomitant drug therapy which may affect neurological system function

Primary outcomes:
measure: Hospitalization frequency change
timeFrame: Baseline and 4, 8, 12 months after intervention and 1-year without intervention
measure: Pneumonia aspiration frequency change
timeFrame: Baseline and 4, 8, 12 months after intervention and 1-year without intervention
measure: Seizure Frequency change
timeFrame: Baseline and 4, 8, 12 months after intervention and 1-year without intervention
measure: Route of feeding change
timeFrame: Baseline and 4, 8, 12 months after intervention and 1-year without intervention
measure: motor function change
timeFrame: Baseline and 4, 8, 12 months after intervention and 1-year without intervention
Secondary outcomes:
measure: quality of life change
timeFrame: Baseline and 1year
Other outcomes:
Locations:
city: Kashan
country: Iran, Islamic Republic of
facility: Kashan University Of Medical Sciences
state: Isfahan
city: Mashhad
country: Iran, Islamic Republic of
facility: Mashhad University Of Medical Sciences
state: Khorasan
city: Tehran
country: Iran, Islamic Republic of
facility: Tehran University Of Medical Sciences
Study officials:
References:
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citation: Villamizar-Schiller IT, Pabon LA, Hufnagel SB, Serrano NC, Karl G, Jefferies JL, Hopkin RJ, Prada CE. Neurological and cardiac responses after treatment with miglustat and a ketogenic diet in a patient with Sandhoff disease. Eur J Med Genet. 2015 Mar;58(3):180-3. doi: 10.1016/j.ejmg.2014.12.009. Epub 2014 Dec 12.
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citation: Shapiro BE, Pastores GM, Gianutsos J, Luzy C, Kolodny EH. Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment. Genet Med. 2009 Jun;11(6):425-33. doi: 10.1097/GIM.0b013e3181a1b5c5.
citation: Wortmann SB, Lefeber DJ, Dekomien G, Willemsen MA, Wevers RA, Morava E. Substrate deprivation therapy in juvenile Sandhoff disease. J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S307-11. doi: 10.1007/s10545-009-1261-2. Epub 2009 Nov 4.
citation: Tallaksen CM, Berg JE. Miglustat therapy in juvenile Sandhoff disease. J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S289-93. doi: 10.1007/s10545-009-1224-7. Epub 2009 Nov 4.
citation: Bembi B, Marchetti F, Guerci VI, Ciana G, Addobbati R, Grasso D, Barone R, Cariati R, Fernandez-Guillen L, Butters T, Pittis MG. Substrate reduction therapy in the infantile form of Tay-Sachs disease. Neurology. 2006 Jan 24;66(2):278-80. doi: 10.1212/01.wnl.0000194225.78917.de.
citation: Jacobs JF, Willemsen MA, Groot-Loonen JJ, Wevers RA, Hoogerbrugge PM. Allogeneic BMT followed by substrate reduction therapy in a child with subacute Tay-Sachs disease. Bone Marrow Transplant. 2005 Nov;36(10):925-6. doi: 10.1038/sj.bmt.1705155. No abstract available.
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