Clinical Trials Logo

Clinical Trial Details — Status: Not yet recruiting

Administrative data

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

Study information

Verified date April 2024
Source Shirley Ryan AbilityLab
Contact Andrea Domenighetti, PhD
Phone 3122381030
Email adomenighe@sralab.org
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


Description:

Cerebral palsy (CP) has an enduring impact on the development of the muscles after birth. Research showed that a drug that is currently approved by the FDA to treat myelodysplastic syndromes in adults and children, can be potentially adapted ("repurposed") to support muscle growth. In a controlled dose-escalation study, we will study the preliminary safety, biological properties, and efficacy of this drug, called 5-Azacytidine (AZA). Our hope and overarching expectations are that one day AZA will become a new approved pharmacological treatment to support muscle growth and improve body movement and quality of life in children with CP. Research participants will have five study visits. 1. The first study visit will be a screening within 30 days of the baseline visit and will determine eligibility for the study. The participant will have their blood drawn to check for normal kidney and liver functioning, do a pregnancy test (if applicable), and then the researcher will complete a medical assessment. 2. If the participant is eligible, they will be invited to a second study visit approximately 15 days prior to their scheduled surgery for contracture release. At this visit, the participants will get their blood drawn, do a pregnancy test (if applicable), have a medical assessment performed, and receive their injection. The injection will be a single sub-cutaneous shot in their leg, near the muscle group that will undergo surgical repair. 3. The third visit will be at the participant's scheduled surgery. A small sample of the muscle (i.e., about the size of a pencil eraser) will be surgically removed by the researcher from a muscle group that is already exposed during the procedure. The biopsy will add approximately two to five minutes to the overall procedure time. The participant will also have their blood drawn. 4. The participants will be seen approximately one week after their surgery to complete a medical assessment. 5. The last visit will be about four weeks after the surgery at their post-operative appointment. At this visit, the participant will have their blood drawn and complete a medical assessment to test their range of motion following the surgery. The amount of blood drawn at each time point will be approximately 3 mL, equating to 12 mL of blood total (less than a tablespoon). The purpose of the blood draws is to evaluate safety and biological efficacy of the study drug. The medical assessment will consist of range of motion assessment and wound check performed by the clinicians. These are the same assessments that the clinicians would typically do as part of usual care prior to and after surgery. The purpose of the medical assessment is to evaluate the efficacy of the study drug and ensure the surgical site is healing.


Recruitment information / eligibility

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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Placebo for the AZA 10mg/m^2
Placebo control group for the 10mg/m^2, one-time subcutaneous injection without the active treatment.
Placebo for the AZA 20mg/m^2
Placebo control group for the 20mg/m^2, one-time subcutaneous injection without the active treatment.
Placebo for the AZA 35mg/m^2
Placebo control group for the 35mg/m^2, one-time subcutaneous injection without the active treatment.
Placebo for the AZA 75mg/m^2
Placebo control group for the 75mg/m^2, one-time subcutaneous injection without the active treatment.
5-Azacytidine 10mg/m^2
5-Azacytidine 10mg/m^2, one-time subcutaneous injection
5-Azacytidine 20mg/m^2
5-Azacytidine 20mg/m^2, one-time subcutaneous injection
5-Azacytidine 35mg/m^2
5-Azacytidine 35mg/m^2, one-time subcutaneous injection
5-Azacytidine 75mg/m^2
5-Azacytidine 75mg/m^2, one-time subcutaneous injection

Locations

Country Name City State
n/a

Sponsors (2)

Lead Sponsor Collaborator
Shirley Ryan AbilityLab Rady Children's Hospital, San Diego

Outcome

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.
See also
  Status Clinical Trial Phase
Recruiting NCT05317234 - Genetic Predisposition in Cerebral Palsy N/A
Recruiting NCT05576948 - Natural History of Cerebral Palsy Prospective Study
Completed NCT04119063 - Evaluating Wearable Robotic Assistance on Gait Early Phase 1
Completed NCT03264339 - The Small Step Program - Early Intervention for Children With High Risk of Developing Cerebral Palsy N/A
Completed NCT05551364 - Usability and Effectiveness of the ATLAS2030 Exoskeleton in Children With Cerebral Palsy N/A
Completed NCT03902886 - Independent Walking Onset of Children With Cerebral Palsy
Recruiting NCT05571033 - Operant Conditioning of the Soleus Stretch Reflex in Adults With Cerebral Palsy N/A
Not yet recruiting NCT04081675 - Compliance in Children With Cerebral Palsy Supplied With AFOs
Completed NCT02167022 - Intense Physiotherapies to Improve Function in Young Children With Cerebral Palsy N/A
Completed NCT04012125 - The Effect of Flexible Thoracolumbar Brace on Scoliosis in Cerebral Palsy N/A
Enrolling by invitation NCT05619211 - Piloting Movement-to-Music With Arm-based Sprint-Intensity Interval Training Among Children With Physical Disabilities Phase 1
Completed NCT04489498 - Comparison of Somatometric Characteristics Between Cerebral Palsy and Normal Children, Cross-sectional, Multi Center Study
Completed NCT03677193 - Biofeedback-enhanced Interactive Computer-play for Youth With Cerebral Palsy N/A
Recruiting NCT06450158 - Robot-assisted Training in Children With CP N/A
Completed NCT04093180 - Intensive Neurorehabilitation for Cerebral Palsy N/A
Completed NCT02909127 - The Pediatric Eating Assessment Tool
Not yet recruiting NCT06377982 - Human Umbilical Cord Blood Infusion in Patients With Cerebral Palsy Phase 1
Not yet recruiting NCT06007885 - Examining Capacity Building of Youth With Physical Disabilities to Pursue Participation Following the PREP Intervention. N/A
Not yet recruiting NCT03183427 - Corpus Callosum Size in Patients With Pineal Cyst N/A
Active, not recruiting NCT03078621 - Bone Marrow-Derived Stem Cell Transplantation for the Treatment of Cerebral Palsy Phase 1/Phase 2