E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adalimumab has the indication for life-long treatment of RA but can adalimumab be discontinued in patients who are in stable clinical remission (DAS28<2.6) with retained low disease activity or will the RA symptoms relapse? If relapse occurs, how is the response if adalimumab is reinstituted? |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
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 |
To determine the proportion patients with RA in stabel clinical remission (DAS28<2.6) after treatment with adalimumab in combination with methotrexate in whom it is possible to discontinue adalimumab treatment without an increase in disease activity. |
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E.2.2 | Secondary objectives of the trial |
To study the frequency of flare after adalimumab discontinuation and to study the effect of reinstitution of adalimumab after flare.
To study the safety of adalimumab in reinstitution of therapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Subject is of age ³ 18 years.
2) Subject has a diagnosis of RA as defined by the 1987-revised ACR-classification
and has a documented positive RF test or erosion on radiograph of hands or feet.
3) Subject is currently treated with adalimumab and MTX (at least 10 mg/week;
orally or subcutaneously) and has received both for at least 6 months (MTX dose
stable for at least 2 months).
4) Subject is in remission as defined by DAS28<2.6 for at least the 3 past months,
based on assessments at baseline and on at least one more occasion 3-6 months
prior to baseline, documented in patient record or registry.
5) Concomitant DMARD (MTX excluded) or oral corticosteroid therapy has been stable
for at least 3 months at study entry.
6) Female subject is either not of childbearing potential, defined as postmenopausal
(at least 1 year since last menses) or surgically sterile (bilateral tubal ligation,
bilateral oophorectomy or hysterectomy), or is of childbearing potential and
practicing one of the following methods of birth control throughout the study and
for 150 days after study completion:
● Condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD)
● Contraceptives (oral, parenteral, patch) for three months prior to study entry
● A vasectomized partner.
7) Subject is judged to be in good general health as determined by the Principal
Investigator based upon the results of medical history, laboratory profile and
physical examination.
8) Subjects must be able and willing to provide written informed consent and comply
with the requirements of this study protocol.
9) Subjects must be able and willing to self-administer SC injections or have a
qualified person available to administer SC injections.
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E.4 | Principal exclusion criteria |
1) Subject has been treated with intra-articular or parenteral administration of
corticosteroids in the preceding 4 weeks. Inhaled corticosteroids for stable
medical conditions are allowed.
2) Oral prednisone or prednisone equivalent > 10 mg/day at baseline.
3) Subject has undergone joint surgery within the preceding two months (at joints
to be assessed within the study).
4) Subject has a history of acute inflammatory joint disease of different origin other
than RA (e.g., mixed connective tissue disease, seronegative spondyloarthritis,
psoriatic arthritis, Reiter's syndrome, fibromyalgia, systemic lupus erythematosus
or any arthritis with onset prior to age 17 years).
5) Subject has been treated with any investigational drug within 30 days or 5 half
lives – whichever is longer prior to study entry (baseline visit).
6) Subject has a poorly controlled medical condition, such as uncontrolled diabetes,
unstable ischemic heart disease, moderate to severe congestive heart failure,
recent cerebrovascular accidents and any other condition which, in the opinion of
the Investigator, would put the subject at risk by participation in the study.
7) Subject has a history of clinically significant hematologic (e.g., severe anemia,
leukopenia, thrombocytopenia), renal or liver disease (e.g., fibrosis, cirrhosis,
hepatitis).
8) Subject has history of neurologic symptoms suggestive of central nervous system
(CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
9) Subject has history of cancer or lymphoproliferative disease other than a
successfully treated non-metastatic cutaneous squamous cell or basal cell
carcinoma and/or localized carcinoma in situ of the cervix.
10) Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent
chronic infections, or recent active infections requiring hospitalization or treatment
with intravenous (IV) anti-infectives within 30 days or oral anti-infectives within 14
days prior to the Baseline visit.
11) Subject is known to have immune deficiency, history of HIV or is
immunocompromised.
12) Female subject who is pregnant or breast-feeding or considering becoming
pregnant or breast feeding during the study or for 150 days after the last dose of
study medication.
13) Subject has a history of clinically significant drug or alcohol usage in the last year
or cannot maintain an alcohol intake of 30 g a day or less throughout the study.
One standard drink is defined as 180 mL/6 oz (approx. 10 g) of wine, 360 mL/12
oz (approx. 15 g) of regular beer, or 45 mL/1.5 oz (approx. 10 g) of spirits.
14) Baseline clinical laboratory analyses show any of the following abnormal
laboratory results:
● Aspartate transaminase (AST) or alanine transaminase (ALT) >1.5x the upper
limit of normal (ULN).
● Serum total bilirubin ³ 1.5 mg/dL (³26 micromol/L).
● Creatinine > 1.5 mg/dL (133 micromol/L) in subjects < 65 years old and > upper
limit of normal range in subjects ³ 65.
● Evidence of chronic Hepatitis B or C serology indicative of previous or current
infection.
15) Subject is considered by the Investigator, for any reason, to be an unsuitable
candidate for the study.
16) Subjects with any prior exposure to Tysabri (natalizumab).
17) Subjects with known hypersensitivity to the excipients of adalimumab as stated
in the label.
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of RA patients in clinical remission whom is possible to discontinue adalimumab without an increase in disease activity at 28 weeks.
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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 | No |
E.6.5 | Efficacy | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
discontinuation of treatment |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Randomized phase followed by observational period (follow-up visit 104-156 weeks after inclusion). |
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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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Continuation of Adalimumab treatment |
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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 | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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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 | 3 |
E.8.9.1 | In the Member State concerned days | |