A Phase 2 Open-label (Core Phase Plus Extension Phase) With 2 Cohorts Study to Assess the Pharmacokinetics and Safety of Givinostat in DMD Patients Ages From at Least 2 Years to Less Than 6 Years Old

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Italfarmaco S.p.A.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

6 Nov 2024 → ongoing

Decision date (initial)

2024-10-07

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-511823-32-00

WHO UTN

U1111-1308-1552

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Others, Pharmacodynamic, Dose response, Therapy, Safety

CORE PHASE: To assess the pharmacokinetic (PK) profile of givinostat at steady state administered in younger DMD boys in the 2 cohorts.

EXTENSION PHASE: To assess the safety and tolerability of givinostat long-term administered in younger DMD boys in the 2 cohorts (ie, adverse events [AE])

Secondary objectives 6

1. CORE PHASE: To assess the safety and tolerability of givinostat administered in younger DMD boys in the 2 cohorts
2. CORE PHASE: To evaluate the effect of givinostat on muscular functional parameters in the 2 cohorts
3. CORE PHASE: To evaluate the effect of givinostat on functional health-related quality of life (HRQOL) in Cohort 1 (for subjects ≥4 years only)
4. EXTENSION PHASE: To further evaluate the safety and tolerability of givinostat long-term administered in younger DMD boys in the 2 cohorts (eg, vital signs, laboratory test values, electrocardiogram [ECG] parameters) cohorts.
5. EXTENSION PHASE: To evaluate the effect of long-term administered givinostat on muscular functional parameters in the 2 cohorts
6. EXTENSION PHASE: To evaluate the effect of long-term administered givinostat on functional HRQOL in Cohort 1 (for subjects >4 years only)

Conditions and MedDRA coding

Duchenne muscular dystrophy (DMD)

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-000551-PIP04-21

Plan to share IPD

No

IPD plan description

NAP

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. CORE PHASE: Male children aged ≥2 to <6 years at screening (subjects ≥6 years of age at screening will not be enrolled into the study)
2. CORE PHASE: Written consent provided by parent/legal guardian and subject written assent, if applicable (according to local regulation)
3. CORE PHASE: A genetic diagnosis of DMD
4. CORE PHASE: Corticosteroid treatment considerations: a. For subjects receiving a stable dose of oral systemic corticosteroids: No significant change in dose or dosing regimen (except for adjustments due to body weight change) for a minimum of 3 months immediately prior to the start of study drug or b. For subjects without current corticosteroids treatment: Must not start corticosteroids during core phase (ie, first 48 weeks)
5. EXTENSION PHASE: Must have participated in the Core Phase study (48 weeks) and have attended the End of Treatment Visit (EOT/V12)
6. EXTENSION PHASE: Give informed consent and /or assent in writing signed by the parent/legal guardian and/or subject (according to local regulation)
7. EXTENSION PHASE: In stable oral systemic corticosteroids treatment with no significant change in dose or dosing regimen (except for adjustments due to body weight change). For subjects without corticosteroids during the Core Phase, the treatment can be started based on the Investigator’s clinical medical judgement.

