Placebo-corrected Mean Change Research Articles

USE OF PAH SPECIFIC THERAPY IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: A META-ANALYSIS

SESSION TITLE: Pulmonary Vascular Disease 1 SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM PURPOSE: Pulmonary endarterectomy (PEA) is the definitive treatment for chronic thromboembolic pulmonary hypertension (CTEPH). However, not all patients are surgical candidates and some may be left with residual pulmonary hypertension after PEA. Treatment options for such patients are limited. The microvasculopathy of CTEPH and pulmonary arterial hypertension (PAH) are similar. A few randomized controlled trials (RCTs) have reported on the use of PAH specific therapy in CTEPH but not all have shown improvement in exercise capacity and/or pulmonary hemodynamics. METHODS: PUBMED was searched for articles published between January 1996 and February 2018, using the term “chronic thromboembolic pulmonary hypertension” and applying the filters: English language, Humans and Clinical Trials. Studies were included if they met the following criteria: randomized, placebo controlled, clinical trial AND pulmonary hypertension (PH) confirmed by right heart catheterization, AND baseline and follow up six minute walk distance (6MWD) AND baseline and follow up pulmonary hemodynamic data. RevMan 5.3 was used to perform the meta-analysis. RESULTS: Five RCTs met our inclusion criteria. There was a total of 293 patients treated for 12-16 weeks with placebo or one of the three drug classes of PAH specific therapy: Riociguat (n= 173), Endothelin receptor antagonist (n= 118), and Phosphodiesterase 5 inhibitor (n= 9). The majority of the cases was inoperable CTEPH. Overall, the placebo corrected mean change in 6MWD was 24.73 meters (95%CI 14.24, 35.21). The mean change in mean pulmonary artery pressure was -4.78 mm Hg (95%CI-6.42, -3.14), in pulmonary vascular resistance -194 dynes.sec/cm5 (95%CI -233.30, -155.09) and in cardiac index 0.39 L/min/m2 (95%CI 0.16, 0.61). CONCLUSIONS: The use of PAH specific therapy in patients with CTEPH results in significant improvement in 6MWD and pulmonary hemodynamics. CLINICAL IMPLICATIONS: PAH specific therapy is beneficial in patients with inoperable CTEPH or persistent CTEPH following PEA. DISCLOSURES: No relevant relationships by Jason Filopei, source=Web Response No relevant relationships by Adil Shujaat, source=Web Response No relevant relationships by David Steiger, source=Web Response

Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain.

Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43+) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT]). Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days. The placebo-corrected mean change from baseline CNFA (μm2) at day 28 was 109 (95% confidence interval [CI], -429, 647), 697 (159, 1236; P = 0.012), and 431 (-130, 992) in the 1, 4, and 8 mg groups, respectively. Intraepidermal GAP-43+ fibers increased in the 4 mg group (P = 0.035). Further, changes in CNFA correlated with changes in GAP-43+ (ρ = 0.575; P = 0.025) and 6MWT (ρ = 0.645; P = 0.009). Pain improved significantly in all groups, with subjects having moderate-severe pain reporting a clinically meaningful placebo-corrected decrease in pain intensity in the 4 mg group (P = 0.157). Cibinetide significantly increased small nerve fiber abundance in the cornea and skin, consistent with a disease modifying effect. The relationships between CNFA and other clinical measures of disease support its use as a surrogate endpoint to assess potential disease modifying therapies for neuropathy.

Efficacy and safety of dapagliflozin in addition to insulin therapy in Japanese patients with type 2 diabetes: Results of the interim analysis of 16-week double-blind treatment period.

IntroductionDapagliflozin treatment when added to insulin therapy in Japanese patients with type 2 diabetes remains to be evaluated.Materials and MethodsThis was a multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled study to evaluate efficacy (at 16 weeks) and long‐term safety (at 52 weeks) of dapagliflozin in addition to insulin therapy. The interim analysis was carried out at week 16 to assess the efficacy and safety profiles. The patients receiving insulin (n = 182) were randomized to either dapagliflozin 5 mg or a placebo at a 2:1 ratio. The primary efficacy end‐point was the change in hemoglobin A1c (HbA1c) from baseline at week 16.ResultsPatients in the dapagliflozin group showed an adjusted decrease in HbA1c of −0.55% from baseline, whereas the placebo showed a marginal increase of 0.05%. The placebo‐corrected mean change of HbA1c from baseline to week 16 in dapagliflozin was −0.60% (P < 0.0001). In addition, the placebo‐corrected mean change of fasting plasma glucose and bodyweight from baseline to week 16 in the dapagliflozin group was −22.7 mg/dL (P < 0.0001) and −1.21 kg (P < 0.0001), respectively. The placebo‐corrected mean daily insulin dose in the dapagliflozin group was numerically decreased (treatment difference: −0.72 IU/day; P = 0.0743). No major episodes or discontinuations as a result of hypoglycemia were reported during the study period.ConclusionsDapagliflozin used as add‐on treatment to insulin therapy showed significantly greater reduction of HbA1c, fasting plasma glucose and bodyweight without severe hypoglycemia compared with the placebo at week 16. These results show the clinical benefit of prescribing dapagliflozin for Japanese patients with insufficient glycemic control even with insulin therapy.

Riociguat in Combination With Endothelin Receptor Antagonists (ERAs) for the Treatment of Pulmonary Arterial Hypertension (PAH): A Subgroup Analysis of PATENT

SESSION TITLE: Pulmonary Arterial Hypertension Posters II SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM PURPOSE: The ACCP suggests that riociguat may be added to the treatment regimen of PAH patients who remain symptomatic despite stable regimens of an inhaled prostanoid or an ERA. PATENT-1 (the Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial) allowed patients to enroll while on stable regimens of ERAs. Here, we report findings from analysis of the subgroup of patients from the PATENT trial who were on background ERA therapy (BERA). METHODS: Patients were assigned to placebo (N=126; n=54 on BERA), to individualized dosing of riociguat up to 2.5 mg TID (N=254; n=113 on BERA), or to an exploratory riociguat group capped at 1.5 mg TID (N=63; n=27 on BERA). Primary outcome was change from baseline (BL) in 6-minute walk distance (6MWD) at week 12. Secondary exploratory outcomes included change from BL in pulmonary vascular resistance (PVR), NT-proBNP, WHO functional class (WHO-FC), and clinical worsening. RESULTS: All apply to patients (riociguat and placebo) on BERA. For the placebo-corrected mean change from baseline to last visit, 6MWD in riociguat patients (1.0 to 2.5 mg TID) increased by 26 meters (95% CI: 5-46 meters). Mean change in PVR for riociguat patients was -174±202 dyn·s·cm-5, versus -46±266 dyn·s·cm-5 for placebo. Mean change in NT-proBNP was 90±2212 pg/mL for riociguat patients versus 172±759 pg/mL for placebo. By last visit, 26% of riociguat patients had improved one WHO-FC (71% maintained FC, while 4% worsened 1 FC) compared with 13% of placebo patients (76% maintained FC, and 9% and 2% worsened 1 and 2 FC, respectively). Among riociguat patients, only 1 (0.9%) had at least 1 clinical worsening event, compared with 3 (5.6%) among placebo patients, including 1 death. CONCLUSIONS: These data suggest that adding riociguat to stable regimens of ERAs in symptomatic PAH patients has favorable effects on 6MWD, PVR, WHO-FC, and perhaps clinical worsening. CLINICAL IMPLICATIONS: Adding riociguat to stable regimens of ERAs may be beneficial in symptomatic PAH patients but additional studies are needed to further explore this possibility. DISCLOSURE: Nicholas Hill: Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Namita Sood: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare No Product/Research Disclosure Information

Linagliptin improves glycemic control after 1 year as add-on therapy to basal insulin in Asian patients with type 2 diabetes mellitus

Objective:To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents.Research design and methods:This was a post hoc analysis of Asian patients from a global ≥52 week study in which patients on basal insulin were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo (NCT00954447). Basal insulin dose remained stable for 24 weeks, after which adjustments could be made according to the investigator’s discretion to improve glycemic control. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) from baseline to 24 weeks.Results:Data were available for 154 Asian patients (80 linagliptin, 74 placebo). Baseline HbA1c (standard deviation [SD]) was 8.6 (0.9)% (70 [10] mmol/mol). The placebo-corrected mean change (standard error [SE]) in HbA1c from baseline was −0.9 (0.1)% (−10 [1] mmol/mol) (95% confidence interval [CI]: −1.2, −0.7; p < 0.0001) at Week 24 and −0.9 (0.1)% (−10 [1] mmol/mol) (95% CI: −1.1, −0.6; p < 0.0001) at Week 52. The frequency of adverse events (linagliptin 81.3%, placebo 91.9%) and hypoglycemia (Week 24: linagliptin 25.0%, placebo 25.7%; treatment end: linagliptin 28.8%, placebo 35.1%) was similar between groups. By Week 52, changes (SE) in mean body weight were similar in both groups (linagliptin −0.67 [0.26] kg, placebo −0.38 [0.25] kg).Conclusions:This study was limited by the post hoc nature of the analysis and the small number of patients in the subgroup. However, the results suggest that linagliptin significantly improves glycemic control in Asian patients with T2DM inadequately controlled by basal insulin, without increasing the risk for hypoglycemia or weight gain.ClinicalTrials identifier:NCT00954447.

Safety and efficacy of initial combination of linagliptin and metformin in patients with type 2 diabetes: A subgroup analysis of Indian patients from a randomized, double-blind, placebo-controlled study.

Context and Objectives:The number of people with diabetes is increasing exponentially in India. Owing to a unique “Asian Indian Phenotype,” Indians develop diabetes a decade earlier and have an earlier onset of complications than Western populations. Therefore, it is essential to evaluate more effective treatment strategies at an earlier stage of disease progression, such as initial combination therapy, in Indian patients. In this study, we evaluated the efficacy and safety of initial combination therapy with linagliptin plus metformin in comparison to linagliptin or metformin monotherapy in Indian patients with type 2 diabetes mellitus.Methods:This is a subgroup analysis of Indian patients who participated in a Phase III, 24-week, double-blind, placebo-controlled, trial. Overall, 249 Indian patients were randomized to one of six treatment arms (Two free combination therapy arms: Linagliptin 2.5 mg twice daily [bid] + either low [500 mg, n = 36] or high [1000 mg, n = 44] dose metformin bid and four monotherapy arms: Linagliptin 5 mg once daily [qd, n = 40], metformin 500 mg [n = 49] or 1000 mg bid [n = 45], or placebo [n = 23]).Results:The placebo-corrected mean change in glycated hemoglobin from baseline (8.9%) to week 24 was −1.83% for linagliptin + metformin 1000 mg bid; −1.46% for linagliptin + metformin 500 mg bid; −1.30% for metformin 1000 mg bid; −1.00% for metformin 500 mg bid; and −0.77% for linagliptin 5 mg qd. None of the patients in the combination therapy arms had hypoglycemia, whereas there was one event in the metformin 1000 mg bid arm. Rates of adverse event were similar across various treatments.Conclusions:In this subgroup analysis of Indian patients, initial combination therapy with linagliptin + metformin was more efficacious in improving glycemic control than the monotherapy arms, with a comparable tolerability profile. The results were comparable to the overall population.

Efficacy and safety of linagliptin as monotherapy or add-on treatment in Asian patients with suboptimal glycemic control: a pooled analysis

