Evaluation of MAS825 Efficacy and Safety in Monogenic IL-18 Driven Autoinflammatory Diseases: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-504419-34-00
- Protocol
- CMAS825D12201
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **efficacy** of MAS825 in the prevention of flares in patients with autoinflammatory diseases, including NLRC4-Gain of Function (GOF), X-linked Inhibitor of Apoptosis Protein (XIAP) deficiency, or Cell division control protein 42 homolog (CDC42) mutation. This is clinically relevant as these conditions are characterized by recurrent inflammatory episodes, and effective prevention of flares can significantly improve patient outcomes and quality of life.
Secondary objectives include:
- Evaluating the safety and tolerability of MAS825.
- Assessing the serological markers of MAS825.
- Evaluating the efficacy of MAS825 to improve the clinical status of patients.
- Determining the efficacy of MAS825 to achieve serological remission.
- Evaluating the effect of MAS825 on concomitant glucocorticoid administration.
- Assessing the effect of MAS825 on the time to first flare.
- Evaluating the efficacy of MAS825 to improve signs and symptoms.
- Assessing the effect of MAS825 on patient-reported outcomes over time.
Participants
The clinical trial involves a total of **9 participants** diagnosed with **autoinflammatory diseases**, specifically NLRC4-Gain of Function (GOF), X-linked Inhibitor of Apoptosis Protein (XIAP) deficiency, or Cell division control protein 42 homolog (CDC42) mutation. The study population includes both male and female subjects, with an age range that encompasses pediatric patients weighing at least 3 kg. Participants were selected based on a genetic diagnosis of the specified conditions, and the trial includes individuals with a clinical history consistent with these autoinflammatory diseases. The trial population is characterized by a vulnerable group, as it includes pediatric patients who require informed consent from parents or legal guardians. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants have evidence of active disease at the time of first treatment, aligning with the trial's objective to assess the efficacy of MAS825 in preventing disease flares.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy, safety, and tolerability of **MAS825**, a **human IgG1 monoclonal antibody against human IL-1 beta and human IL-18**, in patients with monogenic IL-18 driven autoinflammatory diseases, including NLRC4-Gain of Function (GOF), X-linked Inhibitor of Apoptosis Protein (XIAP) deficiency, or CDC42 mutations. This study employs a three-period, multicenter, randomized-withdrawal, double-blinded, placebo-controlled design. The trial is expected to run from January 2021 to June 2027, with a maximum treatment period of 204 days for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as a genetic diagnosis of the specified conditions and evidence of active disease. Following successful screening, participants will enter Period 1, where they will receive **MAS825** or placebo intravenously. The primary endpoint is the occurrence of disease flare during Period 2, assessed by the Physician's Global Assessment and inflammatory markers. Secondary endpoints include serological markers of **MAS825**, glucocorticoid therapy reduction, and time to first flare.
Study visits will include regular follow-up assessments to monitor safety and efficacy, with specific evaluations at Day 29, the end of Period 1, and the end of Period 2. The end-of-study visit will conclude the participant's involvement, unless early termination is warranted due to adverse events, lack of efficacy, or withdrawal of consent. Participants are expected to be involved for the duration of the treatment period, with conditions for early termination clearly outlined to ensure participant safety and data integrity.
Treatment
The clinical trial involves the administration of **MAS825**, a **human IgG1 monoclonal antibody** targeting **human IL-1 beta** and **human IL-18**. This investigational product is provided as a **concentrate for solution for infusion**. The pharmaceutical form is specifically designed for **intravenous use**. The dosing regimen for MAS825 is set at a maximum daily dose of 10 mg/kg, with the total dose not exceeding 10 mg/kg. The treatment period is capped at 204 days. The product is developed by Novartis Pharma AG and is not formulated for pediatric use. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
The study also includes a **placebo** comparator, which is designed to match the MAS825 formulation. The placebo is labeled as "Placebo to MAS825 100 mg/1 mL Concentrate for solution for infusion / Solution for injection." It serves as a control to evaluate the efficacy and safety of MAS825 in a double-blinded manner. The placebo does not contain any active substances and is administered in a manner consistent with the experimental treatment to maintain the study's integrity. Participants' adherence to the placebo regimen is similarly monitored to ensure accurate assessment of the investigational product's effects.
Efficacy
The efficacy of MAS825 in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the **occurrence of disease flare** in patients treated with MAS825 compared to those receiving a placebo during Period 2. This will be evaluated using the Physician's Global Assessment and inflammatory markers. Secondary endpoints include the confirmation of serological markers of MAS825, assessment of Physician's Global Assessment (PGA) and inflammatory markers at Day 29, and at the end of Periods 1 and 2. Additionally, serological remission will be evaluated via inflammatory markers, and the use of glucocorticoid therapy will be monitored to ensure it is ≤0.2 mg/kg/day by the end of Period 1. The time to the first flare during Period 2 will also be recorded, alongside the Physician Severity Assessment of Disease Signs and Symptoms scale and the Patient's/Parent's Global Assessment of Disease Activity (PPGA) scale.
Inclusion and Exclusion Criteria
Inclusion Criteria
- All cohorts: 1.Male and female patients weighing at least 3 kg
- All cohorts: 2.Written informed consent by parent(s)/legal guardian(s) for the pediatric patients and assent by the pediatric patient (depending on local requirements) must be obtained before any study-specific assessment is performed. For adult patients, written informed consent by patients capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representative (if allowed according to local requirements).
- Cohort 1: 3.Patients with a genetic diagnosis of either NLRC4-GOF, XIAP deficiency, or CDC42 mutation.
- Cohort 1: 4.Clinical history and investigations consistent with autoinflammation with infantile enterocolitis (AIFEC/NLRC4-GOF), XIAP or CDC42.
- Cohort 1: 5.At first treatment, evidence of active disease
- Cohort 2: 6.Patients with a genetic diagnosis of NLRC4-GOF, XIAP deficiency, or CDC42 mutations who are being treated with MAS825 in a Novartis managed access program.
Exclusion Criteria
- 1.History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes or to any of the excipients.
- 2.Signs and symptoms, in the judgment of the investigator, of clinically significant systemic recurrent and/or evidence of active bacterial, fungal, parasitic or viral infections, excluding chronic Epstein-Barr Virus (EBV).
- 3.Any conditions or significant medical problems, which in the opinion of the investigator places the patient at unacceptable risk for MAS825 therapy
- 4.Previous treatment with anti-rejection and/or immunomodulatory drugs within the past 28 days or 5 half-lives (whichever is the longer) for immunomodulatory therapeutic antibodies prior to MAS825 treatment with the exceptions of: - glucocorticoids - cyclosporin - targeted binding or blocking therapies, which must be discontinued prior to treatment with MAS825 - drugs listed as prohibited medication in the protocol, for which the washout periods should be followed as outlined in the protocol.
- 5.A positive HIV test result at Screening. Evidence of prior testing within 3 months is sufficient.
- 6.A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. Evidence of prior testing within 3 months is sufficient.
- 7.Presence of tuberculosis infection as defined by a positive TB test at Screening. Evidence of prior testing within 3 months is sufficient.
- 8.Live vaccinations within 1 month prior to MAS825 treatment, during the trial, and up to 3 months following the last dose.
- 9.Female patients of child-bearing potential (or Tanner stage 3 or above) who are or might become sexually active, agree to use highly effective contraceptive methods to prevent pregnancy while on MAS825 therapy.
- 10.Patients weighing >160 kg at Screening.
- For CDC42 mutation patients: Takenouchi-Kosaki syndrome – CDC42 mutations associated with a diverse syndrome characterized by variable development delays, cardiac, brain and hematological abnormalities.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 01 Jan 2021 | 2 |
 France | Not Recruiting | 01 Jan 2021 | 3 |
 Italy | Not Recruiting | 01 Jan 2021 | 1 |
 Spain | Not Recruiting | 01 Jan 2021 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
- | Other | PHF00170MIG | ORAL | 0 | 72 | H02AB |
Placebo to MAS825 100 mg/1 mL Concentrate for solution for infusion / Solution for injection | Placebo | N/A | — | — | — | N/A |
CICLOSPORIN | Other | PHF00007MIG | ORAL | 0 | 72 | SCP138048 |
MAS825 | Test | SOLUTION FOR INJECTION | INTRAVENOUS USE | 10 | 204 | PRD8359811 |