Exclusion criteria 23

1. CORE PHASE: Exposure to any other investigational drug within 3 months prior to the start of study drug
2. CORE PHASE: Inadequate renal function, as defined by serum Cystatin C result >2 × ULN (Note: if the value is >2 × ULN, the serum Cystatin C will be repeated once; if the repeated test result is still >2 × ULN, the subject will be excluded)
3. CORE PHASE: Fasting triglycerides >300 mg/dL (3.42 mmol/L) at screening (Note: if the value is >300 mg/dL, the triglycerides will be repeated once; if the repeated test result is still >300 mg/dL in fasting condition, the subject should be excluded)
4. CORE PHASE: Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening
5. CORE PHASE: Baseline corrected QT interval using Fredericia’s formula (QTcF) >450 msec (as the mean of 3 consecutive readings taken 5 minutes apart) or history of additional risk factors for torsades de pointes (eg, heart failure, hypokalaemia, or family history of long QT syndrome)
6. CORE PHASE: Psychiatric illness or social situations rendering the potential subject unable to understand and comply with the muscle function tests and/or with the study protocol procedures, based on the Investigator’s clinical medical judgement
7. CORE PHASE: Hypersensitivity to any component of the study drug
8. CORE PHASE: Sorbitol intolerance or malabsorption, or have the hereditary form of fructose intolerance
9. EXTENSION PHASE: Platelet count, white blood cells, and/or haemoglobin < LLN at EOT/V12
10. EXTENSION PHASE: Current liver disease or impairment, including but not limited to an elevated total bilirubin (ie, >1.5 × ULN), unless secondary to Gilbert disease or pattern consistent with Gilbert disease
11. EXTENSION PHASE: Inadequate renal function, as defined by serum Cystatin C result >2 × ULN
12. CORE PHASE: Exposure to any dystrophin restoration product (eg, Ataluren, Exon skipping) within 6 months prior to the start of study drug
13. EXTENSION PHASE: Fasting triglycerides >300 mg/dL (3.42 mmol/L)
14. EXTENSION PHASE: Have presence of other clinically significant disease, which, in the Investigator’s opinion, could adversely affect the safety of the subject, making it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results
15. EXTENSION PHASE: Evidence of psychiatric illness or social situations rendering the potential subject unable to understand and comply with the muscle function tests and/or with the study protocol procedures, based on the Investigator’s clinical medical judgement
16. CORE PHASE: Received any gene therapy (eg, Adeno-associated viruses Micro dystrophin delivery) within 12 months prior to the start of study drug
17. CORE PHASE: Use of any pharmacologic treatment, other than corticosteroids, that might have had an effect on muscle strength or function within 3 months prior to the start of study drug (eg, growth hormone)
18. CORE PHASE: Have had surgery that might have an effect on muscle strength or function within 3 months prior to the start of the study drug or planned surgery at any time during the study
19. CORE PHASE: The presence of other clinically significant disease, which, in the Investigator’s opinion, could adversely affect subject’s safety, making it unlikely to complete the study or to be compliant with study-specific requirements that could impair the assessment of study results
20. CORE PHASE: Diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD, based on the Investigator's clinical medical judgement
21. CORE PHASE: Platelet count, white blood cells, and/or haemoglobin < lower limit of normal (LLN) at screening (Note: for abnormal screening laboratory test results [
22. CORE PHASE: Current or history of liver disease or impairment, including but not limited to a baseline elevated total bilirubin (ie, >1.5 × upper limit of normal [ULN]), unless secondary to Gilbert disease or pattern consistent with Gilbert disease
23. CORE PHASE: Body weight <10 kg at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. CORE PHASE: Area under the concentration-time curve from dosing (time 0) to time t at steady state (AUC0-T,ss) after at least 7 days of dosing (at Week 1 and at 6 months) CORE PHASE: Maximum plasma concentration at steady state (Cmax,ss) after at least 7 days of dosing (at Week 1 and at 6 months) CORE PHASE: Elimination half life (t1/2) assessed after at least 7 days of dosing dosing (at Week 1 and at 6 months)
2. EXTENSION PHASE: • Type, incidence, and severity of TEAEs and SAEs from baseline up to Week 144 • Proportion of subjects experiencing TEAEs from baseline to Week 144

Secondary endpoints 4

1. CORE PHASE: • Type, incidence, and severity of treatment-emergent adverse events (TEAEs) and SAEs from baseline to Week 48 • Proportion of subjects experiencing TEAEs from baseline to Week 48 • Change from baseline vital signs and clinical laboratory tests to each postbaseline visit up to Week 48 • Change from baseline electrocardiogram (ECG) to each postbaseline visit up to Week 48
2. CORE PHASE: • Change in physical function as per the Bayley III Gross Motor scale from baseline to Week 48 for subjects aged ≥2 to <3.5 years of age • Change in physical function as per the North Star Ambulatory Assessment (NSAA) total score from baseline to Week 48 for subjects aged ≥3.5 years of age
3. CORE PHASE: • Change in Paediatric Outcomes Data Collection Instrument (PODCI) from baseline to Week 48 for subjects aged ≥4 years of age in Cohort 1 only
4. EXTENSION PHASE: • Type, incidence, and severity of TEAEs and SAEs from baseline up to Week 144 • Proportion of patients experiencing TEAEs from baseline to Week 144 • Change from baseline vital signs and clinical laboratory tests to each postbaseline visit up to Week 144 • Change from baseline ECG to each postbaseline up to Week 144

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Italfarmaco S.p.A.

Sponsor organisation

Italfarmaco S.p.A.

Address

Via Dei Lavoratori 54

City

Cinisello Balsamo

Postcode

20092

Country

Italy

Scientific contact point

Organisation

Italfarmaco S.p.A.

Contact name

Nicoletta Coceani – Clinical Scientist

Public contact point

Organisation

Italfarmaco S.p.A.

Contact name

Patient Advocacy Representative of Italfarmaco S.p.A

Third parties 5

Locations

3 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications