Muscular Atrophy, Spinal
Conditions
Brief summary
The objectives of this trial are: to establish a safety profile for use of Hydroxyurea in children with Types II and III Spinal Muscular Atrophy; to identify reliable outcome measures for HU treatment in Types II and III SMA; and to detect the clinical efficacy of HU treatment in children with Types II and III SMA.
Detailed description
SMA is a neuromuscular disorder characterized by degeneration of spinal cord motor neurons and muscular atrophy. SMA is classified into three clinical subtypes according to the severity and age of onset (Types I, II and III). Type II (intermediate) SMA has its onset in early childhood (prior to 18 months) and is characterized by the failure to stand or walk unassisted. Individuals with Type III SMA (mild SMA or Kugelberg-Welander disease) typically develop symptoms after 18 months of age and display a wide range of clinical heterogeneity. The clinical spectrum ranges from rapid progressive weakness resulting in wheelchair dependence in late childhood to patients being able to walk in adult years and living productive and independent lifestyles for the majority of their lives. In our laboratory, our preliminary results indicate that HU treatment significantly increases both SMN mRNA expression and intact SMN protein levels in vitro. These data confirm previous observations that in vitro treatments of SMA lymphocytes with hydroxyurea resulted in augmentation of the SMN2 gene expression in a dose and time related manner. Based on these exciting pre-clinical data, coupled with the well-documented side-effect profile of HU in children, we are conducting a pilot clinical trial using HU in children with Types II and III SMA. This clinical trial study is intended to establish the safety profile in children with Types II and III SMA; to identify reliable outcome measures; and to detect the possible clinical efficacy of HU treatment in children with Types II and III SMA.
Interventions
DRUGHydroxyurea
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
1 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
1. Laboratory confirmation of a homozygous deletion or mutation of the SMN1 gene 2. (Type II) Can sit independently but cannot walk without support by the age of 16 months and never achieve independent walking thereafter; OR (Type III) Can walk independently within the first 2 years of life, but showing rapid progression of weakness resulting in the loss of independent ambulation by 6 years of age 3. Patient is older than 16 months and younger than 8 years old at the time of enrollment
Exclusion criteria
1. Known hematological disorders, other systemic disorders, or severe birth asphyxia 2. Participation in SMA clinical trials for other experimental drugs 3. Requiring continuous respiratory support before the initiation of HU treatment
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Efficacy: Functional Motor Testing, Including Gross Motor Function Measure (GMFM) and Timed Motor Tests | Up to 6 years, 2 months |
| Safety: Frequency of Adverse Events/Lab Abnormalities | Up to 6 years, 2 months |
Secondary
| Measure | Time frame |
|---|---|
| Pulmonary Function Testing | Up to 6 years, 2 months |
| Motor Unit Number Estimation (MUNE) | Up to 6 years, 2 months |
| Biomarker Assays: SMN Protein and SMN mRNA | Up to 6 years, 2 months |
Countries
United States
Participant flow
Pre-assignment details
Data are presented for all participants because data relating to arm assignment are no longer accessible; the Principal Investigator (PI) has left institution and all efforts to locate the data have been exhausted.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received hydroxyurea, or placebo to match hydroxyurea. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 27 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Efficacy: Functional Motor Testing, Including Gross Motor Function Measure (GMFM) and Timed Motor Tests
Time frame: Up to 6 years, 2 months
Population: Data for this outcome measure are no longer accessible; the PI has left institution and all efforts to locate the data have been exhausted.
Primary
Safety: Frequency of Adverse Events/Lab Abnormalities
Time frame: Up to 6 years, 2 months
Population: Data for this outcome measure are no longer accessible; the PI has left institution and all efforts to locate the data have been exhausted.
Secondary
Biomarker Assays: SMN Protein and SMN mRNA
Time frame: Up to 6 years, 2 months
Population: Data for this outcome measure are no longer accessible; the PI has left institution and all efforts to locate the data have been exhausted.
Secondary
Motor Unit Number Estimation (MUNE)
Time frame: Up to 6 years, 2 months
Population: Data for this outcome measure are no longer accessible; the PI has left institution and all efforts to locate the data have been exhausted.
Secondary
Pulmonary Function Testing
Time frame: Up to 6 years, 2 months
Population: Data for this outcome measure are no longer accessible; the PI has left institution and all efforts to locate the data have been exhausted.