Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase II,randomized, placebo‐controlled trial

Objective

To assess the efficacy, safety, and biologic activity of atacicept in tumor necrosis factor antagonist–naive patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.

Methods

In this phase II study, patients with active RA (n = 311) were randomized 1:1:1:1 to receive placebo, atacicept 150 mg weekly with or without a 4‐week loading period (twice‐weekly dosing), or open‐label adalimumab 40 mg every other week, for 25 weeks. The primary end point was 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C‐reactive protein level (ACR20‐CRP), at week 26. Secondary end points included additional assessments of efficacy, biologic activity, and safety.

Results

The proportion of patients meeting the primary end point (ACR20‐CRP response) did not differ significantly in the atacicept groups and the placebo group (46% in the placebo group, 45% in the atacicept loading group, and 58% in the atacicept nonloading group). In contrast, an ACR20‐CRP response was observed in 71% of patients in the adalimumab group (P < 0.001 versus placebo). ACR50‐CRP response rates were significantly higher in all active‐treatment groups compared with placebo, but ACR70‐CRP response rates were superior only in the adalimumab group. Atacicept treatment reduced the levels of serum IgG, IgA, and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells. The effects of treatment were similar with and without loading. Immunoglobulin levels returned toward baseline values during the treatment‐free followup period (week 38). The most frequent adverse events associated with atacicept represented common illnesses. No serious infections occurred among patients treated with atacicept.

Conclusion

The primary end point (ACR20‐CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.

     

Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: Results of a multicenter,phase ib,double‐blind,placebo‐controlled,dose‐escalating trial

Objective

To assess the safety and tolerability of atacicept in patients with systemic lupus erythematosus (SLE) and the biologic effect of atacicept on B lymphocyte and immunoglobulin levels. Atacicept is a TACI‐Ig fusion protein that inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferation‐inducing ligand.

Methods

This phase Ib, double‐blind, placebo‐controlled, dose‐escalating trial comprised 6 cohorts of patients treated with atacicept or placebo in a 3:1 ratio of active drug to placebo (n = 8 per group; n = 7 in cohort 5). Cohorts 1–4 received a single subcutaneous dose of placebo or either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 9 mg/kg of atacicept. Cohorts 5 and 6 received weekly doses of placebo or either 1 mg/kg or 3 mg/kg of atacicept for 4 weeks. Patients were followed up for 6 weeks (cohorts 1–4) or 9 weeks (cohorts 5 and 6). Patients with mild‐to‐moderate SLE were enrolled.

Results

Biologic activity of atacicept was demonstrated by dose‐dependent reductions in immunoglobulin levels and in mature and total B cell numbers. This effect was most pronounced in the repeated‐dose cohorts and was sustained throughout the followup period. There were no changes in the numbers of T cells, natural killer cells, or monocytes. Mild injection‐site reactions occurred more frequently among the atacicept group than the placebo group. There were no differences in the frequency or type of adverse events and no severe or serious adverse events in patients treated with atacicept.

Conclusion

Atacicept administered subcutaneously was well tolerated and demonstrated biologic activity consistent with the proposed mechanism of action.

     

Atacicept in patients with rheumatoid arthritis: Results of a multicenter,phase ib,double‐blind,placebo‐controlled,dose‐escalating,single‐ and repeated‐dose study

Objective

Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation‐inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.

Methods

In this multicenter, phase Ib, randomized, placebo‐controlled, dose‐escalating trial, 73 patients were enrolled into 6 escalating‐dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2‐week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.

Results

Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment‐related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti–citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose‐related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3‐month treatment. Little effect on the erythrocyte sedimentation rate or C‐reactive protein levels was seen.

Conclusion

Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.

     

Intraarticular injection of anakinra in osteoarthritis of the knee: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee.

Methods

Patients with OA of the knee were enrolled in a multicenter, double‐blind, placebo‐controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients.

Results

Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half‐life of anakinra in serum after intraarticular injection was ∼4 hours.

Conclusion

Anakinra was well tolerated as a single 50‐mg or 150‐mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.

     

Sifalimumab,a Human Anti–Interferon‐α Monoclonal Antibody,in Systemic Lupus Erythematosus: A Phase I Randomized,Controlled, Dose‐Escalation Study

Objective

To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate‐to‐severe systemic lupus erythematosus (SLE).

Methods

In this multicenter, double‐blind, placebo‐controlled, sequential dose‐escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment‐emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.

Results

Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate‐to‐severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment‐emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose‐proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.

Conclusion

The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

     

Long‐term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus

Objective

To evaluate the safety profile of long‐term belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease.

Methods

Patients who were randomized to receive intravenous placebo or belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52‐week double‐blind treatment period were then allowed to enter a 24‐week open‐label extension phase. During the extension period, patients in the belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24‐week extension period were allowed to participate in the long‐term continuation study of monthly belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient‐years in 1‐year intervals.

Results

Of the 364 patients who completed the 52‐week double‐blind treatment period, 345 entered the 24‐week extension, and 296 continued treatment with belimumab in the long‐term continuation study. Safety data through 4 years of belimumab exposure (1,165 cumulative patient‐years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4‐year belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4‐year followup period. Rates of serious infection decreased from 5.9/100 patient‐years to 3.4/100 patient‐years, and no specific type of infection predominated.

Conclusion

Belimumab added to standard therapy was generally well‐tolerated over the 4‐year treatment period in patients with SLE, which suggests that belimumab can be administered long term with an acceptable safety profile.

     

Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA).

Methods

This phase II, multicenter, randomized, double‐blind, placebo‐controlled study included the following: a 12‐week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12‐week treatment‐extension phase, with patients in the placebo group re‐randomized to receive apremilast; and a 4‐week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms.

Results

Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment‐extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re‐randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment‐extension phase (68.3%) reported ≥1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported.

Conclusion

Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.

     

Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: Results of a fifty‐two–week,randomized, controlled study

Objective

To assess the efficacy, safety, and tolerability of etoricoxib, a cyclooxygenase 2 (COX‐2) selective inhibitor, administered continuously over 52 weeks for the treatment of ankylosing spondylitis (AS).

Methods

This 2‐part, multicenter, double‐blind, parallel‐group, 52‐week study evaluated 2 doses of etoricoxib (90 and 120 mg) compared with naproxen at 1,000 mg. A 6‐week, active‐comparator– and placebo‐controlled period (part I) was followed by a 46‐week active‐comparator–controlled period (part II). The primary outcome measures (on 100‐mm visual analog scales) were patient's assessment of spine pain, patient's global assessment of disease activity, and the Bath Ankylosing Spondylitis Functional Index.

Results

Of the 387 patients randomized to receive treatment, 301 (77.8%) completed part I and 284 (75.9%) completed part II. Compared with placebo over 6 weeks, those receiving 90 mg etoricoxib, 120 mg etoricoxib, and naproxen demonstrated significantly (P < 0.001) greater improvement in all primary end points; treatment effects (expressed as the difference in least squares mean change versus placebo) were 21–29 mm for spine pain, 18–25 mm for disease activity, and 11–15 mm for function. Compared with patients receiving naproxen, significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks, in each individual etoricoxib treatment group over 6 weeks, and in the combined etoricoxib group over 1 year (all P < 0.05); results for secondary and exploratory end points were generally consistent with those from the primary analysis. Among all groups, there were no significant differences in the incidence of overall clinical, drug‐related, or serious adverse experiences (AEs) and discontinuations due to AEs. Safety observations during part II were generally consistent with those in part I.

Conclusion

Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks, and compared with naproxen over 1 year. These study results demonstrate that etoricoxib is generally safe, well‐tolerated, and efficacious for the treatment of AS.

     

Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To compare the efficacy of adalimumab versus placebo in reducing spinal and sacroiliac (SI) joint inflammation, by magnetic resonance imaging (MRI) in patients with active ankylosing spondylitis (AS).

Methods

This was a randomized, multicenter, double‐blind, placebo‐controlled study. Patients (n = 82) received 40 mg adalimumab or placebo every other week during an initial 24‐week double‐blind period. MRIs of both the spine and SI joints were obtained at baseline, week 12, and week 52. Spinal and SI joint inflammation were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index.

