Open-label Long-term Extension Study Research Articles

Safety and Efficacy Of Long-Term Open-Label Romiplostim Dosing In Thrombocytopenic Pediatric Patients With Immune Thrombocytopenia (ITP)

Safety and Efficacy Of Long-Term Open-Label Romiplostim Dosing In Thrombocytopenic Pediatric Patients With Immune Thrombocytopenia (ITP)

THU0131 Tofacitinib (CP-690,550), an oral janus kinase inhibitor: Analysis of malignancies across the rheumatoid arthritis clinical programme

BackgroundTofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis (RA).ObjectivesTo evaluate the malignancies that occurred in...

THU0272 Epratuzumab Maintains Improvements in Disease Activity for Over 2 Years in Patients with Moderate-to-Severe Systemic Lupus Erythematosus: Results from an Open-Label Long-Term Extension Study (Sl0008)

BackgroundEpratuzumab is a monoclonal antibody targeting CD22. In EMBLEM™ (a dose-ranging phase IIb study), epratuzumab produced clinically relevant improvements in disease activity in patients with moderate-to-severe systemic lupus erythematosus (SLE).1...

THU0277 Epratuzumab: Sustained Safety Profile and Effect on Corticosteroid Use on Long-Term Treatment in Patients with Moderate-to-Severe Systemic Lupus Erythematosus: Results from an Open-Label Long-Term Extension Study (Sl0008)

BackgroundThe safety and efficacy of epratuzumab, a monoclonal antibody targeting CD22, were assessed in EMBLEM™, a 12-week phase IIb study in patients with moderate-to-severe systemic lupus erythematosus (SLE).1 SL0008 (NCT00660881)...

THU0286 Immunologic Response to Long-Term Epratuzumab Treatment in Sl0008, An Open-Label Long-Term Extension Study in Patients with Moderate-to-Severe Systemic Lupus Erythematosus

BackgroundEpratuzumab is a monoclonal antibody targeting CD22 that may affect B-cell signaling, adhesion and migration.1,2 We report immunologic response in SL0008 (NCT00660881), an open-label extension of EMBLEM™, a 12-week phase...

THU0252 Relationship between Lymphocyte Count and Risk of Infection in Rheumatoid Arthritis Patients Treated with Tofacitinib

BackgroundTofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Cytokines (e.g., interleukin (IL)-2, -4, -7, -15, -21) involved in lymphocyte development, function and...

THU0140 Tofacitinib (CP-690,550), an oral janus kinase inhibitor: Analysis of gastrointestinal adverse events across the rheumatoid arthritis clinical programme

BackgroundTofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator in rheumatoid arthritis (RA).ObjectivesTo describe and report the incidence of gastrointestinal (GI) adverse events (AEs)...

THU0238 Tofacitinib, an Oral Janus Kinase Inhibitor: Safety Comparison in Patients with Rheumatoid Arthritis and an Inadequate Response to Nonbiologic or Biologic Disease-Modifying Anti-Rheumatic Drugs

BackgroundTofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).ObjectivesThis analysis provides comparative safety data on the incidence of safety events for patients (pts) with...

Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension

Background— By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). Methods and Results— Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥800 dyne·s·cm −5 symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12–52; P =0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm −5 (95% confidence interval, −502 to − 255; P <0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. Conclusions— Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00902174 (core study); NCT01392495 (extension).

Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study

To assess the efficacy and safety of alogliptin added to pioglitazone versus pioglitazone monotherapy, in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus diet/exercise. Patients were stabilized on pioglitazone 15 or 30 mg/day plus diet/exercise during a 16-week screening period. Patients with HbA1c of 6.9-10.4% were randomized to 12 weeks' double-blind treatment with alogliptin 12.5 or 25 mg once daily or placebo, added to their stable pioglitazone regimen. The primary endpoint was the change in HbA1c from baseline to week 12. Patients had an option to continue in a 40-week, open-label extension study, with those originally randomized to alogliptin remaining on the same dosage regimen while patients treated with placebo were randomly allocated to alogliptin 12.5 or 25 mg (added to their stable pioglitazone). The change from baseline in HbA1c after 12 weeks was significantly greater with alogliptin 12.5 mg added to pioglitazone and alogliptin 25 mg added to pioglitazone than with placebo added to pioglitazone (-0.91 and -0.97% vs. -0.19%; p < 0.0001). Responder rates (HbA1c <6.9% and HbA1c <6.2%) and changes in fasting and postprandial blood glucose levels showed a similar positive trend in terms of glycaemic control. The benefits seen with alogliptin were sustained during the 40-week extension period. Alogliptin added to pioglitazone was generally well tolerated; hypoglycaemia was infrequent and increases in body weight were minor. Once-daily alogliptin was effective and generally well tolerated when given as add-on therapy to pioglitazone in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus lifestyle measures. Clinical benefits were maintained for 52 weeks.

A Long-Term Open-Label Extension Study Assessing Cognition and Behavior, Tolerability, Safety, and Efficacy of Adjunctive Levetiracetam in Children Aged 4 to 16 Years With Partial-Onset Seizures

The objective of this study was to assess cognition and behavior in children (4-16 years; n = 103) with partial-onset seizures using the Leiter-R International Performance Scale and Achenbach Child Behavior Checklist. The study was a multicenter, open-label, noncomparative 48-week extension study (NCT00152516) of adjunctive levetiracetam (20-100 mg/kg/d, mean 50.2 mg/kg/d). Improvement from baseline in Leiter-R Memory Screen composite score at weeks 24 and 48 (mean [SD] change, +4.8 [12.6] and +4.5 [15.3]) was similar to changes observed with levetiracetam and placebo in a prior study. Child Behavior Checklist Syndrome scores improved from baseline at weeks 24 and 48 (total problems mean [SD] change, -9.3 [22.2] and -10.4 [23.4]). Adjunctive levetiracetam was well tolerated (most frequently reported central nervous system-related treatment-emergent adverse events: headache [24.3%], aggression [7.8%], irritability [7.8%]). Of the patients, 4.9% discontinued because of treatment-emergent adverse events. Levetiracetam provided good and sustained seizure control (median percentage reduction from baseline in partial-onset seizure frequency/wk during maintenance: 86.4%); 24.7% of patients had continuous seizure freedom from all seizure types for ≥40 weeks. In children, adjunctive levetiracetam was associated with long-term stability in cognitive functioning and improvement in emotional/behavioral functioning over time.

Review Article: Second-generation thrombopoietin agents for treatment of chronic idiopathic thrombocytopenic purpura in adults

To review the pharmacology, pharmacokinetics, efficacy, and safety of two new thrombopoietic (TPO) receptor agonists, romiplostim and eltrombopag, in the treatment of chronic idiopathic thrombocytopenic purpura (ITP) in adults. A MEDLINE search was conducted (1966 to March 2009) using the search terms romiplostim, AMG 531, eltrombopag, SB-497115, idiopathic thrombocytopenic purpura. Articles on phases 1-3 clinical trials in patients with ITP were identified and reviewed. References from manufacturer information, and abstracts from recent hematology meetings, were also evaluated. Controlled clinical trials evaluating romiplostim and eltrombopag for treatment of chronic ITP in adults were selected from the data sources. All published relevant abstracts were also included. Limited randomized controlled trials and open-label ongoing long-term extension studies for romiplostim and eltrombopag, have shown that both TPO agonists are effective in improving the platelet count and reducing the bleeding episodes in adult patients with ITP unresponsive to at least one standard treatment. The most common adverse events associated with the drugs are mild to moderate headaches. The use of these agents has also been associated with rare but serious side-effects including bone marrow reticulin fibrosis, thrombotic events, and myeloid malignancies. Until more long-term follow-up data regarding the safety, as well as comparative studies that further define the role of TPO agonists versus other agents in the treatment of chronic ITP are available, these agents should be reserved for patients with ITP refractory or intolerant to standard therapy.

A long-term open-label extension study examining the steroid-sparing effects of corticorelin acetate in patients with cerebral tumors

2079 Background: Corticorelin acetate (CrA) is a synthetic peptide formulation of corticotropin-releasing factor, which is undergoing clinical trials as a treatment for peritumoral edema. The objective of this study was to evaluate long-term safety, tolerability and steroid-sparing potential of CrA in patients with primary or secondary brain tumors and peritumoral edema. Methods: Patients from two randomized double-blind controlled studies who received either CrA (CrA-CrA group) or placebo (PLA) (PLA-CrA group) were permitted to receive open-label CrA 1 mg SC bid after participation in the initial studies. Treating physicians were requested to attempt and maintain the maximum possible reduction of the dexamethasone (dex) dose without knowledge of their patients’ prior treatment regimen in the controlled feeder studies. During this extension study, patients’ dex doses and adverse events were monitored monthly; neurologic function and clinical status were recorded 3 monthly. For this analysis, data up to October 17, 2008, are reported from this ongoing study. Results: Of the 110 patients enrolled, 47 (43%) reduced their dex dose to zero and 67 (61%) were able to reduce their dose to ≤1 mg/day. At entry to this extension study, the daily baseline dex dose was lower for patients who had previously received CrA (3.9 mg; n = 59) than for those who had previously received PLA (6.2 mg; n = 51). The PLA-CrA group showed a greater percent decrease in dex dose than the CrA-CrA group at Week 4 (24.0% vs. 12.6%). At week 8 the mean prescribed dex dose was similar in the two groups (PLA-CrA 3.7 mg vs. CrA-CrA 3.4 mg). Long-term treatment with CrA has been well tolerated with no reported safety concerns. To date, 48 patients remained on study for ≥6 months, 27 patients for ≥12 months, 5 patients for &gt;2 years; 31 patients remain on study. Conclusions: These findings indicate that CrA is safe and well-tolerated, and may enable substantial reduction or cessation of dex therapy for many patients with cerebral tumors. [Table: see text]

