Repurposing 5-Azacytidine for the Treatment of Muscle Contractures in Children With Cerebral Palsy

NCT06377085 | Enrolling By Invitation Phase 1 DMC FDA Drug

• 1 other identifier: 809325
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief 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. 1.What is the optimal dose of AZA injection that can be used safely in children with CP?
2. 2.Can the optimal safe dose of AZA improve the function of muscle-generating stem cells in children with CP?

Conditions

Cerebral Palsy; Contracture

Keywords

5-Azacytidine; Azacitidine; Contracture; Muscle

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Satellite Cell Fusion Index.

  Through study completion, an average of 2 years.

• DNA methylation quantification in Satellite Cells and Blood Mononucleated Cells.

  Through study completion, an average of 2 years.

• DNA methylation profiling in Satellite Cells.

  Through study completion, an average of 2 years.

Other Outcomes (1)

• Chromatin immunoprecipitation sequencing (ChIP-seq), and assay for transposase-accessible chromatin sequencing (ATAC-seq)

  Through study completion, an average of 2 years.

Study Arms (8)

AZA 10mg/m^2

EXPERIMENTAL

5-Azacytidine, subcutaneous injection, 10mg/m\^2, one subcutaneous injection for duration of study (estimated at 46 - 76 days)

Drug: 5-Azacytidine 10mg/m^2

AZA 20mg/m^2

EXPERIMENTAL

5-Azacytidine, subcutaneous injection, 20mg/m\^2, one subcutaneous injection for duration of study (estimated at 46 - 76 days)

Drug: 5-Azacytidine 20mg/m^2

AZA 35mg/m^2

EXPERIMENTAL

5-Azacytidine, subcutaneous injection, 35mg/m\^2, one subcutaneous injection for duration of study (estimated at 46 - 76 days)

Drug: 5-Azacytidine 35mg/m^2

AZA 75mg/m^2

EXPERIMENTAL

5-Azacytidine, subcutaneous injection, 75mg/m\^2, one subcutaneous injection for duration of study (estimated at 46 - 76 days)

Drug: 5-Azacytidine 75mg/m^2

Placebo for 10mg/m^2

PLACEBO COMPARATOR

Placebo, subcutaneous injection, 10mg/m\^2, one subcutaneous injection without the active treatment for duration of study (estimated at 46 - 76 days)

Drug: Placebo for the AZA 10mg/m^2

Placebo for 20mg/m^2

PLACEBO COMPARATOR

Placebo, subcutaneous injection, 20mg/m\^2, one subcutaneous injection without the active treatment for duration of study (estimated at 46 - 76 days)

Drug: Placebo for the AZA 20mg/m^2

Placebo for 35mg/m^2

PLACEBO COMPARATOR

Placebo, subcutaneous injection, 35mg/m\^2, one subcutaneous injection without the active treatment for duration of study (estimated at 46 - 76 days)

Drug: Placebo for the AZA 35mg/m^2

Placebo for 75mg/m^2

PLACEBO COMPARATOR

Placebo, subcutaneous injection, 75mg/m\^2, one subcutaneous injection without the active treatment for duration of study (estimated at 46 - 76 days)

Drug: Placebo for the AZA 75mg/m^2

Interventions

Placebo for the AZA 10mg/m^2 DRUG

Placebo control group for the 10mg/m\^2, one-time subcutaneous injection without the active treatment.

Placebo for 10mg/m^2

Placebo for the AZA 20mg/m^2 DRUG

Placebo control group for the 20mg/m\^2, one-time subcutaneous injection without the active treatment.

Placebo for 20mg/m^2

Placebo for the AZA 35mg/m^2 DRUG

Placebo control group for the 35mg/m\^2, one-time subcutaneous injection without the active treatment.

Placebo for 35mg/m^2

Placebo for the AZA 75mg/m^2 DRUG

Placebo control group for the 75mg/m\^2, one-time subcutaneous injection without the active treatment.

Placebo for 75mg/m^2

5-Azacytidine 10mg/m^2 DRUG

5-Azacytidine 10mg/m\^2, one-time subcutaneous injection

AZA 10mg/m^2

5-Azacytidine 20mg/m^2 DRUG

5-Azacytidine 20mg/m\^2, one-time subcutaneous injection

AZA 20mg/m^2

5-Azacytidine 35mg/m^2 DRUG

5-Azacytidine 35mg/m\^2, one-time subcutaneous injection

AZA 35mg/m^2

5-Azacytidine 75mg/m^2 DRUG

5-Azacytidine 75mg/m\^2, one-time subcutaneous injection

AZA 75mg/m^2

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis of cerebral palsy.
• Either achilles or hamstring spasticity with contracture necessitation surgical lengthening.
• Between 2 and 18 years of age
• 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
• A negative pregnancy test for females of childbearing potential\*.
• 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:
• Total abstinence from sexual intercourse.
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
• 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.
• Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted, and used in accordance with medical direction.
• 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:
• Total abstinence from sexual intercourse.

You may not qualify if:

• Active infection.
• Cardiac disease.
• Allergy to AZA or mannitol.
• Patient or family who is non-compliant.
• Received chemotherapy in the preceding three months.
• Evidence of a hematologic precondition or other malignancy.

Sponsors & Collaborators

• Shirley Ryan AbilityLab: lead
• Rady Children's Hospital, San Diego: collaborator

Study Sites (1)

Rady Children's Hospital - San Diego

San Diego, California, 92123, United States

Location

MeSH Terms

Conditions

Cerebral Palsy; Contracture

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Brain Damage, Chronic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Andrea Domenighetti, PhD

  Shirley Ryan AbilityLab

  PRINCIPAL INVESTIGATOR

• Patrick Curran, MD

  Rady Children's Hospital, San Diego

  PRINCIPAL INVESTIGATOR

• Richard L. Lieber, PhD

  Shirley Ryan AbilityLab

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: For this Phase 1 trial, we will conduct a dose-escalation study in children having CP who receive 5-Azacytidine (AZA) via a single subcutaneous (SQ) injection two weeks before their surgery, already scheduled to release their contractures. We will use a "3 + 3" dose-escalation design where decisions are based on the rate of toxicity at the current dose level independently from prior dose levels. The primary goal of this study is to determine a Maximum Tolerated Dose (MTD), which will be the highest dose level at which less or equal of 33% of patients experience Dose-Limiting Toxicity (DLT).

Study Record Dates

• First Submitted: March 5, 2024
• First Posted: April 22, 2024
• Study Start: July 1, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): July 1, 2027
• Last Updated: July 3, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)