| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Muckle-Wells Syndrome: rare hereditary, autosomal dominant, systemic inflammatory disease, characterized by recurrent episodes of fever, arthralgia, myalgia, urticarial rash, and conjunctivitis. Laboratory findings show an elevation of acute phase proteins such as CRP and SAA, a high ESR, together with leukocytosis, and hypergammaglobulinemia. Severe long term complications include progressive sensorineural deafness, and systemic AA amyloidosis. | |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10064573 | | E.1.2 | Term | Neonatal-onset multisystemic inflammatory disease | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10064570 | | E.1.2 | Term | Familial cold autoinflammatory syndrome | |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To determine the efficacy of ACZ885 administered as intravenous infusion (original protocol) and subcutaneous injection (current amendment) to improve the clinical status of patients with NALP3 (CIAS1, PYPAF1) mutations. | |
| E.2.2 | Secondary objectives of the trial | • To assess the safety, tolerability and immunogenicity of ACZ885 administered as intravenous infusion and subcutaneous injection in patients with NALP3 (CIAS1, PYPAF1) mutations.
• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ACZ885 administered as intravenous infusion and subcutaneous injection in patients with NALP3 (CIAS1, PYPAF1) mutations.
• To assess PK/PD relationships in order to derive a dose and dosing regimen for phase III.
• To conduct exploratory genomic studies to identify gene expression patterns of blood that are associated with treatment response to ACZ885, or that possibly correlate with the severity or progression of autoinflammatory diseases.
• To assess the efficacy of ACZ885 to modify disease progression with regards to deafness, kidney function, neurological and ophthalmological symptoms.
• To assess the efficacy of ACZ885 to modify health-related quality of life. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Male and female patients aged 4 to 75 years (inclusive) at the time of the screening visit, having passed screening examinations. (only adults patients ≥18 years for French center)
2. Female subjects of child-bearing potential may participate if they have a negative pregnancy test at screening and prior to dosing, and are willing to use, if adequate for age, an effective method of contraception (e.g. birth control pills, abstinence, double-barrier contraception, etc.) during the study (from the date of screening) and for at least 3 months following the last dose.
3. Molecular diagnosis of NALP3 mutations and clinical picture resembling MWS/ FCAS/ NOMID requiring medical intervention being either untreated or insufficiently treated.
4. Molecular diagnosis of NALP3 mutations and documented history of a clinical picture resembling MWS/FCAS/NOMID. Patients under anakinra therapy or any other IL-1 blocking therapy being in complete remission and willing to discontinue anakinra/IL-1 blocking therapy until a clinical picture of the disease (relapse) becomes evident.
5. Patients with a very severe phenotype requiring stable doses of oral prednisone (≤ 0.4 mg/kg/day or ≤ 20 mg/day, whichever is lower) for at least one week prior to the screening visit. Steroid therapy may be tapered during treatment with ACZ885 at the discretion of the investigator.
6. Body weight < 100 kg.
7. Able to communicate well with the investigator and comply with the requirements of the study.
8. Smokers may participate in the study.
9. Negative tuberculin skin test reaction (PPD 5 tuberculin units or as according to local standard practice) (< 5 mm induration) at 48 to 72 hours after administration at the screening visit or within 2 months prior to the screening visit, according to national guidelines. Patients who have a positive PPD skin test with a documentation of BCG vaccination, who are at low environmental risk for tuberculosis (TB) infection or reactivation, and have a negative chest X-ray can be included. A positive PPD sample will be defined using the MMWR 2000 guidance, summarized as criteria for tuberculin positivity by risk group. | |
| E.4 | Principal exclusion criteria | 1. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation with the exception of trials with anakinra.
2. Antiinflammatory therapy with colchicine, chlorambucil, dapsone, azathioprine, mycophenolate mofetil, within 3 weeks prior to dosing. In case patients have been treated with therapeutic antibodies (e.g. anti-TNF-alpha antibodies), discontinuation of this therapy is required at least 60 days before dosing.
3. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.
4. A past medical history of clinically significant ECG abnormalities or a family history of a prolonged QT-interval syndrome.
5. History of immunocompromise, including a positive HIV (ELISA and Western blot) test result.
6. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
7. History of drug or alcohol abuse within the 12 months prior to dosing.
8. Active medical condition such as infection, poorly controlled diabetes etc.
9. History of tuberculosis.
10. No live vaccination within 3 months prior to the start of the trial, during the trial and up to 3 months following the last dose. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | LPLV
End of study will be defined once relapse occurs after the last dose and all patients with Muckle-Wells syndrome will be transitioned to the Phase III protocol or have discontinued the study. Patients with a diagnosis of NOMID or FCAS syndrome may stay in this study until an extension phase. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
