A Trial of Hydroxyurea in Spinal Muscular Atrophy

NCT ID: NCT00485511

Last Updated: 2010-02-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-06-30
• Study Completion Date: 2009-06-30

Brief Summary

Spinal muscular atrophy (SMA) is an autosomal recessive disorder in humans which results in the loss of motor neurons. It is caused by reduced levels of the survival motor neuron (SMN) protein as a result of loss or mutation of the SMN1 gene. SMN protein is encoded by two genes, SMN1 and SMN2, which essentially differ by an single nucleotide in exon 7. As a result, the majority of the transcript from SMN2 lacks exon 7. According to clinical severity, SMA was classified to three types, including type I, type II, and type III.

Drugs capable of modifying the transcription pattern of SMN2 to increase the full-length of SMN mRNA expression and the amount of SMN protein may have therapeutic effects for SMA patients. In order to test this hypothesis, we used EBV-transformed lymphoblastoid cell lines derived from the different types of SMA patients to screen the effect of various drugs on SMN2 gene expression. Hydroxyurea (HU) was found to be effective among the drugs we tested. HU is an effective therapeutic agent for patients with thalassemia and sickle cell disease which the toxicity is minimal and is well-tolerated and safely used in children. We had undergone a small-scaled 33 SMA patients randomized pilot trial (HU treatment for 8 weeks and then follow up drug-free 8 weeks) to evaluate the effect of HU in SMA patients and we got a promising preliminary data. We found that HU could significantly increase in the manual muscle testing scores at 4 weeks, and full-length SMN mRNA level in the 30mg/kg/day subgroup at 8 weeks relative to baseline, and it is safe under the dose 30mg/kg/day.

In this study, we plan to enroll 60 type II and III SMA patients and conduct a single-center, randomized, double-blind, placebo-controlled, prospective trial of two-year duration to evaluate the efficacy and safety of HU.The primary end points are the changes in full-length SMN expression, SMN protein, motor function and lung function in SMA patients. We also design a safety monitoring system to investigate the adverse effects and to assure the patients' safety. We hope we can find and prove the efficacy and safety of HU in SMA patients and set up a evaluating model for multi-center trials in the future.

Conditions

Spinal Muscular Atrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Blinding Strategy: DOUBLE

Interventions

Hydroxyurea

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Sixty SMA patients fulfilled the diagnostic criteria of SMA as defined by the International SMA Consortium (Munsat, 1992), and all had homozygous deletion of SMN1 gene but carried SMN2 gene (Chang, 1995; 1997)
• The subjects shall each have the age older than 4 years.
• The subjects (if age > 20 years old) or their parents (if subject age < 20 years old) shall agree with the trial and have signed the informed consents.

Exclusion Criteria

• The subjects shall not have hematological diseases, other severe systemic diseases and congenital anomalies except for SMA.
• The subjects shall not have severe perinatal asphyxia history.
• The subjects shall not be with respiratory assists.
• The subjects shall have normal hepatic and renal functions in the pre-trial examination.
• The subjects shall not have received operation with generalized anesthesia in past half a year.
• The subjects shall not have acceded to other clinical trials in past half a year.
• The subjects shall not get in this trial if they could not complete the course.

• Minimum Eligible Age: 4 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kaohsiung Medical University Chung-Ho Memorial Hospital

OTHER

Sponsor Role: lead

Principal Investigators

Yuh Jyh Jong, MD

Role: PRINCIPAL_INVESTIGATOR

Vice President, Kaohsiung Medical University

Locations

Kaohsiung Medical University Hospital

Kaohsiung City, , Taiwan

Countries

Taiwan

References

Grzeschik SM, Ganta M, Prior TW, Heavlin WD, Wang CH. Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Ann Neurol. 2005 Aug;58(2):194-202. doi: 10.1002/ana.20548.

Reference Type: BACKGROUND

PMID: 16049920 (View on PubMed)

Other Identifiers

DOH96-TD-I-111-TM103

Identifier Type: -

Identifier Source: org_study_id