Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial

Abstract Background This post hoc analysis assessed changes in oral glucocorticoid (OGC) use over time in patients receiving sarilumab 200 mg (dose reduction to 150 mg for laboratory abnormalities or per investigator’s discretion) every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in EXTEND (NCT01146652), a long-term, open-label extension (OLE) study of sarilumab in RA. Methods Patients who had completed placebo-controlled Phase 3 studies of sarilumab +csDMARD (NCT01061736 and NCT01709578) and received sarilumab in EXTEND were included. Reported total daily OGC doses were converted to prednisone equivalent daily doses (PED). Patients were grouped by PED dose at enrollment into the OLE: 0-<5, 5-<10, and ≥10 mg/day (PED <1 mg/day imputed to 0). PED doses were analyzed over 12-week intervals to Week 216. Change from baseline for average PED was tested (Wilcoxon-Pratt-Lehman). Results In total, 891/1353 patients (65.9%) had ≥1 record of OGC use. Of these, 137 (15.4%) received baseline PED of 0-<5 mg/day, 515 (57.8%) 5-<10 mg/day, and 239 (26.8%) ≥10 mg/day. Mean (±SD) PED was 6.3 (±3.1) mg/day at baseline and decreased over time (21.3% mean reduction at 4 years: nominal p < 0.0001). By Weeks 49-60, 660/776 patients (85.1%) had stable PED, 90/776 patients (11.6%) had decreased PED, and 26/776 (3.4%) had increased PED. This difference increased during follow-up: at Weeks 205-216, 109/236 patients (46.2%) had decreased PED and 18/236 (7.6%) had increased PED. Patients with PED ≥5 mg/day were more likely than patients with PED <5 mg/day to decrease their dose. Efficacy (CDAI and DAS28-CRP) was maintained with sarilumab irrespective of OGC tapering. Conclusion Long-term RA treatment with sarilumab was associated with sustained efficacy and decreased OGC dose. The proportion of patients who reduced their OGC dose increased with time and reductions were more common among patients with baseline PED ≥5 mg/day. Disclosures R. Fleischmann: Grants/research support; AbbVie, Acea, Akros, Amgen, Astra Zeneca, Bristol-Myers Squibb, Celgene, Celltrion, Centrexion, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron, Resolve, Roche. C. Selmi: Grants/research support; AbbVie, Alfa-Sigma, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly, Glaxo Smith Kline, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, and UCB. M. Gonzalez-Gay: Grants/research support; AbbVie, Celgene, Eli Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi, and Sobi. H. van Hoogstraten: Corporate appointments; Employee of Sanofi. Shareholder/stock ownership; Sanofi. O. Hagino: Corporate appointments; Employee of Sanofi. Shareholder/stock ownership; Sanofi. T. Rajput: Corporate appointments; Employee of Cytel. G. St John: Corporate appointments; Employee of Regeneron Pharmacueticals Inc. Shareholder/stock ownership; Regeneron Pharmacueticals Inc. F. Buttgereit: Grants/research support; Medac, Pfizer, Roche/Chugai, and Sanofi-Genzyme. M.C. Genovese: Grants/research support; AbbVie, Astellas, Eli Lilly, EMD Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GlaxoSmithKline, Novartis, Pfizer, RPharm, Sanofi Genzyme, and Vertex.

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P.570 Effectiveness of lurasidone 40-80mg/d in the long-term treatment of schizophrenia: a post hoc analysis of 6-month, open-label extension study

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2020.09.416 ◽

2020 ◽

Vol 40 ◽

pp. S323-S324

Author(s):

S. Liang ◽

A. Pikalov ◽

J. Zhao

Keyword(s):

Term Treatment ◽

Extension Study ◽

Open Label ◽

Post Hoc Analysis ◽

Long Term Treatment ◽

Open Label Extension ◽

Post Hoc

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Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study

The Lancet Haematology ◽

10.1016/s2352-3026(20)30323-9 ◽

2020 ◽

Vol 7 (12) ◽

pp. e861-e873 ◽

Cited By ~ 1

Author(s):

Paola Tacchetti ◽

Lucia Pantani ◽

Francesca Patriarca ◽

Maria Teresa Petrucci ◽

Elena Zamagni ◽

...

Keyword(s):

Haematopoietic Stem Cell Transplantation ◽

Haematopoietic Stem Cell ◽

Newly Diagnosed ◽

Open Label ◽

Phase 3 ◽

Open Label Study ◽

Label Study ◽

Long Term Follow Up

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14 Long-term Efficacy of Brexpiprazole in Patients with Schizophrenia with Clinically Relevant Levels of Negative Symptoms

CNS Spectrums ◽

10.1017/s1092852919000099 ◽

2019 ◽

Vol 24 (1) ◽

pp. 180-180

Author(s):

Catherine Weiss ◽

Peter Zhang ◽

Ross A Baker ◽

Mary Hobart ◽

Nanco Hefting ◽

...

Keyword(s):

Negative Symptoms ◽

Extension Study ◽

Short Term ◽

Open Label ◽

Term Study ◽

Post Hoc Analysis ◽

Long Term Study ◽

Open Label Extension ◽

Post Hoc

AbstractBackgroundEffective treatments for patients with high levels of negative symptoms of schizophrenia are lacking. Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all with subnanomolar potency. Long-term treatment with brexpiprazole demonstrated broad efficacy across all five Marder factor groupings, including positive, negative, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. This post-hoc analysis of long-term effects of brexpiprazole in patients with clinically relevant levels of negative symptoms of schizophrenia is based on data from two similarly designed short-term, placebo-controlled studies (Vector; NCT01396421 or Beacon; NCT01393613) for the brexpiprazole-treated patients who continued into an open-label extension study (Zenith; NCT01397786).MethodsIn the short-term studies, patients with acute schizophrenia were randomly assigned to fixed once-daily doses of brexpiprazole 0.25mg (Vector), 1mg (Beacon), 2mg , 4mg or placebo for 6weeks. The long-term study was an open-label, 52-week (amended to 26weeks), safety extension study with flexible-dose (1–4mg/day) brexpiprazole. The post-hoc analyses were performed on brexpiprazole-treated patients from the short-term studies who continued into the long-term study, and who had clinically relevant negative symptoms, defined as PANSS Factor Score for Negative Symptoms (PANSS-FSNS; N1, N2, N3, N4, G7, G16) of ≥24, and score of ≥4 on at least two of three core negative symptom PANSS items at randomization in the parent study. The outcome of the analysis included change from baseline to up to 58weeks in PANSS-FSNS, PANSS Total, and PSP. Safety was also assessed.ResultsA total of 187 patients with clinically relevant levels of negative symptoms in the parent study rolled-over into the open-label extension study and were available for analysis. Eighty-three of these patients remained in the studies for 58weeks. Due to the study amendment, not all patients had the opportunity of complete 52weeks of open-label treatment. Baseline PANSS Total score was 104.4, while baseline PANSS-FSNS was 27.6 and baseline PSP Total score was 41.3. Mean change (SD) from baseline in PANSS-FSNS was –10.9 (5.0), and –44.2 (17.5) for PANSS Total score at Week 58. Change from baseline (SD) to Week 58 for PSP Total score was 24.8 (12.9) with improvement in all domains (socially useful activities, personal and social relationship, self-care, and disturbing and aggressive behaviors). The TEAEs reported ≥5% were schizophrenia (18.9%), insomnia (8.6%), weight increased (5.9%) and akathisia (5.9%).ConclusionThis post-hoc analysis suggests that brexpiprazole has long-term effectiveness on negative symptoms and functioning in patients with schizophrenia and clinically relevant levels of negative symptoms.Funding Acknowledgements: The study was funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S

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Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long‐term follow‐up of the randomized, open‐label, phase 3 CheckMate 025 trial

Cancer ◽

10.1002/cncr.33033 ◽

2020 ◽

Vol 126 (18) ◽

pp. 4156-4167 ◽

Cited By ~ 6

Author(s):

Robert J. Motzer ◽

Bernard Escudier ◽

Saby George ◽

Hans J. Hammers ◽

Sandhya Srinivas ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Advanced Renal Cell Carcinoma ◽

Open Label ◽

Phase 3 ◽

Open Label Phase ◽

Long Term Follow Up

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United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates

Multiple Sclerosis Journal ◽

10.1177/135245850100700107 ◽

2001 ◽

Vol 7 (1) ◽

pp. 33-41 ◽

Cited By ~ 66

Author(s):

Jerry S Wolinsky ◽

Ponnada A Narayana ◽

Kenneth P Johnson ◽

Keyword(s):

Glatiramer Acetate ◽

Term Treatment ◽

Open Label ◽

Clinical Correlates ◽

Long Term Treatment ◽

Open Label Extension ◽

Long Term Follow Up ◽

Relapsing Multiple Sclerosis

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol. Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2447+61 days (mean+standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3+51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1476+63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2433+59 days. The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86+1.78, oGA=1.03+1.28; P=0.002). The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.27, +0.45 oGA=0.28+0.40), but the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66+0.71, oGA reduced by 0.23+0.58; P=0.0002). One or more gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16+2.52, total enhanced tissue volume=97+26 ml). The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001). The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on glatiramer acetate. MRI-metrics indicative of chronic pathology, particularly measures of global cerebral tissue loss (atrophy), were uniformly worse for those originally on placebo. These observations enrich our long-term follow up of the clinical consequences of treatment with glatiramer acetate to include its apparent effects on MRI-defined pathology. They show that the effect of glatiramer acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.

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63 Long-term Outcomes with Aripiprazole Lauroxil for the Treatment of Schizophrenia: A 2-Year, Phase 3, Multicenter Extension Study

CNS Spectrums ◽

10.1017/s109285291900049x ◽

2019 ◽

Vol 24 (1) ◽

pp. 208-209

Author(s):

Peter J Weiden ◽

Amy Claxton ◽

Yangchun Du ◽

John Lauriello

Keyword(s):

Outcome Data ◽

Extension Study ◽

Phase 3 ◽

Post Hoc Analysis ◽

Long Term Study ◽

Long Term Treatment ◽

Scale Scores ◽

Post Hoc

AbstractBackgroundOne of the challenges in schizophrenia long-term trials is that clinical outcomes are often confounded by covert nonadherence to prescribed oral antipsychotics. This is a post hoc analysis (>2 years) of the symptoms and illness trajectory of patients treated with the long-acting injectable (LAI) antipsychotic aripiprazole lauroxil (AL). As adherence to LAIs can be monitored, these data could assess outcome trajectories unaffected by medication discontinuations that may occur with oral antipsychotics.MethodsThe efficacy and safety of once-monthly AL (441 or 882mg) for the treatment of schizophrenia were previously demonstrated in a phase 3 trial, followed by a 52-week, long-term safety study of two AL doses (441 or 882mg once monthly; patients continuing from the phase 3 study remained on their fixed AL dose [NCT01626456]), after which patients could enroll in a second long-term extension study. Patients entering the second long-term study continued on their fixed AL dose, with a variable follow-up period of up to 128 additional weeks (NCT01895452). In this post hoc analysis, the extension studies were combined to provide continuous outcome data over 2 years’ follow-up. The 12-week assessment visit (rather than the first visit) in the first extension study was chosen as the baseline to account for patients entering this study with variable AL exposure histories (with/without prior AL exposure). We report on the trajectory of symptoms and illness severity for >2 years (up to 112weeks) after the 12-week visit using the Positive and Negative Syndrome Scale (PANSS) total and Clinical Global Impression–Severity (CGI-S) scale scores. Course of illness was measured as the difference in PANSS and CGI-S scale scores within dose groups from baseline to end of follow-up, analyzed using MMRM.ResultsOverall, 432/478 patients entering the initial 52-week study were included in the post hoc analysis. For the AL 441 and 882mg groups, respectively, baseline scores (mean±SD) were 59.91±16.25 and 56.27±12.89 (PANSS), and 2.99±0.97 and 2.79±0.79 (CGI-S scale). Approximately 49% of patients (211/432) remained for the entire 112-week follow-up. Over this period, the trajectory of PANSS scores improved significantly compared with baseline for both the 441 and 882mg groups, with changes from baseline (least squares mean±SE) of −5.46±0.92 (P<.0001) and −4.99±0.53 (P<.0001), respectively. CGI-S scale scores had similar improvement: changes from baseline of −0.32±0.07 (P<.0001) and −0.28±0.04 (P<.0001) for the AL 441 and 882mg groups, respectively. Overall, AL was well tolerated, with a safety profile over a 2-year follow-up that was consistent with the initial 52-week safety results.ConclusionThis post hoc analysis demonstrates the safety and continued therapeutic efficacy of long-term treatment with AL in patients with schizophrenia. There were no apparent dose differences in the trajectory of symptom changes over the course of a 2-year follow-up.Funding Acknowledgements: This study was funded by Alkermes, Inc.

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