Safety and Tolerability of Divalproex Sodium Extended‐Release in the Prophylaxis of Migraine Headaches: Results of an Open‐Label Extension Trial in Adolescents

To evaluate the long-term safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches in adolescents. Divalproex sodium has been approved for migraine prophylaxis in adults. A previous double-blind, placebo-controlled study of the efficacy and safety of divalproex sodium extended-release for prevention of migraine in adolescents was followed by the present long-term extension trial, which was designed to collect additional safety and tolerability data. This was a 12-month, Phase 3, open-label extension of a 3-month, double-blind, placebo-controlled, multicenter study of adolescents aged 12 to 17 years with migraine headaches who had either completed the previous study or had discontinued because of lack of efficacy. Subjects from the previous trial who had experienced serious adverse events possibly or probably related to study drug were excluded. Divalproex sodium extended-release 500 mg daily was administered for 15 days then increased to 1000 mg. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety assessments included adverse event collection, laboratory testing, physical and neurological examinations, vital signs, and electrocardiograms, as well as reproductive endocrine analyses for postmenarchal female subjects. Efficacy was evaluated by sequential 4-week migraine headache rates calculated from subjects' headache diaries. A total of 112 subjects enrolled in the trial. The most common adverse events were weight gain (15%), nausea (14%), somnolence (12%), upper respiratory tract infection (11%), increased ammonia (8%), and sinusitis (8%). Five (4%) subjects experienced serious adverse events, and 15 (13%) subjects prematurely discontinued because of an adverse event. Increased ammonia levels were noted in some individuals, and the mean ammonia level for all subjects increased 19.2 microm from baseline. No other clinically significant changes were observed in laboratory values, vital signs, or electrocardiograms. Improvement in mean and median 4-week migraine headache rates occurred by the fourth month and lasted for the duration of the trial. In this long-term open-label extension study, the safety profile of divalproex sodium extended-release in adolescents with migraine was consistent with that observed in the preceding 3-month, double-blind trial and in previous adult studies. Overall, divalproex sodium extended-release was well-tolerated in adolescents aged 12 to 17 years.

Self-Injection of Romiplostim by Patients with Chronic Immune Throbocytopenic Purpura (ITP)

Romiplostim is an investigational Fc-peptide fusion protein (peptibody) that has demonstrated the ability to increase platelet counts over prolonged periods in thrombocytopenic patients with chronic ITP. Self-injection of romiplostim offers a convenient treatment option for some patients. The safety and efficacy of romiplostim self-injections were explored in patients participating in a long-term open-label extension study. Patients with chronic ITP (diagnosis per ASH guidelines) were eligible for the openlabel extension study if they had completed a prior romiplostim study and had platelet counts <50×109/L. Romiplostim was injected subcutaneously once weekly, initially by healthcare providers at study centers, with a starting dose of 1 μg/kg and subsequent dose adjustments to maintain a platelet count between 50 and 250×109/L. After achieving a platelet response, patients who received the same romiplostim dose for ≥3 weeks were permitted to self-inject weekly romiplostim or have the injection administered at home by a caregiver. Patients/caregivers were trained to self-inject and were required to return to the study center for platelet count evaluation and dose adjustment every 4 weeks, and to receive the next month's medication and supplies. Of 143 patients enrolled, 90 (63%) initiated self-injection. Their median age was 53 years (range 21 to 80), and most (62%) were splenectomized. Self-injection was initiated after a median of 12 weeks (range 1 to 99) of romiplostim treatment; and patients continued to receive romiplostim for a median of 64 weeks (range 5 to 117), maintaining self-injection for a median of 74% of their subsequent time on treatment. To compare changes in efficacy and safety following the switch from office-based injection to self-injection, we analyzed data 8 weeks before and 8 weeks after initiation of self-injection. The median average weekly dose was comparable in the 8 weeks before (4 μg/kg, range 1 to 19 μg/kg) and after (5 μg/kg, range 1 to 16 μg/kg) the start of self-injection. The median maximum dose (5 μg/kg) did not change. Platelet counts increased as patients achieved a stable dose of romiplostim and then stabilized once self-injection was initiated: mean (±SD) platelet counts 8 weeks before, at initiation, and 4 and 8 weeks after initiation of self-injection were 85 (±91), 125 (±96), 123 (±121) and 121 (±96), respectively. A similar number of patients experienced adverse events in the 8 weeks before (54/90; 60%) and after (59/90; 66%) initiating self-injection. The most common adverse events before initiation of self-injection were headache (13%), and fatigue and upper respiratory tract infection (both 8%), and after were nasopharyngitis (9%), headache (8%), and diarrhea (6%). The patient incidence of treatment-related adverse events was 14 (16%) 8 weeks before and 9 (10%) 8 weeks after the start of self-injection. Serious adverse events occurred in 2 (2%) patients before and 5 (6%) patients after self-injecting. One treatment-related serious adverse event occurred: an event of thrombosis in a self-injecting patient. No deaths were reported either before or after self-injection. These results indicate that most patients were able to achieve and maintain self-injection of romiplostim with no apparent changes in either their platelet response or safety profiles. Self-injection of romiplostim represented a convenient, effective, and well-tolerated treatment option for ITP patients.

Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes

The anti-anginal efficacy and safety of ranolazine in diabetic and non-diabetic patients included in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial (JAMA 2004;291:309) were studied. Glycaemic control was also assessed in CARISA and its long-term open-label extension study. Patients with chronic angina enrolled in CARISA (189 with diabetes, 634 without diabetes) on background atenolol, diltiazem, or amlodipine therapy were randomized to placebo, ranolazine 750 or 1000 mg twice daily for 12 weeks, during which exercise tolerance, angina frequency, nitroglycerin usage, glucose, HbA(1c), and lipids were measured. Patients completing the randomized study could enroll in an ongoing open-label extension study and were evaluated every 3 months. Ranolazine produced similar improvements in exercise parameters, nitroglycerin use, and angina frequency in diabetic and non-diabetic patients. Adverse events were similar between groups. Fasting glucose and lipids remained unaltered in diabetic patients after 12 weeks of therapy. In a post hoc analysis, ranolazine 750 and 1000 mg reduced HbA(1c) vs. placebo by 0.48+/-0.18% (P=0.008) and 0.70+/-0.18% (P=0.0002), respectively; the HbA(1c) levels appeared to remain unchanged over time during long-term therapy. Anti-anginal efficacy and safety of ranolazine for angina were similar between diabetic and non-diabetic patients. Ranolazine significantly improved glycaemic control in diabetic patients.

Long-Term Open-Label Solifenacin Treatment Associated with Persistence with Therapy in Patients with Overactive Bladder Syndrome

Objective: To examine safety and tolerability findings as primary endpoints, and efficacy outcomes as secondary endpoints, of solifenacin treatment over a period of up to 1 year. Long-term efficacy in the treatment of overactive bladder (OAB) syndrome depends in part on the patient's persistence with pharmacologic therapy. Agents with a favourable therapeutic index supporting high levels of patient satisfaction and persistence are needed. Methods: The present study was a 40-week open-label extension of two 12-week, placebo-controlled, double-blind studies of solifenacin treatment in patients with OAB. Patients who completed the 12-week studies were offered participation in the open-label extension study. All patients who entered the open-label extension study initially received solifenacin 5 mg daily for 4 weeks, after which a flexible dosing regimen allowed patients to individualise their treatment (5 mg or 10 mg) at each of the 3 study visits. Safety and tolerability assessments (the primary variable) included adverse event reporting. Efficacy data were collected from micturition diaries completed at weeks 16, 28, 40, and 52. Results: Ninety-one percent (1637/1802) of patients who completed the two 12-week randomised studies chose to participate in the long-term open-label extension study. A total of 81% of patients completed 40 weeks of open-label treatment. Solifenacin treatment was safe and well tolerated, and rates of anticholinergic side effects were relatively low. Only 4.7% of patients discontinued treatment owing to adverse events. Improvements in major symptoms of OAB were noted for all patients for up to 52 weeks of treatment. In patients randomised to solifenacin in the double-blind studies, there were small incremental improvements in all efficacy parameters (reductions in episodes per 24 hours of urgency, reductions in frequency and urge incontinence, and increases in volume voided per micturition) over the course of the extension study. Efficacy was confirmed when outcomes were assessed as a function of total solifenacin exposure. Patient satisfaction with solifenacin tolerability (85%) and efficacy (74%) were high. These results indicate that long-term treatment with solifenacin was well tolerated and associated with improvements in efficacy parameters based on patient diary data recorded over the 12-month treatment period. Moreover, the high level of patient satisfaction reported appeared to correlate well with the quantified improvements in key symptoms demonstrated in this study. Conclusions: Long-term therapy with solifenacin resulted in a favourable tolerability profile, and was associated with improvements in efficacy parameters based on diary data recorded over a 12-month period. This balance of tolerability and efficacy with solifenacin was associated with excellent persistence with therapy. These results suggest that solifenacin may be useful for the long-term treatment of the chronic symptoms associated with OAB.