A Multicenter, Randomized, Double-Blind, Study Comparing the Efficacy and Safety of Continuing Versus Withdrawing Adalimumab Therapy in Maintaining Remission in Subjects with Non Radiographic Axial Spondyloarthritis

There is a medical need for treatment in nr-axSpA patients who fail
nonsteroidal anti-inflammatory drug (NSAIDs). Clinical trial data indicate that
AS and nr-axSpA patients have comparable burden of disease that requires
treatment irrespective
of radiographic progression. NSAIDs are considered first line therapy for all
axial SpA patients. Traditional disease modifying anti-rheumatic drugs (DMARDs)
such as methotrexate (MTX) and sulfasalazine (SSZ) have not been shown to be
effective for axial SpA.
For AS and nr-axSpA patients who continue to have active disease despite
NSAIDs, adalimumab is an approved therapy.

The objective of this study is to evaluate the efficacy and safety of
continuing versus withdrawing therapy with adalimumab 40 mg given every other
week (eow) SC in maintaining remission in subjects with nr-axSpA.

This clinical trial was designed to evaluate the efficacy and safety of
adalimumab 40 mg every other week (eow) versus placebo in maintaining remission
in patients with nr-axSpA.
Based on past clinical trials of adalimumab in AS and in nr-axSpA patients, 28
weeks of adalimumab treatment in Period 1 is expected to be sufficient to
identify most subjects who will respond and achieve remission (ASDAS Inactive
Disease) with this therapy.

In Period 2, patients who achieve remission after period 1, are randomized to
receive either blinded adalimumab or placebo.
The primary endpoint will be the proportion of subjects who do not experience a
flare by Week 68.
The proposed 40-week duration of the double blind period is based on results of
2 prior trials that demonstrated the occurrence of disease flare in patients
taken off adalimumab and other anti TNF therapy.

The study duration will include a 30-day Screening Period, a 28-week open-label
(OL) 40 mg adalimumab eow treatment period (Period 1), a 40 week double-blind
placebo controlled eow treatment period (Period 2). There is an opportunity to
receive at least 12 weeks of rescue therapy depending on the remission or
flare status.
A 70-day follow-up phone call will be performed.
Length of exposure will be maximal 80 weeks of treatment.

Open-Label * Period 1
Starting on Day 1 through Week 26, subjects will be administered open label
adalimumab 40 mg every other week (eow).
Drug will be subcutaneously self-administered or administered by a qualified
designee every other week at approximately the same time of day.
Subjects will be discontinued from the study if they do not meet the ASDAS
remission criteria on week 20, 24 and 28.
Subjects meeting the criteria will be randomized 1:1 to receive either blinded
adalimumab 40 mg eow or matching placebo.

Double-Blind * Period 2
Starting at Week 28, subjects who are eligible for randomization into Period 2
will receive the first dose of blinded study drug (adalimumab 40 mg eow or
placebo).

Rescue Therapy During Period 2
Starting at Week 36, subjects who meet the flare criteria (flare is defined as
2 consecutive study visits with ASDAS * 2.1) will be given rescue therapy with
open-label adalimumab 40 mg eow for at least 12 weeks and will continue through
the duration of the subject's participation of the study. For subjects who meet
the flare criteria at Weeks 60, 64 or 68, rescue therapy with open label
adalimumab 40 mg eow will be provided for 12 weeks and final study visit will
be at Weeks 72, 76 or 80, respectively.

Benefits and Risks
There is a medical need for the treatment of nr-axSpA. The utility of TNF
blockade with adalimumab in nr-axSpA has been established in a randomized
controlled trial which demonstrated a safety profile similar to that observed
in the extensive clinical and post-marketing experience of adalimumab in a wide
range of disease states including the associated indication of AS. The safety
profile of adalimumab in this and other approved indications is well
established. Adverse events in the categories of autoimmunity, demyelinating
disorders, congestive heart failure, gastrointestinal disorders, hematologic
events, hepatic events, hypersensitivity, immunosuppression, infections,
malignancies, respiratory thoracic and mediastinal disorders, and vascular
disorders have been observed with adalimumab therapy.
For Study M13-375, to ensure nr-axSpA subjects are appropriate candidates for
anti-TNF therapy, subjects are required to meet a minimum level of disease
activity at baseline (ASDAS * 2.1, BASDAI * 4, Patient's Assessment of Total
Back Pain score * 4), have objective evidence of active disease (inflammation
in the SI joints or spine on MRI or elevated hs-CRP), and have had an
inadequate response to at least 2 NSAIDs or a contraindication or intolerance
to NSAIDs. Further detailed information regarding potential risks and benefits
of adalimumab can be found in the Investigator's Brochure.

The potential benefit of the proposed study in nr-axSpA is that it is designed
to evaluate the efficacy and safety of continuing versus withdrawing therapy
with adalimumab 40 mg given eow SC in maintaining remission in subjects with
nr-axSpA. As nr-axSpA is associated with considerable pain, reduction in
health-related quality of life, and work impairment, it would benefit patients
to know if persistent adalimumab therapy is required to maintain remission.