Results

The spine SPARCC score in placebo‐treated patients increased by a mean of 9.4% from baseline, compared with a mean decrease of 53.6% in adalimumab‐treated patients (P < 0.001); the SI joint SPARCC score decreased by a mean of 12.7% from baseline in placebo‐treated patients and by 52.9% in adalimumab‐treated patients (P = 0.017). The response in adalimumab‐treated patients was maintained at week 52. Placebo‐treated patients were switched to open‐label adalimumab treatment at week 24 and experienced similar reductions in spinal and SI joint inflammation by week 52. Similar large reductions in the spine and SI joint SPARCC scores were noted, even in patients who failed to meet the ASsessment in Ankylosing Spondylitis (International Working Group) criteria (nonresponders) at 12 weeks. In adalimumab‐treated patients, a reduced C‐reactive protein concentration at week 12 was significantly associated with improvement in the spine SPARCC score (P = 0.018).

Conclusion

Adalimumab significantly reduced both spinal and SI joint inflammation in patients with active AS after 12 weeks of treatment, and these improvements were maintained for up to 52 weeks.

     

Ofatumumab,a human anti‐CD20 monoclonal antibody,for treatment of rheumatoid arthritis with an inadequate response to one or more disease‐modifying antirheumatic drugs: Results of a randomized,double‐blind,placebo‐controlled,phase I/II study

Objective

To investigate the safety and efficacy of ofatumumab, a novel human anti‐CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to ≥1 disease‐modifying antirheumatic drug.

Methods

This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (IV) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated.

Results

AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24.

Conclusion

Our findings indicate that ofatumumab, administered as 2 IV infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.

     

Evaluation of the efficacy and safety of pamapimod,a p38 MAP kinase inhibitor,in a double‐blind,methotrexate‐controlled study of patients with active rheumatoid arthritis

Objective

To determine the efficacy and safety of pamapimod (a selective inhibitor of the α‐isoform of p38 MAP kinase) as monotherapy in comparison with methotrexate (MTX) treatment in adult patients with active rheumatoid arthritis (RA).

Methods

Patients were randomly assigned to 1 of 4 treatment groups and received 12 weeks of double‐blind treatment. One group received MTX (7.5 mg/week with planned escalation to 20 mg/week), and 3 groups received pamapimod (50, 150, or 300 mg) once daily. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included ACR50 and ACR70 responses, change from baseline in the Disease Activity Score in 28 joints (DAS28), categorical analyses of DAS28/European League Against Rheumatism response, and change from baseline in each parameter of the ACR core set of measures. Safety monitoring included recording of adverse events (AEs), laboratory testing, immunology assessments, administration of electrocardiograms, and assessment of vital signs.

Results

Patients assigned to receive MTX and pamapimod had similar demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in the 50‐, 150‐, and 300‐mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness. Pamapimod was generally well tolerated, but the 300‐mg dose appeared to be more toxic than either the 2 lower doses or MTX.

Conclusion

The present results showed that pamapimod was not as effective as MTX in the treatment of active RA.

     

MQX‐503, a novel formulation of nitroglycerin,improves the severity of Raynaud's phenomenon: A randomized,controlled trial

Objective

Raynaud's phenomenon (RP) affects 3–9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX‐503, in the treatment of RP in an ambulatory setting.

Methods

We conducted a multicenter, randomized, placebo‐controlled study with a 2‐week single‐blind run‐in period to determine baseline severity, followed by a 4‐week double‐blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX‐503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0–10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run‐in period in terms of ambient temperature) compared with baseline.

Results

The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX‐503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX‐503 had a side effect profile similar to that of placebo.

Conclusion

MQX‐503 is well tolerated and more effective than placebo for the treatment of RP.

     

Gabapentin in the treatment of fibromyalgia: A randomized,double‐blind,placebo‐controlled,multicenter trial

Objective

To assess the efficacy and safety of gabapentin in patients with fibromyalgia.

Methods

A 12‐week, randomized, double‐blind study was designed to compare gabapentin (1,200–2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0–10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of ≥30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent‐to‐treat sample, with treatment‐by‐time interaction as the measure of effect.

Results

Gabapentin‐treated patients displayed a significantly greater improvement in the BPI average pain severity score (P = 0.015; estimated difference between groups at week 12 = −0.92 [95% confidence interval −1.75, −0.71]). A significantly greater proportion of gabapentin‐treated patients compared with placebo‐treated patients achieved response at end point (51% versus 31%; P = 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated.

