Efficacy and safety of golimumab in patients with non-radiographic axial spondyloarthritis: a withdrawal and retreatment study (GO-BACK).

OBJECTIVES: The GO-BACK study was designed to evaluate the efficacy and safety of golimumab (GLM) treatment withdrawal in adults with non-radiographic axial spondyloarthritis (nr-axSpA) who demonstrate inactive disease during a 10-month open-label (OL) GLM run-in. METHODS: Eligible participants received OL GLM in period 1. In period 2, participants who achieved inactive disease were randomized 1:1:1 to receive double-blind (DB) treatment with monthly placebo (PBO, treatment withdrawal) or continued GLM treatment given monthly (GLM QMT) or every 2 months (GLM Q2MT). Participants who did not have a disease flare continued DB treatment for ∼12 months. Participants with a disease flare discontinued DB treatment and resumed monthly OL GLM. Primary endpoint compared the proportion of participants without a disease flare in the continued GLM treatment groups (QMT or Q2MT) vs PBO in a multiplicity-controlled, step-down fashion. Safety follow-up continued for ∼3 months after last treatment. RESULTS: A total of 188 patients, out of the 323 enrolled, were eligible for participation in period 2. Both GLM QMT and GLM Q2MT were superior to treatment withdrawal (PBO) in preventing disease flare (P < 0.001), with a treatment-difference vs PBO of 50.4% and 34.4% for the GLM QMT and GLM Q2MT groups, respectively. The time-to-first flare was significantly longer (log-rank P < 0.0001) with GLM treatment compared with PBO. Of 53 participants (in Q2MT or PBO) who had a confirmed disease flare, 51 (96.2%) attained a clinical response within 3 months of restarting OL GLM. Adverse events were consistent with the known GLM safety profile. CONCLUSION: Among participants with active nr-axSpA who attained inactive disease after 10 months of GLM treatment, continued GLM treatment is well tolerated and provides superior protection against disease flares compared with GLM withdrawal. (EudraCT: 2015-004020-65, registered on 30 March 2022; NCT: 03253796, registered on 18 August 2017.).

Comparative clinical efficacy and safety of the proposed biosimilar ABP 710 with infliximab reference product in patients with rheumatoid arthritis.

BACKGROUND: ABP 710 is being developed as a biosimilar to infliximab reference product (RP). Analytical similarity and pharmacokinetic equivalence between the two have been previously demonstrated. Here we report results from a comparative clinical study that evaluated the efficacy and safety of ABP 710 relative to the RP in patients with rheumatoid arthritis (RA). METHODS: In this multicenter, randomized, double-blind, 50-week equivalence study, patients with moderate to severe active RA despite methotrexate received 3-mg/kg infusions of ABP 710 or RP at predetermined intervals based on initial randomization and then with re-randomization at week 22. The primary endpoint was response difference (RD) of ACR20 at week 22, with clinical equivalence evaluated based on 90% CI of - 15%, 15%. Secondary endpoints included Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP), ACR20, ACR50, and ACR70 across time, as well as safety and immunogenicity assessments. RESULTS: A total of 558 patients were randomized for the initial treatment (ABP 710 n = 279; RP n = 279). The estimated RD of ACR20 at week 22 was 9.37% with 90% CI (2.67%, 15.96%). The lower bound was within the pre-specified criteria, thus confirming non-inferiority; the upper bound exceeded the pre-specified criteria by 0.96% such that superiority could not be ruled out statistically. In a post hoc analysis with adjustment for random imbalance in baseline factors, the CI of RD was narrowed (0.75%, 13.62%). Changes from baseline in DAS28-CRP as well as ACR20, ACR50, and ACR70 response rates across time and hybrid ACR evaluations were similar for the initial and initial/re-randomized treatment groups. Adverse events and incidence of anti-drug antibodies were similar between treatment groups. CONCLUSIONS: These efficacy and safety results support similarity with no clinically meaningful differences between ABP 710 and infliximab RP. Although we were unable to statistically confirm non-superiority, post hoc analysis was supportive of non-superiority. DAS28-CRP, ACR20, ACR50, ACR70, and hybrid ACR evaluations over the entire study were consistently comparable as were safety and immunogenicity. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT02937701. Registered August 30, 2016.

Randomised, double-blind, phase III study comparing the infliximab biosimilar, PF-06438179/GP1111, with reference infliximab: efficacy, safety and immunogenicity from week 30 to week 54.

Objective: To investigate the efficacy, safety and immunogenicity of PF-06438179/GP1111 (PF-SZ-IFX) compared with European reference infliximab (Remicade®; ref-IFX) in patients with moderate-to-severe, active rheumatoid arthritis after continued long-term use of PF-SZ-IFX, and in patients who were switched from ref-IFX to PF-SZ-IFX. Methods: REFLECTIONS B537-02 was a double-blind, active-controlled, multinational study in which patients (N=650) were initially randomised to PF-SZ-IFX or ref-IFX for 30 weeks (treatment period [TP] 1). During weeks 30-54 (TP2), the PF-SZ-IFX group (n=280) continued treatment with PF-SZ-IFX (PF-SZ-IFX/PF-SZ-IFX) and patients in the ref-IFX group (n=286) were rerandomised (1:1) to continue ref-IFX (ref-IFX/ref-IFX) (n=143) or switch to PF-SZ-IFX (ref-IFX/PF-SZ-IFX) (n=143) for a further 24 weeks. Efficacy, safety, immunogenicity and pharmacokinetics were evaluated. Results: During TP2, patients in all three treatment groups continued to maintain comparable treatment response. At week 54, the American College of Rheumatology (ACR20) response rates were 71.1% (PF-SZ-IFX/PF-SZ-IFX), 64.3% (ref-IFX/ref-IFX) and 70.6% (ref-IFX/PF-SZ-IFX). Observations for other endpoints, including ACR50/70, Disease Activity Score in 28 Joints Based on High-Sensitivity C Reactive Protein(DAS28-CRP) remission, and mean change in DAS28-CRP and Health Assessment Questionnaire-Disability Index, were also comparable. Treatment-emergent adverse events were reported in 36.8% (PF-SZ-IFX/PF-SZ-IFX), 33.6% (ref-IFX/ref-IFX) and 37.8% (ref-IFX/PF-SZ-IFX) of patients; there were no clinically meaningful differences in the safety profiles between groups. The percentage of patients who were antidrug antibody-positive was generally stable through the treatment period and comparable overall between the PF-SZ-IFX/PF-SZ-IFX (52.1%; neutralising: 80.8%), ref-IFX/ref-IFX (60.1%; neutralising: 84.9%) and ref-IFX/PF-SZ-IFX (58.0%; neutralising 78.3%) groups. Conclusions: The similar efficacy, safety and immunogenicity of PF-SZ-IFX compared with ref-IFX were maintained for up to 54 weeks and were not affected by blinded treatment switch from ref-IFX to PF-SZ-IFX at week 30. Trial registration number: NCT02222493.

A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and infliximab reference product for treatment of moderate to severe active rheumatoid arthritis despite methotrexate therapy.

BACKGROUND: This double-blind, active-controlled, randomized, multinational study evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-06438179/GP1111 (IxifiTM/Zessly®), an infliximab biosimilar, vs infliximab (Remicade®) reference product sourced from the European Union (infliximab-EU) in biologic-naïve patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate therapy. This paper reports results from the initial 30-week treatment period. METHODS: Patients (N = 650) were stratified by geographic region and randomized 1:1 to PF-06438179/GP1111 or infliximab-EU (3 mg/kg intravenous at weeks 0, 2, and 6, then every 8 weeks). Dose escalation to 5 mg/kg was allowed starting at week 14 for patients with inadequate RA response. The primary endpoint was American College of Rheumatology criteria for ≥ 20% clinical improvement (ACR20) response at week 14. Therapeutic equivalence was declared if the two-sided 95% CI for the treatment difference was within the symmetric equivalence margin of ± 13.5%. Statistical analysis was also performed with a two-sided 90% CI using an asymmetric equivalence margin (- 12.0%, 15.0%). RESULTS: Patients (80.3% female; 79.4% seropositive) had a mean RA duration of 6.9 years, and mean baseline Disease Activity Score in 28 joints, four components based on C-reactive protein was 6.0 in both arms. Week 14 ACR20 in the intention-to-treat population was 62.7% for PF-06438179/GP1111 and 64.1% for infliximab-EU. Week 14 ACR20 using nonresponder imputation was 61.1% for PF-06438179/GP1111 and 63.5% for infliximab-EU, and the 95% (- 9.92%, 5.11%) and 90% (- 8.75%, 4.02%) CIs for the treatment difference (- 2.39%) were entirely contained within the prespecified symmetric and asymmetric equivalence margins, respectively. No differences were observed between arms for secondary efficacy endpoints. Overall postdose antidrug antibody (ADA) rates through week 30 were 48.6% and 51.2% for PF-06438179/GP1111 and infliximab-EU, respectively. Efficacy and immunogenicity were similar between treatments for patients with dose escalation (at or after week 14), as well as between treatments for patients without dose escalation. Safety profiles of PF-06438179/GP1111 and infliximab-EU were similar, with no clinically meaningful differences observed between arms, including after ADA development. Serum drug concentrations were similar between arms at each time point during the initial 30-week treatment period. CONCLUSION: PF-06438179/GP1111 and infliximab-EU demonstrated similar efficacy, safety, immunogenicity, and PK with or without dose escalation in patients with moderate to severe active RA on background methotrexate. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02222493 . Registered on 21 August 2014. EudraCT, 2013-004148-49 . Registered on 14 July 2014.

A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.

BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. METHODS: We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. RESULTS: Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. CONCLUSIONS: At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).

Osteoporosis risk assessment and management in primary care: focus on quantity and quality.

INTRODUCTION AND HYPOTHESIS: Early identification of high-risk patients by general practitioners (GPs) plays the key role in the management of osteoporosis (OP). METHODS: We conducted a postal questionnaire survey among 1500 Czech GPs to examine their behaviour related to OP. RESULTS: The overall questionnaire return rate was 38%. The respondents (mean age 52 years; 61.5% women) did not differ from non-respondents. OP knowledge correlated negatively with age (P<0.001). The most common reason for both suspicion of OP and referral for suspected OP is the patient's complaints. When the initial skeletal examination for suspected OP is conducted on the GP's initiative, it is most often X-ray (76%) followed by osteodensitometry (61%). The respondents address five patients (median) per month about this issue. The number of referrals to a specialist for suspected OP during the last quarter was 5 (median). The most commonly reported barriers to OP management were financial limits set by the health insurance agency (71%) and lack of authorization to prescribe selected drugs (71%). CONCLUSIONS: The GPs should pay greater attention to risk factors and be more active in the detection of at-risk patients. It is necessary to motivate the GPs and to overcome the barriers to effective clinical practice.

Self-reported compliance with osteoporosis medication-qualitative aspects and correlates.

OBJECTIVES: The analysis aims to assess (1) compliance with anti-osteoporosis pharmacotherapy and (2) the prevalence of calcium and vitamin D co-medication among Czech women in common clinical practice. METHODS: A cross-sectional multicentre questionnaire survey was performed in consecutive secondary care female patients aged > or =40 years. Three main dimensions of compliance were studied: drug compliance (based on missed doses over the last month), co-medication with calcium/vitamin D and compliance with dosing instructions for safe and effective use of bisphosphonates (BIS). RESULTS: The therapy in 200 osteoporosis patients was alendronate (44.5%), risedronate (24.5%), raloxifene (18%) and calcitonin (13%). The three dimensions of compliance were not associated with each other. None of the compliance-related outcomes correlated with the osteoporosis knowledge score obtained in the Osteoporosis Questionnaire (OPQ) of Pande et al. The most frequently reported reason for non-compliance was "drug not handy". Similar mean compliance rates were achieved with once daily and once weekly BIS. The rates of current calcium and vitamin D co-medication were 73% and 62%, respectively. Calcium co-medication was associated with obtaining information on medications against osteoporosis from other sources besides health care professionals (P = 0.038). Compliance with dosing instructions correlated negatively with age (P = 0.001). CONCLUSION: Compliance with osteoporosis medication in Czech women is suboptimal, in particular the prevalence of co-medication with calcium/vitamin D should be higher. It is needed to implement strategies focused on the patient's beliefs about the disease and perceptions of outcome rather than those promoting the knowledge alone.

Knowledge of osteoporosis correlated with hormone therapy use and health status.

OBJECTIVES: The study objectives were: (a) to evaluate knowledge about osteoporosis and to identify its correlates among women > or =40 years of age attending outpatient centers; (b) to compare the level of knowledge between women already receiving treatment for osteoporosis and first-time attendees. METHODS: A cross-sectional survey was conducted with women recruited from nine outpatient centres in the Czech Republic. The women were divided into two subgroups: patients who have already been diagnosed with osteoporosis (osteopenia) and who are receiving treatment for the disease (OS group); first-time attendees who have been referred for the assessment of osteoporosis (comparison group). The patient's knowledge of osteoporosis was assessed using the Osteoporosis Questionnaire (OPQ) developed by Pande et al. [Pande KC, Takats D, Kanis JA, Edwards V, Slade P, McCloskey EV. Development of a questionnaire (OPQ) to assess patient's knowledge about osteoporosis. Maturitas 2000;37:75-81]. RESULTS: A total of 474 women (median age 63 years) were studied (306 in the OS group, 168 in the comparison group). Knowledge scores based on OPQ (median) were 7 and 6 points in the OS and comparison groups, respectively. When adjusted for age, the statistics showed better knowledge patients in the OS group (P=0.019). In both the OS and comparison groups, knowledge was found to be correlated positively with education (P<0.001) and experience of hormone replacement therapy (HRT) (P<0.001) and negatively with age (P<0.001). Knowledge was higher among women with better health status in the OS group. CONCLUSION: Knowledge about osteoporosis among Czech women aged > or =40 years and attending outpatient centers is relatively poor. To improve it, special attention should be paid to elderly women, those who have not used HRT, poorly educated women and those treated with several drugs.