Cerebral Palsy Clinical Trial
Official title:
Repurposing 5-Azacytidine for the Treatment of Muscle Contractures in Children With Cerebral Palsy
NCT number | NCT06377085 |
Other study ID # | 809325 |
Secondary ID | |
Status | Not yet recruiting |
Phase | Phase 1 |
First received | |
Last updated | |
Start date | May 2024 |
Est. completion date | May 2026 |
In this controlled dose-escalation study, we will study the initial safety, biological properties, and potential efficacy of 5-azacytidine (AZA). Our overarching aspiration is for AZA to evolve into an approved pharmacological treatment, fostering muscle growth and enhancing body movement, ultimately contributing to an improved quality of life in children with CP. The main questions this study aims to answer are: 1. What is the optimal dose of AZA injection that can be used safely in children with CP? 2. Can the optimal safe dose of AZA improve the function of muscle-generating stem cells in children with CP? Each participant will have up to five research visits over the course of the study duration, in which they will participate in: blood draws, pregnancy test(s) (if applicable), medical assessments, and a muscle biopsy during a surgery for muscle contractures. Researchers will compare participants with four different dosages of AZA injections to those with four different dosages of placebo injections. A placebo is a look-alike substance that contains no active drug. They will see if a single injection of AZA at a standard concentration currently approved by the FDA to treat myelodysplastic syndromes, can also safely improve muscle growth and function in children with CP.
Status | Not yet recruiting |
Enrollment | 27 |
Est. completion date | May 2026 |
Est. primary completion date | May 2026 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 2 Years to 18 Years |
Eligibility | Inclusion Criteria: 1. Diagnosis of cerebral palsy. 2. Either achilles or hamstring spasticity with contracture necessitation surgical lengthening. 3. Between 2 and 18 years of age 4. Normal renal and liver function as defined by NCI-CTCAE criteria.71 a. Renal Function (Grade 0 - Normal): i. Creatinine: Within the normal range or = 1.0 times the upper limit of normal (ULN). ii. Glomerular filtration rate (GFR): No significant decrease. b. Liver Function (Grade 0 - Normal): i. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): Within the normal range or = ULN. ii. Total bilirubin: Within the normal range or = 1.0 times ULN 5. A negative pregnancy test for females of childbearing potential*. 6. Females of childbearing potential must agree to use contraception consistently from screening to 6 months after their injection. Highly effective methods of contraception are required for females of childbearing potential: 1. Total abstinence from sexual intercourse. 2. Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 3. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal used in accordance with medical direction. 4. Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted, and used in accordance with medical direction. 7. Males of childbearing potential** must agree to use contraception consistently from screening until 3 months after the injection. Acceptable methods of contraception for males of childbearing potential are: 1. Total abstinence from sexual intercourse. 2. Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film). - Female of childbearing potential is defined as a female capable of becoming pregnant, which includes patients who have had their first menstrual cycle (menarche). - Male of childbearing potential is defined as a subject who has reached spermarche. Exclusion Criteria: 1. Active infection. 2. Cardiac disease. 3. Allergy to AZA or mannitol. 4. Patient or family who is non-compliant. 5. Received chemotherapy in the preceding three months. 6. Evidence of a hematologic precondition or other malignancy. |
Country | Name | City | State |
---|---|---|---|
n/a |
Lead Sponsor | Collaborator |
---|---|
Shirley Ryan AbilityLab | Rady Children's Hospital, San Diego |
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Chromatin immunoprecipitation sequencing (ChIP-seq), and assay for transposase-accessible chromatin sequencing (ATAC-seq) | ChIP-seq will facilitate the genome-wide profiling of changes in chromatin structure and transcription factor binding events in response to AZA treatment and muscle contracture development. This technique is particularly as it can identify alterations in DNA methylation patterns and histone modifications associated with Satellite Cell dysfunction and impaired muscle regeneration. Furthermore, ATAC-seq will offer a complementary approach to ChIP-seq by providing information on chromatin accessibility, which reflects regulatory elements such as enhancers and promoters involved in gene expression control. | Through study completion, an average of 2 years. | |
Primary | Dose-limiting toxicity (DLT). | The percentage of patients experiencing DLT at the predefined dose level will be calculated.
This will determine the Maximum Tolerated Dose (MTD), which will be the highest dose level at which = 33% of patients experience a DLT. DLT is defined as toxic effects, presumably related to AZA, considered unacceptable due to their severity and/or irreversibility, thereby limiting further dose escalation. Thus, the total number of toxicities and the DLT at each step of dose escalation and possible de-escalation will be reported. The scale for the primary endpoint is binary (occurrence of DLT or not). It is measured as a single endpoint, as it is focused on whether or not the predefined dose level causes DLT. The currently recommended clinical dose is 75 mg/m2. For the present study, the following AZA concentrations will be evaluated: 10 mg/m2, 20 mg/m2, 35 mg/m2 and 75 mg/m2. For each dose, 3 experimental and 3 placebo subjects will be recruited. |
Through study completion, an average of 2 years. | |
Secondary | Satellite Cell Fusion Index. | Resident muscle-forming stem cells, called Satellite Cells, will be isolated from the muscle biopsy obtained from subjects and cultured in vitro. Satellite Cell Fusion Index quantifies the proportion of these stem cells that will fuse to form new muscle fibers in vitro (multinucleated structures called myotubes). It provides a measure of the efficiency of subjects' satellite cells to contribute to muscle growth, repair and regeneration. | Through study completion, an average of 2 years. | |
Secondary | DNA methylation quantification in Satellite Cells and Blood Mononucleated Cells. | Global DNA methylation analysis will be quantified (% tot DNA in ng) using DNA from Satellite Cell cultures and Blood Mononucleated Cells (isolated form blood) using an ELISA-based global DNA methylation kit. | Through study completion, an average of 2 years. | |
Secondary | DNA methylation profiling in Satellite Cells. | Following Satellite Cell isolation, expansion in culture and DNA extractions, qualitative methylation analysis procedures will be conducted using an Infinium Human MethylationEPIC Beadchip array (Illumina Inc., CA), which targets over 850,000 DNA methylation sites at the dinucleotide (CpG) level throughout the entire genome. | Through study completion, an average of 2 years. |
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