Aims:To evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in Asian patients with type 2 diabetes mellitus (T2DM), a rapidly increasing population.Methods:Data were pooled for Asian patients receiving linagliptin orally once daily, as monotherapy or added to existing oral antidiabetes therapies, in multinational randomized placebo-controlled clinical trials. Efficacy data were taken from four pivotal trials with 24-week durations to allow for robust efficacy assessment. Safety data were pooled from a wider group of 10 trials with varying durations to capture the largest possible incidence of adverse events (AEs). The primary efficacy endpoint was change from baseline to week 24 in HbA1c. AEs were analyzed descriptively.Results:Mean baseline HbA1c (±SD) in this population was 8.2 ± 0.9%. Placebo-corrected mean change in HbA1c after 24 weeks was −0.79% (95% confidence interval [CI]: −0.92 to −0.67; p < 0.0001). Placebo-corrected mean change in fasting plasma glucose was −17.8 ± 2.4 mg/dL (95% CI: −22.6, −13.0; p < 0.0001). In a small subgroup, mean post-prandial glucose was reduced by a placebo-corrected −56.9 ± 14.0 mg/dL (95% CI: −85.2, −28.5). AEs occurred in 58.0% of linagliptin patients (serious AEs in 2.4%) and 58.2% of placebo patients (serious AEs in 3.0%).Conclusions:This study was limited by the post hoc nature of the analysis, and because the pooling did not differentiate between geographically distant Asian regions. Nonetheless, this analysis provides evidence that linagliptin was efficacious and well tolerated as monotherapy or added to other oral antidiabetes therapies in Asian patients with T2DM.

Efficacy and safety of linagliptin in type 2 diabetes subjects at high risk for renal and cardiovascular disease: a pooled analysis of six phase III clinical trials.

BackgroundIn patients with type 2 diabetes mellitus (T2DM), hypertension and microalbuminuria are predictive markers for increased renal and cardiovascular risk. This post hoc analysis of data from a global development program aimed to evaluate the efficacy and safety of linagliptin in a population with joint prevalence of these two vascular risk factors.MethodsData for patients with baseline microalbuminuria (urine albumin-to-creatinine ratio 30–300 mg/g) and hypertension (systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg and/or a history of hypertension; and/or an antihypertensive treatment at baseline) who participated in any of six randomized, placebo-controlled, phase III trials were analyzed. Participants received linagliptin 5 mg daily (alone or in combination with other oral antidiabetic drugs) or placebo for 18 to 24 weeks.ResultsOf 3,119 patients, 512 had both microalbuminuria and hypertension (linagliptin, 366; placebo, 146). Baseline mean (SD) HbA1c was 8.3 (0.9)% and 8.4 (0.9)%; median (range) urine albumin-to-creatinine ratio was 60 (30–292) mg/g and 64 (30–298) mg/g; mean (SD) systolic blood pressure was 138 (15) mm Hg and 135 (16) mm Hg; and mean (SD) diastolic blood pressure was 81 (10) mm Hg and 81 (10) mm Hg, for linagliptin and placebo, respectively. Placebo-corrected mean change in HbA1c from baseline to week 18 and week 24 was -0.57% (95% CI: -0.75, -0.39; P < 0.0001) and -0.59% (95% CI: -0.80, -0.39; P < 0.0001), respectively. Placebo-corrected mean change in FPG from baseline to week 24 was -21.3 mg/dl (95% CI: -31.0, -11.6; P < 0.0001). The incidence of drug-related adverse events was similar for linagliptin and placebo (10.4% and 8.2%, respectively). Changes in systolic and diastolic blood pressure, cholesterol and triglyceride levels were similar between linagliptin and placebo.ConclusionIn T2DM patients with the two common vascular risk factors of hypertension and microalbuminuria, linagliptin achieved significant improvements in glycemic control. In this vulnerable patient population at high risk for micro- and macrovascular complications, linagliptin was well tolerated.

Evaluation of the Effects of Bitopertin (RG1678) on Cardiac Repolarization: A Thorough Corrected QT Study in Healthy Male Volunteers

BackgroundBitopertin (RG1678) is a selective glycine reuptake inhibitor currently in Phase III development for the treatment of schizophrenia. Thorough QT studies to assess the effects of candidate drugs on cardiac repolarization and proarrhythmic potential are required by regulatory authorities and are a common part of the drug development process. A clinically relevant effect on QT interval is suspected if prolongation of the corrected QT interval (QTc) is ∼5 milliseconds or more, evidenced by an upper 1-sided 95% CI for the mean effect on the QTc of at least 10 milliseconds. ObjectiveThe goal of this study was to investigate the effect of bitopertin on the QTc interval in healthy male volunteers. MethodsThis was a multiple-dose, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study using bitopertin 30 mg (n = 56) or bitopertin 175 mg (n = 56) once daily for 10 days plus placebo on day 11, moxifloxacin 400 mg on day 1 plus placebo once daily for 10 days (n = 29), or placebo once daily for 10 days plus moxifloxacin 400 mg on day 11 (n = 28). Continuous Holter ECGs were obtained on days −1, 1, 10, and 11, and the placebo-corrected mean change from time-matched baseline in the QT interval calculated by using Fridericia's formula (QTcF) on day 10 was the primary end point. Pharmacokinetic parameters of bitopertin were determined on day 10 by using HPLC-MS/MS methods to obtain bitopertin plasma drug concentrations. Adverse events were recorded throughout the study. ResultsA total of 169 predominantly white, healthy male volunteers (mean age, 31.8 years; range, 19–59 years) were randomized to treatment; 162 completed the study. The mean change in placebo-corrected QTcF from baseline to day 10 of bitopertin ranged from −2.8 to 3.9 milliseconds. The upper bound of the 1-sided 95% CI was <10 milliseconds at all time points with both doses. There was no relation between bitopertin concentrations and changes in QTcF or other ECG variables. Assay sensitivity was confirmed by a placebo-corrected mean change from time-matched baseline in QTcF of 10.6 milliseconds (lower bound of the 1-sided 98.3% CI, 6.9 milliseconds) 4 hours after moxifloxacin administration. Peak bitopertin plasma concentrations were achieved ∼4 hours after dosing. The terminal elimination t½ was ∼53 hours. No safety or tolerability concerns were noted with bitopertin at either dose. Dizziness, nausea, and blurred vision were more common in the bitopertin 175-mg group compared with the bitopertin 30-mg or placebo groups. ConclusionMultiple dosing with bitopertin 30 mg or 175 mg did not affect QTcF in these healthy male volunteers. ClinicalTrials.gov identifier: NCT01613040.

The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus

To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of linagliptin in patients with type 2 diabetes mellitus (T2DM). After screening and a 14-day washout, subjects received linagliptin 2.5, 5 or 10 mg or placebo once-daily for 28 days in this randomized, double-blind, parallel, placebo-controlled within-dose groups study. Seventy-seven patients entered the study (linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of linagliptin accumulation. Exposure, maximum and trough plasma concentrations of linagliptin increased less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase-4 reached 91-93% across linagliptin doses at steady state. At the end of the 24-h dosing interval, inhibition was still high (82-90%). There were marked increases in plasma glucagon-like peptide-1 after 28 days of dosing. Compared to placebo, all linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with linagliptin the placebo-corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was -0.31% (2.5-mg dose), -0.37% (5-mg dose) and -0.28% (10-mg dose). The frequency of adverse events was similar for linagliptin (31%) and placebo (34%). There were no notable safety concerns. Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients.

Comparison of QTc Data Analysis Methods Recommended by the ICH E14 Guidance and Exposure–Response Analysis: Case Study of a Thorough QT Study of Asenapine

An assessment of the effects of asenapine on QTc interval in patients with schizophrenia revealed a discrepancy between the results obtained by two different methods: an intersection-union test (IUT) (as recommended in the International Conference on Harmonisation E14 guidance) and an exposure-response (E-R) analysis. Simulations were performed in order to understand and reconcile this discrepancy. Although estimates of the time-matched, placebo-corrected mean change in QTc from baseline (ddQTc) at peak plasma concentrations from the E-R analysis ranged from 2 to 5ms per dose level, the IUT applied to simulated data from the E-R model yielded maximum ddQTc estimates of 7-10ms for the various doses of asenapine. These results indicate that the IUT can produce biased estimates that may induce a high false-positive rate in individual thorough QTc trials. In such cases, simulations from an E-R model can aid in reconciling the results from the two methods and may support the use of E-R results as a basis for labeling.