Conclusion

Gabapentin (1,200–2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia.

     

A randomized,placebo‐controlled,double‐masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis

Objective

To investigate the safety and efficacy of etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (JIA).

Methods

Children who met the American College of Rheumatology diagnostic criteria for JIA with active uveitis, who had anterior chamber cells of ≥1+ or requiring topical corticosteroid ≥3 times daily, and who were on a stable regimen for arthritis treatment were eligible. Study participants received etanercept (0.4 mg/kg) or placebo administered subcutaneously twice weekly for 6 months. All participants received open‐label etanercept for an additional 6 months.

Results

Five patients received placebo and 7 received etanercept. Three of the 7 patients treated with etanercept and 2 of the 5 placebo‐treated patients were considered ophthalmic successes (P = 1.0). One patient in each treatment group was considered a treatment failure. Three of the 7 etanercept‐treated and 2 of the 5 placebo‐treated patients were neither successes nor failures by our definition. There were no serious adverse events for any patient during the entire study period. Reports of minor infections were comparable in each treatment group, 71% for etanercept and 60% for placebo (P = 0.58).

Conclusion

In this small pilot study there was no apparent difference in the anterior segment inflammation between patients treated with etanercept and placebo. The stringent criteria used to measure ophthalmic success of treatment and the small patient population limit the implications of our findings.

     

The effects of intravenous doxycycline therapy for rheumatoid arthritis: A randomized,double‐blind,placebo‐controlled trial

Objective

To determine the feasibility, safety, and potential clinical efficacy of intravenous (IV) doxycycline therapy for rheumatoid arthritis (RA), as well as its possible effects on serum and urinary markers of collagen breakdown.

Methods

The exploratory trial was designed as a 16‐week, single‐center, randomized, double‐blind, placebo‐controlled trial. Eligible subjects with active seropositive or erosive RA were randomly allocated into 3 treatment groups: doxycycline 200 mg IV, azithromycin 250 mg orally, or placebo. The blinded IV study drug was administered once daily for the first 3 weeks by home self‐infusion and then weekly for the next 8 weeks, concurrent with the blinded oral study drug at the prescribed doses. The primary end points were the change between baseline and week 4 in the tender joint count, erythrocyte sedimentation rate, and urinary excretion of pyridinoline.

Results

The trial was stopped prematurely after enrollment of 31 patients. Three subjects were withdrawn because of worsening arthritis, and 1 patient was withdrawn when newly diagnosed with breast cancer. Infusion‐related events occurred in 13 (42%) of 31 patients, but none were serious. There were 4 serious adverse events unrelated to the study drug, including a new diagnosis of breast cancer in 3 cases and hospitalization for abdominal pain in 1 case. No significant differences were observed across treatment groups in any of the 3 primary clinical end points.

Conclusion

Although IV doxycycline therapy was generally well‐tolerated by patients in this trial, it did not show any evidence of reducing disease activity or collagen crosslink production.

     

Evaluation of the efficacy and safety of terguride in patients with fibromyalgia syndrome: Results of a twelve‐week,multicenter, randomized,double‐blind,placebo‐controlled,parallel‐group study

Objective

To assess the efficacy and safety of terguride, a partial dopamine agonist, in patients with fibromyalgia syndrome (FMS).

Methods

In a 12‐week, multicenter, double‐blind, placebo‐controlled, parallel‐group study, 99 patients were randomized at a ratio of 2 to 1 to receive terguride or placebo. Over 21 days, the dosage was titrated to a maximum daily dose of 3 mg of terguride or placebo, and this fixed dosage was continued over 9 weeks. The primary efficacy variable was the intensity of pain (100‐mm visual analog scale). Secondary efficacy variables included the Fibromyalgia Impact Questionnaire (FIQ) score, the tender point score (TPS), and the Hamilton Depression Scale (HDS) score. During the study, patients were evaluated for the presence of cervical spine stenosis by magnetic resonance imaging (MRI).

