To evaluate the long-term safety, tolerability, and efficacy of ABT-494 in RA subjects who have completed Study M13-550 or Study M13-537 Phase 2 RCT with ABT-494.
ID
Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy:
ACR20/50/70 response rates at Weeks 6, 12, 24, 36, 48, 60, 72, 84 and 96 will
be evaluated based on 20/50/70% improvement in TJC, SJC, and >= 3 of the 5
measures of Patient's Assessment of Pain (VAS), Patient's Global Assessment of
Disease Activity, Physician's Global Assessment of Disease Activity, Health
Assessment Questionnaire Disability Index (HAQ-DI), and hsCRP.
Change from Baseline in individual ACR components at Weeks 6, 12, 24, 36, 48,
60, 72, 84 and 96 will also be evaluated: TJC, SJC, Patient's Assessment of
Pain (VAS), Patient's Global Assessment of Disease Activity, Physician's Global
Assessment of Disease Activity, Health Assessment Questionnaire Disability
Index (HAQ-DI), and hsCRP. Baseline data for each subject will be the data
collected at the visit immediately prior to starting treatment with active
ABT-494 (this visit could be in RCT or OLE).
The proportion of subjects achieving Low Disease Activity (LDA) or Clinical
Remission (CR), and the proportion of subjects achieving CR will be evaluated
at Weeks 6, 12, 24, 36, 48, 60, 72, 84 and 96. The criteria will be based on
DAS28 [CRP] or CDAI as follows:
DAS28 [CRP] CDAI
LDA 2.6 <= to < 3.2 2.8 < to <= 10
CR < 2.6 <= 2.8
Change from Baseline in DAS28 [CRP] disease activity score, CDAI and Patient
Reported Outcomes including FACIT-Fatigue Scale, RA-WIS, and EQ-5D will be
analyzed at Weeks 6, 12, 24, 36, 48, 72 and 96.
Pharmacokinetic:
Individual plasma concentrations of ABT-494 will be tabulated and summarized.
Pharmacodynamic/Efficacy:
Changes from Baseline in in-vivo pharmacodynamic biomarkers and RA disease
response biomarkers will be analyzed at Weeks 6, 12, 24, 36, 48, 72 and 96.
Safety:
Safety evaluations will include adverse event monitoring, physical
examinations, vital sign measurements, and clinical laboratory testing
(hematology, chemistry, and urinalysis). Toxicity management guidelines are
included in the protocol.
Secondary outcome
N/A
Background summary
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown
etiology. If left untreated, RA causes damage to cartilage, bone, and adjoining
tissues which ultimately leads to severe disability, impaired function, and
marked reduction in the quality of life of subjects.
Early therapy with disease-modifying antirheumatic drugs (DMARDs) is the
standard of care, although a significant proportion of patients either do not
achieve disease remission or become refractory to available therapies as the
disease progresses.
Novel therapies are therefore required to complement the available
interventions to address the unmet need in the treatment of patients with RA.
Evidence suggests that ABT-494 is a promising approach for the treatment of
patients with this chronic disorder. This open-label extension study is
designed to collect long-term safety, tolerability, and efficacy data.
Collecting long-term safety data is important to assess the risk to benefit
profile of ABT-494. This is the first study with ABT-494 of treatment durations
longer than 24 weeks.
Study objective
To evaluate the long-term safety, tolerability, and efficacy of ABT-494 in RA
subjects who have completed Study M13-550 or Study M13-537 Phase 2 RCT with
ABT-494.
Study design
This is a 96-week extension study to assess the long-term safety, tolerability,
and efficacy of ABT-494 in RA subjects who have completed Study M13-550 or
Study M13-537 RCT with ABT-494.
All eligible subjects will be assigned to ABT-494 6 mg BID immediately
following the Last Visit of Study M13-550 or Study M13-537.
Subjects who are unable to tolerate 6 mg BID will be discontinued from the
study.
At Week 6, if a subject fails to achieve at least 20% improvement from RCT
Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC), ABT-494
dose should be increased to 12 mg BID as long as the Investigator has no safety
concerns.
After 6 weeks of treatment with ABT-494 12 mg BID the improvement in TJC and
SJC will be re-assessed at next scheduled visit (Week 12).
If the subject on 12 mg BID fails to achieve at least 20% improvement in TJC
and SJC from RCT Baseline the subject will be discontinued.
At Week 12, the same process will be followed.
