A Study to Learn About the Safety of Diroximel Fumarate (DRF) and Dimethyl Fumarate (DMF) and Their Effects on Relapses in Pediatric Participants With Relapsing Forms of Multiple Sclerosis (RMS)

Official title

A Phase 3 Study With an Open-Label Extension in Pediatric Participants to Evaluate the Safety, Efficacy, and Pharmacokinetics of Diroximel Fumarate and Dimethyl Fumarate for the Treatment of Relapsing Forms of Multiple Sclerosis

Overview

In this study, researchers will learn more about the study drugs diroximel fumarate (DRF) and dimethyl fumarate (DMF) in children with MS who may be experiencing relapses. Participants will be divided into 2 groups based on their weight: * Group A will include children who weigh 40 kilograms (kg) or less. They will receive DRF in both Part 1 and Part 2 of the study. * Group B will include children who weigh more than 40 kg. They will be randomly assigned to receive DRF, DMF, or fingolimod. Fingolimod is a drug already used to treat MS in adults. In Part 2, they will receive DRF. This is a 2-part study. Part 1 treatment will last 96 weeks. Participants who complete Part 1 may move to Part 2. Part 2 is an extension period. Treatment will last another 96 weeks and will help researchers learn about the long-term safety and effects of treatment. The main goal of the study is to learn about the safety of DRF and DMF and compare their effect on relapses and brain lesions with fingolimod. The main questions researchers want to answer are: * How many participants have adverse events and serious adverse events? * How often do participants relapse after treatment with DRF and DMF compared to fingolimod? Researchers will take brain imaging scans to check for any new areas of brain inflammation and compare the brain lesions before and after treatment. Researchers will also measure the amount of drug in the blood to understand how the body processes it. To check safety, they will monitor participants' growth and development, and compare changes in heart tests, vital signs, and lab tests. They will also use rating scales to monitor depression symptoms. The study will be done as follows: Part 1 (Treatment Period) * After screening, participants will join Part 1 and be divided into 2 groups based on their weight. * Participants in Group A will receive DRF. * Participants in Group B will be randomly assigned to receive either DRF, DMF, or fingolimod. * Neither the researchers nor the participants will know which drug or dose the participants will receive in Group B. Participants in Group B will also receive a placebo so they do not know which drug is being given. A placebo looks like a study drug but contains no real medicine. * All study drugs will be taken by mouth, once or twice a day. Participants who take DRF or DMF will start with a lower dose during the 1st week, then move to a standard dose. * Treatment in Part 1 will last for 96 weeks. Participants will have up to 11 study visits and 7 phone calls. * Participants who do not move onto Part 2 will also have a safety follow-up period of 4 to 8 weeks. This will include 1 study visit and 1 phone call. * The total length of Part 1, including the screening, treatment, and follow-up, will be up to 108 weeks. Part 2 (Extension Period) * Participants who complete Part 1 can move on to Part 2 of the study. * All participants in Part 2 will receive DRF by mouth for 96 weeks. * Participants will have up to 10 more study visits and 1 telephone call during treatment. * They will also have a 4-week safety follow-up, including 1 study visit and 1 phone call. * The total length of Part 2 will be up to 100 weeks.

Detailed description

The primary objectives of this study are to evaluate the safety, tolerability of diroximel fumarate (DRF), the noninferiority of the clinical efficacy of monomethyl fumarate (MMF) (pooled DRF and dimethyl fumarate \[DMF\] treatment) compared to that of fingolimod and long-term safety and tolerability of DRF in participants who completed Week 96 of the Treatment Period. The secondary objectives of this study are to characterize the pharmacokinetic (PK) profile of DRF metabolites (MMF and 2-hydroxyethyl succinimide \[HES\]), additional safety and tolerability of DRF, noninferiority of the radiological efficacy of MMF (pooled DRF and DMF treatment) compared to that of fingolimod, and to further describe the safety and long-term multiple sclerosis (MS) outcomes of DRF in participants who completed Week 96 of the Treatment Period.