Results

No significant differences in the change in pain intensity, FIQ score, TPS, or HDS score between baseline and 12 weeks were observed in the terguride group as compared with the placebo group. Cervical spine stenosis was detected in 22% of the patients. Only patients with cervical spine stenosis responded to terguride treatment. FIQ scores improved significantly (per‐protocol analysis), and pain intensity, the TPS score, and the HDS score showed a trend toward improvement in the terguride group as compared with the placebo group. Terguride treatment was safe. Only those adverse events already known to be side effects of terguride were observed. Premature termination of the study in patients receiving terguride (26%) occurred predominantly during up‐titration and in the absence of comedication for treatment of nausea.

Conclusion

Terguride treatment did not improve pain, the FIQ score, the TPS, or the HDS score in the total study population. However, a subgroup of patients with cervical spine stenosis seemed to benefit from terguride treatment.

     

Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: A phase II,four‐week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To compare the efficacy and tolerability of the novel cyclooxygenase 2‐selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA).

Methods

Adults (n = 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting.

Results

All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo.

Conclusion

Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.

     

LY2439821, a humanized anti–interleukin‐17 monoclonal antibody,in the treatment of patients with rheumatoid arthritis: A phase I randomized,double‐blind,placebo‐controlled,proof‐of‐concept study

Objective

We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti–interleukin‐17 (anti–IL‐17) monoclonal antibody, in a first in‐human trial in rheumatoid arthritis (RA) patients taking oral disease‐modifying antirheumatic drugs (DMARDs).

Methods

This randomized, double‐blind, placebo‐controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.

Results

Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all‐LY2439821–combined groups (−2.3, −2.4, and −2.3, respectively) than in the placebo group (−1.7) at week 10 (P ≤ 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821‐treated patients than in placebo‐treated patients at multiple time points. There was no apparent dose‐response relationship in treatment‐emergent adverse events.

Conclusion

LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL‐17 as a potential novel goal for the treatment of RA.

     

Therapeutic benefit of blocking interleukin‐6 activity with an anti–interleukin‐6 receptor monoclonal antibody in rheumatoid arthritis: A randomized,double‐blind,placebo‐controlled,dose‐escalation trial

Objective

To investigate the safety and efficacy of MRA, a recombinant human anti–interleukin‐6 (anti–IL‐6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL‐6, in patients with established rheumatoid arthritis (RA).

Methods

A randomized, double‐blind, placebo‐controlled, dose‐escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment.

Results

Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1‐ and 1‐mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C‐reactive protein values fell significantly in the 5‐ and 10‐mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1‐, 1‐, 5‐, and 10‐mg/kg MRA cohorts, respectively) required corticosteroid or disease‐modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1‐, 1‐, and 10‐mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug.

Conclusion

This is the first randomized controlled trial showing that inhibition of IL‐6 significantly improved the signs and symptoms of RA and normalized the acute‐phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.

     

Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: Results of a multicenter,randomized, double‐blind,placebo‐controlled magnetic resonance imaging study

Objective

To determine whether the effects of anti–tumor necrosis factor α (TNFα) in reducing the signs and symptoms of ankylosing spondylitis (AS) coincide with a reduction in spinal inflammation as detected by magnetic resonance imaging (MRI).

Methods

Pre‐ and postgadolinium T1 and STIR MR images of the spine were acquired at baseline and at week 24 in patients with AS who participated in a multicenter, randomized, double‐blind, placebo‐controlled study. Patients were randomly assigned at an 8:3 ratio to receive infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, and 6 and then every 6 weeks thereafter. MR images were obtained and evaluated independently by 2 readers who were blinded to the treatment allocation and time sequence of the images.

Results

A total of 194 patients in the infliximab group and 72 patients in the placebo group had evaluable images at baseline and week 24. About 80% of the patients had at least 1 active spinal lesion at baseline, as assessed by MRI. The improvement in the MRI Activity Score after 6 months was significantly greater in the patients who received infliximab (mean 5.02, median 2.72) than in those who received placebo (mean 0.60, median 0.0) (P < 0.001). Almost complete resolution of spinal inflammation was seen in most patients who received infliximab, irrespective of baseline activity.

Conclusion

Patients with AS who received infliximab therapy showed a decrease in spinal inflammation as detected by MRI, whereas those who received placebo showed persistent inflammatory spondylitis.