If a subject still on 6 mg BID fails to achieve at least 20% improvement from
RCT Baseline in TJC and SJC, ABT-494 dose should be increased to 12 mg BID.
The improvement in TJC and SJC will be re-assessed after 6 weeks of treatment
with 12 mg BID at Week 18 (an optional study visit). Subjects who fail to
achieve at least 20% improvement from RCT Baseline in TJC and SJC with 12 mg
BID at Week 18 will be discontinued.
After Week 12 if a subject fails to show at least 20% improvement from RCT
Baseline in TJC and SJC at 2 consecutive scheduled study visits then the
subject will be discontinued.
Starting at Week 6 and during any scheduled visits thereafter, ABT-494 dose may
be increased from 6 mg BID to 12 mg BID if a subject fails to achieve the Low
Disease Activity (LDA) status (CDAI > 10) and has no safety concerns per
Investigator's judgment.
At any visit, ABT-494 dose may be decreased back to 6 mg BID per Investigator's
judgment due to either an adverse event or reaching one of the protocol
specific toxicity management thresholds. Dose increase back to 12 mg BID is
not allowed.
Study visits will occur at BL, Weeks 6, 12, 24, 36, 48, 60, 72, 84 and 96.
Optional Study Visit at Week 18.
Intervention
Investigational Product: ABT-494 3 mg and 12 mg capsules
Doses:
6 mg BID (initial dose assignment for all subjects).
ABT-494 doses of 12 mg BID are allowed during the OLE treatment period (see
above 'Study Design').
Mode of Administration: Oral
Study burden and risks
Initiation of Phase 2 studies with ABT-494 was feasible based on acceptable
safety and tolerability profile of ABT-494 in single ascending dose and
multiple ascending dose studies in healthy volunteers. The current open-label
extension study will allow the collection of long-term safety data to better
assess the risk to benefit profile of ABT-494.
Knollstrasse 50
Ludwigshafen 67061
DE
Knollstrasse 50
Ludwigshafen 67061
DE
Listed location countries
Age
Inclusion criteria
1. Subjects who have completed Study M13-550 or Study M13-537 with ABT-494 and has not developed any discontinuation criteria, defined in Section 5.4.1 of that study.;2. If the subject has evidence of new latent TB infection, the subject must initiate and complete a minimum of 2 weeks (or per local guidelines, whichever is longer) of an ongoing TB prophylaxis before continuing to receive study drug.;3. If female, subject must meet one of the following criteria:;• Postmenopausal (defined as no menses for at least 1 year).;• Surgically sterile (bilateral oophorectomy or hysterectomy).;• Practicing from the time of screening until at least 30 days after the last dose of study drug at least TWO of the following methods of birth control:;- Tubal ligation;- Partner vasectomy (at least 6 months earlier) (the vasectomized male partner should be the sole partner for that female subject);- Intrauterine device;- A male condom with spermicidal jelly or cream;- Diaphragm, contraceptive sponge or cervical cap with spermicidal jelly or cream;- Hormonal contraceptives (injected, oral, transdermal or implanted methods) must have been taking at least 2 months prior to dosing;4. Male subjects must agree to follow protocol-specified pregnancy avoidance measures, including refraining from donating sperm, for up to 30 days post last dose of study drug.;5. Subjects must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.;6. Subject is judged to be in good health as determined by the Investigator based on the results of medical history, physical examination and laboratory profile performed.
Exclusion criteria
1. Pregnant or breastfeeding female.;2. Ongoing infections at Week 0 that have NOT been successfully treated. Subjects with ongoing infections undergoing treatment may be enrolled BUT NOT dosed until the infection has been successfully treated.;3. Anticipated requirement or receipt of any live vaccine during study participation including up to 30 days after the last dose of study drug.;4. Laboratory values from the visit immediately prior to Baseline Visit meeting the following criteria:;* Serum aspartate transaminase (AST) or alanine transaminase (ALT) > 3.0 × ULN;* Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73m2;* Total white blood cell count (WBC) < 2,000/µL;* Absolute neutrophil count (ANC) < 1,000/µL;* Platelet count < 50,000/µL;* Absolute lymphocytes count < 500/µL;* Hemoglobin < 8 gm/dL;5. Enrollment in another interventional clinical study while participating in this study.;6. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive study drug.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-003530-33-NL |
| ClinicalTrials.gov | NCT02049138 |
| CCMO | NL49230.018.14 |