A Study to Assess Safety/Tolerability, pk, Effects on Histology, Clinical Parameters of Givinostat in Children With DMD

NCT01761292 | Completed Phase 1 Results

• 2 other identifiers: DSC/11/2357/432012-002566-12
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 4

Brief Summary

The primary objective of Parts 1 and 2 of the study were to establish the histologic effects of givinostat administered chronically at the selected daily dose. The secondary objectives of Parts 1 and 2 of the study were as follows:

• To establish the effects of givinostat administered chronically at the selected daily dose on functional parameters, such as the 6-Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and performance of upper limb (PUL)
• To establish the safety and tolerability of givinostat administered chronically at the selected daily dose in children with Duchenne muscular dystrophy (DMD)
• To explore the effects of givinostat administered chronically at the selected daily dose on parameters such as magnetic resonance imaging (MRI) and biomarkers
• To explore the acceptability/palatability of the oral suspension
• To explore whether the effects of givinostat on disease progression may be related to the type of DMD mutation. The primary objective of the Extension of the study was to evaluate the safety and tolerability of long-term administration of givinostat administered chronically at the selected daily dose in children with DMD. The secondary objectives of the Extensions were:
• To establish the effects of givinostat administered chronically at the selected daily dose on muscular functional parameters, such as the 6MWT, NSAA, and PUL (Extensions 1, 2, and 3)
• To explore the effects of givinostat administered chronically at the selected daily dose on parameters such as MRI (Extension 1)
• To collect information related to 2 biomarkers, latent Transforming growth factor β (TGFβ) binding protein 4 (LTBP4) and osteopontin genotype (at the beginning of Extension 2 only)
• To collect information related to time to wheelchair and how much time the children spend in wheelchair (Extension 3 - only for the children who were not able to complete the 6MWT)

Conditions

Duchenne Muscular Dystrophy (DMD)

Keywords

rare disease

Outcome Measures

Primary Outcomes (1)

• Change From Baseline to Part 2 in the Value of Muscle Fiber Area (MFA) % Comparing the Histology Biopsies Before and After 12 Months of Treatment With Givinostat.

  The primary endpoint was the change in histology comparing the brachial biceps biopsies before and after ≥12 months of treatment with Givinostat. Muscle biopsies: A first brachial biceps biopsy (baseline) was taken prior to the first dose of study drug. A second brachial biceps biopsy was taken at Visit 10 (12 months) from the opposite arm. The muscle biopsy samples from the biceps muscle were collected by open biopsy. The minimum amount of muscle tissue required was a piece of muscle of at least 0.5 × 0.5 × 0.5 cm.

  After12 months of treatment

Secondary Outcomes (10)

• Change From Baseline to End of Study in Cross Sectional Area (CSA)

  At 12 months

• Change From Baseline to End of Study in Fibrosis, Necrosis, Fatty Replacement

  After 12 months

• Change From Baseline to End of Study in Number of Hypercontracted Fibers

  At 12 months

• Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the 6-Minute Walk Test

  At 12 months

• Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the North Star Ambulatory Assessment (NSAA)

  At 12 months

Study Arms (1)

Givinostat

EXPERIMENTAL

Givinostat will be administered as 2 oral doses daily while the child is in fed state.

Drug: Givinostat

Interventions

Givinostat DRUG

Givinostat, oral suspension 10 mg/mL or oral capsules 50 mg, administered orally under fed conditions at the dose of 25 mg BID, 37.5 mg BID, and 50 mg BID during Part 1 for two weeks, and 25 mg BID and 37.5 mg BID during Part 2 for 12 months. Givinostat, oral suspension 10 mg/mL, administered orally under fed conditions at the dose of 25 mg BID or 37.5 mg BID during Extension 1, and modified as per patient's weight during Extensions 2 and 3 (up to 52 months).

Also known as: ITF2357

Givinostat

Eligibility Criteria

• Age: 7 Years - 11 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male children aged 7 to \<11 years with an immunohistochemical and molecular diagnosis of DMD.
• A parent/guardian and child can comply with all study evaluations/procedures and return for all study activities.
• Able to complete the 2 screening 6MWTs with a minimal distance of at least 250 m each. In addition, the results of these tests must be within ±30 m of each other.
• On a stable dose of systemic corticosteroids for at least 6 months.
• At least 6 months worth of data on the 6MWT (this will be the "historical" 6MWT). From the moment of the historical 6MWT assessment(s), the child must not have received any compound that could potentially affect the 6MWT, with the exception of the stable steroid treatment.
• Parent/guardian has signed the informed consent form and child has assented to be in the study (if applicable).

You may not qualify if:

• Initiation of systemic corticosteroid therapy within 6 months prior to the start of study drug or change in systemic corticosteroid therapy (e.g., initiation, change in type of drug, dose modification not related to body weight change, schedule modification, interruption, discontinuation, or re initiation) within 6 months prior to the start of study drug.
• Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle strength since the time of the historical 6MWT and in any case within 3 months prior to the start of study treatment (e.g., growth hormone). Vitamin D, calcium, and integrators will be allowed.
• Surgery that might have an effect on muscle strength or function within 3 months before study entry or planned surgery at any time during the study.
• Exposure to another investigational drug since the time of the historical 6MWT and in any case within 3 months prior to the start of study treatment.
• History of participation in gene therapy, cell-based therapy or oligonucleotide therapy.
• Presence of other clinically significant disease that in the opinion of the investigator places the child in unacceptable risk for an adverse outcome or that could affect study results.
• Inadequate hematological function
• Absolute neutrophil count: \<1.5 x 109/L
• Platelets: \<100 x 109/L
• Current or history of liver disease or impairment, including but not limited to an elevated total bilirubin.
• Inadequate renal function, as defined by serum creatinine \>2 x the upper limit of normal.
• Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening
• A baseline QTc \>450 msec, (as the mean of 3 consecutive readings 5 minutes apart) or history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome).
• Psychiatric illness/social situations rendering the potential child unable to understand and comply with the study protocol.

Sponsors & Collaborators

• Italfarmaco: lead

Study Sites (4)

Azienda Ospedaliera Universitaria Policlinico G. Martino

Messina, 98125, Italy

Location

IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano

Milan, 20122, Italy

Location

Policlinico Agostino Gemelli

Roma, 00168, Italy

Location

Ospedale Pediatrico Bambino Gesù

Rome, 00165, Italy

Location

Related Publications (1)

• Bettica P, Petrini S, D'Oria V, D'Amico A, Catteruccia M, Pane M, Sivo S, Magri F, Brajkovic S, Messina S, Vita GL, Gatti B, Moggio M, Puri PL, Rocchetti M, De Nicolao G, Vita G, Comi GP, Bertini E, Mercuri E. Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscul Disord. 2016 Oct;26(10):643-649. doi: 10.1016/j.nmd.2016.07.002. Epub 2016 Jul 11.

  PMID: 27566866 RESULT

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne; Rare Diseases

Interventions

givinostat; givinostat hydrochloride

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Paolo Bettica, MD
• Organization: Italfarmaco SpA

p.bettica@italfarmaco.com

+39 02 64431

Study Officials

• Enrico Bertini, MD

  Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2012
• First Posted: January 4, 2013
• Study Start: April 1, 2013
• Primary Completion: December 1, 2014
• Study Completion: November 1, 2017
• Last Updated: November 7, 2023
• Results First Posted: June 23, 2020

Record last verified: 2020-06

Locations

IT (4)