| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The following cryopyrin-associated periodic syndromes:
Familial Cold Autoinflammatory Syndrome,
Muckle-Wells Syndrome,
or Neonatal Onset Multisystem Inflammatory Disease |
|
| 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 |
|
| 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 |
| Long-term safety and tolerability of ACZ885 in patients who participated in the A2102, D2201 or D2304 studies or in newly identified patients with the following cryopyrin-associated periodic syndromes (CAPS): Familial Cold Autoinflammatory Syndrome FCAS), Muckle-Wells Syndrome (MWS) or Neonatal Onset Multisystem Inflammatory Disease (NOMID). |
|
| E.2.2 | Secondary objectives of the trial |
1. Maintenance of response over time defined by the number of patients who do not relapse as determined by the Physician’s global assessment of autoinflammatory disease activity, assessment of skin disease and inflammation markers.
2. to Assess number of patients who require a dose adjustment or an administration frequency adjustment, with subsequent maintenance of response over time as determined by the Physician’s global assessment of autoinflammatory disease activity, assessment of skin disease and CRP and/or SAA.
3. Immunogenicity of ACZ885. PK of ACZ885, in particular, comparison of the new HSA- (human serum albumin) drug formulation with previously used HSA+ formulation.
4. Long-term effects of ACZ885 on disease progression with regards to deafness, kidney function, neurological and ophthalmological symptoms.
5. Long term maintenance of Health-Related Quality of Life
(HRQoL) of ACZ885 by using the HAQ©, SF-36®, FACIT-Fatigue©, and CHQ-PF28©. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients at least 4 years of age at the time of the screening visit.
2. Patient’s informed consent for ≥ 18 years of age before any assessment is
performed.
3. Parent or legal guardian’s written informed consent and child’s assent, if
appropriate, are required before any assessment is performed for patients
<18 years of age.
4. Patients with a diagnosis of FCAS, MWS, or
NOMID.
At study entry, new ACZ885 NAIVE patients should have symptoms requiring pharmacological intervention.
At the time of screening, patients can be either untreated or treated (i.e. under
ACZ885, anakinra, or any other investigational IL-1 blocking therapy). Prior
agreement between the Investigator and Novartis for study eligibility is required
for patients who do not have a molecular diagnosis of NALP3 mutations available
(EITHER TESTING NOT PERFORMED, OR TESTING PERFORMED BUT NEGATIVE) upon study entry. FOR THOSE PATIENTS WHO HAVE NOT BEEN MOLECULLARLY TESTED FOR NALP3 MUTATIONS, MOLECULAR TESTING SHOULD BE PERFORMED DURING THE COURSE OF THE STUDY.)
5. For patients under anakinra therapy or any other investigational IL-1 blocking
therapy, these treatments should be discontinued prior to the baseline visit (see
Section 6.5.8 for specific time points for discontinuing treatments prior to the
baseline visit).
6. Patients from the A2102 study may enter this study upon signing informed
consent irrespective of whether they are in remission or flaring. However, dosing
at Visit 2 (Baseline Visit) can only occur if either 1) the patient is experiencing
disease flare or 2) at least two months have elapsed from their last injection even
in the absence of flare, whichever is earlier.
7. Patients who completed the D2304 study may enter this study upon signing
informed consent. A patient is defined as completing the study if he/she
completed the D2304 study up to and including Visit 15 (End of Study Visit).
8. PATIENTS WHO COMPLETED THE DD201 STUDY MAY ENTER THIS STUDY UPON SIGNING INFORMED CONSENT. A PATIENT IS DEFINED AS COMPLETING THE STUDY IF HE/SHE COMPLETED THE D2201 STUDY UP TO AN INCLUDING THE END OF STUDY VISIT.
9. Patients who discontinued from the A2102, D2201 or D2304 studies and for whom in the
Investigator’s judgment (with prior agreement from Novartis) treatment with
ACZ885 in this study is considered appropriate.
10. Body weight ≥ 15 kg.
11. Able to communicate with the investigator and comply with the requirements of
the study (for children the parent can assist when necessary). |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or nursing (lactating) women.
2. Women of child-bearing potential unless they meet the following definition of postmenopausal state: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or are using one or more of the acceptable methods of contraception detailed in the protocol are used.
3. 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, other
investigational IL-1 blocking therapies, and/or ACZ885.
4. History of being immunocompromised, including a positive HIV at screening
(ELISA and Western blot) test result.
5. A positive HBsAg or Hepatitis C antibody test result.
6. Live vaccinations within 3 months prior to the start of the trial, during the trial, and
up to 3 months following the last dose.
7. History of drug or alcohol abuse within the 12 months prior to dosing.
8. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing for
adults (For children the cut-off amount of donation or loss of blood should be
based on the Investigator's judgment & according to the local regulations. Please
also refer to Appendix 4 for the recommended sample volume per blood draw for
children).
9. History of significant medical conditions, which in the Investigator’s opinion would
exclude the patient from participating in this trial (this can be discussed with
Novartis on a case by case basis in case of uncertainty).
10. History of recurrent and/or evidence of active bacterial, fungal, or viral infections.
11. Positive 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 test has been defined using the [MMWR 2000
guidance], summarized as criteria for tuberculin positivity by risk group:
• equal or greater than 15 mm of induration for persons with no risk factors for
TB
• equal or greater than 10 mm of induration for persons with an increased
probability of recent infection or with other clinical conditions that increased
the risk for TB
• equal or greater than 5 mm of induration for very high risk population (HIV),
contact TB cases, immunosuppression (organ transplantation, steroids
> 15 mg/day of prednisone for 1 month or more).
12.Precaution against tuberculosis should be handled according to the best medical
practice consistent to the local standards in each country with prior consultation
with Novartis. Patients requiring administration of antibiotics against latent
tuberculosis should complete their treatment and should be considered cured
prior to being re-considered for entry into this study.
13. Use of:
• Etanercept in the 4 weeks prior to the baseline visit (Day 1) and thereafter
• Adalimumab in the 8 weeks prior to the baseline visit (Day 1) and thereafter
• Infliximab in the 12 weeks prior to the baseline visit (Day 1) and thereafter
• Rituximab in the 26 weeks prior to the baseline visit (Day 1) and thereafter
• Any other investigational biologics in the 8 weeks prior to the baseline visit
(Day 1) and thereafter (with the exception of anakinra therapy –see below)
• Kineret (anakinra therapy) 1 day prior to the baseline visit (Day 1) and
thereafter
• Leflunomide in the 4 weeks prior to the baseline visit (Day 1) and thereafter.
After the completion of leflunomide treatment a cholestiramine in dose 8 g 3
times per day for 14 days is recommended.
• Thalidomide in the 4 weeks prior to the baseline visit (Day 1) and thereafter
• Cyclosporine in the 4 weeks prior to the baseline visit (Day 1) and thereafter
• i.v. immunoglobulin (i.v. Ig) in the 8 weeks prior to the baseline visit (Day 1)
and thereafter
• 6-Mercaptopurine, azathioprine, cyclophosphamide, or chlorambucil in the
12 weeks prior to the baseline visit (Day 1) and thereafter
• Dapsone, mycophenolate mofetil in the 3 weeks prior to the baseline visit
(Day 1) and thereafter
≥20mg/day or >0.4 mg/kg, whichever applies, in the 1 week
prior to the baseline visit (Day 1) and thereafter
• Use of other investigational non-biological drugs at the time of enrollment,
within 30 days or 5 half-lives of enrollment, whichever is longer.
14. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Assess Long term safety and tolerability |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | 12 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 |
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