| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
|
| 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 demonstrate the efficacy of 80 mg adalimumab monthly dosing compared with placebo as measured by ACR20 response criteria following 12 weeks of therapy. The study is also designed to demonstrate the non-inferiority of monthly dosing of 80 mg adalimumab compared with dosing of 40 mg adalimumab eow as measured by ACR20 response criteria at Week 12. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| At a selected study site in Germany, a subset of seventy−five (75) subjects that have signed the appropriate Informed Consent Form will be enrolled for intensive pharmacokinetic sampling for MTX and non-MTX-subjects. A maximum of forty-five (45) MTX-subjects are to be enrolled for intensive pharmacokinetic sampling, the remaining thirty (30) will consist of non-MTX − subjects. Additional subjects may be required to ensure that seventy-five complete sets of samples are received. |
|
| E.3 | Principal inclusion criteria |
A subject will be eligible for study participation if he/she meets the following criteria:
1. Subject is > 18 years of age.
2. Subject has a diagnosis of RA as defined by the 1987-revised ACR-classification criteria and has disease duration for a minimum of three months.
3. Subject must meet the following two criteria:
a. At least 6 swollen joints out of 66 assessed.
b. At least 6 tender joints out of 68 assessed
4. If a subject is on a DMARD other than Leflunomide and MTX, the subject must
discontinue the DMARD for at least 28 days before the Baseline Visit/first dose of
investigational product (IP) (wash-out period). If a subject is on Leflunomide, the patient must have a wash out period of 3 months prior to Baseline, however the subject may be treated with cholestyramine to shorten this period. If a subject is on MTX, further criterion is explained below.
5. MTX treatment:
a. With MTX: The subject should be on a stable dose of MTX between 15 mg
and 25 mg and route of administration must be maintained (PO,
subcutaneous [SC] or intramuscular [IM]), for at least 6 weeks prior to
Baseline blood draw. Subjects should be treated with MTX per standard recommendations (i.e. according to the packaging insert). Subjects residing
in Germany must be on MTX in order to participate in this trial.
b. Without MTX or Previously on MTX: The subjects may be MTX naïve
from Baseline blood draw or may have been previously been treated with
MTX. If the subject was previously treated with MTX, the MTX dose must
have been withdrawn at least 28 days prior to Baseline blood draw.
6. Female subjects 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 are 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 drug
administration)
● A vasectomized partner
7. Female subjects of childbearing potential must have a negative serum pregnancy
test at the Screening visit and a negative urine pregnancy test at Baseline/first IP
dose.
8. Subject is judged to be in good general health as determined by the Principal
Investigator or designee based upon the results of medical history, laboratory
profile, physical examination, CXR, and 12-lead electrocardiogram (ECG)
performed at Screening.
9. Subjects will be evaluated for latent TB infection with a purified protein derivative
(PPD) test and CXR. For this protocol, evidence of latent TB infection is defined
as an induration (not erythema) of 5 mm or greater, 48-72 hrs after placement.
Subjects who demonstrate evidence of latent TB infection, irrespective of Bacille
Calmette − Guérin (BCG) vaccination status, and negative CXR findings for active
TB and/or suspicious CXR findings will be allowed to participate in the study
provided that one of the following conditions are satisfied;
● Prophylactic treatment is initiated before administration of study drug. In general it is recommended, but not mandated, to start 2 weeks before study drug administration, however the course of prophylaxis need not be completed prior to the onset of study drug.
Prophylactic treatment will be according to the United States CDC recommended
preventive therapy for TB or other local guidelines. Prophylactic treatment should be
captured on the concomitant medications page in the case report form (CRF) and in the source documents. In Germany, subjects with latent or active TB will not be enrolled.
● Subject has documented prophylactic treatment for TB and so need not repeat
this treatment.
● Active TB has been ruled out.
10. Subjects must be able and willing to provide written informed consent and comply
with the requirements of this study protocol.
11. Subjects must be able and willing to self-administer SC injections or have a
qualified person available to administer SC injections. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study.
1. Subject has previous exposure to any systemic anti-TNF therapy (eg, infliximab,
etanercept, certolizumab pegol or golimumab) including adalimumab.
2. Subject has been treated with intra-articular or parenteral administration of
corticosteroids in the preceding 4 weeks from Baseline visit/first IP dose. Inhaled
corticosteroids for stable medical conditions are allowed. Oral of ≤ 10 mg/day
prednisone equivalent are allowed, however should be stable 3 weeks prior to Baseline and there should be no plan to dose adjust the steroids throughout the study
3. Subject has undergone joint surgery within the preceding two months of Screening
Visit (at joints to be assessed within the study).
4. Subject has a history of acute inflammatory joint disease of different origin other
than RA (eg, seronegative spondyloarthropathy, psoriatic arthritis, Reiter's syndrome, systemic lupus erythematosus or any arthritide with onset prior to age
17 years).
5. Subject has a history of an allergic reaction or significant sensitivity to constituents
of study drugs (adalimumab, MTX, or matching placebo).
6. Subject has been treated with any investigational drug of a "chemical" nature
within one month prior to Baseline/1st IP dose.
7. Subject has been treated with any investigational biologic agents (e.g., Rituximab,
Tocilizumab, Abatacept, etc). Should these biologics become approved, they would be
excluded.
8. Subject has a poorly controlled medical condition, such as uncontrolled diabetes,
unstable heart disease, 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.
9. Subject has a history of clinically significant hematologic (e.g., severe anemia,
leukopenia, thrombocytopenia), renal, liver disease (e.g., fibrosis, cirrhosis, hepatitis), or active gastroenteric ulcer.
10. Subject has history of neurologic symptoms suggestive of central nervous system
(CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
11. 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.
12. Subject has a history of listeriosis, histoplasmosis, active 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/first IP dose.
13. Subject currently uses or plans to use anti-retroviral therapy at any time during the study.
14. Subject is known to have any acquired immune deficiency (ie, HIV infection) or
untreated congenital immunodeficiency. Abbott Study Designated Physician
approval required for specific congenital immunodeficiency cases.
15. Female subject who is pregnant or breast-feeding or considering becoming
pregnant during the study or for 150 days after the last dose of study medication.
16. 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.
17. Screening clinical laboratory analyses show any of the following abnormal laboratory
results:
● Aspartate transaminase (AST) or alanine transaminase (ALT) >2.0x the upper
limit of normal (ULN).
● Serum total bilirubin > 1.5 mg/dL, unless the subject has a known deficiency;
or
● Creatinine > 1.5 mg/dL
● Evidence of chronic Hepatitis B.
If the screening labs are not met, the subject may be re-screened (once) for lab
values within the 33-day screening period. The screening period may also be extended if labs cannot be obtained for administrative reasons (Holidays,
scheduling, etc).
18. Subject is considered by the Investigator, for any reason, to be an unsuitable
candidate for the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy analysis will be a comparison of the response rates according to the ACR20 criteria. The improvement in RA (fulfillment of ACR20 criteria) at Week 12 will be compared to the findings before 1st study drug administration (Baseline). |
|
| 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 | 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 |
| non-inferiority of monthly dosing of 80 mg adalimumab compared with dosing of 40 mg adalimumab eow |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Different dose of the same IMP |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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
|
| The end-of-study is defined as the date of the last subject's last scheduled visit or the actual date of follow-up contact, whichever is longer. |
|
| 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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