Givinostat for Duchenne Muscular Dystrophy

(ULYSSES Trial)

Recruiting in Palo Alto (17 mi)

+21 other locations

Age: < 18

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Italfarmaco

Must be taking: Corticosteroids

Must not be taking: Dystrophin restoration, Gene therapy

Disqualifiers: Respiratory failure, Cardiomyopathy, Liver disease, others

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This is a randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy, safety, and tolerability of givinostat in non-ambulant male paediatric (aged 9 to \<18 years) patients with DMD. 138 patients will be randomised 2:1 to givinostat or placebo and will be treated for 18 months. * Planned screening duration: approximately 4 weeks (±14 days) * Planned treatment duration: 18 months (approximately 72 weeks) * Planned follow-up duration: 4 weeks (±7 days) (for patients not participating in the long-term safety study) * Total duration of study participation: up to 83 weeks (ie, 20-21 months)

Will I have to stop taking my current medications?

The trial requires that if you are on medication for DMD-associated heart issues, it must be stable for at least 1 month before starting the study. If you are on corticosteroids, they must be stable for at least 6 months. Other medications that might affect muscle strength or function should not have been used within 3 months before starting the study.

Is Givinostat safe for humans?

Givinostat has been studied in boys with Duchenne Muscular Dystrophy and in animal models, showing positive effects on muscle health and reduced inflammation, but specific safety data for humans is not detailed in the available studies. ^{1 2 3 4 5}

How is the drug Givinostat unique in treating Duchenne Muscular Dystrophy?

Givinostat is unique because it is a histone deacetylase (HDAC) inhibitor that not only reduces muscle fibrosis (scarring) but also promotes muscle regeneration and improves mitochondrial function, which are not typically targeted by other treatments for Duchenne Muscular Dystrophy. ^{1 2 3 4 6}

Research Team

Eligibility Criteria

This trial is for non-ambulant male children and teens aged 9 to <18 with Duchenne Muscular Dystrophy (DMD). They must have a genetic diagnosis of DMD, be unable to walk or run 10 meters in under 30 seconds without help, and have been on stable corticosteroid treatment for at least 6 months. Participants need parental consent and agree to use contraception during the study.

Inclusion Criteria

Able to give informed assent and/or consent in writing signed by the patient and/or parent/legal guardian

I have been on a stable dose of corticosteroids for at least 6 months.

My arm and hand abilities score is between 3 to 6.

Exclusion Criteria

Exposure to another investigational drug within 3 months prior to start of study treatment

My kidneys are not working well.

I use testosterone only for delayed puberty treatment.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Baseline

Randomisation is performed

1 day

1 visit (in-person)

Treatment

Participants receive either givinostat or placebo for 18 months

72 weeks

Regular visits (in-person)

End of Study

End of study visit at Week 72, offering enrolment in the long-term safety study

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Givinostat (Histone Deacetylase Inhibitor)

Trial Overview The trial tests Givinostat's effectiveness, safety, and tolerability against a placebo in patients who can't walk due to DMD. It's randomized and double-blind, meaning neither doctors nor participants know who gets the real drug or placebo. The treatment lasts for 18 months with follow-ups.

Participant Groups

Group I: Givinostat Experimental Treatment 1 Intervention

Patients will receive concomitant corticosteroid treatment as part of the standard of care.

Group II: Placebo Placebo Group 1 Intervention

Patients will receive concomitant corticosteroid treatment as part of the standard of care.

Who Is Running the Clinical Trial?

Italfarmaco

Lead Sponsor

Trials

36

Recruited

4,500+

Fortrea

Industry Sponsor

Trials

22

Recruited

5,800+

Findings from Research

In a study involving 20 ambulant boys with Duchenne Muscular Dystrophy (DMD), treatment with Givinostat for over 12 months significantly increased muscle tissue and reduced fibrotic tissue, indicating a positive histological effect.

The treatment was found to be safe and well-tolerated, although no improvements in functional tests were observed, suggesting that while Givinostat may help with muscle structure, further research is needed to assess its impact on muscle function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histological effects of givinostat in boys with Duchenne muscular dystrophy. Bettica, P., Petrini, S., D'Oria, V., et al.[2018]

Givinostat has been shown to promote mitochondrial biogenesis in dystrophic muscle by modifying the epigenetic profile of the PGC-1α promoter, which is crucial for energy production in cells.

The study identifies two phases of mitochondrial damage in Duchenne Muscular Dystrophy, highlighting the importance of targeting both early mitochondrial mass depletion and later accumulation of dysfunctional mitochondria to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Givinostat as metabolic enhancer reverting mitochondrial biogenesis deficit in Duchenne Muscular Dystrophy. Giovarelli, M., Zecchini, S., Catarinella, G., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Histological effects of givinostat in boys with Duchenne muscular dystrophy. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Givinostat as metabolic enhancer reverting mitochondrial biogenesis deficit in Duchenne Muscular Dystrophy. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Pluripotent stem cell-induced skeletal muscle progenitor cells with givinostat promote myoangiogenesis and restore dystrophin in injured Duchenne dystrophic muscle. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic-pharmacodynamic analysis of givinostat. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Low doses of arginine butyrate derivatives improve dystrophic phenotype and restore membrane integrity in DMD models. [2014]