E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10050894 |
E.1.2 | Term | Anti-neutrophil cytoplasmic antibody positive vasculitis |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the relapse rate (defined by clinical and biochemical parameters) over 24 months in patients with acute AAV presenting at first diagnosis of relapse, after 12 months of treatment with abatacept in combination with steroids and methotrexate or placebo in combination with steroids and methotrexate. |
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E.2.2 | Secondary objectives of the trial |
To assess the clinical efficacy of abatacept combined with MTX + steroids vs placebo and MTX + steroids by measuring: 1. The sustained remission rate 2. Time to remission 3. The average steroid dosage at 6, 12, 18 and 24 months in abatacept and placebo groups respectively 4. Time to ANCA negativity by immunofluorescence or negative anti-PR3 or anti-MPO Ab test by ELISA. 5. Proportion of patients defaulting to cyclophosphamide therapy. 6. Proportion of patients unable to stick with trial protocol. 7. Degree of chronic disease activity 8. Health related quality of life
To assess the safety and tolerability of abatacept in this study population, evaluated by number of adverse events
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with Acute AAV, presenting at first diagnosis or relapse (not grumblers, to maximize effect seen), defined by clinical presentation, ANCA positivity (anti-MPO or anti-PR3 positive) and a BVAS score of > 8.
2. Males and females (not nursing and not pregnant) at least 18 years of age. Women of child bearing potential are eligible if they are practicing effective contraceptive measures
3. Written informed consent given
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E.4 | Principal exclusion criteria |
1. Subjects with severe life-threatening disease, i.e. lung haemorrhage at the time of presentation, renal impairment with SCr>150 mcmol/l, or severe CNS dysfunction thought to be due to vasculitis
2. Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease, or other medical conditions that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study.
3. Subjects with any other non-vasculitic multisystem autoimmune disease.
4. Subjects with any serious acute bacterial infection unless treated and completely resolved with antibiotics prior to enrollment
5. Subjects with any severe chronic or recurrent bacterial infection, e g. bronchiectasis, osteomyelitis, chronic pyelonephritis
6. Subjects with Hepatitis B or C or HIV.
7. Subjects with Herpes zoster infection that resolved less than 2 months prior to enrollment.
8. Subjects who have received any live vaccines within 3 months of the first dose of study medication or who will have need of a live vaccine at any time in the year following enrollment
9. Subjects with current clinical or laboratory evidence of active or latent tuberculosis (TB) and subjects with a history of active TB treated within the last 3 years should be excluded. Subjects who received treatment for active TB greater than 3 years ago may be eligible for inclusion in this study if there is documentation of the prior anti-TB treatment confirming that it was appropriate in duration and type.
10. Subjects with any previous malignancy, with the exception of non-melanoma skin malignancies, adequately treated previously
11. Subjects with a mammogram that is suspicious for malignancy and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations. Mammograms (females only) must be performed within 6 months of study entry or if documentation is not on file
12. Pregnancy or breast feeding. Adequate contraception is necessary; 13. Subjects with MTX treatment in prior 3 months
14. Subjects with allergies to study medications.
15. Prior therapy with rituximab within the last 6 months (CD19 count must be normal before enrollment regardless of time of last dose). ; anti-TNF therapy, or IL-1 receptor antagonists within the last 3 months.
16. Subjects participating concurrently in another clinical trial.
17. Subjects with a history of intolerance to methotrexate.
18. Subjects who have at any time received treatment with abatacept.
19. Subjects who have received treatment with any investigational drug within 28 days (or less than 5 terminal half-lives of elimination) of the Day 1 dose.
20. Subjects with any of the following laboratory values: - Hgb < 8.5 g/dL. -WBC < 3,000/mm3 (3 x 109/L) -Platelets < 100,000/mm3 (100 x 109/L). -Serum ALT or AST > 2 times upper limit of normal. -Any other laboratory test results that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study.
21. Subjects using approved or investigational biologics
22. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Response to treatment measured by: Relapse rates in patients who have achieved remission over 24 month study period. Proportion of patients in sustained remission at 6, 12, 18 and 24 months; time to remission; The average steroid dosage at 6, 12,18 and 24 months; Time to ANCA negativity by immunofluorescence or negative anti-PR3 or anti-MPO Ab test by ELISA; Urinary MCP-1 measurement to assess disease activity in those with kidney disease.
In both groups, disease will be monitored using the well established and validated BVAS 2003, in conjunction with biochemical, immunological, radiological and other physiological parameters, which we regularly use to assess disease activity. The definitions of remission (BVAS<1), persistent disease (BVAS>4) and acute disease have been previously established and published |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
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) | 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 | 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 | No |
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
| 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 | Yes |
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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Last visit of last patient enrolled in trial. |
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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 | 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 | 3 |