Study to Evaluate the Efficacy, Safety and Tolerability of MAS825 in Patients With Monogenic IL-18 Driven Autoinflammatory Diseases, Including NLRC4-GOF, XIAP Deficiency, or CDC42 Mutations (MASter-1)

• ClinicalTrials.gov Identifier: NCT04641442
• Recruitment Status: Recruiting
• First Posted: November 23, 2020
• Last Update Posted: April 12, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: November 20, 2020
• First Posted Date: November 23, 2020
• Last Update Posted Date: April 12, 2024
• Actual Study Start Date: December 18, 2020
• Estimated Primary Completion Date: June 27, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 29, 2023)

Cohort 1: Occurrence of disease flare in patients with MAS825 treated patients compared with placebo during Period 2 assessed by Physician's Global Assessment and inflammatory markers [ Time Frame: Period 2 ]

To determine the efficacy of MAS825 in prevention of flares in patients with monogenic IL-18 driven autoinflammatory diseases, including NLRC4-GOF, XIAP deficiency or CDC42 mutations

Original Primary Outcome Measures (submitted: November 20, 2020)

Occurrence of disease flare in patients with MAS825 treated patients compared with placebo during Period 2 assessed by Physician's Global Assessment and inflammatory markers [ Time Frame: Period 2 ]

To determine the efficacy of MAS825 in prevention of flares in NLRC4-GOF patients

Current Secondary Outcome Measures (submitted: June 29, 2023)

• All cohorts: Number and severity of safety assessments and adverse events [ Time Frame: Screening through EOS (End of Study) ]
  To evaluate the safety and tolerability of MAS825
• All cohorts: Confirmation of serological markers of MAS825 [ Time Frame: Day 1 through EOS ]
  Evaluate the serological markers of MAS825
• Cohort 1: PGA and inflammatory markers [ Time Frame: Day 29, end of Period 1, end of Period 2 ]
  Evaluate the efficacy of MAS825 to improve the clinical status of patients with NLRC4-GOF, XIAP deficiency or CDC42 mutations
• Cohort 1: Serological remission via inflammatory markers [ Time Frame: Day 29, end of Period 1, and end of Period 2 ]
  Evaluate efficacy of MAS825 to achieve serological remission
• Cohort 1: Glucocorticoid therapy <0.2mg/kg by end of period 1 [ Time Frame: End of Period 1 ]
  Evaluate the effect of MAS825 on concomitant glucocorticoid administration
• Cohort 1: Time to first flare [ Time Frame: Period 2 ]
  Evaluate effect of MAS825 on the time to first flare
• All cohorts: Physician Severity Assessment of Disease Signs and Symptoms scale [ Time Frame: Screening through EOS ]
  Evaluate the efficacy of MAS825 to improve signs and symptoms of the disease
• All cohorts: Patient / Parent global assessment of disease activity (PPGA) scale [ Time Frame: Screening through EOS ]
  Evaluate effect of MAS825 on patient reported outcomes over time

Original Secondary Outcome Measures (submitted: November 20, 2020)

• Number and severity of safety assessments and adverse events [ Time Frame: Screening through EOS (End of Study) ]
  To evaluate the safety and tolerability in patients with NLRC4-GOF
• Confirmation of serological markers of MAS825 [ Time Frame: Until End of Study ]
  Evaluate the serological markers of MAS825
• PGA and inflammatory markers at Day 29, end of Period 1 and 2 [ Time Frame: Day 29, end of Period 1, end of Period 2 ]
  Evaluate efficacy of MAS825 to improve clinical status of NLRC4-GOF patients
• Serological remission via inflammatory markers [ Time Frame: Day 29, end of Period 1, and end of Period 2 ]
  Evaluate efficacy of MAS825 to achieve serological remission
• Glucocorticoid therapy <0.2mg/kg by end of period 1 [ Time Frame: End of Period 1 ]
  Evaluate the effect of MAS825 on concomitant glucocorticoid administration
• Time to first flare during period 2 [ Time Frame: Period 2 ]
  Evaluate effect of MAS825 on the time to first flare in patients with NLRC4-GOF
• Physician Severity Assessment of Disease Signs and Symptoms scale [ Time Frame: Screening through EOS ]
  Evaluate the efficacy of MAS825 to improve signs and symptoms of NLRC4-GOF
• Patient' / Parent's global assessment of disease activity (PPGA) scale [ Time Frame: Screening through EOS ]
  Evaluate effect of MAS825 on patient reported outcomes in patients with NLRC4-GOF over time

