Randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy, safety and tolerability of givinostat in non-ambulant patients with Duchenne Muscular Dystrophy

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

9 Feb 2024 → ongoing

Decision date (initial)

2023-12-11

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Italfarmaco

External identifiers

EU CT number

2023-503521-19-00

WHO UTN

U1111-1295-1799

ClinicalTrials.gov

NCT05933057

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Therapy, Others, Pharmacodynamic, Safety

To demonstrate the efficacy of givinostat in reducing muscle decline in non-ambulant DMD patients.

Secondary objectives 2

1. To evaluate the safety and tolerability of givinostat in non-ambulant DMD patients
2. To further investigate the efficacy of givinostat in non-ambulant DMD patients.

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 8

1. Children and adolescent males aged ≥ 9 to <18 years at screening (patients ≥ 18 years of age at screening will not be enrolled into the study)
2. Are able to give informed assent and/or consent in writing signed by the patient and/or parent/legal guardian (according to local regulations)
3. A genetic diagnosis of DMD
4. Non-ambulant defined as being wheelchair bound and: a. Unable to perform the 10-meter walk/run test (10MWT), or b. Unable to complete the 10MWT in 30 seconds or less, without any support or devices
5. Performance of the Upper Limb test (PUL version 2.0) entry item scores 3 to 6
6. If on medication for DMD-associated cardiomyopathy, stable for ≥1 month immediately prior to start of study treatment
7. Stable corticosteroids, defined as: a. Receiving systemic corticosteroids for a minimum of 6 months immediately prior to start of study treatment b. No significant change in dose or dosing regimen (except for adjustments due to body weight change) for a minimum of 6 months immediately prior to start of study treatment
8. Willing to use adequate contraception. Contraceptive methods must be used from randomisation visit through 3 months after the last dose of study drug.

Exclusion criteria 24

1. Exposure to another investigational drug within 3 months prior to start of study treatment
2. Have exposure to any dystrophin restoration product within 6 months prior to the start of study treatment
3. Having received any gene therapy prior to start of study treatment
4. Use of any pharmacologic treatment or supplement, (other than corticosteroids), other than corticosteroids, that might have had an effect on muscle strength or function within 3 months prior to the start of study treatment (eg, growth hormone); vitamin D, calcium and any other supplements will be allowed.
5. Use of testosterone, unless used as a replacement therapy for the treatment of delayed puberty. The testosterone dose and regimen should be stable within 6 months prior to the start of study treatment.
6. Elbow-flexion contractures >30° in the dominant arm
7. Inability to perform consistent PUL 2.0 measurement within ±2 points without shoulder domain or within ±3 points with shoulder domain during paired testing at screening
8. Forced Vital Capacity % of predicted <40%
9. Requirement for daytime ventilator assistance
10. Episode of respiratory failure within the 8 weeks prior to screening
11. Symptomatic cardiomyopathy or heart failure and/or left ventricular ejection fraction <45%
12. Baseline corrected QT interval using Fredericia’s formula (QTcF) >450 msec (as the mean of 3 consecutive readings 5 minutes apart) or history of additional risk factors for torsades de pointes (eg, heart failure, hypokalaemia, or family history of long QT syndrome)
13. Major surgical procedure (including scoliosis surgery) planned within 1 year of the start of study treatment
14. Poorly controlled asthma or underlying lung disease such as bronchitis, bronchiectasis, emphysema, recurrent pneumonia that in the opinion of the Investigator might impact respiratory function
15. Platelets, white blood cells and/or haemoglobin < lower limit of normal (LLN) at screening
16. Fasting triglycerides >300 mg/dL (3.42 mmol/L) at screening
17. 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
18. Inadequate renal function, as defined by serum Cystatin C result >2 × ULN
19. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening
20. Hypersensitivity to any component of study medication
21. Sorbitol intolerance or malabsorption, or the hereditary form of fructose intolerance
22. Diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD, based on Investigator judgement
23. Psychiatric illness or social situations rendering the potential patient unable to understand and comply with the muscle function tests and/or with the study protocol procedures, based on Investigator judgement
24. Have contraindications to Magnetic Resonance Imaging (MRI) scan (eg, claustrophobia, metal implants, or uncontrolled seizure disorder), based on Investigator’s judgement

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change of PUL total score at 18 months of treatment of givinostat compared to placebo group

Secondary endpoints 2

1. •Change from baseline of Peak Expiratory Flow percent predicted (PEF%p) at 18 months of treatment of givinostat compared to placebo group • Change from baseline of Forced Vital Capacity percent predicted (FVC%p) at 18 months of treatment of givinostat compared to placebo group • Cumulative loss of PUL items over 18 months of treatment of givinostat compared to placebo group
2. •Type incidence and severity of TEAEs •Proportion of patients experiencing TEAEs (baseline to EOS/F-Up) • Changes in vital signs, lab tests, ECG, ECHO •Time to assisted ventilation, rate and severity of respiratory infection and duration and use of antibiotics of givinostat to placebo group •Time to onset of diarrhoea •Height and weight Z-scores

Investigational products

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

Test 1

Placebo 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

Paolo Tornese

Public contact point

Organisation

Italfarmaco S.p.A.

Contact name

Serena Franciosi

Third parties 6

Locations

9 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Documents 266 files

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

Application history

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