Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis. METHODS: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. PRIMARY ENDPOINT: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12. RESULTS: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. PRIMARY ENDPOINT: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups. CONCLUSIONS: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib. TRIAL REGISTRATION NUMBERS: NCT03980483, NCT03970837.

Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: a phase III randomised trial (contRAst 3).

OBJECTIVES: To investigate the efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors. METHODS: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12. RESULTS: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups. CONCLUSIONS: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population. TRIAL REGISTRATION NUMBER: NCT04134728.

Changes in inpatient medicine prescribing during COVID-19 lockdown.

BACKGROUND: New Zealand went into lockdown March 2020 successfully eliminating the circulation of the coronavirus disease 2019 (COVID-19) virus. During lockdown there were reduced rates of respiratory infections and hospital admission numbers were low. At the time, rumours of benefit and harm of medicines for COVID-19 were widespread in the lay and medical media. AIM: To describe changes in inpatient prescribing in an acute general medicine service during the New Zealand COVID-19 lockdown in 2020. METHODS: Rates of prescribing of medicines during the 33 days of lockdown were compared with a 33-day control period before lockdown. Prescriptions, patients and bed days were calculated from the hospital patient administration and electronic prescribing and administration systems. RESULTS: In the general medicine service, acute admissions were 20% lower during lockdown (from 1216 pre-lockdown to 974). There was a small decrease in the rate of prescriptions per patient (10.1 vs 10.4, P = 0.01) during lockdown, and the average length of stay was shorter (3.2 vs 3.6 days). Nebulised administration decreased by 75% (1.3% vs 5.3% of admissions) but unexpectedly there was no change in the prescribing rates of antibacterial medicines, e.g. amoxicillin (26% vs 26%). There were no changes in rates of prescribing of medicines being rumoured to potentially improve (e.g. hydroxychloroquine) or worsen (e.g. angiotensin-converting enzyme inhibitors) COVID-19 outcomes. CONCLUSIONS: Acute medical admissions decreased 20% during lockdown for COVID-19, with a proportional decrease in prescriptions. Reduced rates of respiratory tract infections did not lead to decreased prescribing of antibacterial medicines. Rumour-based prescribing did not eventuate.

Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma.

Long-term oral corticosteroid (OCS) use in patients with severe asthma is associated with significant adverse effects.This 40-week, randomised, double-blind trial evaluated the OCS-sparing potential of tralokinumab in patients with severe, uncontrolled asthma requiring maintenance OCS treatment plus inhaled corticosteroids/long-acting ß2-agonists. Overall, 140 patients were randomised to tralokinumab 300 mg or placebo (n=70 in each group) administered subcutaneously every 2 weeks. The primary end-point was percentage change from baseline in average OCS dose at week 40, while maintaining asthma control. Secondary end-points included proportion of patients with a prescribed maintenance OCS dose of ≤5 mg, those with a ≥50% reduction in prescribed maintenance OCS dose and asthma exacerbation rate. Safety was also assessed.At week 40, the percentage reduction from baseline in the final daily average OCS dose was not significantly different between tralokinumab and placebo (37.62% versus 29.85%; p=0.271). There were no significant between-treatment differences for any secondary end-point. Overall, reporting of adverse events and serious adverse events were similar for the tralokinumab and placebo groups. Although a greater proportion of tralokinumab-treated patients reported upper respiratory tract infections (35.7% versus 14.3%), there were no reported cases of pneumonia.Overall, tralokinumab did not demonstrate an OCS-sparing effect in patients with severe asthma.

Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine.

OBJECTIVES: The P2X(7) purinergic receptor antagonist AZD9056 was evaluated in a phase IIa study and subsequently in a phase IIb study to assess the effects of orally administered AZD9056 on the signs/symptoms of rheumatoid arthritis (RA), with American College of Rheumatology 20% response criteria (ACR20) as the primary outcome. METHODS: Both studies were randomised, double-blind, placebo-controlled, parallel-group studies in patients with RA receiving methotrexate or sulphasalazine. Phase IIa was an ascending-dose trial in two cohorts (n=75) using AZD9056 administered daily over 4 weeks. Phase IIb included an open-label etanercept treatment group. Patients were randomised to receive treatment for 6 months with 50, 100, 200 or 400 mg AZD9056 (oral, once a day) or matching placebo (oral, once a day), or subcutaneous etanercept (50 mg once a week). RESULTS: In phase IIa, 65% of AZD9056 recipients at 400 mg/day responded at the ACR20 level compared with 27% of placebo-treated patients. A significant reduction in swollen and tender joint count was observed in the actively treated group compared with placebo, whereas no effect on acute-phase response was observed. Of 385 randomised patients in the phase IIb study, 383 received treatment. AZD9056 (all doses) had no clinically or statistically significant effect on RA relative to placebo as measured by the proportion of patients meeting the ACR20 criteria at 6 months and further supported by secondary end points. In both studies AZD9056 was well tolerated up to 400 mg/day. CONCLUSIONS: AZD9056 does not have significant efficacy in the treatment of RA, and the P2X(7) receptor does not appear to be a therapeutically useful target in RA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00520572.

Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial.

BACKGROUND: There is a pressing need for new forms of treatment for COPD. Based on the known pathophysiology of COPD, inhibition of matrix metalloproteinases is a theoretically promising approach. This Phase IIa study evaluated the effects of AZD1236, a selective MMP-9 and MMP-12 inhibitor, on the biomarkers of inflammation and emphysematous lung tissue degradation in patients with moderate-to-severe COPD. METHODS: This was a multinational, randomized, double-blind, placebo-controlled signal-searching study conducted in men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2-6-week period to eliminate any remaining effects of previous medication, 55 patients received oral AZD1236 75 mg or matching placebo twice daily for 6 weeks. Differential cell count and TNF-α levels in induced sputum and 24-h urinary desmosine excretion were the main study variables, but a range of exploratory biomarkers was also assessed in induced sputum, blood and urine. Secondary variables included lung function and patient-recorded Clinical COPD Questionnaire (CCQ) responses and diary records of symptoms, adverse events, use of rescue medication and AZD1236 plasma concentrations. RESULTS: The majority of variables showed little change compared to placebo although there was a possible, but not statistically significant reduction in urinary desmosine excretion and reductions in the number and percentage of lymphocytes in sputum and blood with AZD1236. No effect was seen on clinical parameters after 6 weeks of treatment. The proportion of patients experiencing adverse events was similar in both treatment groups. CONCLUSIONS: AZD1236 dosed orally at 75 mg twice daily was generally well tolerated over 6 weeks in patients with moderate-to-severe COPD. No clinical efficacy of AZD1236 was demonstrated in this short-term signal-searching study, although possible evidence of an impact on desmosine may suggest the potential value of selective inhibitors of MMPs in the treatment of COPD in longer term trials.

Safety and tolerability of an oral MMP-9 and -12 inhibitor, AZD1236, in patients with moderate-to-severe COPD: a randomised controlled 6-week trial.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). This phase IIa study investigated the safety and tolerability of oral AZD1236, an MMP-9 and MMP-12 inhibitor, in patients with COPD. Efficacy analyses were included on an exploratory basis. METHODS: This was a multinational, randomised, double-blind, parallel-group study conducted in 74 men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2-week run-in period, patients received oral AZD1236 75 mg, or matching placebo, twice daily for 6 weeks (on top of background medication with short-acting bronchodilators and/or inhaled corticosteroids, if applicable). In addition to safety and tolerability endpoints (AEs, vital signs and laboratory assessments) efficacy was assessed as a secondary objective (spirometry, 6MWT, BODE index and biomarkers in blood and urine. Clinical COPD Questionnaire (CCQ), peak expiratory flow (PEF) and daily diary cards of symptom severity were completed by the patients. RESULTS: The incidence of adverse events (AEs) was similar in AZD1236 and placebo recipients; 28 in 13 patients (37%) and 21 in 17 patients (44%), respectively; the difference in actual number reported accounted for primarily by mild AEs in the AZD1236 group. The most commonly experienced AEs in both groups were COPD exacerbations, headache and viral infections. One patient in the AZD1236 group experienced a serious AE of interstitial nephritis (comprising of acute renal failure, rash, fever and blood eosinophilia) considered to be related to treatment. After 6 weeks, AZD1236 had demonstrated no significant effect on lung function, 6MWT, BODE index or biomarkers compared with placebo. No meaningful differences were observed in patient-reported CCQ score, PEF, COPD symptoms or use of rescue medication. CONCLUSIONS: For most of these COPD patients, with the particular exception of one who experienced a serious AE, AZD1236 at 75 mg twice daily was generally well tolerated and had an acceptable safety profile. Therapeutic efficacy could not be demonstrated, possibly due to the stable disease and background medications of the patients enrolled in this small, short-term study.

Tralokinumab for the treatment of severe, uncontrolled asthma: the ATMOSPHERE clinical development program.

Tralokinumab, a fully human IgG4 monoclonal antibody, specifically neutralizes IL-13. The ATMOSPHERE clinical development program comprised four randomized, placebo-controlled clinical trials and an open-label study that aimed to assess the efficacy and safety of tralokinumab for the treatment of severe, uncontrolled asthma. The two pivotal trials (STRATOS 1 and STRATOS 2; NCT02161757 and NCT02194699) evaluated the efficacy and safety of tralokinumab, with STRATOS 1 identifying a subgroup most likely to demonstrate enhanced response to treatment. Further trials have assessed the ability of tralokinumab to reduce oral corticosteroid use (TROPOS; NCT02281357) and determined its mechanistic effects (MESOS; NCT02449473). An open-label study in Japanese individuals (NCT02902809) assessed the long-term safety and tolerability of tralokinumab in this population.

Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

BACKGROUND: The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear. Tralokinumab is a human monoclonal antibody that neutralises interleukin 13. We aimed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration, blood and sputum eosinophil concentrations, eosinophil activation, and airway remodelling. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 15 centres across the UK, Denmark, and Canada. We enrolled participants of either sex aged 18-75 years with inadequately controlled moderate-to-severe asthma for 12 months or more, requiring treatment with inhaled corticosteroids at a stable dose. We randomly assigned participants (1:1) to receive tralokinumab (300 mg) or placebo by an interactive web-based system or voice response system. Participants and study personnel were masked to treatment allocation. Both tralokinumab and placebo were administered subcutaneously every 2 weeks. The primary outcome measure was change from baseline to week 12 in bronchial biopsy eosinophil count. Secondary outcome measures included change in blood and sputum eosinophil counts. Exploratory outcomes included fractional exhaled nitric oxide (FENO) and blood IgE concentrations. Safety analyses were carried out in all participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT02449473, and with the European Clinical Trials Database, EudraCT 2015-000857-19. FINDINGS: Between Sept 25, 2015, and June 21, 2017, 224 participants were enrolled and screened. Of these participants, 79 were randomly assigned to receive tralokinumab (n=39) or placebo (n=40). Tralokinumab did not significantly affect bronchial eosinophil count compared with placebo at week 12 (treatment effect ratio 1·43, 95% CI 0·63-3·27; p=0·39). Compared with placebo, tralokinumab did not significantly affect blood eosinophil count (treatment effect ratio 1·21, 95% CI 1·00-1·48; p=0·055) or sputum eosinophil count (0·57, 0·06-6·00; p=0·63), but FENO concentration (0·78, 0·63-0·96; p=0·023) and total blood IgE concentration (0·86, 0·77-0·97; p=0·014) were significantly reduced. 33 (85%) of 39 patients receiving tralokinumab and 32 (80%) of 40 receiving placebo reported at least one adverse event during the treatment period. No deaths in either treatment group were observed. Treatment-related adverse events occurred more frequently in the tralokinumab group than in the placebo group (11 [28%] of 39 vs seven [18%] of 40). INTERPRETATION: Tralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma. FUNDING: AstraZeneca.

The effects of the spleen tyrosine kinase inhibitor fostamatinib on ambulatory blood pressure in patients with active rheumatoid arthritis: results of the OSKIRA-ABPM (ambulatory blood pressure monitoring) randomized trial.

Clinical trials of fostamatinib in patients with rheumatoid arthritis showed blood pressure (BP) elevation using clinic measurements. The OSKIRA-ambulatory BP monitoring trial assessed the effect of fostamatinib on 24-hour ambulatory systolic BP (SBP) in patients with active rheumatoid arthritis. One hundred thirty-five patients were randomized to fostamatinib 100 mg twice daily (bid; n = 68) or placebo bid (n = 67) for 28 days. Ambulatory, clinic, and home BPs were measured at baseline and after 28 days of therapy. Primary end point was change from baseline in 24-hour mean SBP. Fostamatinib increased 24-hour mean SBP by 2.9 mm Hg (P = .023) and diastolic BP (DBP) by 3.5 mm Hg (P < .001) versus placebo. Clinic/home-measured BPs were similar to those observed with ambulatory BP monitoring. After treatment discontinuation (1 week), clinic BP values returned to baseline levels. Fostamatinib induced elevations in 24-hour mean ambulatory SBP and DBP. BP elevations resolved with fostamatinib discontinuation.

Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy. METHODS: Patients taking MTX were randomized (1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co-primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS). RESULTS: In this study, 918 patients were randomized and received ≥1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P = 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P = 0.25 and P = 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (≥140/90 mm Hg) occurred at ≥1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group. CONCLUSION: With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at 24 weeks, whereas a significant difference in the SHS was not seen. The overall level of response to treatment with fostamatinib was lower than had been observed in the phase II program, but similar adverse events were reported.