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Evaluate the Efficacy, Safety and Tolerability of MAS825 in Patients With Monogenic IL-18 Driven Autoinflammatory Diseases, Including NLRC4-GOF, XIAP Deficiency, or CDC42 Mutations
• Official Title: A Three-period Multicenter Study, With a Randomized-withdrawal, Double-blind, Placebo-controlled Design to Evaluate the Clinical Efficacy, Safety and Tolerability of MAS825 in Patients With Monogenic IL-18 Driven Autoinflammatory Diseases, Including NLRC4-GOF, XIAP Deficiency, or CDC42 Mutations
• Brief Summary: This study is a Phase 2 trial designed to evaluate the clinical efficacy, safety, and tolerability of MAS825 in patients with NLRC4-GOF, XIAP deficiency, or CDC42 mutations.

Detailed Description

This is a three-period study, with an open-label, single-arm active treatment in Period 1 followed by a randomized-withdrawal, double-blinded, placebo-controlled design in Period 2, and an open label, long-term safety follow-up in Period 3. The total study duration is approximately 3 - 4 years.

Patients who enter Period 2 will be randomized to MAS825 or matching placebo in a 1:1 ratio.

Cohort 1 patients will complete all periods of the study, which will take approximately 4 years.

Cohort 2: Patients who are receiving MAS825 in a Novartis Managed Access Program with a diagnosis of NLRC4-GOF, XIAP deficiency, or CDC42 mutation who meet criteria will be eligible to directly enter into Period 3 for open-label long-term safety follow-up. Cohort 2 patients will be in the study for approximately 3 years.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This study includes:

• Screening
• Period 1: Open-Label Treatment Period to identify responders to MAS825
• Period 2: Randomized Withdrawal Period consists of a randomized treatment withdrawal period to primarily assess the efficacy of MAS825 compared to placebo.
• Period 3: Open-Label, Long-Term Safety follow-up
• End of Study

Patients will participate in all 3 periods of the study if they have never been treated with MAS825 before.

Patients who are enrolled from the Managed Access program will participate in Period 3 only after completing screening and baseline assessments.

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

Subject, investigator, and sponsor blinding via manual randomization during Period 2, Randomized Withdrawal Period

Primary Purpose: Treatment

• Condition: NLRC4-GOF, AIFEC (Autoinflammation With Infantile Enterocolitis), XIAP Deficiency, CDC42 Mutations

Intervention

• Biological: MAS825
  Experimental drug
• Biological: Placebo
  matching placebo

Study Arms

• Experimental: MAS825
  Experimental drug
  Intervention: Biological: MAS825
• Placebo Comparator: Placebo
  matching placebo
  Intervention: Biological: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 29, 2023): 18
• Original Estimated Enrollment (submitted: November 20, 2020): 10
• Estimated Study Completion Date: September 16, 2028
• Estimated Primary Completion Date: June 27, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

For all Patients:

1. Male and female patients weighing at least 3 kg

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/her legal/authorized representative (if allowed according to local requirements).

   Cohort 1 specific inclusion criteria:

3. Patients with a genetic diagnosis of either NLRC4-GOF, XIAP deficiency, or CDC42 mutation
4. Clinical history and investigations consistent with autoinflammation and infantile enterocolitis (AIFEC/NLRC4-GOF), XIAP or CDC42. XIAP patients must have persistent disease or be resistant to escalating therapy.

5. At first treatment, evidence of active disease as assessed by inflammatory markers and PGA

   Cohort 2 specific inclusion criteria:

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 (MAP).

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 active bacterial, fungal, parasitic or viral infections, excluding chronic Epstein-Barr Virus (EBV).

   - COVID-19 specific: If in line with health and governmental authority guidance, it is highly recommended that testing to exclude COVID-19 using PCR or comparable approved methodology be completed within 1 week prior to first dosing.

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 (or as listed in the prohibited medications section) prior to MAS825 treatment with the exceptions of glucocorticoids, cyclosporin and targeted binding or blocking therapies.
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 at Screening. 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. Pregnant or nursing (lactating) females.
10. Female patients of child-bearing potential (or Tanner stage 2 or above) who are or might become sexually active, agree to use highly effective contraceptive methods to prevent pregnancy while on MAS825 therapy
11. Patients weighing >160 kg at Screening.
12. For CDC42 mutation patients: Takenouchi-Kosaki syndrome - CDC42 mutations associated with a diverse syndrome characterized by variable development delays, cardiac, brain and hematological abnormalities.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

• Listed Location Countries: Canada, Czechia, France, Italy, Japan, Spain, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04641442
• Other Study ID Numbers: CMAS825D12201
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: April 2024