Interventions

• Drug Diroximel Fumarate
  Oral capsule
• Drug Dimethyl Fumarate
  Oral capsule
• Drug Fingolimod
  Oral capsule
• Drug Placebo matching DRF
  Oral capsule
• Drug Placebo matching DMF
  Oral capsule
• Drug Placebo matching fingolimod
  Oral capsule

Primary outcome measures

• TP Cohort A and OLE Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation [Time frame: Cohort A: From first dose of study drug up to end of follow-up (up to Week 104), OLE: Baseline (Week 96) up to the end of OLE period (up to Week 196)]
• TP Cohort B: Annualized Relapse Rate (ARR) Through Week 96 [Time frame: Baseline (Day 1) up to Week 96]

Secondary outcome measures (12)

• TP Cohorts A and B: Maximum Observed Concentration at Steady State (Cmax,ss) of Monomethyl Fumarate (MMF) [Time frame: Predose and at multiple timepoints post dose up to Week 96]
• TP Cohorts A and B: Minimum Observed Concentration at Steady State (Cmin,ss) of MMF [Time frame: Predose and at multiple timepoints post dose up to Week 96]
• TP Cohorts A and B: Cmax,ss of 2-Hydroxyethyl Succinimide (HES) [Time frame: Predose and at multiple timepoints post dose up to Week 96]
• TP Cohorts A and B: Cmin,ss of HES [Time frame: Predose and at multiple timepoints post dose up to Week 96]
• TP Cohorts A, B and OLE Period: Number of Participants with Potentially Clinically Serious (PCS) Change from Baseline in Vital Sign Parameters [Time frame: Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Number of Participants With Change From Baseline in Clinically Relevant Electrocardiogram (ECG) Abnormalities [Time frame: Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Number of Participants with PCS Change from Baseline in Clinical Laboratory Parameters [Time frame: Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Change From Baseline in Height [Time frame: Cohorts A and B: Baseline up to Week 104, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Change From Baseline in Weight [Time frame: Cohorts A and B: Baseline up to Week 104, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Change From Baseline in Tanner Score [Time frame: Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Change From Baseline in Bone Age [Time frame: Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Number of Participants with Change From Baseline in Endocrine Tests [Time frame: Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]

Eligibility criteria

Inclusion criteria

Treatment Period:

• Must have a diagnosis of pediatric MS (as defined by the revised consensus definition of pediatric MS).
• Must have an Expanded Disability Status Scale (EDSS) score between 0 and 5.0, inclusive.
• Must have experienced at least 1 of the following conditions:

• greater than or equal to 1 relapse in the 12 months prior to the Baseline Visit (Day 1),
• greater than or equal to 2 relapses in the 24 months prior to the Baseline Visit (Day 1), or
• evidence of gadolinium (Gd)-enhancing lesions of the brain on magnetic resonance imaging (MRI) within 6 months prior to the Baseline Visit (Day 1).
• Participants must be neurologically stable with no evidence of relapse within 30 days prior to the Baseline Visit (Day 1).

Open-Label Extension Period:

\- Participants who completed the study treatment in Cohorts A or B through the Week 96 Visit.

Exclusion criteria

Treatment Period:

• History of progressive MS.
• History of disorders mimicking MS, such as other demyelinating disorders (e.g., acute disseminated encephalomyelitis and neuromyelitis optical spectrum disorder), systemic autoimmune disorders (e.g., Sjögren's disease and lupus erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders.
• History of severe allergic or anaphylactic reactions or any allergic reactions that in the opinion of the Investigator are likely to be exacerbated by any component of the study treatment.
• History of, or ongoing, malignant disease, including solid tumors, skin malignancies, and hematologic malignancies.
• History of gastrointestinal (GI) surgery (except appendectomy or cholecystectomy that occurred more than 6 months prior to the Screening Visit), inflammatory bowel disease (Crohn's disease, ulcerative colitis), or another clinically significant and active GI condition at the Investigator's discretion.
• Known hypersensitivity to fumaric acid derivatives or any excipients of DRF or DMF.
• Diagnosis of macular edema prior to randomization.

Open-Label Extension Period:

• Any significant changes in medical history occurring after enrollment in the Treatment Period, including laboratory test abnormalities or current clinically significant conditions that, in the opinion of the Investigator, would have excluded the participant's participation in the Treatment Period. The Investigator must reassess the participant's medical fitness for participation and consider any factors that would preclude treatment.
• Participants who discontinued study treatment due to tolerability issues.
• Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the participant unsuitable for participation in the OLE Period.

NOTE: Other protocol-defined Inclusion/Exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07483632 · 272MS304 · 2023-509409-60

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