E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
The primary objective of this study is to identify the best dose and schedule of administration of TNF-K in terms of anti-TNFα antibody response induced by two or three injections of TNF-K (Day 0, 28 or Day 0, 7, 28) at three dose levels (90, 180 or 360 mcg). |
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E.2.2 | Secondary objectives of the trial |
• To characterize the immune response after two or three injections at each dose level until the anti-TNF antibody response declines to ≤ cut off level and at least until Month12.
• To evaluate the clinical response to immunization with TNF-K.
• To assess the safety after two or three injections at each dose level.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients will be eligible for entry into the study if they meet the following criteria:
1. Diagnosis of RA according to the revised 1987 criteria of the American College of Rheumatology (ACR) (Arnett 1988) since at least six months prior to first study product administration.
2. Patients who the Investigator believes are able and willing to comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits).
3. A male or female between 18 and 70 years of age at the time of the first immunization.
4. Active RA disease as evidenced by a Disease Activity Score 28 (DAS 28) ≥ 3.2.
5. History of treatment with TNFα antagonist (infliximab, adalimumab, etanercept, certolizumab, golimumab).
6. A wash-out period before the first administration of the study product of:
• at least ten weeks since the last administration of certolizumab or golimumab
• at least eight weeks since the last administration of infliximab
• at least four weeks since the last administration of adalimumab or etanercept
7. History of positive response defined as an ACR20 or a DAS 28 decrease ≥ 1.2 or by the investigator opinion with previous TNFα antagonist treatment.
8. Secondary treatment failure to maximum one previous TNFα antagonist treatment as defined by:
• Investigator opinion.
OR
• DAS28 increase ≥ 0.6 during the last six months.
OR
• Decrease in European League Against Rheumatoid (EULAR) score.
9. If the patient is female, she must be of non-childbearing potential, i.e., either surgically sterilized or one year post-menopausal; or, if of childbearing potential, she must have used adequate contraceptive precautions (e.g., intrauterine contraceptive device, oral contraceptives, diaphragm or condom in combination with contraceptive jelly, cream or foam) for 30 days prior to immunization, have a negative pregnancy test (serum) and must agree to continue such precautions during the whole study period .
10. Written informed consent obtained from the patient.
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E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from participation in the study:
1. Treatment with non-biological DMARDs within four weeks prior to first study product administration. MTX is allowed provided it is administered at a stable dosage ≤ 20mg/week since at least 4 weeks.
2. Treatment with any rheumatoid arthritis biological therapy other than TNFα antagonists at any time prior to first study product administration.
3. Administration of high doses of intra-articular corticosteroids for the treatment of an acute mono-arthritis (e.g. knee) within 3 months prior to first study product administration. High dose of corticosteroids is defined as >50 mg triamcinolone or equivalent)
4. History of documented severe bacterial infection within 28 days prior to first immunization.
5. History of primary resistance or intolerance to any TNFα antagonist.
6. History of or current congestive heart failure, controlled or not.
7. Corticosteroids (prednisone, or equivalent, ≤10 mg per day) are allowed if they are administered at stable dosage since at least 4 weeks prior to the first immunization. Inhaled and topical steroids are allowed.
8. Known history of tuberculosis (TB).
9. Suspicion of TB at chest X-rays at screening or within three months prior to first administration of study product.
10. Suspicion of latent or active tuberculosis as defined by:
• Positive Mantoux/Purified Protein Derivative (PPD) test (≥5mm induration measured 48 to 72 hours after intradermal injection of tuberculin) at screening or within one year prior to first administration of study product.
• and/or positive interferon-γ (IFN γ) TB diagnostic test (as measured by the ELISpot method) at screening or within 30 days prior to first administration of study product.
11. Positive for Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) including Hepatitis B surface Antigen (HBsAg) and anti-Hepatitis B core (anti-HBc) antibodies.
12. Use of any investigational or non-registered product (drug or vaccine) other than the study product(s) within 30 days preceding the first dose of study product(s), or planned use during the study period.
13. Administration of any live vaccine within three months prior to first administration of study product (e.g. oral poliomyelitis vaccine, measles-mumps-rubella vaccine, yellow fever vaccine, rotavirus vaccine, varicella vaccine, zoster vaccine, Bacillus Calmette-Guérin (BCG) vaccine, oral typhoid vaccine).
14. Any confirmed or suspected immunosuppressive or immunodeficient condition.
15. Pregnancy, lactation or planned pregnancy during the study.
16. History of malignancy, except surgically treated cutaneous basal cell carcinoma
17. History of allergic disease or reactions likely to be exacerbated by any component of the study product, including seafood allergy
18. Current serious neurologic or mental disorders.
19. Acute disease at the time of enrolment (acute disease is defined as the presence of a moderate or severe illness with or without fever). The study product can be administered to persons with a minor illness such as diarrhea, mild upper respiratory infection with or without low-grade febrile illness, i.e. Oral or Axillary temperature <37.5°C.
20. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality as determined by physical examination or laboratory tests, at the discretion of the Investigator.
21. Abnormal laboratory values, in particular:
• Hemoglobin < 10g/dl
• White blood cells (WBC) count < 3.0x109/L.
• Platelet count < 100x109/L.
• Serum creatinine level >145µmoles/L.
• Serum Alanine amino transferase (ALT) or Aspartate amino transferase (AST) >2.5ULN.
• Alkaline phosphatases >2.5ULN.
• OR any other abnormality that is clinically relevant according to the Investigator’s opinion.
22. History of chronic alcohol consumption and/or drug abuse
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be the proportion of patients with at least a 3-fold increase in antibody response to TNFα vs cut off at Day 38 (immune response). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis at month 3 |
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E.5.2 | Secondary end point(s) |
Interim analysis at Month 3
Clinical efficacy
• Proportion of patients with a 1.2 decrease in DAS28 at Month 3 vs baseline (Day 0).
• Absolute change in DAS28 at Month 3 vs baseline (Day 0).
• Absolute change in Swollen Joint Counts (SJC) and in Tender Joint Counts (TJC) at Month 3 vs baseline (Day 0).
• Proportion of patients achieving ACR20, ACR 50 and ACR 70 at Month 3 vs baseline (Day 0).
• Proportion of patients with a good/moderate EULAR response at Month 3 vs baseline (Day 0).
• Absolute change in CRP level at Month 3 vs baseline (Day 0).
• Absolute change in ESR at Month 3 vs screening.
• Proportion of patients with or without ADAs at screening with a >= 1.2 decrease in DAS28 at Month 3 vs baseline (Day 0).
Immune response
• Proportion of patients with at least a 3-fold increase in antibody response to TNF vs cut-off at Month 2 (Day 56) and at Month 3 (Day 84).
• Proportion of patients with a positive neutralizing antibody response.
Safety analysis
• Occurrence, intensity and relationship to TNF-K immunization of any solicited local and general signs and symptoms during a seven-day follow up period (i.e. day of immunization and 6 subsequent days) after each TNF-K injection.
• Occurrence, intensity and relationship to TNF-K immunization of unsolicited local and general signs and symptoms occurring until Month 3.
• Occurrence and relationship to TNF-K immunization of all SAE occurring until Month 3.
• Change from screening in hematological and biochemical levels in all groups at Month 3.
• Hematological and biochemical levels within or outside the normal ranges in all groups.
Final analysis at Month 12
Clinical efficacy
• Proportion of patients with a >=1.2 decrease in DAS28 vs baseline (Day 0).
• Absolute change in DAS28 vs baseline (Day 0).
• Absolute change in Swollen Joint Counts (SJC) and in Tender Joint Counts (TJC) vs baseline (Day 0).
• Proportion of patients with ACR20, ACR 50 and ACR 70 vs baseline (Day 0).
• Proportion of patients with a good/moderate EULAR response vs baseline (Day 0).
• Absolute change in CRP level vs baseline (Day 0).
• Absolute change in ESR vs screening.
• Proportion of patients with a >=1.2 decrease in DAS28 score vs DAS28 score decrease observed under previous treatment with a TNFα antagonist.
• Proportion of patients with the same maximum clinical improvement in terms of DAS28 observed during previous treatment with a TNFα antagonist.
• Absolute change in DAS28 vs DAS28 absolute change observed under previous treatment with a TNFα antagonist.
• Absolute change in SJC and in TJC vs SJC and TJC absolute change observed under previous treatment with a TNFα antagonist.
• Proportion of patients with ACR 20, ACR 50 and ACR 70 vs status observed under previous treatment with a TNFα antagonist.
• Proportion of patients with a good/moderate EULAR response vs status observed under previous treatment with a TNFα antagonist.
• Proportion of patients withdrawn for lack of efficacy.
Immune responses
The timings of blood samplings and analyses are specified in Table 2 and Table 5.
• Anti-TNFα antibody concentrations.
• Proportion of good responders defined as patients with dilution of anti- TNFα antibodies titers >=2000
• Proportion of patients with a positive anti-TNFα
• Anti-TNFα neutralizing antibody levels.
• Anti-KLH antibody concentrations.
• Absolute changes in levels of cytokines (TNFα, TNF- RII, IL-6, IL-17, IL-23 and others) vs baseline (Day 0).
• Proportion of patients with a positive T cell response as measured by lymphoproliferation.
Safety analysis
• Occurrence, intensity and relationship to TNF-K immunization of unsolicited local and general signs and symptoms occurring throughout the study period.
• Occurrence and relationship to TNF-K immunization of all SAE occurring throughout the study period.
• Change from screening in hematological and biochemical levels in all groups.
• Hematological and biochemical levels within or outside the normal ranges in all groups. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Interim Analysis at Month3
Final Analysis et Month 12 |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 | No |
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 |
Argentina |
Belgium |
Bulgaria |
Chile |
Croatia |
France |
Romania |
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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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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |