Open-label Long-term Extension Study Research Articles

New treatments/targets for primary biliary cholangitis.

SummaryPrimary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.

Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder

Buprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2–24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery–Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, “drug withdrawal” AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.

Safety and efficacy of tofacitinib for up to 9.5\u2009years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study

BackgroundFinal data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA).MethodsEligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators’ discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients’ average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy.ResultsBetween February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained.ConclusionsTofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions.Trial registrationNCT00413699, funded by Pfizer Inc (date of trial registration: December 20, 2006)

Tofacitinib, an oral Janus kinase inhibitor, in patients from Mexico with rheumatoid arthritis: Pooled efficacy and safety analyses from Phase 3 and LTE studies.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. Data from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. 119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. In Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population.

Tofacitinib, an oral Janus kinase inhibitor, in patients from Mexico with rheumatoid arthritis: Pooled efficacy and safety analyses from Phase 3 and LTE studies

ObjectivesTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. MethodsData from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. Results119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. ConclusionsIn Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population.

Tofacitinib, an Oral Janus Kinase Inhibitor, in the Treatment of Ulcerative Colitis: An Interim Analysis of an Open-Label, Long-Term Extension Study With up to 4.9 Years of Treatment

Introduction: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib was demonstrated as induction and maintenance therapy in patients (pts) with moderate to severe UC in 3 Phase 3, randomized, placebo-controlled studies [1]. Safety and efficacy of tofacitinib for UC are being evaluated in an ongoing, open-label, long-term extension (OLE) study [2]. Methods: We present an update (as of Nov 10 2017) of previous safety and efficacy data [2] of the OLE study (NCT01470612) in completers or treatment failures in OCTAVE Sustain (NCT01458574) and nonresponders in OCTAVE Induction 1/2. Eligibility was determined per Week (Wk) 8 data from OCTAVE Induction 1/2, or Wk 52 data (for completers) or early termination data from OCTAVE Sustain. Pts in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding subscore of 0) at Wk 52 of OCTAVE Sustain (per central read) were assigned to tofacitinib 5 mg twice daily (BID) in the OLE study; all others were assigned to 10 mg BID. At Month 2, all pts underwent endoscopy; induction nonresponders were mandated to withdraw if they did not show a clinical response. Binary efficacy endpoints were derived from Mayo score per local read. Results: Of 944 pts who received ≥1 dose of study drug (for up to 4.9 years), 326 (34.5%) discontinued due to insufficient clinical response, and 65 (6.9%) due to adverse events (AEs) excl. worsening UC. Serious and severe AEs occurred in 14.8% and 9.9% of pts, respectively. Serious infections were reported in 5 (2.9%) and 23 (3.0%) pts, herpes zoster in 10 (5.7%) and 47 (6.1%) pts, and major adverse cardiovascular events in 1 (0.6%) and 1 (0.1%) pts, in the 5 and 10 mg BID groups, respectively. Malignancies excl. nonmelanoma skin cancer (NMSC) were reported in 1 (0.6%) and 12 (1.6%) pts, and NMSC in 4 (2.3%) and 9 (1.2%) pts, in the 5 and 10 mg BID groups, respectively (no clustering of malignancy type). No new safety risks were identified. Available efficacy data up to Month 24 are shown (Table). Conclusion: In pts with moderate to severe UC in the OLE study, no new safety risks emerged compared with those observed with tofacitinib in rheumatoid arthritis. Efficacy data from the OLE study continue to support long-term efficacy with tofacitinib 5 or 10 mg BID up to 24 months beyond Wk 52 of OCTAVE Sustain.571 Figure 1 No Caption available.

Dual inhibition of tumour necrosis factor and interleukin-17A with ABT-122: open-label long-term extension studies in rheumatoid arthritis or psoriatic arthritis.

To evaluate the safety and maintenance of efficacy with ABT-122, a bi-specific monoclonal antibody targeting TNF and IL-17A, in patients with RA or PsA in open-label, 24-week extensions [open-label extensions (OLEs)] of 12-week, randomized, double-blind studies. All patients received ABT-122 (RA, 120 mg; PsA, 240 mg) subcutaneously every other week on background MTX. Safety assessments included adverse events (AEs) and laboratory parameters. Efficacy was evaluated with ACR responses, 28-joint DAS using high-sensitivity CRP [DAS28 (hsCRP)], and Psoriasis Area and Severity Index (PsA study). The RA OLE study enrolled 158 patients; the PsA OLE study enrolled 168 patients. In the RA OLE study, the incidence of treatment emergent AEs (TEAEs; 41%) appeared similar to the double-blind study (36-43%). In the PsA OLE study, 57% of patients reported ⩾1 TEAE (double-blind study, 42-53%). Most TEAEs were mild or moderate in severity. There were no neutrophil abnormalities greater than grade 2. Grade 3 and/or 4 laboratory abnormalities were reported for lymphocytes, alanine aminotransferase, aspartate aminotransferase, bilirubin and haemoglobin; the number of these severe laboratory values was low (0.6-3.0%), except grade 3 lymphocyte count decreased (11.5%) in the RA study. In both OLE studies, efficacy assessed by ACR responses and other disease activity scores was maintained over the 24 weeks. ABT-122 demonstrated acceptable tolerability and maintenance of efficacy for up to 36 weeks in patients with RA or PsA receiving background MTX. ClinicalTrials.gov, http://clinicaltrials.gov, NCT02433340 and NCT02429895.

Tu1627 - Linaclotide is Effective and Safe for Patients with Chronic Constipation in Japan: A Phase III Randomized, Double-Blind, Placebo-Controlled Study with a Long-Term Open-Label Extension Study

Tu1627 - Linaclotide is Effective and Safe for Patients with Chronic Constipation in Japan: A Phase III Randomized, Double-Blind, Placebo-Controlled Study with a Long-Term Open-Label Extension Study

Safety and maintenance of response for tofacitinib monotherapy and combination therapy in rheumatoid arthritis: an analysis of pooled data from open-label long-term extension studies

ObjectiveTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. This post hoc analysis evaluated patients receiving tofacitinib monotherapy or combination therapy, as well as those who...

Duration of effect of abobotulinumtoxinA (Dysport®) in adult patients with upper limb spasticity (ULS) post-stroke or traumatic brain injury

Current botulinum toxin labeling indicates injections once every 12 weeks but few studies have assessed the treatment interval after repeated injections. In a recent double-blind (DB) study followed by an open-label (OL) extension abobotulinumtoxinA (aboBoNT-A, Dysport ® ) was efficacious and demonstrated a favourable safety profile in adult patients with upper limb spasticity (ULS) after single and repeated injections (Gracies et al. Lancet Neurol 2015; Brashear et al. Am Acad Neurol 2016). This additional analysis focuses on the retreatment intervals after repeated injections of aboBoNT-A. Phase III, international, multicentre, DB, single-treatment study of aboBoNT-A in adults with ULS, followed by a long-term OL extension study with a maximum of 4 additional treatment cycles over a maximum of 18 months. Retreatment was per investigator's clinical judgment and possible at weeks 12, 16, 20, and 24. Among the subjects who received aboBoNT-A in the DB study and were treated in cycle 1 of the OL extension, 37% were re-injected at week 16 or later (17% at week 16, 10% at week 20, 10% at week 24 or later). For those who received a second cycle of treatment in the OL phase, 35% of subjects were re-injected at week 16 or later (20% at week 16, 7.0% at week 20, 8% at week 24 or later). For those who received a third cycle of treatment in the OL phase, 24% of subjects were re-injected at week 16 or later (19% were retreated at week 16, 3% at week 20, 2% at week 24 or later). These data show that 24% to 37% of subjects did not require reinjection before week 16 across multiple cycles. This long duration of clinical effect leads to longer intervals between injections, and thus may reduce the burden associated with frequency of injections for patients and their caregivers/families. This also highlights the needs for a tailored approach in the treatment of patients with ULS.

Safety and Efficacy of Long-Term Open-Label Dosing of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

Safety and Efficacy of Long-Term Open-Label Dosing of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy

Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and −7.8 (−44.3, 28.8) kg/m2 × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis.Trial Registration: ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002.

Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated. Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee. Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0-3: 2.8%; Months 3-6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1-3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE). Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

Tofacitinib in patients with moderate to severe chronic plaque psoriasis: 2-year efficacy and safety in an open-label long-term extension study

Tofacitinib in patients with moderate to severe chronic plaque psoriasis: 2-year efficacy and safety in an open-label long-term extension study

Lomitapide for use in patients with homozygous familial hypercholesterolemia: a narrative review

ABSTRACTLomitapide is a drug recently approved for the treatment of patients with homozygous familial hypercholesterolemia. In this article we discuss briefly the pharmacology of this drug followed by a comprehensive narrative review of the available preclinical and clinical data on its safety and efficacy. Only data published as full papers are presented, with the exception of one long-term open-label extension study, which is available only in abstract form.

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. There was no dose comparison beyond week 52. Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.

Effects of Donepezil on Extrapyramidal Symptoms in Patients with Dementia with Lewy Bodies: A Secondary Pooled Analysis of Two Randomized-Controlled and Two Open-Label Long-Term Extension Studies

Background/Aims: The aim of this study was to clarify the effects of donepezil on extrapyramidal symptoms in patients with dementia with Lewy bodies (DLB). Methods: Using pooled datasets from phase 2 and 3, 12-week randomized, placebo-controlled trials (RCT, n = 281) and 52-week open-label long-term extension trials (OLE, n = 241) of donepezil in DLB, the effects of donepezil on the incidence of extrapyramidal adverse events (AEs) and on the Unified Parkinson's Disease Rating Scale (UPDRS) part III were assessed, and potential baseline factors affecting the AEs were explored. Results: The RCT analysis did not show significant differences between the placebo and active (3, 5, and 10 mg donepezil) groups in extrapyramidal AE incidence (3.8 and 6.5%, p = 0.569) and change in the UPDRS (mean ± SD: -0.2 ± 4.3 and -0.6 ± 6.5, p = 0.562). In the OLE analysis (5 and 10 mg donepezil), the incidence did not increase chronologically; all AEs leading to a dose reduction or discontinuation except one were relieved. The UPDRS was unchanged for 52 weeks. An exploratory multivariate logistic regression analysis of the RCTs revealed that donepezil treatment was not a significant factor affecting the AEs. Baseline severity of parkinsonism was a predisposing factor for worsening of parkinsonism without significant interactions between donepezil and baseline severity. Conclusion: DLB can safely be treated with donepezil without relevant worsening of extrapyramidal symptoms, but treatment requires careful attention to symptom progression when administered to patients with relatively severe parkinsonism.

THU0147 Tofacitinib, an Oral Janus Kinase Inhibitor: Analysis of Malignancies across the Rheumatoid Arthritis Clinical Programme

BackgroundTofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).ObjectivesAn evaluation of malignancies in the tofacitinib RA programme from the Phase (P) 2, P3, and...

OP0154 Integrated Safety Analysis of Tofacitinib in RA Clinical Trials with A Cumulative Exposure of 12,664 Patient-Years

BackgroundTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Phase (P) 2, P3, and open-label long-term extension (LTE) studies described the safety profile of...

THU0148 Tofacitinib, an Oral Janus Kinase Inhibitor: Analysis of Malignancies in Japanese Patients across the Rheumatoid Arthritis Clinical Programme

BackgroundTofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).ObjectivesTo evaluate the malignancies that occurred in Japanese patients in the tofacitinib RA programme from the...