Givinostat for Duchenne Muscular Dystrophy

Recruiting at 38 trial locations

Age: Any Age

Sex: Male

Trial Phase: Phase 2 & 3

Sponsor: Italfarmaco

Must be taking: Givinostat

Must not be taking: Growth hormone

Disqualifiers: Heart failure, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

206 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop using any medications other than corticosteroids that might affect muscle strength or function within 3 months before joining the study. Vitamin D, calcium, and other supplements are allowed.

Is Givinostat safe for humans?

Givinostat has been studied in boys with Duchenne Muscular Dystrophy and in mouse models, showing positive effects on muscle health and reduced inflammation. While these studies focus on effectiveness, they suggest that Givinostat is generally safe at certain doses, but more human safety data would be beneficial. ^{1 2 3 4 5}

How does the drug Givinostat differ from other treatments for Duchenne Muscular Dystrophy?

Givinostat is unique because it is a histone deacetylase (HDAC) inhibitor that helps reduce muscle fibrosis (scarring) and promotes muscle regeneration, which is different from other treatments that mainly focus on genetic approaches. It also acts as a metabolic enhancer by improving mitochondrial function, which is crucial for energy production in muscle cells. ^{1 2 3 4 6}

What is the purpose of this trial?

This trial tests the safety and effectiveness of GIVINOSTAT, a liquid medicine taken by mouth, in patients with Duchenne's muscular dystrophy who have used it before. The medicine aims to improve muscle function and slow down muscle damage.

Eligibility Criteria

This trial is for boys aged ≥6 with Duchenne Muscular Dystrophy who've been in a previous Givinostat study. They must have specific muscle fat levels, be able to consent, and use contraception if needed. Excluded are those with hypersensitivity to the drug's components, certain intolerances or diseases, heart failure, liver issues, psychiatric conditions affecting compliance, recent non-steroid muscle treatments, other neurological disorders or abnormal blood tests.

Inclusion Criteria

Must have participated in one of the previous studies with GIVINOSTAT in DMD and have attended the End of Study Visit or must have been screened in study DSC/14/2357/48 and met all the inclusion criteria and none of the exclusion criteria

Never been randomized because the enrollment in the off-target group was completed

I am 6 years old or older.

Exclusion Criteria

I am not using any experimental drugs except Givinostat.

I do not have any other serious illnesses that could interfere with the study.

Baseline QTcF >450 msec or history of additional risk factors for torsades de pointes

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive GIVINOSTAT oral suspension (10 mg/mL) twice daily in a fed state. Dosage adjustments based on weight and platelet count monitoring.

1 year

Weekly visits for the first month, bi-weekly for the second month, then as needed

Follow-up

Participants are monitored for safety and effectiveness after treatment, with specific attention to adverse events and stabilization of any treatment-related issues.

4 weeks

Open-label extension

Long-term continuation of GIVINOSTAT treatment for safety, tolerability, and efficacy assessment in DMD patients.

Long-term

Treatment Details

Interventions

• Givinostat

Trial Overview The trial is testing the long-term safety and effectiveness of Givinostat in patients with Duchenne Muscular Dystrophy. It's an open-label study meaning everyone knows they're getting Givinostat and it focuses on those who've previously taken part in related studies.

Participant Groups

Group I: givinostat Experimental Treatment 1 Intervention

Givinostat oral suspension (10 mg/mL) twice daily in a fed state

Givinostat is already approved in United States for the following indications:

Approved in United States as Duvyzat for:

• Duchenne muscular dystrophy (DMD) in patients 6 years of age and older

Who Is Running the Clinical Trial?

Italfarmaco

Lead Sponsor

Trials

36

Recruited

4,500+

Cromsource

Industry Sponsor

Trials

18

Recruited

3,200+

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]

Long-term treatment with the HDAC inhibitor givinostat in mdx mice, a model for Duchenne muscular dystrophy, showed effective recovery of muscle function and structure at doses between 5 and 10 mg/kg/day, while lower doses (1 mg/kg/day) were less effective.

Givinostat treatment led to increased muscle cross-sectional area, reduced fibrosis and fatty infiltration, improved endurance in treadmill tests, and decreased inflammation in the muscles, supporting its potential as a therapeutic option for muscular dystrophies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat. Consalvi, S., Mozzetta, C., Bettica, P., et al.[2021]

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]

Givinostat-treated muscle progenitor cells (Givi-MPC) derived from human induced pluripotent stem cells (hiPSCs) showed enhanced proliferation and migration abilities compared to control cells, indicating their potential for effective muscle repair in Duchenne muscular dystrophy (DMD).

Transplantation of Givi-MPC into injured muscle in mice resulted in significant restoration of dystrophin, reduced inflammation, and less muscle damage, demonstrating their therapeutic efficacy in repairing muscle tissue affected by DMD.

NCBI (Pubmed)

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. Xuan, W., Khan, M., Ashraf, M.[2023]

Givinostat, a histone deacetylase inhibitor, showed significant improvements in muscle biopsy parameters in boys with Duchenne muscular dystrophy (DMD) during a Phase II study, indicating its potential efficacy in treating this condition.

The pharmacokinetic model developed from seven clinical studies suggests that dosing of givinostat should be adjusted based on body weight, and monitoring platelet counts is essential, as about 14-15% of patients experienced a significant decrease in platelet count after 6 months of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic-pharmacodynamic analysis of givinostat. Fiorentini, F., Germani, M., Del Bene, F., et al.[2023]

In a study using mdx mice, low doses of prodrugs combining arginine and butyrate significantly improved muscle function, with force and fatigue resistance increasing by approximately 60% and 3.5-fold, respectively, while also reducing heart muscle necrosis by about 90%.

The treatment also enhanced muscle membrane integrity and increased levels of utrophin and other important proteins in both mice and human myotubes, demonstrating that these low-dose prodrugs effectively target the nitric oxide pathway and inhibit histone deacetylases, offering a promising approach for treating Duchenne muscular dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low doses of arginine butyrate derivatives improve dystrophic phenotype and restore membrane integrity in DMD models. Vianello, S., Consolaro, F., Bich, C., et al.[2014]

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]