E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Muckle-Wells Syndrome (Autoinflammatory Disease) |
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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 | 10064569 |
E.1.2 | Term | Muckle-Wells syndrome |
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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 assess efficacy (% of patients who relapse) of ACZ885 compared with placebo in Part II as determined by the Physician’s global assessment of autoinflammatory disease activity, assessment of skin disease and inflammation markers (C-reactive protein (CRP) and/or serum amyloid A (SAA). |
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E.2.2 | Secondary objectives of the trial |
To assess the safety, tolerability and immunogenicity of ACZ885. To assess overall efficacy (response rate) of ACZ885 in Part I and Part III as determined by the Physician’s global assessment of autoinflammatory disease activity, assessment of skin disease and inflammation markers. To evaluate the Pharmacokinetics and Pharmacodynamics of ACZ885. To assess the effect of ACZ885 on disease progression with regards to deafness, kidney function, neurological and ophthalmological symptoms.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients aged 4 to 75 years at the time of the screening visit. 2. Patient's informed consent for less than 18 years of age 3. Patient or legal guardian's written informed consent and child's assent, if appropraite, are required prior to study participants under the age of 18 years. 4.Molecular diagnosis of NALP3 mutations and clinical picture resembling MWS. 5. MWS patients who participated in the CACAZ8852102 study, will have the option to participate in this study upon flare (see Study design Section 4). 6. For patients under anakinra therapy or any other investigational IL-1 blocking therapy, willingness to discontinue the treatment. 7. Female subjects must be either -Surgically sterilised or hysterectomized at least 6 months prior to screening. -Postmenopausal i.e. must have no regular menstrual bleeding for at least 1 yr prior to inclusion -Women of childbearing potential must be using an effective method of contraception. 8. Body weight greater than 15 kg and less than 100kg 9. Able to communicatewith the investigator and comply with requirements of the study |
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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, investigational IL-1 blocking theapy and the CACACZ885A2102 study. 2. Use of the following therapies: • Etanercept in the 4 weeks prior to the baseline visit (Day 1) • Adalimumab in the 8 weeks prior to the baseline visit (Day 1) • Infliximab in the 12 weeks prior to the baseline visit (Day 1) • Any other investigational biologics in the 8 weeks prior to the baseline visit (Day 1) (with the exception of anakinra therapy and IL-1 blocking therapies –see below) • Patients who are on IL-1 blocking biological therapies (including anakinra therapy) need to discontinue this treatment. As soon as the criteria for relapse are fulfilled, patients can enter the study and receive ACZ885 treatment. This run-in phase reduces the classical wash-out phase to a medically meaningful time and avoids unnecessary suffering for the patient in case a predefined wash-out period per protocol is too long for an individual subject. • Leflunomide in the 4 weeks prior to the baseline visit (Day 1) • Thalidomide in the 4 weeks prior to the baseline visit (Day 1) • Cyclosporine in the 4 weeks prior to the baseline visit (Day 1) • i.v. immunoglobulin (i.v. Ig) in the 8 weeks prior to the baseline visit (Day 1) • 6-Mercaptopurine, azathioprine, cyclophosphamide, or chlorambucil in the 12 weeks prior to the baseline visit (Day 1) • Colchicine, dapsone, mycophenolate mofetil in the 3 weeks prior to the baseline visit (Day 1) • Corticosteroids ≥20mg/day or >0.4 mg/kg, whichever applies, in the 1 week prior to the baseline visit (Day 1) 3. Donation of loss of 400 mL or more of blood within 8 weeks prior to dosing for adults (see appendix 9 for total volume for children) 4. Past medical history of clinically significant abnormalities or a familly history of a prolonged QT-interval syndrome 5. History of being immunocompromised, including HIV at screening 6. A positive Hepatitis B surface antigen 7. No live vaccinations within 3 mths prior to start of trial, during trial and up to 3 mths following last dose. 8. History of alcohol abuse within 12 mths prior to dosing 9. History of significant medical conditions, which in the investigators opinion would exclude the patient from participating 10. History of recurrent and/or evidence of active naterial, fungal or viral infections. 11. Positive tuberculin skin test reaction.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary variable is the proportion of patients with disease flare in the withdrawal period (Part II). Patients who prematurely discontinue study in the withdrawal phase due to any reason will be considered as having disease flare.
The primary objective of the study is to show superiority of ACZ885 compared to placebo regarding the primary variable in Part II. The two treatment groups will be compared using an exact test (based on hypergeometric probabilities) about the common odds ratio, adjusting for cohort. The null hypothesis to be tested is that the common odds ratio is equal to 1, i.e. the probability of having disease flare is the same for both groups versus the common odds ratio is not equal to 1, i.e. the probability of having disease flare is different for both groups. Exact two-sided p-value, the common odds ratio and exact 95% confidence interval for the common odds ratio will be computed. The primary analysis will be based on the ITT population of Part II. |
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity assessment |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Randomised withdrawal design. Double blind in Part II. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 13 |
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 |
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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
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LPLV at the end of part III. At the end of part III an extension study is planned to allow patients to continue treatment. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |