Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trial

Abstract Background/objective REFLECTIONS B538–02 is a randomized, double-blind comparative study of the adalimumab (ADL) biosimilar PF-06410293, (ADL-PF), and reference ADL sourced from the European Union (ADL-EU) in patients with active RA. Therapeutic equivalence was demonstrated based on ACR20 responses at week 12 (primary endpoint). We report long-term safety, immunogenicity, and efficacy of ADL-PF in patients who continued ADL-PF treatment throughout 78 weeks or who switched from ADL-EU to ADL-PF at week 26 or week 52. Methods Eligible patients (2010 ACR/EULAR RA diagnosis criteria for ≥ 4 months; inadequate response to MTX, ≤ 2 doses non-ADL biologic), stratified by geographic regions were initially randomized (1:1) in treatment period 1 (TP1) to ADL-PF or ADL-EU (40 mg subcutaneously, biweekly), both with MTX (10–25 mg/week). At week 26 (start of TP2), patients receiving ADL-EU were re-randomized to remain on ADL-EU or transition to ADL-PF for 26 weeks. At week 52 (start of TP3), all patients received open-label treatment with ADL-PF for 26 weeks and were followed after last treatment dose to week 92. To evaluate maintenance of response after switching or remaining on ADL-PF, ACR20, DAS28-4(CRP), and other measures of clinical response/remission were assessed through week 78 as secondary endpoints. Three groups were evaluated: biosimilar, week 26 switch, and week 52 switch. Results Overall, 507 patients participated in TP3. ACR20 response rates at week 52 were 88.4%, 88.2%, and 87.6% for the biosimilar, week 26, and week 52 switch groups, respectively. ACR20 response rates and DAS28-4(CRP) scores were sustained and comparable across groups in TP3. Incidence of treatment-emergent adverse events (AEs) during TP3 and follow-up was 42.6% (biosimilar), 37.0% (week 26 switch), and 50.8% (week 52 switch); 3 (0.6%) patients (all week 52 switch) reported treatment-related serious AEs. ADL-PF was generally well tolerated, with a comparable safety profile across groups. Overall, incidences of patients with anti-drug antibodies in TP3 and follow-up were comparable among groups (46.1%, 46.5%, and 54.2%, respectively). Conclusions There were no clinically meaningful differences in safety, immunogenicity, and efficacy for patients who were maintained on ADL-PF for 78 weeks and those who had switched from ADL-EU at week 26 or week 52. Trial registration ClinicalTrials.gov, NCT02480153. First posted on June 24, 2015; EU Clinical Trials Register; EudraCT number: 2014-000352-29. Start date, October 27, 2014

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A double-blind, randomized controlled trial of the use of imiquimod cream for the treatment of anal canal high-grade anal intraepithelial neoplasia in HIV-positive MSM on HAART, with long-term follow-up data including the use of open-label imiquimod

AIDS ◽

10.1097/qad.0b013e32833d466c ◽

2010 ◽

pp. 1 ◽

Cited By ~ 6

Author(s):

Paul A Fox ◽

Mayura Nathan ◽

Nicholas Francis ◽

Naveena Singh ◽

Justin Weir ◽

...

Keyword(s):

Controlled Trial ◽

Intraepithelial Neoplasia ◽

Hiv Positive ◽

Imiquimod Cream ◽

Open Label ◽

Double Blind ◽

Randomized Controlled ◽

Long Term Follow Up

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Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.139345 ◽

2011 ◽

Vol 70 (10) ◽

pp. 1826-1830 ◽

Cited By ~ 99

Author(s):

Joel M Kremer ◽

Anthony S Russell ◽

Paul Emery ◽

Carlos Abud-Mendoza ◽

Jacek Szechinski ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Radiographic Progression ◽

Incidence Rates ◽

Inadequate Response ◽

Open Label ◽

Serious Adverse Events ◽

Double Blind ◽

American College Of Rheumatology ◽

Inadequate Responders

ObjectiveTo evaluate abatacept treatment over 3 years in patients with rheumatoid arthritis (RA) refractory to methotrexate (MTX).MethodsPatients randomised to abatacept or placebo (+MTX) during the 1-year double-blind period of the Abatacept in Inadequate responders to Methotrexate (AIM) trial received open-label abatacept (+MTX) in the long-term extension (LTE). Safety was assessed for patients who received ≥1 dose of abatacept, regardless of randomisation group. Efficacy was assessed for patients randomised to abatacept who entered the LTE.Results433 and 219 patients were randomised and treated with abatacept or placebo, respectively; 378 and 161 entered the LTE. At year 3, 440/539 patients were ongoing. No unexpected safety events were observed in the LTE. By year 3, incidence rates of adverse event and serious adverse events were 249.8/100 and 15.1/100 patient-years, respectively. Incidence rates were generally stable over time. At year 3, 84.8%, 63.4% and 37.5% of patients achieved American College of Rheumatology (ACR) criteria of 20, 50 and 70, respectively, compared with 82.3%, 54.3% and 32.4% of patients at year 1. Mean changes in Genant-modified Sharp scores were reduced progressively over 3 years, with significantly greater inhibition during year 3 compared with year 2 (p=0.022 for total score).ConclusionIn MTX-inadequate responders with RA, abatacept provided consistent safety and sustained efficacy over 3 years. The data suggest an increasing inhibitory disease-modifying effect on radiographic progression.

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Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double-blind, placebo-controlled phase III trial (RAJ3)

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-215163 ◽

2019 ◽

Vol 78 (10) ◽

pp. 1320-1332 ◽

Cited By ~ 32

Author(s):

Yoshiya Tanaka ◽

Tsutomu Takeuchi ◽

Sakae Tanaka ◽

Atsushi Kawakami ◽

Manabu Iwasaki ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Response Rates ◽

Janus Kinase ◽

Phase Iii ◽

Inadequate Response ◽

Efficacy And Safety ◽

Double Blind ◽

Acr20 Response ◽

Once Daily ◽

Conventional Dmards

ObjectivesTo investigate the efficacy and safety of peficitinib, an oral Janus kinase inhibitor, in patients with rheumatoid arthritis (RA).MethodsIn this double-blind phase III study, patients with RA and an inadequate response to prior disease-modifying anti-rheumatic drugs (DMARDs) were randomised to peficitinib 100 mg once daily, peficitinib 150 mg once daily, placebo or open-label etanercept for 52 weeks’ treatment; placebo-treated patients were switched at week 12 to peficitinib 100 or 150 mg once daily. The primary endpoint was American College of Rheumatology (ACR)20 response at week 12/early termination (ET). Secondary endpoints (assessed throughout) included ACR20, ACR50 and ACR70 response, changes from baseline in disease activity scores (DAS)28 and ACR core parameters, adverse events (AEs) and changes in clinical or laboratory measurements.ResultsIn total, 507 patients received treatment. ACR20 response rates at week 12/ET were significantly higher in the peficitinib 100 mg (57.7%) and 150 mg (74.5%) groups versus placebo (30.7%) (p<0.001). ACR50/70 response rates were also higher for both peficitinib doses versus placebo. Improvements in ACR response were maintained until week 52. Changes from baseline in DAS28-C-reactive protein/erythrocyte sedimentation rate and the ACR core set were significantly greater for both peficitinib doses versus placebo at week 12/ET (p<0.001). AE incidence was similar across treatment arms. Incidence of serious infection and herpes zoster-related disease was higher with peficitinib versus placebo, but with no clear dose-dependent increase.ConclusionsIn patients with RA and inadequate response to DMARDs, peficitinib 100 mg once daily or 150 mg once daily was efficacious in reducing RA symptoms and was well tolerated compared with placebo.Trial registration numberNCT02308163.

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Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study

CNS Spectrums ◽

10.1017/s1092852917000220 ◽

2017 ◽

Vol 23 (1) ◽

pp. 39-50 ◽

Cited By ~ 19

Author(s):

Andrew J. Cutler ◽

Suresh Durgam ◽

Yao Wang ◽

Raffaele Migliore ◽

Kaifeng Lu ◽

...

Keyword(s):

Partial Agonist ◽

Phase Iii ◽

Open Label ◽

Two Phase ◽

Double Blind ◽

Safety Issues ◽

Preferential Binding ◽

Dose Study

ObjectiveCariprazine, a dopamine D3/D2 partial agonist atypical antipsychotic with preferential binding to D3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of cariprazine was established in three randomized, double-blind, placebo-controlled, 6-week trials in patients with acute exacerbation of schizophrenia. This 53-week study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia.MethodsThis was a multicenter, open-label, flexible-dose study of cariprazine 3–9 mg/d in adults with schizophrenia. Participants included new patients and patients who had completed one of two phase III lead-in studies (NCT01104766, NCT01104779). Eligible patients entered a no-drug screening period of up to 1 week followed by 48 weeks of flexibly dosed, open-label cariprazine treatment (3–9 mg/d) and 4 weeks of safety follow-up.ResultsA total of 586 patients received open-label cariprazine treatment, ~39% of whom completed the study. No unexpected safety issues or deaths were reported. The most common (≥10%) adverse events (AEs) observed were akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73 (12.5%) patients discontinued the study due to AEs during open-label treatment. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. Mean body weight increased by 1.5 kg during the study, prolactin levels decreased slightly, and measures of efficacy remained stable.ConclusionsLong-term cariprazine treatment at doses up to 9 mg/d appeared to be generally safe and well tolerated in patients with schizophrenia.

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Long-term efficacy and safety in patients with rheumatoid arthritis continuing on SB4 or switching from reference etanercept to SB4

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211591 ◽

2017 ◽

Vol 76 (12) ◽

pp. 1986-1991 ◽

Cited By ~ 55

Author(s):

Paul Emery ◽

Jiří Vencovský ◽

Anna Sylwestrzak ◽

Piotr Leszczyński ◽

Wieslawa Porawska ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Response Rates ◽

Comparable Efficacy ◽

Efficacy And Safety ◽

Open Label ◽

Double Blind ◽

Term Efficacy ◽

Open Label Extension ◽

Extension Period

ObjectivesSB4 (Benepali, Brenzys) is a biosimilar of reference etanercept (ETN). In a randomised, double-blind, 52-week study, SB4 demonstrated comparable efficacy and safety to ETN in patients with rheumatoid arthritis (RA). The open-label extension period evaluated long-term efficacy, safety and immunogenicity when continuing SB4 versus switching from ETN to SB4.MethodsIn the randomised, double-blind phase, patients received weekly subcutaneous administration of 50 mg SB4 or ETN with background methotrexate for up to 52 weeks. Patients in the Czech Republic and Poland who completed the 52-week visit were enrolled in the open-label extension period and received SB4 for 48 additional weeks. Efficacy, safety and immunogenicity were assessed up to week 100.ResultsOf 245 patients entering the extension period, 126 continued to receive SB4 (SB4/SB4) and 119 switched to SB4 (ETN/SB4). American College of Rheumatology (ACR) response rates were sustained and comparable between SB4/SB4 and ETN/SB4 with ACR20 response rates at week 100 of 77.9% and 79.1%, respectively. Other efficacy results, including radiographic progression, were also comparable between the groups. After week 52, rates of treatment-emergent adverse events were 47.6% (SB4/SB4) and 48.7% (ETN/SB4); one patient/group developed non-neutralising antidrug antibodies. No cases of active tuberculosis or injection-site reactions were reported during the extension period. One patient (SB4/SB4) died of hepatic cancer.ConclusionsSB4 was effective and well tolerated over 2 years in patients with RA. Efficacy, safety and immunogenicity were comparable between the SB4/SB4 and ETN/SB4 groups, showing no risk associated with switching patients from ETN to SB4.Trial registration numberNCT01895309; 2012-005026-30

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P.006 Efficacy of adjunctive brivaracetam in adult patients with secondarily generalized tonic-clonic seizures at baseline: pooled results from long-term follow-up trials

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.107 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S15

Author(s):

BD Moseley ◽

A Diaz ◽

S Elmoufti ◽

J Whitesides

Keyword(s):

Controlled Trials ◽

Open Label ◽

Efficacy Data ◽

Double Blind ◽

Double Blind Placebo ◽

Long Term Follow Up ◽

Clonic Seizures ◽

Post Hoc

Background: Previous post-hoc analysis of three 12-week, double-blind, placebo-controlled trials showed adjunctive brivaracetam (BRV) reduced focal and secondarily generalized tonic-clonic seizures (SGTCS; Type IC) in patients with baseline SGTCS. This analysis explored long-term efficacy of adjunctive BRV in these patients. Methods: Patients (≥16 years) with focal seizures with SGTCS at Baseline were identified from 12-week double-blind, placebo-controlled trials (NCT00490035/NCT00464269/NCT01261325) and subsequent open-label, long-term follow-up (LTFU) trials (NCT00175916/NCT00150800/NCT01339559). Outcomes were assessed at protocol-specified time-points (up to 60 months). We report post-hoc efficacy data for patients receiving BRV (50–200 mg/day). Results: At double-blind Baseline, 409 patients had SGTCS (mean epilepsy duration: 22.2 years); 28.4%, 38.9%, and 32.8% had 0–1, 2–4, and ≥5 previous AEDs. Baseline median seizure frequency/28 days was 8.1 (focal) and 3.0 (SGTCS only). 325/409 patients (79.5%) entered LTFU. In the 12-month (n=150), 24-month (n=89), 36-month (n=73), 48-month (n=68) and 60-month (n=57) exposure cohorts, median percent reduction from Baseline in SGTCS frequency/28 days was 81.1%, 84.0%, 89.2%, 91.0%, and 90.6%, respectively. ≥50% responder rates for SGTCS were 75.3%, 78.7%, 80.8%, 79.4%, and 78.9%. No safety concerns were identified. Conclusions: Adjunctive BRV (50–200 mg/day) reduced SGTCS frequency during LTFU (up to 60 months) in patients with SGTCS at Baseline.

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Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial

Ukrains'kyi Visnyk Psykhonevrolohii ◽

10.36927/2079-0325-v28-is3-2020-5 ◽

2020 ◽

pp. 27-37

Author(s):

Suresh Durgam ◽

Willie Earley ◽

Rui Li ◽

Dayong Li ◽

Kaifeng Lu ◽

...

Keyword(s):

Safety Profile ◽

Relapse Prevention ◽

Controlled Trial ◽

Fixed Dose ◽

Open Label ◽

Double Blind ◽

Double Blind Placebo ◽

Randomized Controlled ◽

Time To Relapse

Cariprazine, a dopamine D3/D2 receptor partial agonist with preference for D3 receptors, has demonstrated efficacy in randomized controlled trials in schizophrenia. This multinational, randomized, double-blind, placebo-controlled, parallel-group study evaluated the efficacy, safety, and tolerability of cariprazine for relapse prevention in adults with schizophrenia; total study duration was up to 97 weeks. Schizophrenia symptoms were treated/stabilized with cariprazine 3—9 mg/d during 20-week open-label treatment consisting of an 8-week, flexible-dose run-in phase and a 12-week fixed-dose stabilization phase. Stable patients who completed open-label treatment could be randomized to continued cariprazine (3, 6, or 9 mg/d) or placebo for double-blind treatment (up to 72 weeks). The primary efficacy parameter was time to relapse (worsening of symptom scores, psychiatric hospitalization, aggressive/violent behavior, or suicidal risk); clinical measures were implemented to ensure safety in case of impending relapse. A total of 264/765 patients completed open-label treatment; 200 eligible patients were randomized to double-blind placebo (n = 99) or cariprazine (n = 101). Time to relapse was significantly longer in cariprazine — versus placebo-treated patients (P = .0010, log-rank test). Relapse occurred in 24.8% of cariprazine- and 47.5% of placebo-treated patients (hazard ratio [95% CI] = 0.45 [0.28, 0.73]). Akathisia (19.2%), insomnia (14.4%), and headache (12.0%) were reported in ≥ 10% of patients during open-label treatment; there were no cariprazine adverse events ≥ 10% during double-blind treatment. Long-term cariprazine treatment was significantly more effective than placebo for relapse prevention in patients with schizophrenia. The long-term safety profile in this study was consistent with the safety profile observed in previous cariprazine clinical trials. ClincalTrials.gov identifier: NCT01412060. Key words: schizophrenia; cariprazine; long-term treatment; relapse prevention; randomized controlled trial; oral antipsychotics

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